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within category "Lung Disease & Asthma"
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Outcome Study Assessing a 75 Milligrams (mg) Dose of Macitentan in Patients With Pulmonary Arterial Hypertension (UNISUS)
The purpose of this study is to demonstrate superiority of macitentan 75 milligrams (mg) in
prolonging the time to the first clinical events committee (CEC)-adjudicated morbidity or
mortality (M/M) event in participants with symptomatic pulmonary arterial hypertension (PAH)
compared to macitentan 10 mg.
• Target population: greater than or equal to (>=) 18 (or the legal age of consent in
the jurisdiction in which the study is taking place) years of age
• Target population: Symptomatic Pulmonary Arterial Hypertension (PAH) in World Health
Organization Functional Class (WHO FC) II, III, or IV
• Target population: PAH subtype falling in one of the below classifications:
Idiopathic; Heritable; Drug- or toxin-induced; Related to: Connective tissue disease,
HIV infection, Portal hypertension, and Congenital heart disease with
small/coincidental cardiac defect with systemic-to-pulmonary shunt ( for example
atrial septal defect, ventricular septal defect, patent ductus arteriosus,
atrioventricular septal defect) which does not account for the elevated pulmonary
vascular resistance (PVR) or persistent PAH documented by an Right heart
catheterization (RHC) >= 1 year after simple systemic-to pulmonary shunt repair
• PAH diagnosis confirmed by hemodynamic evaluation at rest at any time prior to
screening: Mean pulmonary artery pressure (mPAP) greater than (>) 20 millimeters of
mercury (mm Hg), and; Pulmonary artery wedge pressure (PAWP) or left ventricular end
diastolic pressure (LVEDP) less than or equal to (<=) 15 mm Hg, and PVR >= 3 Wood
Units (that is, >= 240 dyn*sec/cm^5)
• Able to perform the 6-minute walking test (6MWT) with a minimum distance of 50 meters
and maximum distance of 440 meters at screening
Exclusion Criteria:
• Known presence of three or more of the following risk factors for heart failure with
preserved ejection fraction at screening, based on records that confirm documented
medical history: Body mass index (BMI) > 30 kilograms per meter square (kg/m^2),
Diabetes mellitus of any type, Essential hypertension (even if well controlled);
Coronary artery disease, that is, any of the following: history of stable angina, or
known more than 50 percent (%) stenosis in a coronary artery, or history of myocardial
infarction, or history of or planned coronary artery bypass grafting and/or coronary
artery stenting
• Presence of moderate or severe obstructive lung disease (forced expiratory volume in 1
second [FEV1] / forced vital capacity [FVC] < 70%; and FEV1 < 60% of predicted after
bronchodilator administration) ) in participants with a known or suspected history of
significant lung disease as documented by a spirometry test performed within 1 year
prior to screening
• Known moderate to severe hepatic impairment, defined as Child-Pugh Class B or C, based
on records that confirm documented medical history
• Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >
1.5*upper limit of normal (ULN) at screening
• Hemoglobin < 100 gram per liter (g/L) (< 10 gram per deciliter [g/dL]) at screening
Safety, Tolerability and Pharmacokinetics of a Monoclonal Antibody Specific to B-and T-Lymphocyte Attenuator (BTLA) as Monotherapy and in Combination With an Anti-PD1 Monoclonal Antibody for Injection in Subjects With Advanced Malignancies
The primary objective is to assess the safety and tolerability of TAB004 as monotherapy and
in combination with toripalimab in subjects with selected advanced solid malignancies,
including lymphoma, and to evaluate the recommended Phase 2 dose.
The secondary objectives are to: 1) describe the pharmacokinetic (PK) profile of TAB004
monotherapy and in combination with toripalimab and to describe the PK profile of toripalimab
when administered with TAB004, 2) evaluate antitumor activity of TAB004 monotherapy and in
combination with toripalimab; and 3) determine the immunogenicity of TAB004 monotherapy and
in combination with toripalimab and to determine the immunogenicity of toripalimab when
administered with TAB004.
The exploratory objectives are to: 1) evaluate pharmacodynamic effects of TAB004 on its
target receptor BTLA, as well as effects on the immune system; 2) evaluate biomarkers that
may correlate with activity of TAB004 as monotherapy and in combination with toripalimab; 3)
evaluate the utility of BTLA ligand, herpesvirus-entry mediator (HVEM), and additional
exploratory biomarkers that could aid in selection of appropriate subjects for TAB004
monotherapy and in combination with toripalimab.
• 1. Able to understand and willing to sign the Informed Consent Form;
• 2. Male or female ≥ 18 years;
• 3. Subjects with histologically or cytologically confirmed advanced unresectable or
metastatic solid tumor, including lymphoma that have progressed following prior
treatment. In Part A, subjects must have received, or be ineligible for or intolerant
of all available approved or standard therapies known to confer clinical benefit
including immunotherapy, or for whom no standard therapy exists; in Part B, subjects
with advanced or metastatic solid tumors, including but not limited to lymphoma,
melanoma, NSCLC, or other tumors with agreement of the Sponsor, who must have received
at least one line of therapy for advanced or metastatic disease, but are not required
to have received all standard therapies known to confer clinical benefit; In Part C,
subjects must have received at least one line of therapy for advanced or metastatic
disease but are not required to have received all standard therapies known to confer
clinical benefit; In Part D, subjects with advanced or metastatic solid tumors that
may include but not limited to lymphoma, melanoma, NSCLC, RCC or UC who must have
received at least one line of therapy for advanced or metastatic disease, but are not
required to have received all standard therapies known to confer clinical benefit.
• 4. Measurable disease per RECISTv1.1 and iRECIST, or RECIL 2017 for lymphoma
• 5. ECOG performance status of 0 or 1 with life expectancy of 3 months in the opinion
of the investigator.
