Here are the studies that match your search criteria. If you are interested in participating, please reach out to the contact listed for the study. If no contact is listed, contact us and we'll help you find the right person.
A Trial to Investigate Long Term Efficacy and Safety of Lonapegsomatropin in Adults With Growth Hormone Deficiency
This is a phase 3 open-label multicenter extension study designed to evaluate the long-term
safety and efficacy of Lonapegsomatropin administered once-weekly. The study participants are
adults (males and females) with confirmed growth hormone deficiency (GHD) having completed
the treatment period in study TCH-306 (foresiGHt).
• Signing of the trial specific informed consent
• Completion of the treatment period and Visit 7 assessments of trial TCH-306, including
collection and upload of Visit 7 DXA scan
• Fundoscopy at Visit 7 in trial TCH-306 without signs/symptoms of intracranial
hypertension or diabetic retinopathy stage 2 / moderate or above
Exclusion Criteria:
• Diabetes mellitus if any of the following are met:
1. Poorly controlled diabetes, defined as HbA1C higher than 7.5% according to
central laboratory at Visit 6 in trial TCH-306
2. Use of diabetes mellitus drugs other than metformin and/or dipeptidyl peptidase-4
(DPP-4) inhibitors
• Active malignant disease or history of malignancy. Exceptions are:
1. Resection of in situ carcinoma of the cervix uteri
2. Complete eradication of squamous cell or basal cell carcinoma of the skin
• Known history of hypersensitivity and/or idiosyncrasy to the investigational product
(somatropin or excipients)
• Female who is pregnant, plans to become pregnant, or is breastfeeding
• Female participant of childbearing potential (i.e., fertile, following menarche and
until becoming post-menopausal unless permanently sterile) not willing throughout the
trial to use contraceptives as required by local law or practice. Details included in
Appendix 4/section 10.4 of the protocol
• Male participant not willing throughout the trial to use contraceptives as required by
local law or practice. Details included in Appendix 4/ section 10.4 of the protocol
• Any disease or condition that, in the judgement of the investigator, may make the
participant unlikely to comply with the requirements of the protocol or any condition
that presents undue risk from the investigational product or trial procedures
Drug: Lonapegsomatropin
Endocrine System Diseases, Adult Growth Hormone Deficiency, Hormone Deficiency, Other Endocrine System
Preventing Cognitive Decline by Reducing BP Target Trial (PCOT)
The PCOT study is a multi-site randomized trial of patients 70 years or older with high BP.
The main goal of the study Preventing Cognitive Decline by Reducing BP Target Trial (PCOT) is
to conduct a large pragmatic clinical trial (PCT) to test the hypothesis that patients who
receive care with a combination of clinical decision support (CDS) and team-based care
delivered in primary care practices will have better blood pressure control and a lower
incidence of mild cognitive impairment and dementia than patients receiving usual medical
care. Patients will be recruited from UT Southwestern Medical Center and Parkland Health &
Hospital System.
• High BP defined as at least 2 BP readings of SBP >= 130 or DBP >=80 during the 24
months prior to enrollment
• Clinic visit with primary care provider within the last 24 months
• Ability to write and speak English or Spanish
• 70 years of age or older 5 •Ability to understand and willingness to provide informed
consent
• Owns a smartphone or tablet
Exclusion Criteria:
• Blood pressure consistently <130/80 mmHg
• Presence of dementia, Alzheimer's disease, or significant neurological disease
• Major and unstable heart disease (e.g., acute heart failure (systolic or diastolic),
acute on chronic heart failure (systolic or diastolic), acute coronary syndrome or
cardiac arrest, liver or renal transplantation
• Under 70 years of age
• Inability to write or speak English or Spanish
• Chronic kidney disease stage 5 or ESKD
• Chemotherapy
• Any conditions judged by the medical providers to contraindicate participation due to
risk to patient safety or lack of adherence
• Expected life expectancy under a year
Other: Clinical Support Decision Tool
Hypertension, Blood Pressure, Cognitive Decline
UT Southwestern; Parkland Health & Hospital System
A Study of TAK-341 in Treatment of Multiple System Atrophy
The main aim is to see how TAK-341 works after 52 weeks in participants with multiple system
atrophy as measured by the Unified Multiple System Atrophy Rating Scale Part I (UMSARS).
The study will enroll approximately 138 patients. Participants will receive a total of 13
intravenous infusions every 4 weeks approximately, these may be either of TAK-341 or placebo,
after each infusion some blood samplings will be taken and other assessments completed.
This trial will be conducted in North America, Europe and Asia.
Inclusion criteria:
Diagnostic:
1. The participant has a diagnosis of possible or probable MSA using the modified Gilman
et al, 2008 diagnostic criteria.
2. The participant's onset of first MSA symptoms occurred ≤4 years before screening, as
assessed by the investigator.
3. Evidence of MSA specific symptoms and deficits as measured by the UMSARS scale.
Exclusion criteria:
Medical History:
1. The participant has any contraindication to study procedures.
Diagnostic Assessments:
1. Presence of confounding diagnosis and/or conditions that could affect participant's
safety during the study per investigator judgement.
2. The participant's participation in a previous study of a disease-modifying therapy
(with proven receipt of active treatment) will compromise the interpretability of the
data from the present study, per consultation with medical monitor or designee.
Other:
1. The participant has participated in another study investigating active or passive
immunization against α-synuclein (αSYN) for progressive disease (PD) or MSA, or has had
immunoglobulin G therapy, within 6 months before screening.
Cobimetinib in Refractory Langerhans Cell Histiocytosis (LCH), and Other Histiocytic Disorders (NACHO-COBI)
This is a research study of a drug called cobimetinib in children and adults diagnosed with
Langerhans cell histiocytosis (LCH), and other histiocytic disorders that has returned or
does not respond to treatment. Cobimetinib blocks activation of a protein called
Mitogen-activated protein kinase (MEK) that is part of incorrect growth signals in
histiocytosis cells. Four different groups of patients will be enrolled.
INCLUSION CRITERIA:
Age at study entry
• For Group 1: Participant must be at least 6 months of age and less than 21 years of
age at the time of enrollment
• For Group 2: Participant may be at least 6 months of age at the time of enrollment
• For Group 3: Participant must be at least 6 months of age and less than 21 years of
age at the time of enrollment
• For Group 4: Participant must be 21 years of age or older at the time of enrollment
• Participant must be able to take an enteral dose and formulation of medication. Study
medication is only available as an oral suspension or tablet which may be taken by
mouth or other enteral route such as nasogastric or gastric tube.
• Biopsy proven LCH -AND
• Failure of at least front-line therapy for LCH with evaluable disease. -OR
• Diagnosis of LCH-associated neurodegenerative disease with radiologic or clinical
progression within the past 3 months. -OR
• Biopsy proven JXG, ECD, RDD, histiocytic sarcoma, or other histiocytic lesion (newly
diagnosed or relapsed/refractory disease) with evaluable active disease.
Performance Level:
-Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50% for patients ≤ 16 years of
age.
Adequate Hematologic Function Defined as:
• ANC ≥ 0.75 x 10^9/L (unsupported/without growth factor stimulant)
• Platelet count ≥ 75 x 10^9/L (unsupported/without transfusion within the past 7 days).
• Patients with marrow disease must have platelet count of >/= 75 x 10^9/L (transfusion
support allowed) and must not be refractory to platelet transfusions.
• Hemoglobin ≥ 8 g/dL (unsupported/without transfusion within the past 7 days)
• Patients with marrow disease must have hemoglobin ≥ 8 g/dL (transfusion support
allowed).
Adequate Renal Function Defined as:
•Calculated creatinine clearance (or radioisotope GFR) ≥ 70 mL/min/1.73m^2 or serum
creatinine based on age/gender as follows:
Maximum Serum Creatinine (mg/dL) Age 2 to < 6 years: Male 0.8 mg/d, Female 0.8; 6 to < 10
years: Male 1 mg/dL,Female 1; 10 to < 13 years: Male 1.2 mg/dL; Female 1.2; 13 to < 16
years: Male 1.5 mg/dL ; Female 1.4; ≥ 16 years: Male 1.7 mg/dL; Female 1.4;
Adequate Liver Function Defined as:
• Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for
age
• AST and ALT ≤ 3x ULN (≤ 5 x ULN for participants with liver involvement)
• Serum albumin ≥ 2 g/dL.
For patients with liver disease caused by histiocytic disorder:
• Patients may be enrolled with abnormal bilirubin, AST, ALT and albumin with documentation
of histiocytic liver disease.
Adequate Cardiac Function Defined as:
•Fractional shortening (FS) of ≥ 30% or ejection fraction of ≥ 50% by echocardiogram at
baseline, as determined by echocardiography or multigated acquisition scan (MUGA) within 28
days prior to enrollment. Depending on institutional standard, either FS or LVEF is
adequate for enrollment if only one value is measured; if both values are measured, then
both values must meet criteria above
Pregnancy/Birth Control
• Female patients of childbearing potential require a negative urine or serum pregnancy
test for eligibility and again at database registration, if more than 2 weeks has
elapsed.
• Female patients of childbearing potential must agree to follow the contraceptive
requirements using two forms of effective contraceptive methods for the duration of
the study treatment. Male patients with sexual partners who are pregnant or who could
become pregnant (i.e., women of child-bearing potential) must agree to use two forms
of effective methods of contraception (one of which must be a barrier method) during
the treatment period and for at least 3 months after the last dose of the study drug
to avoid pregnancy and/or potential adverse effects on a developing embryo. Agreement
to true abstinence (not periodic abstinence or withdrawal method) is an acceptable
method of birth control.
EXCLUSION CRITERIA:
•Prior and Concomitant Use of Drugs with CYP3A4 inducing/inhibiting activity: Patient
taking strong inducers or inhibitors of CYP3A4 within 14 days prior to study enrollment,
including but not limited to the following: erythromycin, clarithromycin, ketoconazole,
azithromycin, itraconazole, grapefruit juice or St. John's wort.
• Prior Therapy Restrictions Completion of previous chemotherapy, immunotherapy,
radiotherapy, or targeted therapy for LCH (or other histiocytic disorder) at least 28
days (except where specified below) prior to study enrollment, with resolution of all
associated toxicity to ≤ Grade 1 prior to study enrollment (exception for alopecia and
ototoxicity which do not need to be resolved ≤ Grade 1). Patients must have fully
recovered from the acute toxic effects of all prior anti-cancer therapy and must meet
the following minimum duration from prior anti-cancer directed therapy prior to
enrollment. If after the required timeframe, the laboratory eligibility criteria are
met, the patient is considered to have recovered adequately.
• Radiation therapy within the 28 days prior to enrollment.
• Any prior treatment with Cobimetinib.
• Treatment with a long-acting hematopoietic growth factor within 14 days prior to
initiation of study drug or a short-acting hematopoietic growth factor within 7
days prior to enrollment.
• Treatment with hormonal therapy (except hormone replacement therapy or oral
contraceptives), immunotherapy, biologic therapy, investigational therapy, or
herbal cancer therapy within 28 days or < 5 half-lives, whichever is longer,
prior to study enrollment.
• Treatment with high-dose chemotherapy and stem-cell rescue (autologous stem cell
transplant) or allogeneic stem cell transplant within 90 days prior to
enrollment. Anti-GVHD agents post-transplant: Patients who are receiving
cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease
post bone marrow transplant are not eligible for this trial.
• For patients with brain tumors (intracranial masses), use of anticoagulants
within 7 days prior to enrollment.
• Corticosteroid therapy <0.5 mg/kg/day averaged during the month prior to study
enrollment is permissible but must be discontinued fourteen (14) days prior to
enrollment. Patients with documented brain lesions receiving corticosteroids for
management of cerebral edema must be on a stable dose for fourteen (14) days
prior to enrollment.
• Patient has received treatment with investigational therapy within 4 weeks prior
to initiation of study drug.
• Patients taking anticoagulants or have a pre-existing bleeding disorder unrelated
to histiocytic disease.
• Exclusions for other illness
• Other active malignancy or history of secondary malignancy.
• Refractory nausea and vomiting, malabsorption, external biliary shunt
• Infection: Patients who have a known active infection (excluding documented
fungal infection of the nail beds) within 28 days prior to enrollment that has
not completely resolved.
• Major surgical procedure or significant traumatic injury within 28 days prior to
enrollment, or anticipation of need for major surgical procedure during the
course of the study. Placement of a vascular access device or minor surgery is
permitted within fourteen (14) days prior to study enrollment (provided that the
wound has healed).
• History of significant bowel resection that would preclude adequate absorption or
other significant malabsorptive disease.
• History of pneumonitis.
• Ophthalmologic considerations: Patients with known significant ophthalmologic
conditions or known risk factors for retinal vein occlusion are not eligible.
Specifically, patients with a history of retinal vein occlusion (RVO), retinal
detachment, retinal pathology on ophthalmologic exam, retinopathy of prematurity,
central serous chorioretinopathy (CSSCR), neovascular retinopathy, intraocular
pressure > 21 mmHg, and predisposing factors to RVO (e.g., uncontrolled
hypertension, diabetes, or hyperlipidemia, coagulopathy) will be excluded.
Patients with longstanding and stable ophthalmologic findings secondary to
existing conditions are eligible with appropriate written documentation and
approval from Study Chair.
• History of solid organ transplantation: Patients who have received a prior solid
organ transplantation are not eligible.
• Any other disease, metabolic or psychological dysfunction, physical examination
finding, or clinical laboratory finding giving reasonable suspicion of a disease
or condition that in the opinion of the investigator contraindicates use of an
investigational drug or places the patient at unacceptable risk from treatment
complications.
• History of clinically significant cardiac dysfunction, including the following:
• Clinically significant cardiac arrhythmias including brady-arrhythmias and/or
patients who require anti-arrhythmic therapy (with the exception of beta blockers
or digoxin). Patients with controlled atrial fibrillation are not excluded.
• Unstable arrhythmia
• Unstable angina, or new-onset angina within 3 months prior to initiation of study
treatment
• Symptomatic congestive heart failure, defined as New York Heart Association Class
II or higher
• Myocardial infarction within 3 months prior to initiation of study treatment
• Known chronic human immunodeficiency virus (HIV).
• History of Grade ≥ 2 CNS hemorrhage or history of any CNS hemorrhage within 28 days of
enrollment.
• Female patients who are pregnant or lactating. Pregnant or lactating women will not be
entered on this study because there is no available information regarding human fetal
or teratogenic toxicities.
Drug: Cobimetinib
Histiocytic Sarcoma, Juvenile Xanthogranuloma, Brain and Nervous System, Bones and Joints, Liver, Lung/Thoracic, Other Hematopoietic, Langerhan's Cell Histiocytosis, Erdheim-Chester Disease, Rosai Dorfman Disease, Neuro-Degenerative Disease, Histiocytic Disorders, Malignant
Abatacept in Immune Checkpoint Inhibitor Myocarditis (ATRIUM)
The primary aim is to test whether abatacept, as compared to placebo, is associated with a
reduction in major adverse cardiac events (MACE) among participants hospitalized with
myocarditis secondary to an immune checkpoint inhibitor (ICI). The primary outcome, MACE, is
a composite of first occurrence of cardiovascular death, non-fatal sudden cardiac arrest,
cardiogenic shock, significant ventricular arrythmias, significant bradyarrythmias, or
incident heart failure.