• 6. Adequate organ and marrow function, as defined below:
1. Hemoglobin 8.0 g/dL within first 2 weeks prior to first dose of TAB004 (are not
requiring a transfusion within 14 days prior to dosing)
2. Absolute neutrophil count (ANC) 1.0 x 109 /L (1,000 /mm3)
3. Absolute lymphocyte count ≥ 0.6 x 109/L (600/mm3)
4. Platelet count 75 x 109 /L (75,000 /mm3), and not requiring platelet transfusions
within the 5 days prior to dosing
5. Total bilirubin ≤ 1.5 x ULN except subjects with documented Gilbert's syndrome
who must have a baseline total bilirubin ≤ 3.0 mg/dL
6. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN;
for subjects with hepatic metastases, ALT and AST ≤ 5 x ULN
7. Serum creatinine ≤ 1.5 x ULN OR calculated creatinine clearance (CrCl) or 24 hour
urine CrCl ≥ 40 mL/minute Cockcroft-Gault formula will be used to calculate CrCl.
24-hour urine CrCl will be derived using the measured creatinine clearance
formula
8. International normalized ratio (INR) ≤ 2.0 and activated partial thromboplastin
time (aPTT) ≤ 1.5 x ULN; applies only to subjects who do not receive therapeutic
anticoagulation; subjects receiving therapeutic anticoagulation (such as
low-molecular weight heparin or warfarin) should be on a stable dose
• 7. Willingness to provide consent for biopsy samples (In Part A, fresh pre-treatment
biopsies will be requested from subjects with safely accessible lesions. For subjects
who cannot provide a fresh pre-treatment biopsy, request for the most recent
accessible archival specimen will be required. In Part B, C and D, fresh pre-treatment
biopsies will be required from subjects with safely accessible lesions. The most
recent archival specimens will also be requested).
• 8. Females of childbearing potential who are sexually active with a nonsterilized male
partner must use effective contraception from time of screening, and must agree to
continue using such precautions for 90 days after the final dose of TAB004 or
toripalimab; cessation of birth control after this point should be discussed with a
responsible physician. Periodic abstinence, the rhythm method, and the withdrawal
method are not acceptable methods of birth control.
• 9. Females of childbearing potential are defined as those who are not surgically
sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete
hysterectomy) or postmenopausal (defined as at least 12 months with no menses
confirmed by follicle-stimulating hormone [FSH] levels. FSH testing will be conducted
at the Screening visit to confirm post-menopausal status).
• 10. Subjects must use effective contraception. Nonsterilized males who are sexually
active with a female partner of childbearing potential must use effective
contraception from Day 1 and for 90 days after receipt of the final dose of TAB004 or
toripalimab.
Exclusion Criteria:
• 1. Concurrent enrollment in another clinical study, unless it is an observational (non
interventional) clinical study or the follow-up period of an interventional study.
• 2. Any concurrent anti-cancer therapy, such as but not limited to chemotherapy,
targeted therapy, radiotherapy, immunotherapy, or biologic therapy. Radiation
treatment for palliative intent is allowed provided that lesions other than those
receiving radiation are available to measure response. Concurrent use of hormones for
non-cancer-related conditions (e.g., insulin for type 2 diabetes and hormone
replacement therapy) is acceptable.
Note: Local treatment of isolated lesions for palliative intent is acceptable (e.g., by
local surgery or radiotherapy).
• 3. Receipt of any investigational anticancer therapy within 28 days prior to the first
dose of TAB004 or, provided documentable, 5 half lives whichever is shorter, except
for lymphoma in which the exclusionary period is 2 weeks for immune checkpoint
inhibitors only.
• 4. Current or prior use of immunosuppressive medication within 2 weeks prior to the
first dose of TAB004, with the exception of intranasal and inhaled corticosteroids or
systemic corticosteroids not to exceed 10 mg/day of prednisone or equivalent.
• 5. Prior exposure to anti-BTLA, or anti-HVEM antibodies for subjects enrolled into
Part A and B only; prior treatment with anti-PD-1 or anti-PDL-1is allowed,including
toripalimab for all subjects.
• 6. Prior allogeneic bone marrow transplantation or prior solid organ transplantation.
• 7. Subjects with another malignancy, or history or other malignancy within 3 years
that is not expected to relapse. Subjects with non-melanomatous skin cancer or
cervical cancer that has been curatively surgically resected are eligible.
• 8. Major surgery (as defined by the investigator) within 28 days prior to first dose
of TAB004 or has not recovered to at least Grade 1 from adverse effects from such
procedure, or anticipation of the need for major surgery during study treatment.
• 9. Unresolved toxicities from prior anticancer therapy, defined as having not resolved
to baseline or to NCI-CTCAE v5.0 Grade 0 or 1, or to levels dictated in the
inclusion/exclusion criteria with the exception of neuropathies that are stable or
improving and alopecia. Subjects with irreversible toxicity that is not reasonably
expected to be exacerbated by TAB004 may be included (e.g., hearing loss) after
consultation with the medical monitor.
• 10. Active or prior documented autoimmune disease, such as but not limited to systemic
lupus erythematosus, multiple sclerosis, inflammatory bowel diseases, rheumatoid
arthritis, autoimmune hepatitis, systemic sclerosis, autoimmune vasculitis, autoimmune
neuropathies or type 1 insulin-dependent diabetes mellitus.
Note: Subjects with the following are not excluded: vitiligo; alopecia; Grave's disease not
requiring systemic treatment other than thyroid hormone replacement (within the past 2
years) psoriasis not requiring systemic treatment; controlled celiac disease; subjects with
a history of autoimmune hypothyroidism requiring only thyroid hormone replacement therapy;
And type 2 diabetes, provided that it is adequately controlled.
• 11. Clinically significant (intracranial, gastrointestinal) bleeding within 2 weeks
prior to screening.
• 12. Known history of tuberculosis.
• 13. Subjects with history of or current drug-induced interstitial lung disease or
pneumonitis ≥ Grade 2.
• 14. Subjects who have discontinued prior immune therapy due to immune mediated adverse
reaction(s).
• 15. Subjects who are known to be human immunodeficiency virus positive.
• 16. Subjects with evidence of hepatitis B or C virus infection, unless their hepatitis
is considered to have been cured. (Note that subjects with prior hepatitis B virus
infection must have HBV viral load < 100 IU/mL before study enrollment, and must be
treated according to local standards; hepatitis C virus infection must have, before
study enrollment, no detectable viral load and must be treated according to local
standards).