1. Must have provided informed consent in a manner approved by the Investigator's
Institutional Review Board (IRB) prior to any study-related procedure being performed.
If a participant is unable to provide informed consent due to his/her medical
condition, the participant's legally authorized representative may consent on behalf
of the study participant, as permitted by local law and institutional Standard
Operating Procedures;
2. Aged greater than or equal to 18 years at the time of informed consent;
3. Recent use of an FDA-approved immune checkpoint inhibitor (ICI, defined as
administered an immune checkpoint inhibitor ≤ 6 months of myocarditis diagnosis),
alone or in combination with other cancer therapies (i.e. chemotherapy, radiation
therapy or targeted therapy). The FDA-approved ICI could be given as part of a
clinical trial but not in combination with a new investigational agent which may cause
myocarditis;
4. A diagnosis of myocarditis.
5. Hospitalized at the time of randomization;
6. On 1000 mg of solumedrol per day for myocarditis or with an intent to initiate 1000 mg
of solumedrol per day for myocarditis within 24 hours of first administration of study
drug;
7. Serum evidence of ongoing myocardial injury: Serum evidence of ongoing myocardial
injury will be defined as an institutional troponin (either conventional or
high-sensitivity troponin I or T, using the standard institutional assay) with a value
that is ≥5 times the upper limit of the reference standard normal for that
institution. The troponin assay may be adjusted based on sex depending on
institutional standards. This value of troponin of ≥5 times above the institutional
upper limits of normal value must be noted within 10 days prior to potential
randomization. The 10-day period can be in the outpatient or inpatient setting. For
example, a participant with a troponin value that on one occasion was ≥5 times the
upper limits of institutional normal in the 10-day window prior to potential
randomization (whether in the inpatient or outpatient setting), but later decreases
below that threshold, typically due to starting corticosteroids, would still be
considered eligible;
8. The following laboratory parameters, not older than 48 hours at the time of
randomization, and measured as part of usual care:
• Total white blood cell (WBC) count >2,500/μl
• Absolute neutrophil count (ANC) >1,500/μL
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) <20 times the
upper limit of the institutional normal ranges;
9. Women of childbearing potential (i.e., not postmenopausal, or surgically sterilized)
must have a negative highly sensitive urine or serum pregnancy test prior to
randomization. Participating women of childbearing potential must be willing to
consistently use effective methods of contraception from screening until at least 90
days after administration of the last dose of study drug. Participating men must also
be willing to consistently use effective methods of contraception from screening until
at least 90 days after administration of the last dose of study drug; and
10. Must be willing and able to abide by all study requirements and restrictions.
Exclusion Criteria:
1. Must not have experienced any of the following (as defined in the section on the
primary endpoint) in the 30-day period prior to randomization:
• A sudden cardiac arrest
• Cardiogenic shock as defined. A significant bradyarrhythmia (Mobitz type II
second degree atrioventricular block or third degree (complete) atrio-ventricular
(AV) block, for which an intervention with a temporary or permanent pacemaker is
completed or recommended).
• A significant tachyarrhythmia (ventricular fibrillation of any duration or
sustained ventricular tachycardia (>30 seconds, >120 beats per minute); or a
ventricular tachyarrhythmia requiring intervention.
2. Recent (≤2 month) exposure to abatacept or belatacept.
3. Concurrent or recent (≤2 month) use of the following non-corticosteroid
immunosuppressive therapies prior to randomization: mycophenolate, JAK STAT inhibitors
(including but not limited to upadacitinib, tofacitinib, baricitinib, and filgotinib),
tacrolimus, anti-thymocyte globulin, alemtuzumab, infliximab, and plasma exchange. The
use of intravenous immunoglobulin is permitted prior to randomization and during study
treatment.
4. Currently enrolled in another interventional study utilizing systemic agents for the
management of ICI-related toxicities.
5. Female who is pregnant, breastfeeding, or is considering becoming pregnant during the
study or for approximately 90 days after the last dose of study drug.
6. Male who is considering fathering a child or donating sperm during the study or for
approximately 30 days after the last dose of study drug.
7. Any active, chronic, or recurrent viral infection that, based on the investigator's
clinical assessment, makes the participant an unsuitable candidate for the study.
These may include hepatitis B virus (HBV) or hepatitis C virus (HCV), recurrent or
disseminated (even a single episode) herpes zoster, and disseminated (even a single
episode) herpes simplex. Active HBV and HCV are defined as: HBV: hepatitis B surface
antigen (HBs Ag) positive (+) or detected sensitivity on the HBV deoxyribonucleic acid
(DNA) polymerase chain reaction (PCR) qualitative test for Hepatitis B core antibody
(HBc Ab) positive (+) participants; HCV: HCV ribonucleic acid (RNA) detectable in any
participant with anti-HCV antibody (HCV Ab). Patients with active Covid-19 infection
will be excluded. This is defined as the period of ongoing symptoms in the setting of
a positive Covid-19 test, or until 10 days after symptom onset and after resolution of
fever for at least 24 hours, without the use of fever-reducing medications.
8. Known active tuberculosis (TB), history of incompletely treated TB, suspected or known
extrapulmonary TB, suspected or known systemic bacterial or fungal infections;
9. Receipt of any live vaccine within four weeks prior to the first dose of study drug,
or expected need of live vaccination during study participation including at least 90
days after the last dose of IV study drug.
10. Any medical condition that could interfere with, or for which the treatment might
interfere with, the conduct of the study or interpretation of the study results, or
that would, in the opinion of the Investigator, increase the risk of the participant
by participating in the study.
11. Any factors that, in the Investigator's opinion, are likely to interfere with study
procedures, such as history of noncompliance with scheduled appointments.
Drug: Abatacept plus, Drug: Placebo
Cancer, Brain and Nervous System, Eye and Orbit, Anus, Bones and Joints, Breast - Female, Breast - Male, Cervix, Colon, Corpus Uteri, Esophagus, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Melanoma, skin, Other Digestive Organ, Other Endocrine System, Other Female Genital, Other Male Genital, Other Respiratory and Intrathoracic Organs, Other Skin, Other Urinary, Ovary, Pancreas, Prostate, Rectum, Stomach, Thyroid, Urinary Bladder, Small Intestine, Soft Tissue, Unknown Sites, Myocarditis Acute
1. Age ≥ 18 years.
2. ECOG Performance Score of 2 or better/Karnofsky Performance score of 50-60 or better.
3. Biopsy-proven non-hematopoietic malignancy, except for germ cell cancer. Small cell
lung carcinoma is eligible for this study.
4. Six or more metastases on diagnostic or treatment planning imaging, which include
either CT Brain (with contrast) or MR Brain (with or without contrast) imaging.
5. Largest tumor <= 4 cm.
6. No prior SRS to the lesions which will be treated on protocol.
7. Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry, for
the duration of study participation, and for 90 days following completion of therapy.
Should a woman become pregnant or suspect she is pregnant while participating in this
study, she should inform her treating physician immediately.
A female of child-bearing potential is any woman (regardless of sexual orientation,
marital status, having undergone a tubal ligation, or remaining celibate by choice)
who meets the following criteria:
• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e.,
has had menses at any time in the preceding 12 consecutive months).
8. Ability to understand and the willingness to sign a written informed consent.
Exclusion Criteria:
1. Prior whole brain radiotherapy
2. Patients with leptomeningeal metastasis. (NOTE: For the purposes of exclusion, LMD is
a clinical diagnosis, defined as positive CSF cytology and/or equivocal radiologic or
clinical evidence of leptomeningeal involvement. Patients with leptomeningeal symptoms
in the setting of leptomeningeal enhancement by imaging (MRI) would be considered to
have LMD even in the absence of positive CSF cytology, unless a parenchymal lesion can
adequately explain the neurologic symptoms and/or signs. In contrast, an asymptomatic
or minimally symptomatic patient with mild or nonspecific leptomeningeal enhancement
(MRI) would not be considered to have LMD. In that patient, CSF sampling is not
required to formally exclude LMD, but can be performed at the investigator's
discretion based on level of clinical suspicion.)
3. Patients with life expectancy < 4 months.
4. Psychiatric illness/social situations that, in the opinion of the investigator, would
limit compliance with study requirements.
5. Subjects must not be pregnant or nursing due to the potential for congenital
abnormalities and the potential of this regimen to harm nursing infants.
Radiation: Stereotactic Radiosurgery
Brain Metastases
UT Southwestern; Parkland Health & Hospital System
Sleep for Stroke Management and Recovery Trial (Sleep SMART)
The purpose of this study is to determine whether treatment of obstructive sleep apnea (OSA)
with positive airway pressure starting shortly after acute ischemic stroke or high risk TIA
(1) reduces recurrent stroke, acute coronary syndrome, and all-cause mortality 6 months after
the event, and (2) improves stroke outcomes at 3 months in patients who experienced an
ischemic stroke.
1. TIA with ABCD2 ≥4 or ischemic stroke, within the prior 14 days.
Exclusion Criteria:
1. pre-event inability to perform all of own basic ADLs
2. unable to obtain informed consent from subject or legally authorized representative
3. incarcerated
4. known pregnancy
5. current mechanical ventilation (can enroll later if this resolves) or tracheostomy
6. current use of positive airway pressure, or use within one month prior to stroke
7. anatomical or dermatologic anomaly that makes use of CPAP interface unfeasible
8. severe bullous lung disease
9. history of prior spontaneous pneumothorax or current pneumothorax
10. hypotension requiring current treatment with pressors (can enroll later if this
resolves)
11. other specific medical circumstances that conceivably, in the opinion of the site PI,
could render the patient at risk of harm from use of CPAP
12. massive epistaxis or previous history of massive epistaxis
13. cranial surgery or head trauma within the past 6 months, with known or possible CSF
leak or pneumocephalus
14. recent hemicraniectomy or suboccipital craniectomy (i.e. those whose bone has not yet
been replaced), or any other recent bone removal procedure for relief of intracranial
pressure
15. current receipt of oxygen supplementation >4 liters per minute
16. current contact, droplet, respiratory/airborne precautions
Pragmatic Evaluation of Events And Benefits of Lipid-lowering in Older Adults (PREVENTABLE)
PREVENTABLE is a multi-center, randomized, parallel group, placebo-controlled superiority
study. Participants will be randomized 1:1 to atorvastatin 40 mg or placebo. This large study
conducted in community-dwelling older adults without cardiovascular disease (CVD) or dementia
will demonstrate the benefit of statins for reducing the primary composite of death,
dementia, and persistent disability and secondary composites including mild cognitive
impairment (MCI) and cardiovascular events.
• Community-dwelling adults
• Age ≥75 years
• English or Spanish as primary language
Exclusion Criteria:
• Clinically evident cardiovascular disease defined as prior myocardial Infarction (MI),
prior stroke, prior revascularization procedure, or a secondary prevention indication
for a statin (clinician determined)
• Hospitalization for a primary diagnosis of heart failure in the prior 12 months (Note:
History of heart failure in the absence of recent hospitalization or clinically
evident cardiovascular disease is not an exclusion)
• Dementia (clinically evident or previously diagnosed)
• Dependence in any Katz Basic Activities of Daily Living [ADL] (with the exception of
urinary or bowel continence)
• Severe hearing impairment (preventing phone follow up)
• Unable to talk (preventing phone follow up)
• Severe visual impairment (preventing cognitive testing)
• Statin use in the past year or for longer than 5 years previously (participant
reported)
• Ineligible to take atorvastatin 40 mg (clinician determined)
• Documented intolerance to statins
• Active Liver Disease
• Long-term use of daily colchicine, verapamil at any dose, or diltiazem at a dose
>240mg/day.
A Phase 3 Trial of Pamrevlumab or Placebo in Combination With Systemic Corticosteroids, in Subjects With Non-ambulatory Duchenne Muscular Dystrophy (DMD)
To evaluate the efficacy and safety of pamrevlumab versus placebo in combination with
systemic corticosteroids in subjects with non-ambulatory Duchenne muscular dystrophy (age 12
years and older).
1. Males at least 12 years of age, non-ambulatory at screening initiation
2. Written consent by patient and/or legal guardian as per regional/ country and/or
IRB/IEC requirements
3. Male subjects with partners of childbearing potential must use contraception during
the conduct of the study, and for 3 months after the last dose of study drug.
4. Medical history includes diagnosis of DMD and confirmed Duchenne mutation using a
validated genetic test
5. Brooke Score for Arms and Shoulders ≤5
6. Able to undergo MRI test for the upper arm extremities (Biceps Brachii muscle) and
cardiac muscle
7. Able to perform spirometry
8. Average (of Screening and Day 0) percent predicted FVC between 45 and 85, inclusive
9. Left ventricular ejection fraction ≥50% as determined by cardiac MRI at screening or
within 3 months prior to randomization (Day 0)
10. Prior diagnosis of cardiomyopathy, subjects must be on a stable regimen dose for
cardiomyopathy/ heart failure medications (e.g., angiotensin converting enzyme
inhibitors, aldosterone receptors blockers, angiotensin-receptor blockers, and
betablockers) for at least 1 month prior to screening
11. On a stable dose of systemic corticosteroids for a minimum of 6 months, with no
substantial change in dosage for a minimum of 3 months (except for adjustments for
changes in body weight) prior to screening. Corticosteroid dosage should be in
compliance with the DMD Care Considerations Working Group recommendations
(e.g.prednisone or prednisolone 0.75 mg/kg per day or deflazacort 0.9 mg/kg per day)
or stable dose. A reasonable expectation is that dosage and dosing regimen would not
change significantly for the duration of the study.
12. Received pneumococcal vaccine (PPSV23) (or any other pneumococcal polysaccharide
vaccine as per national recommendations) and is receiving annual influenza
vaccinations
13. Adequate renal function: cystatin C ≤1.4 mg/L
14. Adequate hematology and electrolytes parameters:
1. Platelets >100,000/mcL
2. Hemoglobin >12 g/dL
3. Absolute neutrophil count >1500 /μL
4. Serum calcium (Ca), potassium (K), sodium (Na), magnesium (Mg) and phosphorus (P)
levels are within a clinically accepted range
15. Adequate hepatic function:
1. No history or evidence of liver disease
2. Gamma glutamyl transferase (GGT) ≤3x upper limit of normal (ULN)
3. Total bilirubin ≤1.5xULN
Exclusion Criteria:
1. Previous exposure to pamrevlumab
2. BMI ≥40 kg/m2 or weight >117 kg
3. History of allergic or anaphylactic reaction to human, humanized, chimeric or murine
monoclonal antibodies
4. Exposure to any investigational drug (for DMD or not), in the 30 days prior to
screening initiation or use of approved DMD therapies (e.g., eteplirsen, ataluren,
golodirsen) within 5 half-lives of screening, whichever is longer, with the exception
of the systemic corticosteroids, including deflazacort
5. Severe uncontrolled heart failure (NYHA Classes III-IV), including any of the
following:
1. Need for intravenous diuretics or inotropic support within 8 weeks prior to
screening
2. Hospitalization for a heart failure exacerbation or arrhythmia within 8 weeks
prior to screening
6. Arrhythmia requiring anti-arrhythmic therapy
7. Requires ≥16 hours continuous ventilation
8. Hospitalization due to respiratory failure within the 8 weeks prior to screening
9. Poorly controlled asthma or underlying lung disease such as bronchitis,
bronchiectasis,emphysema, recurrent pneumonia that in the opinion of the investigator
might impact respiratory function
10. The Investigator judges that the subject will be unable to fully participate in the
study and complete it for any reason, including inability to comply with study
procedures and treatment, or any other relevant medical or psychiatric conditions
AHEAD 3-45 Study: A Study to Evaluate Efficacy and Safety of Treatment With Lecanemab in Participants With Preclinical Alzheimer's Disease and Elevated Amyloid and Also in Participants With Early Preclinical Alzheimer's Disease and Intermediate Amyloid
The primary purpose of this study is to determine whether treatment with lecanemab is
superior to placebo on change from baseline of the Preclinical Alzheimer Cognitive Composite
5 (PACC5) at 216 weeks of treatment (A45 Trial) and to determine whether treatment with
lecanemab is superior to placebo in reducing brain amyloid accumulation as measured by
amyloid positron emission tomography (PET) at 216 weeks of treatment (A3 Trial).