• 17. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
ulcerative colitis). Infection-related bowel inflammation, such as Clostridium
difficile colitis, is not excluded provided that it has been fully resolved for ≥ 6
weeks.
• 18. History of anaphylaxis, or eczema that cannot be controlled with topical
corticosteroids asthma.
• 19. Adult asthma that is moderate or severe, or asthma that has required:
hospitalization in the last 2 years; invasive mechanical ventilation ever; systemic
corticosteroids in the past year for exacerbations; or more than two short acting beta
agonist (e.g., albuterol) administrations per month for breakthrough asthma symptoms.
A history of childhood asthma or the presence of mild adult asthma that at baseline
has symptoms that can be controlled well with inhaled corticosteroids or short acting
beta agonists will not be excluded.
• 20. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure according to New York Heart
Association Functional Classification ≥ 3, uncontrolled hypertension, unstable angina
pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, or psychiatric
illness/social situations that would limit compliance with study requirements,
substantially increase risk of incurring adverse events from TAB004, or compromise the
ability of the subject to give written informed consent.
• 21. Untreated central nervous system and leptomeningeal metastases or requiring
ongoing treatment for these metastases, including corticosteroids. Subjects with
previously treated brain metastases may participate provided they are clinically
stable for at least 28 days prior to study entry, have no evidence of new or enlarging
metastases, and are off steroids.
• 22. Receipt of live attenuated vaccination within 28 days prior to study entry or
within 30 days of receiving TAB004.
• 23. Any condition or treatment or diagnostic test that, in the opinion of the
investigator or sponsor, would interfere with evaluation of TAB004 or interpretation
of subject safety or study results.
• 24. Pregnancy or breast feeding women.
LISA in the Delivery Room for Extremely Preterm Infants (DRLISA)
The purpose of this study is to evaluate the effect of LISA used in the delivery room (DR) in
decreasing the intubation rates in preterm infants at 23-25 weeks gestational age (GA),
during first 72 hours compared to the standard approach of stabilization on nasal CPAP in the
DR and administering surfactant in the NICU.
Infants in both groups will be resuscitated per NRP algorithm. Infants who maintain a stable
HR and respiratory effort on CPAP will qualify for the intervention. Infants in Group 1
(Intervention arm) will receive LISA in DR. CPAP will be titrated between 5-8 cm H20 after
LISA. Infants in Group 2 (Control arm) will be transferred to NICU on CPAP. The CPAP level
will be increased stepwise every 30 minutes to 7 cm H2O if FiO2 ≥0.3. Infants requiring CPAP
7 at FiO2 ≥0.3 will receive LISA. CPAP will be titrated between 5-8 cm H20 after LISA.
Infants in both arms requiring CPAP 7 and FiO2 >0.8 at 20 MOL in the delivery room will be
intubated in DR. Any infant with a heart rate not responding with appropriate PPV will be
intubated in the DR. CXR will be obtain on admission and umbilical lines will be placed.
Infants in both arm who require FiO2 ≥0.6 for ≥1 hour, apnea requiring stimulation 3 times
within one hour or ≥6 over 6 hour period, any apnea requiring PPV, or CO2 >0.65 in two
consecutive blood gases drawn over two hours will be considered as reasons for intubation
after LISA.
Primary outcome is the need for MV within 72 hours of life, secondary outcome includes need
for MV during first week of life and during hospital stay, bronchopulmonary dysplasia (BPD),
intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), spontaneous intestinal
perforation (SIP), need for treatment of patent ductus arteriosus (PDA), composite death or
BPD and mortality. This is a feasibility trial with the intention to enroll 30 infants in
each arm of the study over three years.
• Infants born 23 -25 weeks GA
• Resuscitated without requiring intubation and maintaining HR >100, oxygen saturation
per NRP goal saturation limits and regular respiratory effort on CPAP
Premedication for Less Invasive Surfactant Administration Study (PRELISA) (PRELISA)
The purpose of this study is to conduct a double blinded randomized control trial to
determine the safety and efficacy of using IV fentanyl and atropine prior to Less Invasive
Surfactant Administration (LISA) procedure in preterm infants with Respiratory Distress
Syndrome compared to the local standard of care to perform this procedure without any
premedication.
Hypothesis: In infants greater than or equal to 29 weeks gestational age requiring the Less
Invasive Surfactant Administration procedure, premedication with a combination of IV atropine
and IV fentanyl will be associated with fewer combined bradycardia events, defined as
heartrate less than 100 beats per minute for longer than 10 seconds, and hypoxemia events,
defined as saturations less than or equal to 80% for longer than 30 seconds, during the
procedure compared with placebo.
Specific Aims:
- To determine if infants receiving IV fentanyl and atropine prior to LISA will have a
decrease in hypoxemia and bradycardia events during the procedure compared to infants
receiving placebo
- To determine if infants receiving premedication prior to Less Invasive Surfactant
Administration will have higher procedure first attempt success rate compared with
infants receiving placebo
- To determine the effect of premedication on cerebral oxygenation compared to placebo
during and for 12 hours after Less Invasive Surfactant Administration using cerebral
Near Infrared Spectroscopy
- To determine the effect of premedication prior to Less Invasive Surfactant
Administration on the need for mechanical ventilation for 24 hours after the procedure
• Infants ≥29 weeks gestational age between 0-72 hours of life on CPAP for respiratory
support who qualify for the LISA procedure as determined by the primary team using
Parkland OPTISURF guidelines
Exclusion Criteria:
• Infants requiring intubation prior to surfactant therapy
• Infants with known severe congenital anomalies (including complex congenital heart
disease, airway, and central nervous system anomalies)
• Infants born to mothers with known opioid addiction or in a methadone treatment
program
Drug: IV Atropine and Fentanyl Premedication Arm, Drug: IV Normal Saline Placebo Arm
Premedication for Less Invasive Surfactant Administration, Fentanyl and Atropine for Less Invasive Surfactant Administration, Cerebral Near Infrared Spectroscopy monitoring in neonates, Premedication for LISA, Fentanyl and Atropine for LISA, Cerebral NIRS monitoring in neonates
This study will monitor device performance and outcomes of the SAPIEN 3 Transcatheter Heart
Valve (THV) System in subjects with a dysfunctional right ventricular outflow tract (RVOT)
conduit or previously implanted surgical valve in the pulmonic position with a clinical
indication for intervention.
1. Dysfunctional RVOT conduit or previously implanted surgical valve
2. RVOT/PV with ≥ moderate regurgitation and/or a mean RVOT/PV gradient of ≥ 35 mmHg
Exclusion Criteria:
1. Inability to tolerate an anticoagulation/antiplatelet regimen
2. Active bacterial endocarditis or other active infections
Cefiderocol Pharmacokinetics in Adult Patients With Cystic Fibrosis
There is established evidence that adult patients with Cystic Fibrosis (CF) may have altered
antibiotic pharmacokinetics compared with non-CF patients. Cefiderocol is a newly approved
broad spectrum intravenous siderophore cephalosporin antibiotic, which has potent in vitro
activity against multidrug resistant Pseudomonas aeruginosa, Burkholderia cepacia complex,
Achromobacter species, and Stenotrophomonas maltophilia, all pathogens implicated in CF
pulmonary exacerbations. This study will determine the pharmacokinetics and tolerability of
cefiderocol in 12 adult CF patients admitted for a pulmonary exacerbation at one of 4
participating hospitals in the US. Patients will remain on standard of care IV antibiotics
and receive 4-6 doses of cefiderocol 2 grams infused over 3 hours every 6-8 hours, depending
on kidney function. Blood will be sampled after the final dose to determine concentrations
and pharmacokinetics of cefiderocol. Safety and tolerability will be assessed throughout the
2 day study.
• Documented diagnosis of CF
• Acute pulmonary exacerbation as the primary reason for admission to the hospital with
requirement to receive systemic antibiotic treatment
Exclusion Criteria:
• Females that are pregnant and/or breastfeeding
• History of any moderate or severe hypersensitivity or allergic reaction to any
β-lactam antibiotic (a history of mild rash to a cephalosporin followed by uneventful
re-exposure is not a contraindication)
• History of a lung transplant at any time in the past or any other organ
transplantation (e.g., liver) within the last 6 months
• Moderate to severe renal dysfunction defined as a creatinine clearance < 60 mL/min (as
calculated by the Cockcroft-Gault equation using actual body weight) or requirement
for continuous renal replacement therapy or hemodialysis
• A hemoglobin less than 8 gm/dL at baseline
• Any rapidly-progressing disease or immediately life-threatening illness (defined as
imminent death within 48 hours in the opinion of the investigator)
Inclusion Criteria :
• Male or female age ≥18 years
• Able and willing to provide written informed consent, which includes compliance with
study requirements and restrictions listed in the consent form
• Greater than or equal to 6-month history of documented sarcoidosis including
histological confirmation in the subject's medical records
• Symptomatic as indicated by Medical Research Council Dyspnea scale >1 (i.e., Grade 2
or more) in the prior 6 months
• Body Mass Index (BMI) <40 kg/m2 at Screening
• Vaccinations for COVID-19 with completion of the primary series at least 2 weeks prior
to randomization
Exclusion Criteria
• Hospitalized for any respiratory illness <30 days prior to Screening
• Greater than or equal to 20% fibrosis as indicated on HRCT-scan assessed by central
read prior to randomization
• Hemoglobin <9.5 g/dL
• Participation in another interventional clinical trial (IP/Device) within 6 months
prior to Screening
• ECG abnormalities that warrant further clinical investigation or management at
Screening
• Systolic blood pressure (SBP) <90 or >180mm Hg; Diastolic blood pressure (DBP) <60
• Has documented laboratory-confirmed SARS-CoV-2 infection as determined by polymerase
chain reaction (PCR) or other approved clinical testing <3 months prior to
randomization
• Other significant pulmonary disease likely to interfere with the primary endpoint
• Females who are pregnant or breastfeeding or intend to be during the course of the
study
• Any other acute or chronic medical condition, psychiatric condition, or laboratory
abnormality, that in the judgment of the Investigator or Sponsor, may increase the
risk associated with study participation or investigational product administration, or
may interfere with the interpretation of study results, and would make the participant
inappropriate for entry into this study
Other protocol-defined inclusion/exclusion criteria may apply.
Efficacy + Safety of Liposome Cyclosporine A to Treat Bronchiolitis Obliterans Post Single Lung Transplant (BOSTON-1) (BOSTON-1)
The objective of the trial is to assess efficacy and safety of add-on aerosolized liposomal
cyclosporine A (L-CsA) to Standard of Care (SoC) therapy as compared to SoC therapy alone in
the treatment of Bronchiolitis obliterans syndrome (BOS) in single lung transplant
recipients.
1. Adult patients ≥ 18 years who received a single lung transplant at least 12 months
prior to Screening.
2. Patients with BOS diagnosis defined as CLAD-BOS phenotype with:
1. Screening FEV1 between 85-51% of personal best FEV1 value post-transplant OR
2. Screening FEV1 >85% of personal best FEV1 associated with EITHER a ≥ 200 mL
decrease in FEV1 in the previous 12 months OR according to medical history
showing BOS progression.
3. Diagnosis of CLAD-BOS must be made at least 12 months after lung transplantation and
1. within 12 months prior to the screening visit OR
2. more than 12 months from screening and patient must have shown a decline in FEV1
≥ 200ml in the previous 12 months before screening, which is not due to acute
infection or acute organ rejection.
4. Patients in whom the diagnosis of BOS has been confirmed by the elimination of other
possible causes of obstructive or restrictive lung disease (CLAD •RAS phenotype, see
Protocol Specific Definitions).
5. Patients should be on a maintenance regimen of immunosuppressive agents including
tacrolimus, a second agent such as but not limited to MMF or azathioprine, and a
systemic corticosteroid such as prednisone as third agent. The regimen must be stable
within 4 weeks prior to randomization with respect to the therapeutic agents.