Inclusion criteria:
Participants must meet all of the following criteria to be included in this study:
1. Male or female, age 55 to 80 years inclusive at the time of informed consent
• Those 55 to 64 must have 1 of the following additional risk factors, given the
relatively low rates of amyloid positivity less than (<) 65 years:
• First degree relative diagnosed with dementia onset before age 75, or
• Known to possess at least 1 apolipoprotein E4 variant (APOE4) allele, or
• Known before screening to have elevated brain amyloid according to previous PET
or cerebrospinal fluid (CSF) testing. Individuals with historical amyloid PET
scans with intermediate brain amyloid (example, from preclinical Alzheimer's
disease (AD) studies such as A4 or EARLY) are eligible to be screened, provided
the participant did not participate in any clinical studies involving
anti-amyloid therapies subsequent to the PET assessment
2. Global Clinical Dementia Rating (CDR) score of 0 at screening
3. Mini Mental State Examination score greater than or equal to (>=) 27 (with educational
adjustments) at screening
4. Wechsler Memory Scale-Revised Logical Memory subscale II (WMS-R LM II) score at
screening of >=6
5. A45 Trial: Elevated brain amyloid pathology by amyloid PET: defined as approximately
greater than (>) 40 Centiloids on screening scan
A3 Trial: Intermediate levels of brain amyloid pathology by amyloid PET: defined as
approximately 20 to 40 Centiloids on screening scan
6. Has a study partner that is willing to participate as a source of information and has
approximately weekly contact with the participant (contact can be in-person, via
telephone or electronic communication). The study partner must have sufficient contact
such that the investigator feels the study partner can provide meaningful information
about the participant's daily function
7. Provide written (or electronic, if allowed per country-specific regulations) informed
consent
8. Willing and able to comply with all aspects of the protocol
Exclusion criteria:
Participants who meet any of the following criteria will be excluded from this study:
1. Females who are breastfeeding or pregnant at screening or baseline
2. Females of childbearing potential who:
• Within 28 days before study entry, did not use a highly effective method of
contraception
For sites outside of the European union (EU), it is permissible that if a highly
effective method of contraception is not appropriate or acceptable to the participant,
then the participant must agree to use a medically acceptable method of contraception
3. History of transient ischemic attacks (TIA), stroke, or seizures within 12 months of
screening
4. Current or history within the past 2 years of psychiatric diagnosis or symptoms that,
in the opinion of the investigator, could interfere with study procedures
5. Contraindications to 3 Tesla magnetic resonance imaging (MRI) scanning, including
cardiac pacemaker/defibrillator, ferromagnetic metal implants (example, in-skull and
cardiac devices other than those approved as safe for use in MRI scanners), or exhibit
other significant pathological findings on brain MRI at Screening
6. Hypersensitivity to any monoclonal antibody treatment
7. Any immunological disease which is not adequately controlled, or which requires
treatment with immunoglobulins, systemic monoclonal antibodies (or derivatives of
monoclonal antibodies), systemic immunosuppressants, or plasmapheresis during the
study
8. Bleeding disorder that is not under adequate control (including a platelet count
<50,000 or international normalized ratio [INR] >1.5) at screening
9. Results of laboratory tests conducted during screening that are outside the following
limits:
• Thyroid stimulating hormone (TSH) above normal range
• Abnormally low (below lower limit of normal [LLN]) serum vitamin B12 levels for
the testing laboratory (if participant is taking vitamin B12 injections, level
should be at or above the LLN for the testing laboratory). A low vitamin B12 is
exclusionary, unless the required follow-up labs (homocysteine and methylmalonic
acid [MMA]) indicate that it is not physiologically significant
10. Known to be human immunodeficiency virus (HIV) positive
11. Any other clinically significant abnormalities that in the opinion of the investigator
require further investigation or treatment or may interfere with study procedures or
safety
12. Malignant neoplasms within 3 years of screening (except for basal or squamous cell
carcinoma in situ of the skin, or localized prostate cancer in male participants with
treatment cycles completed at least 6 months before screening). Participants who had
malignant neoplasms but who have had at least 3 years of documented uninterrupted
remission before screening need not be excluded
13. Answer "yes" to Columbia-Suicide Severity Rating Scale (C-SSRS) suicidal ideation Type
4 or 5, or any suicidal behavior assessment within 6 months before screening, at
screening, or at baseline, or has been hospitalized or treated for suicidal behavior
in the past 5 years before screening
14. Known or suspected history of drug or alcohol abuse or dependence within 2 years
before screening or a positive urine drug test at screening. Participants who test
positive for benzodiazepines, opioids, or tetrahydrocannabinol (THC) in urine drug
testing need not be excluded unless in the clinical opinion of the investigator this
is due to potential drug abuse
15. Taking prohibited medications
16. Participation in a clinical study involving:
• Any anti-amyloid immunotherapy (example, therapeutic monoclonal antibody or
active anti-amyloid vaccine) at any time, unless it can be documented that the
participant was randomized to placebo or never received study drug
• Any immunoglobulin therapy, or vaccine within 6 months before Screening, unless
it can be documented that the participant was randomized to placebo or never
received study drug
• Lecanemab
• Any new chemical entities or investigational drug for AD within 6 months before
screening unless it can be documented that the participant received only placebo
• Any other investigational medication or device study in the 8 weeks or 5
half-lives (whichever is longer) of the medication before randomization unless it
can be documented that the participant was in a placebo treatment arm
17. Planned surgery during the prerandomization phase or within 3 months of randomization,
which requires general anesthesia
Drug: Lecanemab, Drug: Placebo
Preclinical Alzheimer's Disease, Brain and Nervous System, Early Preclinical Alzheimer's Disease
Influence of Cooling Duration on Efficacy in Cardiac Arrest Patients (ICECAP)
A multicenter, randomized, adaptive allocation clinical trial to determine if increasing
durations of induced hypothermia are associated with an increasing rate of good neurological
outcomes and to identify the optimal duration of induced hypothermia for neuroprotection in
comatose survivors of cardiac arrest.
• Coma after resuscitation from out of hospital cardiac arrest
• Cooled to <34 deg C with 240 minutes of cardiac arrest
• Definitive temperature control applied
• Age ≥ 18 years
• Informed consent from legal authorized representative (LAR) including intent to
maintain life support for 96 hours
• Enrollment within 6 hours of initiation of cooling
Exclusion Criteria:
• Hemodynamic instability
• Pre-existing neurological disability or condition that confounds outcome determination
• Pre-existing terminal illness, unlikely to survive to outcome determination
• Planned early withdrawal of life support
• Presumed sepsis as etiology of arrest
• Prisoner
Traditional Versus Early Aggressive Therapy for Multiple Sclerosis Trial (TREAT-MS)
FDA-approved multiple sclerosis (MS) disease-modifying therapies (DMTs) target the relapsing
phase of MS but have minimal impact once the progressive phase has begun. It is unclear if,
in the relapsing phase, there is an advantage of early aggressive therapy with respect to
preventing long-term disability. The infectious risks and other complications associated with
higher-efficacy treatments highlight the need to quantify their effectiveness in preventing
disability.
The TRaditional versus Early Aggressive Therapy for MS (TREAT-MS) trial is a pragmatic,
randomized controlled trial that has two primary aims: 1) to evaluate, jointly and
independently among patients deemed at higher risk vs. lower risk for disability
accumulation, whether an "early aggressive" therapy approach, versus starting with a
traditional, first-line therapy, influences the intermediate-term risk of disability, and 2)
to evaluate if, among patients deemed at lower risk for disability who start on first-line MS
therapies but experience breakthrough disease, those who switch to a higher-efficacy versus a
new first-line therapy have different intermediate-term risk of disability.
• Aged 18-60 years
• Meets 2017 McDonald criteria for relapsing-remitting MS [patients with clinically
isolated syndrome (CIS) are not eligible]
• Must be EITHER John Cunningham (JC) virus antibody negative or low positive (index
antibody titer <0.9), OR negative for: Hepatitis B and C, tuberculosis
• HIV negative
• No chemotherapy in past year; if patient has prior history of chemotherapy or
malignancy, documentation in chart explaining why potential risks of higher-efficacy
therapy are justified
Exclusion Criteria:
• Prior treatment with rituximab, ocrelizumab, ofatumumab, alemtuzumab, mitoxantrone or
cladribine
• Prior treatment with any other MS DMT for more than 6 months
• Prior treatment with experimental aggressive therapies (e.g., T-cell vaccine, total
lymphoid radiation, stem cells)
• Treatment with teriflunomide within past 2 years (even for ≤ 6 months), unless rapid
wash out done (i.e., with cholestyramine or activated charcoal)
• Treatment in the past 6 months with any MS DMT
• Prior treatment with any other investigational immune-modulating /suppressing drug for
MS not listed above
• Pregnant or breast-feeding
• Women of child-bearing age who are planning or strongly considering conception during
the study time frame
Other: Early Aggressive Therapy or Traditional Therapy
Clinical Study of Cannabidiol in Children, Adolescents, and Young Adults With Fragile X Syndrome (RECONNECT)
This is a randomized, double-blind, placebo-controlled, multiple-center study, to assess the
efficacy and safety of Cannabidiol administered as ZYN002 for the treatment of children,
adolescent, and young adult patients with Fragile X Syndrome (FXS). Eligible participants
will participate in up to an 18-week treatment period, where all participants will receive
placebo or active study drug. Patients ages 3 to < 23 years will be eligible to participate.
• Male or female children and adolescents aged 3 to < 23 years, at the time of
Screening.
• Patient resides with caregiver who will continue to provide consistent care throughout
the study.
• Judged by the Investigator to be in generally good health at Screening based upon the
results of medical history, physical exam, 12-lead ECG and clinical laboratory test
results. -Laboratory results outside the reference range must be documented as not
clinically significant by both the Investigator and Sponsor.
• Participants must have a diagnosis of FXS through molecular documentation of full
mutation of the FMR1 gene documented through genetic testing at Screening.
• Patients with a history of seizure disorders must currently be receiving treatment
with a stable regimen of no more than two anti-seizure medications (ASMs) for the four
weeks preceding study Screening; or must be seizure-free for one year if not currently
receiving ASMs.
• Patients taking psychoactive medication(s) should be on a stable regimen of not more
than three such medications for at least fours weeks preceding Screening and must
maintain that regimen throughout the study. Psychoactive medications include (but are
not limited to) antipsychotics, antidepressants, anxiolytics, attention-deficit /
hyperactivity disorder (ADHD) medications, and medications for sleep.
• If patients are receiving non-pharmacological, behavioral and/or dietary
interventions, they must be stable and have been doing so for three months prior to
screening.
• Patients have a body mass index between 12-30 kg/m2 (inclusive).
• Females of childbearing potential must have a negative serum pregnancy test at the
Screening Visit and a negative serum or urine pregnancy test at all designated visits.
• Patients and parents/caregivers must be adequately informed of the nature and risks of
the study and given written informed consent prior to Screening.
• Patients and parents/caregivers agree to abide by all study restrictions and comply
with all study procedures, and in the Investigator's opinion, are reliable and willing
and able to comply with all protocol requirements and procedures.
Exclusion Criteria:
• Females who are pregnant, nursing or planning a pregnancy; females of childbearing
potential and male patients with a partner of childbearing potential who are unwilling
or unable to use an acceptable method of contraception as outlined below for the
duration of therapy and for three months after the last dose of study medication.
Standard acceptable methods of contraception include abstinence (defined as refraining
from heterosexual intercourse from screening to three months after the last dose of
study medication) or the use of a highly effective method of contraception, including
hormonal contraception, diaphragm, cervical cap, vaginal sponge, condom, spermicide,
vasectomy, or intrauterine device. The reliability of sexual abstinence needs to be
evaluated in relation to the duration of the clinical trial and the preferred and
usual lifestyle of the subject. Periodic abstinence (calendar, symptothermal,
post-ovulation methods) is not an acceptable method of contraception.
• Patient has transitioned to independent living or living in a residential facility
such as a university setting or congregate care.
• History of significant allergic condition, significant drug-related hypersensitivity,
or allergic reaction to any compound or chemical class related to ZYN002 or its
excipients.
• Exposure to any investigational drug or device less than or equal to 30 days prior to
Screening or at any time during the study.
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST) or total bilirubin
levels greater than or equal to 2 times the upper limit of normal or alkaline
phosphatase levels greater than or equal to 3 times the upper limit of normal.
• Use of cannabis or any THC or CBD-containing product within 3 months of Screening
Visit or during the study (aside from ZYN002).
• Patient has a positive drug screen, including ethanol, cocaine, THC, barbiturates,
amphetamines (unless prescribed), benzodiazepines (except midazolam or comparable
administered for blood draws and ECG collection), and opiates.
• Patient is using the following AEDs (medications for the treatment of seizures and/ or
epilepsy): clobazam, phenobarbital, ethosuximide, felbamate, carbamazepine, phenytoin,
or vigabatrin.
• Patient is using a strong inhibitor/inducer of CYP3A4 or sensitive substrate of CYP3A4
including but not limited to the following medications: midazolam (except single doses
administered for the purposes of obtaining blood samples and ECG's), oral
ketoconazole, fluconazole, nefazadone, rifampin, alfentanil, alfuzosin, amiodarone,
cyclosporine, dasatinib, docetaxol, eplerenone, ergotamine, everolimus, fentanyl,
halofantrine, irinotecan, lapatinib, levomethadyl, lumefantrine, nilotinib, pimozide,
quinidine, ranolazine, sirolimus, tacrolimus, temsirolimus, toremifene, tretinioin,
vincristine, vinorelbine, St. John's Wort, and grapefruit Juice/products.
• Patients may not be taking any benzodiazepines (except single doses administered for
the purposes of obtaining blood samples and ECGs) at screening or throughout the
study.
• Patient is expected to initiate or change pharmacologic or non-pharmacologic
interventions during the course of the study.
• Patient has an advanced, severe, or unstable disease that may interfere with the study
outcome evaluations.