6. Patients capable of understanding the purposes and risks of the clinical trial, who
have given written informed consent and agree to comply with the clinical trial
requirements/visit schedules, and who are capable of aerosol inhalation. Patients must
consent to retrieve prespecified data from the historic medical record (e.g.,
information related to the transplant surgery; spirometry data; medication use).
7. Women of childbearing potential must have a negative serum or urine pregnancy test
within 7 days prior to randomization and must agree to use one of the methods of
contraception listed in Appendix II through their End of Study Visit.
8. Patients have no concomitant diagnoses that are considered fatal within one year (12
months) of Screening.
Exclusion Criteria:
1. Patients with confirmed other causes for loss of lung function, such as acute
infection, acute rejection, restrictive allograft syndrome (CLAD •RAS phenotype, see
Protocol Specific Definition ), etc.
2. Patients with acute antibody-mediated rejection at Screening. In this context,
clinically stable patients (as judged by the Investigator) with detectable levels of
donor specific antibodies (DSA) at the Screening Visit are eligible for the study.
3. Active acute bacterial, viral, or fungal infection not successfully resolved at least
4 weeks prior to the Screening Visit. Patients with chronic infection or colonization
who are clinically stable as per judgement of the Investigator are eligible for the
study.
4. Mechanical ventilation within 12 weeks prior to Randomization.
5. Patients with uncontrolled hypertension.
6. Patient has baseline resting oxygen saturation of < 89% on room air or use of
supplemental oxygen at rest.
7. Evidence of functional airway stenosis (e.g., bronchomalacia/tracheomalacia, airway
stents, or airways requiring balloon dilatations to maintain patency) with onset after
the initial diagnosis of BOS and ongoing at Screening and/or Baseline Visit.
8. Known hypersensitivity to L-CsA or to cyclosporine A.
9. Patients with chronic renal failure, defined as serum creatinine > 2.5 mg/dL at
screening, or requiring chronic dialysis.
10. Patients with liver disease and serum bilirubin > 3-fold upper limit of normal range
or transaminases > 2.5 upper limit of normal range.
11. Patients with active malignancy within the previous 2 years, including post-transplant
lymphoproliferative disorder, with the exception of treated, localized basal and
squamous cell carcinomas.
12. Pregnant women or women who are unwilling to use appropriate birth control to avoid
pregnancy through their End of Study Visit.
13. Women who are currently breastfeeding.
14. Receipt of an investigational drug as part of a clinical trial within 4 weeks prior to
the Screening Visit. This is defined as any treatment that is implemented under an
Investigational New Drug (IND) or compassionate use.
15. Patients who have received extracorporeal photophoresis (ECP) for treatment of BOS
within 1 month prior to Randomization.
16. Patients who are currently participating in an interventional clinical trial.
17. Psychiatric disorders or altered mental status precluding understanding of the
informed consent process and/or completion of the necessary procedures.
18. Any co-existing medical condition that in the Investigator's judgment will
substantially increase the risk associated with the patient's participation in the
clinical trial.
Drug: Liposomal Cyclosporine A, Drug: standard of care
A Study of ZN-c3 in Participants With Solid Tumors
This is a Phase 1/2 open-label, multicenter study, evaluating the safety, tolerability,
efficacy, pharmacokinetics (PK) and pharmacodynamics of ZN-c3 alone and in combination with
other drugs.
In order to be eligible to participate in any phase of this study, an individual must meet
all of the following criteria:
1. Provision of written informed consent.
2. Age ≥ 18 years or the minimum legal adult age (whichever is greater) at the time of
informed consent.
3. Adequate hematologic and organ function as defined by the following criteria:
1. Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L; excluding measurements obtained
within 7 days after daily administration of filgrastim/sargramostim or within 3
weeks after administration of pegfilgrastim.
2. Platelet count ≥ 100 × 10^9/L; excluding measurements obtained within 3 days
after transfusion of platelets.
3. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × upper
limit of normal (ULN). If liver function abnormalities are due to underlying
liver metastases, AST and ALT ≤ 5 x ULN.
4. Total serum bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN in the case of Gilbert's disease.
5. Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 60 mL/min.
4. Female subjects of childbearing potential must have a negative serum beta human
chorionic gonadotropin test.
5. Male subjects and female subjects of childbearing potential must agree to use an
effective method of contraception per institutional standard prior to the first dose
and for 90 days after the last dose of ZN-c3.
Individuals must meet the additional criteria in order to be eligible to participate in
Phase 1:
1. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
2. Measurable or evaluable disease per RECIST version 1.1.
Individuals must meet these additional criteria in order to be eligible to participate in
Phase 2 Single Agent part of the study:
1. ECOG performance status ≤ 1.
2. Measurable disease per RECIST version 1.1.
Individuals must meet these additional criteria in order to be eligible to participate in
Phase 2 combination with a PARP inhibitor:
1. ECOG performance status ≤ 1.
2. Measurable disease per RECIST version 1.1.
Individuals must meet these additional criteria in order to be eligible to participate in
Phase 2 combination with a PD-1 inhibitor:
1. ECOG performance status ≤ 1.
2. Measurable disease per RECIST version 1.1.
Key
Exclusion Criteria:
1. Any of the following treatment interventions within the specified time frame prior to
Cycle 1 Day 1:
1. Major surgery within 28 days.
2. Radiation therapy within 21 days.
3. Any prior systemic therapy regardless of the stop date, but the subject must have
recovered to eligibility levels from prior toxicity.
4. Autologous or allogeneic stem cell transplant within 3 months.
5. Current use of an investigational agent that is not expected to be cleared by the
first dosing of study drug or that has demonstrated to have prolonged side
effects. Subjects should have recovered from the side effects to a Grade 0 or 1
(except alopecia).
2. A serious illness or medical condition(s) including, but not limited to, the
following:
1. Brain metastases that require immediate treatment or are clinically or
radiologically unstable.
2. Leptomeningeal disease that requires or is anticipated to require immediate
treatment.
3. Myocardial impairment of any cause resulting in heart failure by New York Heart
Association Criteria Class III or IV.
4. Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or
study drug administration, or may interfere with the interpretation of study
results, and in the judgment of the Investigator would make the subject
inappropriate for entry into this study.