• Patient has acute or progressive neurological disease, psychosis, schizophrenia or any
other psychiatric disorder or severe mental abnormalities (other than FXS) that are
likely to require changes in drug therapy or interfere with the study objectives or
ability to adhere to protocol requirements.
• Patient has a positive result for the presence of HBsAg, HCV, or HIV antibodies.
• Patient has known history of cardiovascular disease, advanced arteriosclerosis,
structural cardiac abnormality, cardiomyopathy, serious heart rhythm abnormalities,
coronary artery disease, cardiac conduction problems, exercise-related cardiac events
including syncope and pre-syncope, risk factors for Torsades de pointes (TdP) (e.g.,
heart failure, hypokalemia, family history of Long QT Syndrome), or other serious
cardiac problems.
• Any clinically significant condition or abnormal findings at the Screening Visit that
would, in the opinion of the Investigator, preclude study participation or interfere
with the evaluation of the study medication.
• Any skin disease or condition including eczema, psoriasis, melanoma, acne, contact
dermatitis, scarring, imperfections, lesions, tattoos, or discoloration that may
affect treatment application, application site assessments or absorption of the trial
drug.
• History of treatment for, or evidence of, drug abuse within the past year.
• Previous participation in a ZYN002 study (with the exception of patients who were
screen failures in Study ZYN2-CL-016 and did not enter Study ZYN2-CL-017).
• Patient responds "yes" to Question 4 or 5 on the C-SSRS (Children) during Screening or
at any time on study.
Drug: ZYN002 - transdermal gel, Drug: Placebo
Fragile X Syndrome
Human Genetics and Inherited Disorders, Other human genetics and inherited disorders
Post-Surgical Stereotactic Radiotherapy (SRT) Versus GammaTile-ROADS (Radiation One and Done Study)
This trial will be a randomized controlled study comparing the efficacy and safety of
intraoperative radiation therapy using GammaTilesTM (GT) versus SRS 3-4 weeks following
metastatic tumor resection which is the current standard of care.
1. Patients aged 18 years old and above. Eligibility is restricted to this age group
given that the battery of neurocognitive tests utilized in this protocol are not
developed or validated for use in a younger population.
2. One to four newly diagnosed brain metastases, identified on the screening MRI, from an
extracranial primary tumor.
3. One lesion, designated the index lesion, is planned for surgical resection and is to
be between 2.5 cm and 5.0 cm on the screening MRI. Index lesions > 2.0 cm but <2.5 cm
are also eligible if surgery is deemed clinically necessary and appropriate for an
attempted gross total resection by the neurosurgeon.
4. Non-index lesions must measure < 4.0 cm in maximal extent on the screening MRI brain
scan. The unresected lesions will be treated with SRT as outlined in the treatment
section of the concept.
5. All metastases must be located > 5 mm from the optic chiasm and outside the brainstem.
Dural based metastasis are eligible.
6. Previous and/or concurrent treatment with systemic therapies (e.g., chemotherapy,
targeted therapeutics, immunotherapy) is permitted and must follow protocol guidelines
as follows: Systemic therapy is allowed a minimum of one week from last systemic
therapy cycle to surgical resection, and one week after surgical resection to allow a
minimum of one week before starting/resuming systemic therapy, depending on the
specific systemic agent(s), as recommended by medical/neuro-oncology. Systemic therapy
is not allowed 1 day before SRT, the same day as the SRT, or 1 day after the
completion of the SRT or longer, depending on the specific systemic agent(s), as
recommended by medical/neuro-oncology. Agents that are delivered by implant or depot
injections (such as hormonal therapies) are excluded from these restrictions.
7. KPS score of ≥70.
8. Stable systemic disease or reasonable systemic treatment options predicting a life
expectancy of ≥6 months.
9. Ability to complete an MRI of the head with contrast
10. Adequate renal and hepatic function to undergo surgery, in investigators opinion.
11. For women of childbearing potential only, a negative urine or serum pregnancy test
done < 7 days prior to randomization is required. Women must be willing to notify
investigator immediately if they become pregnant at any time during the trial period.
12. Men and women of childbearing potential must be willing to employ adequate
contraception throughout the study and for men for up to 3 months after completing
treatment.
13. Subjects must be fluent in English language to allow for completion of neurocognitive
tests and completion of QOL questionnaires. Non-English speaking subjects are not
permitted to participate given that participation in the real time integrated
neurocognitive function tests is mandatory for all patients. The psychometric
properties for translated tests are either not known or not as robust.
14. Willingness and ability to provide written informed consent and HIPAA authorization
prior to performance of any study-related procedures.
Exclusion Criteria
1. Age <18 years.
2. KPS<70
3. Past radiation or surgical therapy to the index lesion or the newly diagnosed
non-index lesion(s) is exclusionary. However, up to a total of 2 prior courses of SRT
treatment to previously diagnosed lesions are allowed as long as any treated lesions
are were >15mm from the index lesion.
4. Patients with >4 newly diagnosed metastases on screening MRI
5. Pregnant patients.
6. Primary germ cell tumor, small cell carcinoma, or lymphoma.
7. Leptomeningeal metastasis (LMD). Note: For the purposes of exclusion, LMD is a
clinical diagnosis, defined as radiologic or clinical evidence of leptomeningeal
involvement with or without positive cerebrospinal fluid (CSF) cytology.
8. Prior WBRT for brain metastases.
9. Concomitant therapy that, in the investigator's opinion, would interfere with the
evaluation of the safety or efficacy of the study device.
10. Comorbid psychiatric or neurologic disease or injury impacting cognition, in the
opinion of the treating physician, that might impair patient's ability to understand
or comply with the requirements of the study or to provide consent
11. Subjects who, in the investigator's opinion, are unable to understand the protocol or
to give informed consent, have a history of poor cooperation, noncompliance with
medical treatment, or difficulty in returning for follow up care.
1. Clinical diagnosis of PTHS with a documented disease-causing genetic etiology for the
disorder.
2. Males or females aged 3-17 years.
3. Body weight of 12kg or higher at screening
4. Subjects with a Clinical Global Impression- Severity (CGI-S) score of 4 or greater at
the Screening visit.
5. Not actively undergoing regression or loss of skills, defined as no persistent loss of
previously acquired developmental skills for a period within 3 months of the Screening
visit
6. Each subject must be able to swallow the study medication provided as a liquid
solution.
7. Caregiver(s) must have sufficient English language skills.
Exclusion Criteria:
1. Body weight <12kg at screening
2. Clinically significant abnormalities in safety laboratory tests and vital signs at
Screening.
3. Abnormal QTcF interval or prolongation at Screening.
4. Any other clinically significant finding on ECG at the Screening visit.
5. Positive for severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) and previous
COVID 19 infection with last 12 months that required hospitalization.
6. Unstable or changes Psychotropic treatment 2 weeks prior to screening
7. Excluded concomitant treatments.
8. Actively undergoing regression or loss of skills.
9. Unstable seizure profile.
10. Current clinically significant renal conditions and abnormalities
11. Current clinically significant cardiovascular, hepatic, gastrointestinal, respiratory,
endocrine disease, or clinically significant organ impairment.
12. Current clinically significant hypo- or hyperthyroidism, Type 1 or Type 2 diabetes
mellitus requiring insulin (whether well controlled or uncontrolled), or uncontrolled
Type 1 or Type 2 diabetes.
13. Has planned surgery during the study.
14. History of, or current, cerebrovascular disease or brain trauma.
15. History of, or current catatonia or catatonia-like symptoms.
16. History of, or current, malignancy.
17. Current major or persistent depressive disorder (including bipolar depression).
18. Significant, uncorrected visual or uncorrected hearing impairment.
19. Allergy to strawberry.
20. Positive pregnancy test
21. Subject is judged by the Investigator or Medical Monitor to be inappropriate for the
study
Study of Ravulizumab in Pediatric Participants With HSCT-TMA
This study will evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of
ravulizumab administered by intravenous infusion to pediatric participants, from 1 month to <
18 years of age, with HSCT-TMA. The treatment period is 26 weeks, followed by a 26-week
off-treatment follow-up period.
1. 1 month of age up to < 18 years of age at the time of signing the informed consent.
2. Received HSCT within the past 6 months.
3. Diagnosis of TMA that persists despite initial management of any triggering condition.
4. Body weight ≥ 5 kilograms.
5. Female participants of childbearing potential and male participants with female
partners of childbearing potential must use highly effective contraception starting at
Screening and continuing until at least 8 months after the last dose of ravulizumab.
6. Participants must be vaccinated against meningococcal infections if clinically
feasible, according to institutional guidelines for immune reconstitution after HSCT.
Participants must be re-vaccinated against Haemophilus influenzae type b and
Streptococcus pneumoniae if clinically feasible, according to institutional guidelines
for immune reconstitution after HSCT. All participants should be administered coverage
with prophylactic antibiotics according to institutional post-transplant infection
prophylaxis guidances, including coverage against Neisseria meningitidis for at least
2 weeks after meningococcal vaccination. Participants who cannot receive meningococcal
vaccine should receive antibiotic prophylaxis coverage against Neisseria meningitidis
the entire Treatment Period and for 8 months following the final dose of ravulizumab.
Exclusion Criteria:
1. Known familial or acquired 'a disintegrin and metalloproteinase with a thrombospondin
type 1 motif, member 13' deficiency (activity < 5%).
2. Known Shiga toxin-related hemolytic uremic syndrome.
3. Positive direct Coombs test.
4. Diagnosis or suspicion of disseminated intravascular coagulation.
5. Known bone marrow/graft failure.
6. Diagnosis of veno-occlusive disease.
7. Human immunodeficiency virus (HIV) infection (evidenced by HIV-1 or HIV-2 antibody
titer).
8. Unresolved meningococcal disease.
9. Presence or suspicion of sepsis (treated or untreated) within 7 days prior to
Screening.
10. Pregnancy or breastfeeding.
11. Hypersensitivity to murine proteins or to 1 of the excipients of ravulizumab.
12. Previously or currently treated with a complement inhibitor.
Drug: Ravulizumab, Other: Best Supportive Care
Brain and Nervous System, Kidney, Leukemia, Other, Hodgkins Lymphoma, Leukemia, Not Otherwise Specified, Lymphoid Leukemia, Myeloid and Monocytic Leukemia, Non-Hodgkins Lymphoma, Other Hematopoietic, Thrombotic Microangiopathy
A Study to Test if Fremanezumab is Effective in Preventing Episodic Migraine in Patients 6 to 17 Years of Age
The primary objective of the study is to evaluate the effectiveness of fremanezumab as
compared to placebo for the preventive treatment of episodic migraine (EM).
Secondary objectives are to further demonstrate the efficacy of Fremanezumab as compared to
placebo for the preventive treatment of EM, to evaluate the safety and tolerability of
Fremanezumab in the preventive treatment of EM and to evaluate the immunogenicity of
Fremanezumab and the impact of antidrug antibodies (ADAs) on clinical outcomes in
participants exposed to Fremanezumab.
The total duration of the study is planned to be up to 36 months.
• The participant has a clinical history of recurrent headache consistent with the
diagnosis of migraine for at least 6 months before screening, consistent with ICHD-3
criteria (Headache Classification Committee of the IHS 2013), and a history of ≤=14
headache days per month in each of the 3 months prior to screening (visit 1).
• The participant or parent/caregiver maintain a prospectively collected headache diary
• The participant does not have chronic daily headache. For the purposes of this study,
chronic daily headache is operationally defined as <4 headache-free days during the
28-day baseline period.
NOTE: Additional criteria apply; please contact the investigator for more information.
Exclusion Criteria:
• The participant is using medications containing opioids (including codeine) or
barbiturates (including Fiorinal®, Fioricet®, or any other combination containing
butalbital) for the treatment of migraine during the 3 months prior to the day of the
screening visit.
• The participant or parent/caregiver maintain a prospectively collected headache diary
• The participant has used an intervention/device (eg, scheduled nerve block or
transcranial magnetic stimulation) for the treatment of migraine or in the head or
neck area for any condition during the 2 months prior to the day of the screening
visit.
• The participant has a current history of a clinically significant psychiatric
condition, any prior history of a suicide attempt, or a history of suicidal ideation
with a specific plan within the past 2 years, at the discretion of the investigator.
• The participant has an ongoing infection or a known history of human immunodeficiency
virus infection, tuberculosis, Lyme disease, or chronic hepatitis B or C, or a known
active infection of coronavirus disease 2019 (COVID-19).
• The participant has a past or current history of cancer.
• The participant is pregnant or nursing.
• The participant has a history of hypersensitivity reactions to injected proteins,
including mAbs, or a history of Stevens-Johnson Syndrome or toxic epidermal necrolysis
syndrome, or the participant is concomitantly using lamotrigine.
• The participant received a live attenuated vaccine (eg, intranasal flu vaccine, and
measles, mumps, and rubella vaccine) within the 12-week period prior to screening.
Note: If a medical need arises during the study, the participant may receive a live
attenuated vaccine.
• The patient has a current or past medical history of hemiplegic migraine.
NOTE: Additional criteria apply; please contact the investigator for more information.
Drug: Fremanezumab, Drug: Placebo
Migraine, Brain and Nervous System, Cardiovascular
A Study to Test if Fremanezumab is Effective in Preventing Migraine in Children and Adolescents
The primary objective of the study is to evaluate the long-term safety and tolerability of
subcutaneous fremanezumab in the preventive treatment of migraine in pediatric participants 6
to 17 years of age (inclusive at enrollment in the pivotal study).
Secondary objectives are to evaluate the efficacy of subcutaneous fremanezumab in pediatric
participants with migraine and to evaluate the immunogenicity of fremanezumab and the impact
of ADAs on clinical outcomes in pediatric participants exposed to fremanezumab.
The total duration of the study is planned to be up to 60 months.
Inclusion Criteria for Participants Rolling Over from the Pivotal Efficacy Studies
(TV48125-CNS-30082 or TV48125-CNS-30083):
• Participants have completed the pivotal efficacy study and, in the opinion of the
Investigator or the Sponsor, are able to complete the study in a safe and compliant
way.
• Participants may continue with a stable dose/regimen of the preventive medication they
were taking during the pivotal efficacy studies.
• The participant continues to meet appropriate criteria carried forward from the
pivotal efficacy study/
• The participant has received all recommended age-appropriate vaccines according to
local standard of care and schedule.
• The participant weighs at least 17.0 kg on the day of study enrollment.
NOTE: Additional criteria apply; please contact the investigator for more information.
Inclusion Criteria for Participants Rolling Over from the Phase 1 Pediatric Pharmacokinetic
Study (Study TV48125-CNS-10141):
• The participant/caregiver has demonstrated compliance with the electronic headache
diary during the 28-day baseline period by entry of headache data on a minimum of 21
out of 28 days (approximately 75% diary compliance).
• The participant has received all recommended age-appropriate vaccines according to
local standard of care and schedule.
• The participant weighs at least 17.0 kg on the day of study enrollment.
• The participant has a body mass index ranging from the 5th to 120% of the 95th
percentile, inclusive, on the day of study enrollment.
• Not using preventive medications or using no more than 2 preventive medications for
migraine or other medical condition, as long as the dose and regimen have been stable
for at least 2 months prior to screening (visit 1).
NOTE: Additional criteria apply; please contact the investigator for more information.