5. Significant gastrointestinal abnormalities
6. Active or uncontrolled infection.
3. Unresolved toxicity of Grade > 1 attributed to any prior therapies (excluding Grade 2
neuropathy, alopecia or skin pigmentation).
4. Prior therapy with ZN-c3 or known hypersensitivity to any drugs similar to ZN-c3 in
class.
5. Subjects with active (uncontrolled, metastatic) second malignancies or requiring
therapy.
Drug: ZN-c3
Small Cell Lung Cancer, Fallopian Tube Cancer, Non Small Cell Lung Cancer, Malignant Melanoma, Metastatic Breast Cancer, Triple Negative Breast Cancer, Epithelial Ovarian Cancer, Urothelial Carcinoma, Solid Tumor, Corpus Uteri, Peritoneal Cancer
• Histologically or cytologically documented locally advanced or metastatic solid tumor
malignancy.
• Progressed or was intolerant to all available therapies known to confer clinical
benefit appropriate for their tumor type, and for which the patient was eligible and
willing to receive, or refused SOC treatments that are perceived to have marginal
clinical benefit.
• Adequate bone marrow, kidney and liver function.
• Performance status of 0 or 1.
• Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade 1
except for AEs not constituting a safety risk by Investigator judgement.
Exclusion Criteria:
• Prior treatment targeting ILT2 and/or ILT4 or targeting HLA-G.
Drug: NGM707, Drug: NGM707 plus pembrolizumab, Drug: NGM707, Drug: NGM707, Drug: NGM707, Drug: NGM707 plus pembrolizumab, Drug: NGM707 plus pembrolizumab
Esophageal Cancer, Breast Cancer, Melanoma, Gastric Cancer, Colorectal Cancer, Ovarian Cancer, Glioblastoma, Cervical Cancer, Renal Cell Carcinoma, Non Small Cell Lung Cancer, Mesothelioma, Cholangiocarcinoma, Pancreatic Ductal Adenocarcinoma, Brain and Nervous System, Breast - Female, Breast - Male, Kidney, Liver, Lung/Thoracic, Melanoma, skin, Other Digestive Organ, Other Skin, Ovary, Pancreas, Squamous Cell Carcinoma of Head and Neck, Endocervical Cancer
A Study to Learn About How Well Riociguat Works, How Safe it is and How it is Used Under Real World Conditions in Patients in the United States Who Are Receiving Riociguat for High Blood Pressure in the Arteries That Carry Blood From the Heart to the Lungs (Pulmonary Arterial Hypertension, PAH) (ROAR)
Pulmonary arterial hypertension (PAH) is a type of high blood pressure in the arteries that
carry blood from the heart to the lungs. PAH occurs when the openings in the blood vessels of
the lungs get smaller and smaller. These smaller openings can be caused by the following:
- The walls of the arteries tightening
- The walls of the arteries becoming stiff and narrow from an overgrowth of cells The
increased pressure in the pulmonary arteries strains the right side of the heart and it
begins to fail, causing difficulty breathing and other symptoms. As PAH progresses,
symptoms get worse.
There is no cure for PAH, but several medications like endothelin receptor antagonists
(ERAs), prostacyclin analogues (PCAs) and riociguat, a soluable guanylate cyclase stimulator,
are available to help slow the progression of changes in the pulmonary arteries and help
reduce symptoms. Riociguat can be taken together with ERAs and PCAs.
In this study, the researchers want to learn about how well riociguat works, how safe it is
when patients take it in 1 of these ways:
- alone
- with ERA
- with PCA
- with ERA and PCA The dosage for each patient will be decided by their doctor. The
researchers will review information collected from the patients who have decided with
their doctor to start riociguat treatment for their PAH. The study will include about
500 patients in the United States who are at least 18 years old. All of the patients
will have either just started taking riociguat or will have been taking it for less than
3 months No investigational products will be administered in this study. Patients will
be treated with the Standard of Care (SOC) for PAH. The SOC is the currently appropriate
treatment in accordance with scientific evidence and agreed upon in collaboration
between medical experts for PAH. There will be no study-mandated visits or treatments.
The patients will be in the study for up to 2 years. During this time, they will visit their
doctor every 3 to 6 months as part of the Standard of Care. At these visits, the patients
will answer questions about their PAH symptoms and whether they have any medical problems.
They will also do exercise tests to see how well they are able to breathe and how tired they
get while exercising. The doctors will perform other usual examinations which are part of the
Standard of Care such as echocardiograms (images of the heart to show how the heart is
working) and a right heart catheters (to measure the pressures in the heart) and will take
the usual blood and urine samples.
• Patients aged ≥18 years at the time of riociguat treatment initiation
• Diagnosis of PAH per National Institute for Health and Care Excellence (NICE) 2018
classification
• Decision to initiate treatment with riociguat as per investigator's routine treatment
practice made prior to enrollment in the study
• Initiation of riociguat, as per the FDA-approved US label:
• At enrollment OR
• ≤90 days prior to enrollment, with a documented titration regimen (defined as all
documented dose changes including, but not limited to: starting dose and dates
and highest tolerated dose and dates)
• Signed informed consent
Exclusion Criteria:
• Previously treated with and discontinued use of riociguat for any reason prior to
study enrollment (discontinuation defined as an interruption of therapy ≥30 days)
• Participating in any of the following:
1. Blinded clinical trial
2. Clinical trial involving an unapproved drug
3. Investigational program with interventions outside of routine clinical practice
• Life expectancy <12 months
• Contraindicated to receive riociguat per the FDA approved US label
• Use of nitrates or NO donors in any form
• Use of PDE5 inhibitors
• PH associated with idiopathic interstitial pneumonias
• Unable or unwilling to provide informed consent
Safety and Durability of Sirolimus for Treatment of LAM (MIDAS)
The MIDAS study aims to follow LAM patients who are currently taking, have previously failed
or been intolerant of, or may (at some time in the future) take mTOR inhibitors (sirolimus or
everolimus) as part of their clinical care. Adult female TSC patients may also enroll, with
or without lung cysts.
• Female, age 18 or over
• Diagnosis of LAM
• Signed and dated informed consent
• On chronic therapy, newly treated or may be considered for therapy with mTOR
inhibitors or previously intolerant of or having failed mTOR inhibitor therapy
Exclusion Criteria:
• Inability to attend at least one RLD Clinic visit per year
• Inability to give informed consent
• Inability or unwillingness to perform pulmonary function testing
Second Generation LMA Versus Endotracheal Tube in Obese Patients
This prospective, randomized, comparative study is intended to enroll a total of 148 patients
with a BMI 30-49.9 kg/m2 undergoing surgery at Parkland Hospital. The efficacy and
performance of a second-generation LMA will be compared to endotracheal intubation. A
standardized anesthetic protocol that is usual and customary for the type of operation the
patient is having will be provided to the anesthesia teams of enrolled subjects. The
remainder of the anesthetic care of the subject will not deviate from the standard of care.
• 18-80 years old
• Obese (BMI > or equal to 30 kg/m2
• Scheduled for a non-emergent surgery that requires general anesthesia (e.g.,
orthopedic, breast, urological, colorectal, ENT, vascular, general surgery)
• Willing and able to consent in English or Spanish
• No current history of advanced pulmonary or cardiac disease
Exclusion Criteria:
• Age less than 18 or older than 80
• BMI ≥50 or < 30 kg/m2
• Patient does not speak English or Spanish
• Expected surgical duration longer than 4 hours
• Planned postoperative ICU admission
• Patient refusal
• Monitored anesthesia care (MAC) or regional anesthesia planned
• Pregnant or nursing women
• "Stat" (emergent) cases
• Known or suspected difficult airway
• Full stomach/significant aspiration risk (gastroparesis, emergency surgery, untreated
moderate to severe gastroesophageal reflux disease, hiatal hernia)
• No history of gastric surgery
• Surgery in position other than supine (e.g., Trendelenburg)
• Laparoscopic surgery
Multicenter Trial of Congenital Pulmonic Valve Dysfunction Studying the SAPIEN 3 THV With the Alterra Adaptive Prestent (ALTERRA)
To demonstrate the safety and functionality of the Edwards Alterra Adaptive Prestent in
conjunction with the Edwards SAPIEN 3 Transcatheter Heart Valve (THV) System in patients with
a dysfunctional right ventricular outflow tract/pulmonary valve (RVOT/PV) who are indicated
for treatment of pulmonary regurgitation (PR).
1. The patient/patient's legally authorized representative has been informed of the
nature of the study, agrees to its provisions and has provided written informed
consent.
2. Pediatric or adult patent whose weight is ≥ 20 kg (44 lbs).
3. The patient has a dysfunctional RVOT/PV.
4. RVOT/PV proximal and distal landing zone diameter ≥ 27 mm and ≤ 38 mm and/or minimum
of 35 mm from contractile tissue to lowest pulmonary artery takeoff immediately prior
to Alterra Prestent insertion.
Exclusion Criteria:
1. Active infection requiring current antibiotic therapy (if temporary illness, patient
may be a candidate 2 weeks after discontinuation of antibiotics).
2. History of or active endocarditis (active treatment with antibiotics) within the past
180 days.
3. Leukopenia (WBC < 2000 cells/μL), anemia (Hgb < 7 g/dL), thrombocytopenia (platelets <
50,000 cells/μL) or any known blood clotting disorder.
4. Inappropriate anatomy for introduction and delivery of the Alterra Adaptive Prestent
or the SAPIEN 3 THV.
Device: Edwards Alterra Adaptive Prestent with SAPIEN 3 THV
Asthma is a chronic inflammatory airway disease that leads to episodic symptom exacerbations,
which exerts a substantial burden on quality of life and can influence other health domains
if not adequately controlled. Asthma prevalence rates have increased in the past decade,
affecting 8.4% (25.7 million people) of the United States population. The economic costs of
asthma have been estimated annually with $56 billion in the US alone. Despite progress in
pharmacological treatment, overall asthma control remains unsatisfactory and treatment
non-adherence is extremely high. Asthma is particularly under diagnosed and understudied in
aging adults. This problem will increase in coming decades given demographic trends and will
disproportionally contribute to the societal and personal economic costs associated with
asthma treatment and management. In the proposed 4-year project we will evaluate, in a
two-session assessment recruiting a total of 126 asthma patients and 66 healthy controls aged
40-69 years, the extent to which asthma and aging are associated with changes in cognition
and brain chemistry, structure, and function.
• For asthma patients: diagnosis of asthma (verified by a medical documentation) for at
least 2 years; for healthy volunteers: no significant medical or psychiatric history.
• Ages 40 to 69 years old.
• Proficient in English.
• Education level of at least 10th grade level.
Exclusion Criteria:
• Treatment with oral corticosteroids in the previous 6 weeks, because of the potent
effects of this drug on airway reactivity.
• Spirometry: Peak expiratory flow (PEF) below 60% of predicted.
• Diagnosis of vocal cord dysfunction (identified by abnormalities in spirometric
flow-volume curves), clinically significant chronic obstructive pulmonary disease, or
emphysema.
• Presence or history of medical or neurological disorder that may affect brain function
and the physiological systems of interest (e.g. angina, myocardial infarction,
congestive heart failure, transient ischemic attacks, cerebrovascular accidents,
emphysema, or chronic obstructive pulmonary disease, history of seizures or head
trauma, endocrine disorders or renal disease, chemotherapy or radiation presently or
in the past 5 years, uncontrolled diabetes, blood pressure above 160/90 (self-reported
or measured at session 1).
• Corrected vision poorer than 20/30 on Snellen Eye Chart.
• Presence or history of Schizophrenia, Psychosis, Dementia, Bipolar I, Bipolar II, PTSD
or Acute Stress Disorder
• Current or recent history (within 1 year) of Substance Related Disorders, current
recreational drug use (defined as past 30 days) or consuming more than 20 alcoholic
drinks per week.
• Current treatment with anti-psychotics, sedatives, benzodiazepines with a half-life
longer than 6 hours.
• Previous electroconvulsive therapy.