Inclusion Criteria for Participants Rolling Over from the Pivotal Efficacy Studies
(TV48125-CNS-30082 and TV48125-CNS-30083) for Safety and antidrug antibody (ADA) Assessment
Only:
• Participants may be included in this study if they sign and date the informed consent
document or upon consent of a parent or guardian, if the participant is younger than the
age of consent, accompanied by assent of the participant.
Exclusion Criteria:
Exclusion Criteria for Participants Rolling Over from the Pivotal Efficacy Studies
(TV48125-CNS-30082 or TV48125-CNS-30083):
• In the judgment of the investigator, the participant has a clinically significant
abnormal finding on study entry, including hematology, blood chemistry, coagulation
tests, or urinalysis values/findings (abnormal tests may be repeated for
confirmation).
• The participant has a current history of a clinically significant psychiatric
condition, any prior history of a suicide attempt, or a history of suicidal ideation
with a specific plan within the past 2 years, at the discretion of the investigator.
• The participant has an ongoing infection or a known history of human immunodeficiency
virus infection, tuberculosis, Lyme disease, or chronic hepatitis B or C, or a known
active infection of coronavirus disease 2019 (COVID-19).
• The participant has a history of hypersensitivity reactions to injected proteins,
including mAbs, or a history of Stevens-Johnson Syndrome or toxic epidermal necrolysis
syndrome, or the participant is concomitantly using lamotrigine.
• The participant received a live attenuated vaccine (eg, intranasal flu vaccine, and
measles, mumps, and rubella vaccine) within the 12-week period prior to screening.
Note: If a medical need arises during the study, the participant may receive a live
attenuated vaccine.
• The participant is pregnant or nursing.
• In the judgment of the investigator, the participant has an abnormal finding on the
baseline 12-lead ECG considered clinically significant.
• The patient has a current or past medical history of hemiplegic migraine.
NOTE: Additional criteria apply; please contact the investigator for more information.
Exclusion Criteria for Participants Rolling Over from the Phase 1 Pharmacokinetic Study
(TV48125-CNS-10141):
• The participant has any clinically significant cardiovascular (including congenital
cardiac anomalies or thromboembolic events), endocrine, gastrointestinal,
genitourinary, hematologic, hepatic, immunologic, neurologic, ophthalmic, pulmonary,
renal disease, or complications of an infection, at the discretion of the
investigator.
• The participant has a current history of a clinically significant psychiatric
condition, any prior history of a suicide attempt, or a history of suicidal ideation
with a specific plan within the past 2 years, at the discretion of the investigator.
• The participant has an ongoing infection or a known history of human immunodeficiency
virus infection, tuberculosis, Lyme disease, or chronic hepatitis B or C, or a known
active infection of coronavirus disease 2019 (COVID-19).
• The participant has a history of hypersensitivity reactions to injected proteins,
including mAbs, or a history of Stevens-Johnson Syndrome or toxic epidermal necrolysis
syndrome, or the participant is concomitantly using lamotrigine.
• The participant received a live attenuated vaccine (eg, intranasal flu vaccine, and
measles, mumps, and rubella vaccine) within the 12-week period prior to screening.
Note: If a medical need arises during the study, the participant may receive a live
attenuated vaccine.
• The participant is pregnant or nursing.
• In the judgment of the investigator, the participant has an abnormal finding on the
baseline 12-lead ECG considered clinically significant.
• The patient has a current or past medical history of hemiplegic migraine.
NOTE: Additional criteria apply; please contact the investigator for more information.
Exclusion Criteria for Participants Rolling Over from the Pivotal Efficacy Studies
(TV48125-CNS-30082 and TV48125-CNS-30083) for Safety and antidrug antibody (ADA) Assessment
Only: Not Applicable
The ExTINGUISH Trial of Inebilizumab in NMDAR Encephalitis (ExTINGUISH)
Determine the difference in the modified Rankin score at 16 weeks in participants with
anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis treated with "first-line"
immunomodulatory therapies provided as standard-of-care, and either inebilizumab
(investigational agent) or placebo.
• Inclusion Criteria 1. Diagnosis of NMDAR encephalitis, defined by both (a) and (b):
1. A subacute onset of change in mental status consistent with autoimmune
encephalitis,
2. A positive cell-based assay for anti-NMDA receptor IgG antibody in the CSF
confirmed in study-specified laboratories.
2. Age ≥ 18 years 3. Written informed consent and any locally required
authorization (e.g., Health Insurance Portability and Accountability Act [HIPAA]
in the United States of America (USA), European Union [EU] Data Privacy Directive
in the EU) obtained from the participant/legal representative prior to performing
any protocol-related procedures, including screening evaluations.
4. Females of childbearing potential who are sexually active with a nonsterilized
male partner must agree to use a highly effective method of contraception
beginning at screening or upon discharge from hospitalization/inpatient
rehabilitation (for participants who were incapacitated at the time of
screening), and to continue precautions for 6 months after the final dose of
investigational product.
5. Nonsterilized males who are sexually active with a female partner of
childbearing potential must agree to use a highly effective method of
contraception at screening or upon discharge from hospitalization/inpatient
rehabilitation (for participants who were incapacitated at the time of
screening), and to continue precautions for 3 months after the final dose of
investigational product. Male patients with female partners of childbearing
potential must have that female partner use at least one form of highly effective
contraception, starting at least one menstrual cycle before (the male patient's)
first study drug administration and continuing until at least 3 months after
their male partner's last dose of the study drug.
6. Willing to forego other immunomodulatory therapies (investigational or
otherwise) for NMDAR encephalitis during the study.
7. Patient must have received at least 3 days of methylprednisolone 1000 mg IV or
equivalent corticosteroid within 30 days prior to randomization (Day 1). In
addition, patients must have received EITHER of the following treatments within
30 days before randomization.
1. IVIg, at a minimum dose of 2 g/kg
2. Plasma exchange or plasmapheresis, with a minimum of 5 treatments. NOTE: These
treatments may be provided during the screening period, but must be completed
prior to randomization.
8. mRS of ≥3 at the screening visit, indicating at least moderate disability. 9.
Ability and willingness to attend study visits and complete the study
Exclusion Criteria:
1. Any condition that, in the opinion of the investigator, would interfere with
the evaluation or administration of the investigational product,
interpretation of participant safety or study results, or would make
participation in the study an unacceptable risk. This specifically includes
recent history (last 5 years) of herpes simplex virus encephalitis or known
central nervous system demyelinating disease (e.g., multiple sclerosis).
2. Presence of an active or chronic infection that is serious in the opinion of
the investigator.
3. Concurrent/previous enrollment in another clinical study involving an
investigational treatment within 4 weeks or 5 published half-lives of the
investigational treatment, whichever is the longer, prior to randomization.
4. Lactating or pregnant females, or females who intend to become pregnant
anytime from study enrollment to 6 months following last dose of
investigational agent.
5. Known history of allergy or reaction to any component of the investigational
agent formulation or history of anaphylaxis following any biologic therapy.
6. At screening (one repeat test may be conducted to confirm results prior to
randomization within the same screening period), any of the following:
1. Aspartate transaminase (AST) > 2.5 × upper limit of normal (ULN)
2. Alanine transaminase (ALT) > 2.5 × upper limit of normal (ULN)
3. Total bilirubin > 1.5 × ULN (unless due to Gilbert's syndrome)
4. Platelet count < 75,000/μL (or < 75 × 109/L)
5. Hemoglobin < 8 g/dL (or < 80 g/L)
6. Total white blood count <2,500 cells/mm3
7. Total immunoglobulin < 600 mg/dL
8. Absolute neutrophil count < 1200 cells/μL
9. CD4 T lymphocyte count < 300 cells/µL
7. Receipt of the following at any time prior to randomization:
1. Alemtuzumab
2. Total lymphoid irradiation
3. Bone marrow transplant
4. T-cell vaccination therapy
8. Receipt of rituximab or any experimental B-cell depleting agent, unless the
CD19 B-cell level has returned to above the lower limit of normal prior to
randomization.
9. Receipt of any of the following within 3 months prior to randomization
1. Natalizumab (Tysabri®)
2. Cyclosporine
3. Methotrexate
4. Mitoxantrone
5. Cyclophosphamide
6. Azathioprine
7. Mycophenolate mofetil
10. Severe drug allergic history or anaphylaxis to two or more food products or
medicines (including known sensitivity to acetaminophen/paracetamol,
diphenhydramine or equivalent antihistamine, and methylprednisolone or
equivalent glucocorticoid).
11. Known history of a primary immunodeficiency (congenital or acquired) or an
underlying condition such as human immunodeficiency virus (HIV) infection or
splenectomy that predisposes the participant to infection.
13. Confirmed positive test for hepatitis B serology (hepatitis B surface antigen
and core antigen) and/or hepatitis C PCR positive at screening.
14. History of cancer, apart from ovarian or extra-ovarian teratoma (also known
as a dermoid cyst) or germ cell tumor, or squamous cell carcinoma of the skin or
basal cell carcinoma of the skin. Squamous cell and basal cell carcinomas should
be treated with documented success of curative therapy > 3 months prior to
randomization.
15. Any live or attenuated vaccine within 3 weeks prior to Day 1 (administration
of killed vaccines is acceptable).
16. Bacillus of Calmette and Guérin (BCG) vaccine within 1 year of enrollment.
17. Recurrence of previously treated NMDAR encephalitis within the last 3 or 5
years, or suspicion of symptomatic untreated NMDAR encephalitis of greater than 3
months duration at the time of screening.
Drug: Inebilizumab, Drug: Placebo
Autoimmune Encephalitis, Brain and Nervous System, Encephalitis
• 18 to 55 years of age
• Diagnosis of RMS according to the 2017 McDonald diagnostic criteria
• At least: 1 documented relapse within the previous year. OR 2 documented relapses
within the previous 2 years, OR 1 active Gadolinium (Gd)-enhancing lesion in the 12
months.
• EDSS score of 0 to 5.5 (inclusive)
• Neurologically stable within 1 month
Exclusion Criteria:
• Diagnosis of primary progressive multiple sclerosis (PPMS)
• Disease duration of more than 10 years in participants with EDSS score of 2 or less at
screening
• History of clinically significant CNS disease other than MS
• Ongoing substance abuse (drug or alcohol)
• History of malignancy of any organ system (other than complete resection of localized
basal cell carcinoma of the skin or in situ cervical cancer),
• Participants with history of confirmed Progressive Multifocal Leukoencephalopathy
(PML) or Neurological symptoms consistent with PML
• suicidal ideation or behavior
• Evidence of clinically significant cardiovascular, neurological, psychiatric,
pulmonary , renal, hepatic, endocrine, metabolic, hematological disorders or
gastrointestinal disease that can interfere with interpretation of the study results
or protocol adherence
• Participants who have had a splenectomy
• Active clinically significant systemic bacterial, viral, parasitic or fungal
infections
• Positive results for syphilis or tuberculosis testing
• Uncontrolled disease states, such as asthma, or inflammatory bowel disease, where
flares are commonly treated with oral or parenteral corticosteroids
• Active, chronic disease of the immune system (including stable disease treated with
immune therapy (e.g. Leflunomide, Methotrexate)) other than MS (e.g. rheumatoid
arthritis, systemic lupus erythematosus, etc.) with the exception of well-controlled
diabetes or thyroid disorder.
• Participants with a known immunodeficiency syndrome (AIDS, hereditary immune
deficiency, drug induced immune deficiency), or tested positive for HIV antibody
• History or current treatment for hepatic disease including but not limited to acute or
chronic hepatitis, cirrhosis or hepatic failure or participants with moderate or
severe hepatic impairment (Child-Pugh class C) or any chronic liver or biliary
disease.
• History of severe renal disease or creatinine level
• Participants at risk of developing or having reactivation of hepatitis
• Hematology parameters at screening:
• Hemoglobin: < 10 g/dl (<100g/L)
• Platelets: < 100000/mm3 (<100 x 109/L)
• Absolute lymphocyte count < 800/mm3 (<0.8 x 109/L)
• White blood cells: <3 000/mm3 (<3.0 x 109/L)
• Neutrophils: < 1 500/mm3 (<1.5 x 109/L)
• B-cell count < 50% lower limit of normal (LLN) or total IgG & total IgM < LLN
(only required for participants who had a history of receiving B-cell therapies,
such as rituximab, ocrelizumab or ofatumumab, prior to screening)
• History or current diagnosis of significant ECG abnormalities
• Resting QTcF ≥450 msec (male) or ≥460 msec (female) at pre-treatment (prior to
randomization)
• Use of other investigational drugs
• Requirement for anticoagulant medication or use of dual anti-platelet therapy
Significant bleeding risk or coagulation disorders,
• History of gastrointestinal bleeding
• Major surgery within 8 weeks prior to screening
• History of hypersensitivity to any of the study drugs or excipients
• Pregnant or nursing (lactating) female participants, prior to randomization
• Women of childbearing potential not using highly effective contraception
• Sexually active males not agreeing to use condom
• Have received any live or live-attenuated vaccines within 6 weeks of randomization or
requirement to receive these vaccinations during study
• Use of strong CYP3A4 inhibitors or strong CYP3A4 inducers within two weeks prior to
randomization
Inclusion to Extension part:
• patient who complete the Core Part of the study on double-blind study treatment and
conduct the Accelerated Elimination Procedure (AEP)
Other inclusion and exclusion criteria may apply
Drug: Remibrutinib, Drug: Teriflunomide
Relapsing Multiple Sclerosis, Brain and Nervous System
A Study to Test the Efficacy, Safety, and Pharmacokinetics of Rozanolixizumab in Adult Study Participants With Leucine-Rich Glioma Inactivated 1 Autoimmune Encephalitis
The purpose of the study is to assess the efficacy of rozanolixizumab as measured by seizure
freedom, change in cognitive function, use of rescue medication, onset of seizure freedom and
to assess safety and tolerability.
• Study participant must be ≥18 to ≤89 years of age, at the time of signing the informed
consent
• Study participant must be seropositive for leucine-rich glioma inactivated 1 (LGI1)
antibody measured by LGI1 serum autoantibody cell-binding assay
• Study participant must have ≥2 seizures/week during the Screening Period or have
experienced such seizures that stopped following intravenous methylprednisolone (IVMP)
initiation:
• Either faciobrachial dystonic seizures (FBDS) with or without other focal
(partial) seizures including focal to bilateral tonic clonic
• Or focal (partial) seizures including focal to bilateral tonic clonic and fulfil
the following new-onset Autoimmune encephalitis (AIE) criteria:
1. Subacute onset (rapid progression of less than 3 months) of working memory
deficits (short-term memory loss), altered mental status (defined as
decreased or altered level of consciousness, lethargy, or personality
change), or psychiatric symptoms.
AND b. At least one of the following: i. New focal central nervous system (CNS) finding, as
per the investigator's assessment ii. Seizures not explained by a previously known seizure
disorder iii. Cerebrospinal fluid (CSF) pleocytosis (white blood cell count of >5
cells/mm3) iv. Magnetic resonance imaging (MRI) features suggestive of encephalitis (Brain
MRI hyperintense signal on T2-weighted fluid-attenuated inversion recovery sequences highly
restricted to one or both medial temporal lobes [limbic encephalitis], or in multifocal
areas involving grey matter, white matter, or both compatible with demyelination or
inflammation).