• Presence of history of orthopaedic circumstances and metallic inserts interfering with
MR scanning (prior surgeries and/or implant pacemakers, pacemaker wires, artificial
heart value, brain aneurysm surgery, middle ear implant, non-removable hearing aid or
jewelry, braces or extensive dental work, cataract surgery or lens implant, implanted
mechanical or electrical device, artificial limb or joint, foreign metallic objects in
the body such as bullets, BB's, shrapnel, or metalwork fragments, pregnancy,
claustrophobia, uncontrollable shaking, or inability to lie still for one hour.
• Not proficient in English.
• In the opinion of the principal investigator, participant is otherwise unsuitable for
this study.
Other: Functional and Structural Magnetic Resonance Imaging (research grade), Other: Cognitive Function Testing (non-diagnostic), Other: Asthma and Psychological Questionnaires (non-diagnostic)
• Ages 8 to ≤ 21 years
• Participant must be able to speak and understand English
• Be willing to participate and able to comply with the study protocol
• For participants with PE: Children with acute, radiologically confirmed pulmonary
embolism (PE) with our without DVT
• For control group: Children who are prescribed physical activity restrictions for 2 up
to 12 weeks following any minor outpatient surgery or, minor injury (surgery or injury
is referred to as "diagnosis" hereafter)
Exclusion Criteria:
• Congenital heart disease with abnormal pulmonary circulation or with in-situ pulmonary
artery thrombosis
• Chronic kidney disease
• Chronic inflammatory or an autoimmune disorder (such as systemic lupus erythematosus,
juvenile rheumatoid disorder, inflammatory bowel disease, and sickle cell disease)
• A metabolic or endocrinological disorder such as diabetes mellitus or thyroid disorder
• History of or active cancer
• Pregnant
• Musculoskeletal limitations to exercise expected to be present uptil 4 months
post-diagnosis
• Weight ≥ 300 lbs
• Contraindications to magnetic resonance imaging
• Frequent severe exacerbations of asthma defined by two or more bursts of systemic
glucocorticoids (more than three days each) in the previous year or at least one
hospitalization, intensive care unit stay or mechanical ventilation in the previous
year. Patients should also be excluded if there are daily symptoms of asthma requiring
daily use of short-acting bronchodilators such as albuterol or levalbuterol
administration. The use of controller medications such as daily inhaled
corticosteroids for mild persistent asthma is not exclusionary.
• Has any other medical condition, which in the opinion of the investigator may
potentially compromise the safety or compliance of the patient or may preclude the
patient's successful completion of the clinical study
Additional exclusion criteria for participants with PE:
• Prior history of DVT or PE (upper extremity, cerebral sinus venous thrombosis and
abdominal thromboses encountered as a neonate are not exclusion criteria)
• Lack of anticoagulant treatment for the acute VTE due to contraindications
The purposes of this project are 1) to compare the impact of maternal obesity versus
excessive gestational weight gain on obstructive sleep apnea (OSA) in obese and non-obese
women; 2) to investigate the mechanism(s) by which obesity and OSA increase cardiovascular
risk during pregnancy; and 3) to identify biomarker(s) for obesity-related OSA in pregnant
women.
• Both obese and non-obese (normal weight) early pregnant women aged ≥18 years old will
be permitted to participate in this project.
• No restriction with respect to race and socioeconomic status
• Women with a prior history of complicated pregnancy (i.e., gestational hypertension,
preeclampsia, HELLP syndrome, gestational diabetes, preterm birth, intrauterine growth
restriction, etc.) will be allowed to participate.
• Obese women with previously diagnosed OSA will be allowed to participate if they are
not currently on any recognized treatments such as Continuous Positive Airway Pressure
(CPAP), oral appliances or nasal expiratory positive airway pressure.
• Those who have had surgery for OSA in the past will be excluded.
• Women taking low-dose aspirin will be allowed to participate in this project.
Exclusion Criteria:
• Current multiple pregnancy;
• Known major fetal chromosomal or anatomical abnormalities;
• Recurrent miscarriage (three or more);
• Chronic essential hypertension (systolic BP >140 mmHg and/or diastolic BP >90 mmHg);
• Any evidence of cardiovascular and pulmonary diseases by history or by physical
examination;
• Kidney disease (serum creatinine >1.5 mg/dL);
• Coagulation disorders;
• Diabetes mellitus (fasting glucose ≥126 mg/dL or 2-hour oral glucose tolerance test
glucose level ≥200 mg/dL) or other systemic illness;
• Any evidence of neurological disease;
• Psychiatric disease or psychological disorders;
• History of drug or alcohol abuse within the last 2 years; and
• Given the effects of exercise training on sympathetic neural control,
endurance-trained athletes will be excluded. As this project focuses on sleep apnea in
pregnancy, Women with other significant sleep disorders such as restless legs syndrome
by Rest Leg Syndrome Diagnostic Index and insomnia by the Insomnia Severity Index or
Pittsburgh Sleep Quality Index will be excluded; In addition, women who report taking
a sleeping aid >1 time per month will be excluded.
Study to Evaluate Biological & Clinical Effects of Significantly Corrected CFTR Function in Infants & Young Children (BEGIN)
This is a two-part, multi-center, prospective longitudinal, exploratory study of highly
effective cystic fibrosis transmembrane conductance regulator (CFTR) modulators and their
impact on children with cystic fibrosis (CF).
• Part A:
• Less than 5 years of age at the first study visit.
• Documentation of a CF diagnosis.
Part B:
• Participated in Part A OR less than 6 years of age at the first study visit.
• Documentation of a CF diagnosis.
• CFTR mutations consistent with FDA labeled indication of highly effective modulator
therapy (ivacaftor or elexacaftor/tezacaftor/ivacaftor).
• Physician intent to prescribe ivacaftor or elexacaftor/tezacaftor/ivacaftor.
Exclusion Criteria:
• Part A and Part B:
Use of an investigational drug within 28 days prior to and including the first study visit.
Use of ivacaftor or elexacaftor/tezacaftor/ivacaftor within the 180 days prior to and
including the first study visit.
Use of chronic oral corticosteroids within the 28 days prior to and including the first
study visit.
Drug: Ivacaftor or elexacaftor/tezacaftor/ivacaftor