AND c. Reasonable exclusion of alternative causes
• Study participant is deemed appropriate for initiation of IVMP based on clinical
symptoms and history or has initiated IVMP treatment at a dose of 500 to 1000 mg/day
within 14 days prior to randomization. If the study participant has initiated a
steroid taper, the study participant cannot be receiving an oral steroid dose lower
than 60 mg/day when randomized.
• Study participant with onset of disease between 0 to 12 months prior to Screening
• Study participant weighs at least 35 kg (for males and females) at Screening
• A male participant must agree to use contraception during the treatment period and for
at least 90 days after the final dose of study treatment and refrain from donating
sperm during this period
• A female participant is eligible to participate if she is not pregnant, not
breastfeeding, and at least one of the following conditions applies:
i) Not a woman of childbearing potential (WOCBP) OR ii) A WOCBP who agrees to follow
the contraceptive guidance during the treatment period and for at least 90 days after
the final dose of study treatment
Exclusion Criteria:
• Study participant has a known hypersensitivity to any components of the study
medication or any other anti-neonatal Fc receptor (FcRn) medications. This includes a
known history of hyperprolinemia, since L-proline is a constituent of the
rozanolixizumab formulation
• Study participant has a confirmed prior diagnosis of epilepsy or new onset seizures
that are unrelated to LGI1 autoimmune encephalitis (AIE) or has any known or suspected
medical cause for the onset of seizures other than possible AIE
• Study participant has active neoplastic disease or history of neoplastic disease
within 5 years of study entry (except for basal or squamous cell carcinoma of the skin
or carcinoma in situ of the uterine cervix which has been definitively treated with
standard of care approaches)
• Study participant has 12-lead electrocardiogram (ECG) with findings considered
clinically significant upon medical review
• Study participant has renal impairment, defined as glomerular filtration rate (GFR)
<30mL/min/1.73m2 at the Screening Visit.
• Study participant has a clinically relevant active infection (eg, sepsis, pneumonia,
abscess) or has had a serious infection (resulting in hospitalization or requiring
parenteral antibiotic treatment) within 6 weeks prior to the first dose of IMP
• Study participant has a history of chronic ongoing infections (eg, Hepatitis B or C,
human immune deficiency virus [HIV], active or latent tuberculosis [TB]) or who tests
positive for HIV, Hepatitis B or C at the Screening Visit
• Presence of Hepatitis B surface antigen at the Screening Visit
• Positive Hepatitis C antibody test result at Screening or within 3 months prior
to the IMP dose
• Study participant has current unstable liver or biliary disease, per investigator
assessment, defined by the presence of ascites, encephalopathy, coagulopathy,
hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis
• Study participant has positive tuberculosis (TB) test at the Screening Visit
• Study participant has any of the following active gastrointestinal (GI) disorders:
inflammatory bowel disease, GI ulceration, or diverticulitis
• Study participant has a history of solid organ transplant or hematopoietic stem cell
transplant
• Study participant has undergone a splenectomy
• Study participant has a current or medical history of primary immune deficiency
• Study participant has been treated with prohibited immunosuppressants, biologics, and
other therapies
• Study participant has received a live vaccination within 8 weeks prior to the Baseline
Visit; or intends to have a live vaccination during the course of the study or within
8 weeks following the final dose of investigational medicinal product (IMP)
• Study participant has previously received rozanolixizumab drug product
• Alanine transaminase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase
(ALP) are >2x upper limit of normal (ULN)
• If study participant has >ULN for ALT, AST, or ALP that does not meet the
exclusion limit at Screening, the tests must be repeated prior to dosing to
ensure there was no further ongoing clinically relevant increase. In case of a
clinically relevant increase as per the investigator's judgement, the study
participant must be excluded.
• Tests that result in ALT, AST, or ALP up to 25 % above the exclusion limit
(>2xULN) may be repeated once for confirmation. This includes rescreening. If any
of the repeated tests (ALT, AST, or ALP) are >2xULN,the study participant must be
excluded
• For randomized study participants with a Baseline result >ULN for ALT, AST, ALP,
or total bilirubin but <1.5xULN, a Baseline diagnosis and/or the cause of any
clinically meaningful elevation will have to be understood and recorded in the
electronic case report form (eCRF)
• Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is
fractionated and direct bilirubin <35 %)
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities
(with the exception of Gilbert's syndrome or asymptomatic gallstones).
• Study participant has a total IgG level ≤5.5 g/L at the Screening Visit
• Study participant has absolute neutrophil count <1500 cells/mm^3 at the Screening
Visit
• Participant has QT interval corrected for heart rate using Fridericia's formula (QTcF)
>450 msec (for male participants) or QTcF >470 msec (for female participants) or QTcF
>480 msec in participants with bundle branch block
1. Histologically confirmed GBM (MGMT unmethylated, IDH wild type) at first, second,
third, or fourth recurrence after concurrent chemoradiotherapy. Patients with an
initial diagnosis of a lower-grade glioma are eligible if a subsequent biopsy
determined the progressive tumor to be GBM.
2. Imaging confirmation of first tumor progression or regrowth as defined by the Response
Assessment in Neuro-Oncology (RANO) criteria. A minimum of 12 weeks must have elapsed
from the completion of radiotherapy to study entry to minimize the potential for MRI
changes related to radiation necrosis that might be misdiagnosed as progression of
disease, unless there is a new lesion outside the radiation field or unequivocal
evidence of viable tumor on histopathological sampling.
3. Karnofsky Performance Status (KPS) ≥ 60%.
4. Patients must be willing and able to provide written informed consent and to comply
with the study protocol as judged by the investigator.
5. Age ≥ 18 years.
6. Patients must be able to swallow oral medications.
7. For women who are of child-bearing potential and who are sexually active and who are
not surgically sterile (absence of ovaries and/or uterus): to use an adequate method
of contraception (oral contraceptives, intrauterine contraceptive device, barrier
method of contraception in conjunction with spermicidal jelly) during the treatment
period and for at least 6 months after last dose of study drug. Should a woman become
pregnant or suspect she is pregnant while participating in this study, she should
inform her treating physician immediately. For male patients who are partners of
premenopausal women: agreement to use a barrier method of contraception during the
treatment period and for at least 6 months after the last dose of study drug.
7.1 A female of child-bearing potential is any woman (regardless of sexual
orientation, having undergone a tubal ligation, or remaining celibate by choice) who
meets the following criteria:
• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e.,
has had menses at any time in the preceding 12 consecutive months).
8. Patients who have undergone recent surgery for recurrent or progressive tumor are
eligible provided that:
8.1 Surgery must have confirmed the recurrence.
8.2 A minimum of 28 days must have elapsed from the day of surgery to study entry. For
core or needle biopsy, a minimum of 7 days must have elapsed prior to study entry.
8.3 Craniotomy or intracranial biopsy site must be adequately healed and free of
drainage or cellulitis, and the underlying cranioplasty must appear intact at the time
of randomization.
9. Patients must have recovered (Common Terminology Criteria for Adverse Events CTCAE
version 6] Grade ≤1) from the acute effects of chemotherapy except for residual
alopecia or Grade 2 peripheral neuropathy prior to randomization. Minimum times from
prior therapies include:
9.1 Greater than or equal to 28 days elapsed from the administration of any
investigational agent.
9.2 Greater than or equal to 28 days elapsed from the administration of any prior
cytotoxic agents, except ≥ 42 days from nitrosoureas. NOTE: Prior treatment with
Novo-TTF therapy is allowed at initial diagnosis but must be discontinued prior to
study entry.
10. GBMs of the study patients must have EGFR gene amplification, which will be detected
by next generation sequencing of tumor tissue from resected sample.
11. Prior use of bevacizumab is allowed, however patient must be off of this medication
for 180 days.
12. Patients must have adequate organ and marrow function as defined by the following
criteria:
• ANC ≥1.5 × 10(9)/L
• Platelets ≥100 × 10(9)/L
• Hemoglobin ≥8 g/dL
• Total bilirubin ≤1.5 × ULN Patients with Gilbert's syndrome with a total
bilirubin ≤2.0 times ULN and direct bilirubin within normal limits are permitted.
ALT and AST ≤3 × ULN
Exclusion Criteria:
1. Prior treatment with an EGFR or JAK inhibitor.
2. Subjects may not be receiving any other investigational agents for the treatment of
the cancer under study.
3. Patients unable to undergo brain MRI scans with IV gadolinium contrast.
4. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to Tofacitinib
5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that, in the opinion of the
investigator, would limit compliance with study requirements.
6. Subjects must not be pregnant or nursing due to the potential for congenital
abnormalities and the potential of this regimen to harm nursing infants.
7. Prior history of hypertensive crisis, hypertensive encephalopathy, or inadequately
controlled hypertension (defined as systolic blood pressure > 150 mmHg and/or
diastolic blood pressure > 100 mmHg while on antihypertensive medication).
8. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to
swallow the formulated product, or previous significant gastrointestinal resection
that would preclude adequate absorption of the trial medications.
9. History of another malignancy in the previous 3 years, with a disease-free interval of
< 3 years. Patients with prior history of in situ cancer or basal or squamous cell
skin cancer are eligible.
10. Concurrent use of Bevacizumab.
Stereotactic Radiosurgery (SRS) Dose-Escalation Study for Brain Metastasis (SRS)
SRS dose escalation for brain metastases in radiation-naïve patients will establish true
tolerable doses, which may exceed the current standard doses. This may lead to an improvement
in local control, patient survival, and/or quality-of life.
Inclusion Criteria
1. Biopsy-proven non-hematopoietic malignancy, except for small cell lung cancer, germ
cell cancer, or unknown primary tumor.
2. Radiographic evidence by MRI (or by CT scan with CT contrast if ineligible or
intolerant of MRI) of brain metastasis. (If patient is unable to tolerate MRI
contrast, an MRI without contrast is acceptable if lesions are visible)
3. All brain metastases must be outside the brain stem (midbrain, pons and medulla).
4. Patient must have 10 or less brain metastases.
5. The maximum diameter of any lesion must be less than or equal to 3.0 cm.
6. Previous treatment with surgery, radiation, chemotherapy, immunotherapy or any
targeted agents are allowed provided that:
• Radiation was not to the brain.
• Surgery to the brain was > 7 days prior to SRS and there remains at least one
additional brain metastasis that can be targeted with SRS
7. Age ≥ 18 years.
8. ECOG Performance Score of 2 or better/Karnofsky Performance Status score of 50-60 or
better.
9. All men, as well as women of child-bearing potential must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry and for the duration of study participation. Should a woman become pregnant or
suspect she is pregnant while participating in this study, she should inform her
treating physician immediately.
A female of child-bearing potential is any woman (regardless of sexual orientation,
marital status, having undergone a tubal ligation, or remaining celibate by choice)
who meets the following criteria:
• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e.,
has had menses at any time in the preceding 12 consecutive months).
Medically acceptable birth control (contraceptives) includes:
• Approved hormonal contraceptives (such as birth control pills, patch, or ring:
Depo-Provera, Implanon), or
• Barrier methods (such as a condom or diaphragm) used with a spermicide (a
substance that kills sperm)
10. Ability to understand and the willingness to sign a written informed consent.
Exclusion Criteria
1. Patients had craniotomy and surgery to the brain within 7 days from the date of SRS.
2. Patients with leptomeningeal metastasis.
NOTE: For the purposes of exclusion, LMD is a clinical diagnosis, defined as positive
CSF cytology and/or equivocal radiologic or clinical evidence of leptomeningeal
involvement. Patients with leptomeningeal symptoms in the setting of leptomeningeal
enhancement by imaging (MRI) would be considered to have LMD even in the absence of
positive CSF cytology, unless a parenchymal lesion can adequately explain the
neurologic symptoms and/or signs. In contrast, an asymptomatic or minimally
symptomatic patient with mild or nonspecific leptomeningeal enhancement (MRI) would
not be considered to have LMD. In that patient, CSF sampling is not required to
formally exclude LMD, but can be performed at the investigator's discretion based on
level of clinical suspicion.
3. Patients with a contraindication to both MRI (with or without contrast) and CT scan
(with contrast)
4. Patients with life expectancy < 3 months.
5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that, in the opinion of the
investigator, would limit compliance with study requirements.
6. Subjects must not be pregnant or nursing at the time of SRS treatment due to the
potential for congenital abnormalities and the potential of this regimen to harm
nursing infants.
Radiation: Stereotactic Radiosurgery
Brain Neoplasms, Adult, Malignant, Lymphoma, Sarcoma, Multiple Myeloma, Brain and Nervous System, Other, Eye and Orbit, Anklylosing Spondylitis, Anus, Bones and Joints, Breast - Female, Breast - Male, Cardiovascular, Cervix, Colon, Corpus Uteri, Ear, Esophagus, Gall Bladder, Head and Neck, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Melanoma, skin, Nose, Other Digestive Organ, Other Endocrine System, Other Female Genital, Other Male Genital, Other Respiratory and Intrathoracic Organs, Other Skin, Other Urinary, Ovary, Pancreas, Prostate, Rectum, Stomach, Throat, Thyroid, Urinary Bladder, Uterine (Endometrial), Vulva, Hodgkins Lymphoma, Lymphoid Leukemia, Small Intestine, Soft Tissue
UT Southwestern; Parkland Health & Hospital System
Radiation Therapy With Concomitant and Adjuvant Temozolomide Versus Radiation Therapy With Adjuvant PCV Chemotherapy in Patients With Anaplastic Glioma or Low Grade Glioma
Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy,
such as temozolomide, work in different ways to stop the growth of tumor cells, either by
killing the cells or by stopping them from dividing. It is not yet known whether giving
radiation with concomitant and adjuvant temozolomide versus radiation with adjuvant PCV is
more effective in treating anaplastic glioma or low grade glioma.
• United States (US) and Canadian sites:
* This review is mandatory prior to registration to confirm eligibility; patients must
be willing to submit tissue samples for mandatory central pathology review submission;
it should be initiated as soon after surgery as possible
• Tissue must have been determined to have local 1p/9q co-deletion and IDH mutation
prior to submission for central path review
• Tumor tissue must show co-deletion of chromosomes 1p and 19q; for eligibility,
the 1p/19q analysis results will be accepted from the local site, as determined
by either a locally available or reference laboratory (for US, must be Clinical
Laboratory Improvement Act [CLIA] certified); acceptable methods for
determination of 1p/19q loss include fluorescent in-situ hybridization (FISH), by
genomic sequencing or methylomic analyses; US and Canadian sites must send a copy
of the official report to the pathology coordinator and quality assurance
specialist (QAS)
• Tumor must also show evidence of IDH mutation by immunohistochemistry or genomic
analyses; this should be performed at the local site (US: performed in a CLIA
certified laboratory); the site must send a copy of the official report to the
pathology coordinator and QAS
Registration
Inclusion Criteria:
• Newly diagnosed and =< 3 months from surgical diagnosis; patients are also eligible if
they have had a prior surgical procedure > 3 months earlier for low grade glioma, as
long as the patient has not received prior radiation or prior chemotherapy
• Histological evidence of World Health Organization (WHO) grade III anaplastic glioma
or WHO grade II low grade glioma with locally diagnosed combined 1p/19q loss and the
presence of an either IDH1 or IDH2, both as established by a local or referenced
laboratory qualified for the study
* Note: mixed gliomas are eligible, regardless of the degree of astrocytic or
oligodendrocytic predominance, as long as the tumor is also co-deleted for 1p and 19q
• Patients with codeleted low grade gliomas must also be considered "high risk" by
exhibiting one or more of the following characteristics:
• Age >= 40 and any surgical therapy
• Age < 40 with prior and subtotal resection or biopsy (i.e., anything less than
gross total resection)
• Documented growth following prior surgery (NOTE: patients with prior surgery
cannot have received prior radiation, chemotherapy or targeted therapy)
• Intractable seizures
• Surgery (partial or gross total resection or biopsy) must be performed >= 2 weeks
prior to registration; patient must have recovered adequately from the effects of
surgery
• Absolute neutrophil count (ANC) >= 1,500/mm^3 obtained =< 21 days prior to
registration
• Platelet (PLTs) count >= 100,000/mm^3 obtained =< 21 days prior to registration
• Hemoglobin (Hgb) > 9.0 g/dL obtained =< 21 days prior to registration
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) obtained =< 21 days
prior to registration
• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 3
x ULN obtained =< 21 days prior to registration
• Creatinine =< 1.5 x ULN obtained =< 21 days prior to registration
• Negative serum or urine pregnancy test done =< 7 days prior to registration, for women
of childbearing potential only
• Willingness and ability to personally complete neurocognitive testing (without
assistance) and willingness to complete the QOL testing, (either personally or with
assistance)
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1 or 2
• Written informed consent
• Willingness to return to enrolling institution for follow-up during the active
monitoring phase (that is, the active treatment and observation portion) of the
study); patients who have been formally transferred to another active and approved
site participating in this study would not need to return to the enrolling institution
for this purpose
• Willingness to allow the provision of tissue samples for correlative research, as long
as adequate tissues are available; patients will not be excluded from participation in
the study, if they are willing to allow provision of tissues for the correlative
research, but there are insufficient quantities of tissue for the correlative analyses
(e.g., a patient otherwise eligible and willing who had biopsy only) Willingness to
allow the provision of blood samples for correlative research; patients are not
excluded from participation in the study, if they are willing to provide the mandatory
biospecimens for translational/correlative research, but for logistical reasons the
specimens(s) were not obtainable or if the volume collected was insufficient
Registration
Exclusion Criteria:
• The following categories are ineligible:
• Pregnant women
• Nursing women
• Men or women of childbearing potential who are unwilling to employ adequate
contraception or contraceptive method during this study and 6 months following
the completion of chemotherapy treatments
• History of prior radiation therapy or chemotherapy for glioma; note: patients who have
a history of prior low grade glioma (with or without a distant history of prior
surgery for that glioma), but who have never received prior chemotherapy or radiation
therapy for the glioma are eligible for the study
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
of the investigator, would make the patient inappropriate for entry into this study or
interfere significantly with the proper assessment of safety and toxicity of the
prescribed regimens
• Concomitant serious immunocompromised status (other than that related to concomitant
steroids) that would compromise the safety of the patient on the study
• Patients known to be human immunodeficiency virus (HIV) positive and currently
receiving retroviral therapy are not eligible; note: patients known to be HIV
positive, but without clinical evidence of an immunocompromised state, are eligible
for the study
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements
• Receiving any other investigational agent that would be considered as a treatment for
the primary neoplasm
• Other active malignancy within 5 years of registration; exceptions: non-melanotic skin
cancer or carcinoma-in-situ of the cervix; note: if there is a history of prior
malignancy, the patient is not eligible if they are receiving other specific treatment
(with the exclusion of hormonal therapy or Her-2 inhibitors) for their cancer or if
they have received prior total body irradiation which included the brain
• History of myocardial infarction =< 6 months, or congestive heart failure requiring
use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
• Recent history of hepatitis infection or if the treating physician determined that the
patient would be at significant risk of reactivation of hepatitis
DHA For The Treatment of Pediatric Concussion Related to Sports Injury
In recent years, media attention has focused on the long-term sequelae of repeated
concussive episodes in professional athletes. The growing understanding of the damage done
by what was once considered a "ding" during a game or match, and the neurologic consequences
of "playing through" or returning to play too soon has led to additional interest in and
concern for pediatric athletes (18 or under) who experience sports-related concussions
during game or practice play.
Because it has only been in recent years that the full scope of damage done by repeated
concussive episodes has come to light, very little research has been done on treatment of
concussion in either adults or children. Brain injuries in children can be especially
problematic, as the brain may continue to develop until the child reaches the age of 24 or
older, so concussion during this time of development may be particularly damaging.
Docosahexaenoic acid (DHA) is an omega-3 fatty acid commonly found in both fish oils and
algae. DHA is known to improve development of the eyes and brain in young children. It is
thought to be an effective anti-inflammatory and anti-oxidant, and since it occurs naturally
and causes very few harmful side effects, it may be a useful compound in the treatment of
pediatric concussion.
This is a feasibility trial of DHA for the treatment of sports concussion in a pediatric
population. The investigators' primary aim is to determine acceptability of randomization
for this compound as well as rate of enrollment given our clinical population. The
investigators' secondary aim is to examine preliminary outcomes. The investigators
hypothesize that subjects who take 2 g of DHA daily for 3 months will see a shorter time to
full recovery and return to play and a shorter time to resolve balance disturbance. These
are good, albeit unvalidated, clinical indicators of concussive recovery.
1. Male or females age 14-18 inclusive
2. Diagnosed with concussion due to sports-related injury. Concussion is defined as:
1. Direct blow to the head, face, neck or a blow elsewhere on the body with an
"impulsive" force transmitted to the head.
2. Rapid onset of short-lived impairment of neurologic function in one or more of
the following clinical domains that resolves spontaneously:
i. Symptoms: somatic (eg, headache), cognitive (eg, feeling like in a fog and/or
emotional symptoms (eg, lability).
ii. Physical signs (eg, loss of consciousness, amnesia).
iii. Behavioral changes (eg, irritability).
iv. Cognitive impairment (eg, slowed reaction times).
v. Sleep disturbance (eg, drowsiness). c) No abnormality on standard structural
neuroimaging studies, if such neuroimaging studies are completed for a
clinically-indicated reason. Note: neuroimaging is not a part of this study protocol.
Study participants will not undergo neuroimaging as part of this study.
3. Concussion within 4 days of enrollment
4. Presenting for treatment to the Sports Medicine Center at Children's Medical Center
Exclusion Criteria:
1. Subjects not actively participating in an organized sport at time of enrollment
2. Subjects who received a concussion from an event other than playing a sport (motor
vehicle accident, fall, etc.)
3. Subjects who participate in or received a concussion during participation in
motorized sports (i.e., motorcross, dirt biking, jet skiing, etc.)
4. Subjects with radiographic evidence of traumatic brain injury (i.e., skull fracture,
intracranial hemorrhage, cerebral contusion, etc).
5. Subjects with a prior diagnosed concussion in the previous 6 months.
6. Pregnant women.
7. Subjects sensitive to aspirin
8. Subjects diagnosed with high blood pressure and currently being treated with blood
pressure medications
9. Subjects allergic to soy bean oil or corn oil.
10. Subjects currently taking fish oil or DHA supplements.
Reduced Craniospinal Radiation Therapy and Chemotherapy in Treating Younger Patients With Newly Diagnosed WNT-Driven Medulloblastoma
This phase II trial studies how well reduced doses of radiation therapy to the brain and
spine (craniospinal) and chemotherapy work in treating patients with newly diagnosed type of
brain tumor called WNT)/Wingless (WNT)-driven medulloblastoma. Recent studies using
chemotherapy and radiation therapy have been shown to be effective in treating patients with
WNT-driven medulloblastoma. However, there is a concern about the late side effects of
treatment, such as learning difficulties, lower amounts of hormones, or other problems in
performing daily activities. Radiotherapy uses high-energy radiation from x-rays to kill
cancer cells and shrink tumors. Drugs used in chemotherapy, such as cisplatin, vincristine
sulfate, cyclophosphamide and lomustine, work in different ways to stop the growth of tumor
cells, either by killing the cells, by stopping them from dividing, or by stopping them from
spreading. Giving reduced craniospinal radiation therapy and chemotherapy may kill tumor
cells and may also reduce the late side effects of treatment.
• Patients must be greater than or equal to 3 years and less than 22 years of age at the
time of enrollment
• Patients must be newly diagnosed and have:
• Eligibility confirmed by rapid central pathology and molecular screening review
on APEC14B1 and via the Molecular Characterization Initiative:
• Classical histologic type (non LC/A) WNT medulloblastoma
• Positive nuclear beta-catenin by immunohistochemistry (IHC)
• Positive for CTNNB1 mutation
• Negative for MYC and MYCN by fluorescence in situ hybridization (FISH)
• Patient must have negative lumbar cerebrospinal fluid (CSF) cytology
• Note: CSF cytology for staging should be performed no sooner than 14 days post
operatively to avoid false positive CSF; ideally, CSF should be obtained between
day 14 and day 21 to allow for final staging status before enrollment onto the
study; patients with positive CSF cytology obtained 0 to 14 days after surgery
should have cytology repeated to determine eligibility and final CSF status;
patients with negative CSF cytology from lumbar puncture obtained 0 to 14 days
after surgery do not need cytology repeated; patients with negative CSF cytology
from lumbar puncture obtained prior to surgery do not need cytology repeated
post-operatively
• Patients must have eligibility confirmed by Rapid Central Imaging Review on APEC14B1;
patients must have =< 1.5 cm^2 maximal cross-sectional area of residual tumor; whole
brain magnetic resonance imaging (MRI) with and without gadolinium and spine MRI with
gadolinium must be performed
• Patients must be enrolled, and protocol therapy must be projected to begin, no later
than 36 days after definitive diagnostic surgery (day 0)
• Peripheral absolute neutrophil count (ANC) >= 1000/uL
• Platelet count >= 100,000/uL (transfusion independent)
• Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions)
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
• 3 to < 6 years of age: maximum (max) serum creatinine 0.8 mg/dL (males and
females)
• 6 to < 10 years of age: max serum creatinine 1 mg/dL (males and females)
• 10 to < 13 years of age: max serum creatinine 1.2 mg/dL (males and females)
• 13 to < 16 years of age: max serum creatinine 1.5 md/dL (males) and 1.4 md/dL
(females)
• >= 16 years of age: max serum creatinine 1.7 mg/dL (males) and 1.4 mg/dL
(females)
• The threshold creatinine values were derived from the Schwartz formula for
estimating GFR utilizing child length and stature data published by the
Centers for Disease Control and Prevention (CDC)
• Total or direct bilirubin =< 1.5 x upper limit of normal (ULN) for age, and
• Serum glutamate pyruvate (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (3x ULN);
for the purpose of this study, the ULN for SGPT is 45 U/L
• Central nervous system function defined as:
• Patients with seizure disorder may be enrolled if on anticonvulsants and well
controlled
• Patients must not be in status epilepticus, a coma or on assisted ventilation at
the time of study enrollment
• Patients must have receptive and expressive language skills in English, French, or
Spanish to complete the QoL and neurocognitive assessments; if a patient meets these
criteria but the parent/guardian speaks a language other than English, French, or
Spanish, the patient may still be enrolled and tested, and the parent-report measures
should be omitted
• All patients and/or their parents or legal guardians must sign a written informed
consent; assent, when appropriate, will be obtained according to institutional
guidelines
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met
Exclusion Criteria:
• Patients with metastatic disease by either MRI evaluation (brain and spine) or lumbar
CSF cytology are not eligible; patients who are unable to undergo a lumbar puncture
for assessment of CSF cytology are ineligible
• Patients must not have received any prior radiation therapy or chemotherapy
(tumor-directed therapy) other than surgical intervention and/or corticosteroids
• Pregnancy and Breast Feeding
• Female patients who are pregnant are ineligible due to risks of fetal and
teratogenic adverse events as seen in animal/human studies
• Lactating females are not eligible unless they have agreed not to breastfeed
their infants
• Female patients of childbearing potential are not eligible unless a negative
pregnancy test result has been obtained
• Sexually active patients of reproductive potential are not eligible unless they
have agreed to use an effective contraceptive method for the duration of their
study participation
• Patients with a history of moderate to profound intellectual disability (i.e.,
intelligence quotient [Q)]=< 55) are not eligible for enrollment; PLEASE NOTE:
Children with a prior history of attention deficit hyperactivity disorder (ADHD) or a
specific learning disability (e.g., dyslexia) are eligible for this study. Children
with posterior fossa syndrome (also known as cerebellar mutism) are eligible for this
study
Optimal Delay Time to Initiate Anticoagulation After Ischemic Stroke in Atrial Fibrillation (START)
Title:
Optimal Delay Time to Initiate Anticoagulation after Ischemic Stroke in Atrial Fibrillation
(START): a pragmatic, adaptive randomized clinical trial.
Primary Objective:
• To determine the optimal time to initiate anticoagulation with a Non-Vitamin K Oral
Anticoagulant (NOAC) after ischemic stroke in patients with non-valvular atrial fibrillation.
Secondary Objectives:
- To compare the rates of primary adverse outcomes in a per protocol analysis
- To compare 30 day clinical outcomes by the modified Rankin scale among the
time-to-treatment groups
- To compare 30 day clinical outcomes by the PROMIS-10 scale among the time-to-treatment
groups.
- To compare 90 day clinical outcomes by the modified Rankin scale among the
time-to-treatment groups
- To explore the optimal timing in subgroups of age, sex, outcome category, and NOAC
choice
1. New disabling neurological deficit attributable to new ischemic stroke.
2. Minimum lesion diameter of 1.5cm on qualifying imaging. If lesion not visible on
imaging, NIHSS must be greater than 4.
3. Non-valvular atrial fibrillation (paroxysmal, persistent, or permanent).
4. Not currently anticoagulated and/or will not be anticoagulated prior to starting their
NOAC at the randomized time of initiation (except for DVT prophylaxis).
Note: Patients who had been taking an anticoagulant prior to their qualifying index
event (for any reason) are eligible for START, assuming the drug is no longer having a
therapeutic effect in the patient's system by 48 hours from stroke onset.
5. Treating physician plans to anticoagulate with a FDA-approved novel oral anticoagulant
(NOAC): apixaban, dabigatran, edoxaban, or rivaroxaban, or other FDA-approved NOAC.
6. Qualifying brain CT or MRI scan < 48hr from stroke onset (time last known well). If
patient has been treated with thrombolytic or endovascular therapy for this stroke,
then the qualifying scan is that which is performed after therapy to rule out
clinically significant hemorrhagic transformation.
7. Ability to randomize within 60 hours of symptom onset.
Exclusion Criteria:
1. Any clinical or imaging evidence of spontaneous intracranial hemorrhage in the
previous 6 months.
Note: Patients with hemorrhagic transformation of current or previous ischemic stroke
may be included per Investigator's judgment. Sporadic microbleeds may be included per
Investigator's judgment. As a general recommendation, a cerebral microbleed is
considered to be ≤ 5mm, but sometimes up to 10mm, in greatest diameter on gradient
recalled echo (GRE), or T2*, MRI sequences. Any blood visualized on a CT will be
classified as a macrobleed.
2. Infarct volume (estimated) is greater than 50% of middle cerebral artery territory on
qualifying scan. If the full extent of the lesion is not visible, any patient with a
NIHSS > 23 must be excluded.
Note: The lesion does not need to be restricted to the mCA, but if the lesion volume
is estimated to be greater than half of the mCA territory, the patient should be
excluded.
Note: In non-EVT patients, any NIHSS following the index stroke may be used to qualify
the patient for START. For example, a patient that presents with a NIHSS of 10 who
then receives tPA and improves to a NIHSS of 2 is still eligible for START. For
patients whom had endovascular therapy, the qualifying NIHSS assessment is that which
is obtained with their qualifying scan following therapy.
3. Anticipated need for major surgery over the next 30 days that would require delay,
discontinuation, or extended suspension of anticoagulant of more than 5 days.
4. Symptomatic edema expected from size and location of ischemic stroke.
5. Decreased level of consciousness present or expected.
6. Life expectancy less than 90 days.
7. Follow-up in person or by telephone for 90 days is not feasible.
Testing the Addition of 131I-MIBG or Lorlatinib to Intensive Therapy in People With High-Risk Neuroblastoma (NBL)
This phase III trial studies iobenguane I-131 or lorlatinib and standard therapy in treating
younger patients with newly-diagnosed high-risk neuroblastoma or ganglioneuroblastoma.
Radioactive drugs, such as iobenguane I-131, may carry radiation directly to tumor cells and
not harm normal cells. Lorlatinib may stop the growth of tumor cells by blocking some of the
enzymes needed for cell growth. Giving iobenguane I-131 or lorlatinib and standard therapy
may work better compared to lorlatinib and standard therapy alone in treating younger
patients with neuroblastoma or ganglioneuroblastoma.
• Patients must be enrolled on ANBL00B1 (NCT00904241) or APEC14B1 (NCT02402244) prior to
enrollment on ANBL1531 (NCT03126916)
• Patient must be >= 365 days and =< 30 years of age at diagnosis
• Patients must have a diagnosis of neuroblastoma or ganglioneuroblastoma (nodular)
verified by tumor pathology analysis or demonstration of clumps of tumor cells in bone
marrow with elevated urinary catecholamine metabolites; the following disease groups
are eligible:
• Patients with International Neuroblastoma Risk Group (INRG) stage M disease are
eligible if found to have either of the following features:
• MYCN amplification (> 4-fold increase in MYCN signals as compared to
reference signals), regardless of additional biologic features; OR
• Age > 547 days regardless of biologic features
• Patients with INRG stage MS disease with MYCN amplification
• Patients with INRG stage L2 disease with MYCN amplification
• Patients > 547 days of age initially diagnosed with INRG stage L1, L2 or MS
disease who progressed to stage M without prior chemotherapy may enroll within 4
weeks of progression to stage M
• Patients >= 365 days of age initially diagnosed with MYCN amplified INRG stage L1
disease who progress to stage M without systemic therapy may enroll within 4
weeks of progression to stage M
• Patients initially recognized to have high-risk disease must have had no prior
systemic therapy (other than topotecan/cyclophosphamide initiated on an emergent basis
and within allowed timing); patients observed or treated with a single cycle of
chemotherapy per a low or intermediate risk neuroblastoma regimen (e.g., as per
ANBL0531, ANBL1232 or similar) for what initially appeared to be non-high risk disease
but subsequently found to meet the criteria will also be eligible; patients who
receive localized emergency radiation to sites of life-threatening or
function-threatening disease prior to or immediately after establishment of the
definitive diagnosis will be eligible
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 or a serum creatinine based on age/sex as follows:
• 1 to < 2 years: male = 0.6; female = 0.6
• 2 to < 6 years: male = 0.8; female = 0.8
• 6 to < 10 years: male = 1; female = 1
• 10 to < 13 years: male = 1.2; female = 1.2
• 13 to < 16 years: male = 1.5; female = 1.4
• >= 16 years: male = 1.7; female = 1.4
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age, and
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 10 x
ULN; for the purposes of this study, ULN for SGPT (ALT) is 45
• Shortening fraction of >= 27% by echocardiogram, or ejection fraction of > 50% by
echocardiogram or radionuclide angiogram
• No known contraindication to peripheral blood stem cell (PBSC) collection; examples of
contraindications might be a weight or size less than the collecting institution finds
feasible, or a physical condition that would limit the ability of the child to undergo
apheresis catheter placement (if necessary) and/or the apheresis procedure
Exclusion Criteria:
• Patients with INRG stage L2 tumors without amplification of MYCN regardless of tumor
histology (may meet criteria for high risk classification but are not eligible for
this trial)
• Patients with bone marrow failure syndromes
• Patients for whom targeted radiopharmaceutical therapy would be contraindicated due to
underlying medical disorders
• Female patients who are pregnant since fetal toxicities and teratogenic effects have
been noted for several of the study drugs; a pregnancy test is required for female
patients of childbearing potential
• Lactating females who plan to breastfeed their infants
• Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation
Non-Contrast Perfusion Using Arterial Spin Labeled MR Imaging for Assessment of Therapy Response in Glioblastoma
MRI including ASL will be performed before, during and after the treatment, in a total of 7
MRI sessions until 8 months after the first session. Thereafter, patients will be followed
through standard clinical examinations for the next 3 years or until demise, whichever occurs
first.
Clinically, GBM patients are imaged every 8-weeks, beginning at 10 weeks after the completion
of chemoradiation, since morphological (i.e. size) changes are not anticipated earlier.
However, our preliminary experience and others have shown functional changes including
perfusion and diffusion as early as 3-weeks after the initiation of the treatment . Thus, our
T10, T18, T26 and T34 MRI sessions will be performed along with the clinical imaging
sessions, while the T3 and T6 MRI sessions will be performed additionally for this proposal.
All MR imaging sessions will be scheduled within ±1 or ±2 weeks of the target time period, as
indicated in the table.
MRI including ASL will be performed before, during and after the treatment, in a total of 7
MRI sessions until 8 months after the first session. The research MR imaging may take
approximately an additional 15 minutes per each imaging session. However, the T3, and T6 MR
imaging sessions will be performed additionally for the purpose of this study, with each
taking approximately one hour. Thereafter, patients will be followed through standard
clinical examinations for the next 3 years or until demise, whichever occurs first.
• Patients with histologically proven GBM
• Newly diagnosed GBM. Prior surgery is allowed, but should not have started any other
treatment such as chemotherapy, radiation treatment, and anti-angiogenic therapy.
• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
• Women of child-bearing potential must agree to undergo a urine pregnancy screening per
standard Radiology departmental protocol, in place to prevent imaging of pregnant
patients. A female of child-bearing potential is any woman (regardless of sexual
orientation, having undergone a tubal ligation, or remaining celibate by choice) who
meets the following criteria: 1) Has not undergone a hysterectomy or bilateral
oophorectomy; or 2) Has not been naturally postmenopausal for at least 12 consecutive
months (i.e., has had menses at any time in the preceding 12 consecutive months).
• Scheduled to undergo chemoradiation.
Exclusion Criteria:
• Subjects who have had prior chemotherapy or radiotherapy.
• Subjects may not be receiving any other investigational agents at the time of
enrollment.
• Subjects must not be pregnant since pregnancy is a contraindication to administration
of gadolinium-based contrast agents.
• Any contraindication to MRI per Radiology Department's routine protocol, e.g.
MRI-incompatible objects, including but not limited to medical devices (e.g.
pacemakers, automated implantable cardioverter defibrillators, etc.) and other foreign
bodies.
• Known severe allergic reaction to Gadolinium-based contrast agents.
• Patients with sickle cell disease and patients with other hemolytic anemias (low red
blood count in body).
• Patients with uncontrollable claustrophobia, severe lower back pain, and
uncontrollable tremors, to the point that it would render them unable to tolerate an
MRI study.
Procedure: MRI with Arterial Spin Labeling (ASL)
Glioblastoma, Brain and Nervous System
magnetic resonance imaging, arterial spin labeling
Study Of Palbociclib Combined With Chemotherapy In Pediatric Patients With Recurrent/Refractory Solid Tumors
A study to learn about safety and find out maximum tolerable dose of palbociclib given in
combination with chemotherapy (temozolomide with irinotecan or topotecan with
cyclophosphamide) in children, adolescents and young adults with recurrent or refractory
solid tumors (phase 1). Phase 2 to learn about the efficacy of palbociclib in combination
with irinotecan and temozolomide when compared with irinotecan and temozolomide alone in the
treatment of children, adolescents, and young adults with recurrent or refractory Ewing
sarcoma (EWS).
Inclusion:
1. Histologically confirmed relapsed or refractory solid tumor as follows:
• For dose escalation and dose determination parts: Histologically confirmed
relapsed or refractory solid tumor (including CNS tumors but not lymphomas).
Patients with Diffuse Intrinsic Pontine Glioma do not require histological only
radiographic confirmed relapse to enroll.
• For dose expansion and tumor specific cohorts: Histologically confirmed relapsed
or refractory solid tumor including but not limited to EWS, rhabdoid tumor,
rhabdomyosarcoma, neuroblastoma, and medulloblastoma. Patients with Diffuse
Intrinsic Pontine Glioma do not require histological only radiographic confirmed
relapse to enroll. EWS is not eligible for TOPO and CTX tumor-specific cohorts.
• For randomized Phase 2 part: Histologically confirmed Ewing sarcoma at diagnosis
or at relapse, with presence of EWSR1-ETS or FUS-ETS rearrangement.
Histopathology confirmation of both EWSR1-ETS or FUS-ETS rearrangement partners
is required OR availability of formalin fixed paraffin embedded (FFPE) tumor
tissue sample for central testing. Patient must have relapsed or have refractory
disease and at least evaluable disease in at least one site other than bone
marrow that can be followed by imaging.
2. Age ≥2 and <21 years at the time of study entry.
3. Lansky performance status ≥50% for patients ≤16 years of age, or Eastern Cooperative
Oncology Group (ECOG) 0, 1 or 2 for patients >16 years of age.
4. Adequate bone marrow function.
• Absolute neutrophil count ≥1000/mm3;
• Platelet count ≥100,000/mm3 (transfusion independent, no platelet transfusion in
past 7 days prior study entry);
• Hemoglobin ≥8.5 g/dL (transfusion allowed).
5. Adequate renal function: Serum creatinine level based on age/gender must within
protocol specified limits.
6. Adequate liver function, including:
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
≤2.5 × upper limit of normal (ULN) or ≤5 × ULN for age, if attributable to
disease involvement of the liver;
• Total bilirubin ≤1.5 × ULN for age, unless the patient has documented Gilbert's
syndrome.
7. Patients enrolled to Phase 1 portion of the study and tumor specific cohorts must have
measurable disease as defined by RECIST version 1.1 or modified RANO criteria for CNS
disease or INRC for neuroblastoma. Patients with EWS enrolled to Phase 2 portion of
the study are eligible with evaluable disease (eg, bone only disease with no soft
tissue component).
8. Recovered to CTCAE Grade ≤1, or to baseline, from any non-hematological acute
toxicities of prior surgery, chemotherapy, immunotherapy, radiotherapy,
differentiation therapy or biologic therapy, with the exception of alopecia.
9. Serum/urine pregnancy test (for all girls ≥8 years of age) negative at screening and
at the baseline visit.
Exclusion:
1. Phase 1 and tumor specific cohorts: For palbociclib with IRN and TMZ combination,
prior treatment with a CDK4/6 inhibitor or progression while on treatment with an
IRN-containing regimen that includes TMZ. Patients who have received the combination
of IRN and TMZ and did not progress while on these medications are eligible. For
patients enrolling in the palbociclib with TOPO and CTX combination, prior treatment
with a CDK4/6 inhibitor or progression while on treatment with a TOPO-containing
regimen that includes CTX. Patients who have received the combination of TOPO and CTX
and did not progress while on these medications are eligible. Phase 2 portion: prior
treatment with a CDK4/6 inhibitor or progression while on treatment with an
IRN-containing or TMZ-containing regimen. Patients who have received IRN and/or TMZ
and did not progress while on these medications are eligible.
2. Prior intolerability to IRN and/or TMZ plus/minus palbociclib with IRN and TMZ
combination and prior intolerability to TOPO and/or CTX for TOPO and CTX combination.
3. Use of strong cytochrome P450 (CYP) 3A inhibitors or inducers. Patients who are
receiving strong uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) inhibitors
within 12 days of Cycle 1 Day 1 (C1D1) are not eligible for the palbociclib with IRN
and TMZ combination. Patients who are receiving strong UGT1A1 inhibitors within 12
days of C1D1 are eligible for the palbociclib with TOPO and CTX combination (See
Section 5.7.1 for list of products.)
4. Systemic anti cancer therapy within 2 weeks prior to study entry and 6 weeks for
nitrosoureas.
5. Prior irradiation to >50% of the bone marrow (see Appendix 9).
6. Participation in other studies involving investigational drug(s) within 2 weeks or 5
half lives, whichever is longer, prior to study entry.
7. Major surgery within 4 weeks prior to study entry. Surgical biopsies or central line
placement are not considered major surgeries.
8. For IRN and TMZ with/without palbociclib combinations: known or suspected
hypersensitivity to palbociclib, IRN and/or TMZ. For combination of palbociclib with
TOPO and CTX: known or suspected hypersensitivity to palbociclib, TOPO and/or CTX.
9. Patients with known symptomatic brain tumors or brain metastases and require steroids,
unless they have been on a stable or on a decreasing steroid dose for >14 days.
10. Patients with previously diagnosed brain metastases are eligible if they have
completed their prior treatment and have recovered from the acute effects of radiation
therapy or surgery prior to study entry for these metastases for at least 14 days post
radiation and 4 weeks post-surgery and are neurologically stable.
11. Hereditary bone marrow failure disorder.
12. QTc >470 msec.
13. History of clinically significant or uncontrolled cardiac disease, including:
• History of or active congestive heart failure; if patient had congestive heart
failure resolve and >1 year from resolution, patient will be considered eligible;
• Clinically significant ventricular arrhythmia (such as ventricular tachycardia,
ventricular fibrillation or Torsades de Pointes);
• Diagnosed or suspected congenital or acquired prolonged QT syndrome;
• Need for medications known to prolong the QT interval;
• Uncorrected hypomagnesemia or hypokalemia because of potential effects on the QT
interval;
• Left ventricular ejection fraction <50% or shortening fraction <28%.
14. Recent or ongoing clinically significant gastrointestinal disorder that may interfere
with absorption of orally administered drugs (eg, gastrectomy).
15. Severe acute or chronic medical or laboratory test abnormality that may increase the
risk associated with study participation or investigational product administration or
may interfere with the interpretation of study results, and in the judgment of the
Investigator, would make the patient inappropriate for entry into this study.
16. Investigator site staff members directly involved in the conduct of the study and
their family members, site staff members otherwise supervised by the investigator, or
patients who are Pfizer employees, including their family members, directly involved
in the conduct of the study.