Phase 2 Study With Minimal Residual Disease (MRD) Driven Adaptive Strategy in Treatment for Newly Diagnosed Multiple Myeloma (MM) With Upfront Daratumumab-based Therapy
This phase 2 trial will test whether the combination of DaraRd (daratumumab + lenalidomide + dexamethasone) as induction therapy, followed by DRVd (daratumumab + lenalidomide + bortezomib + dexamethasone) consolidation therapy, if needed, will result in more patients achieving minimal residual disease (MRD)-negative status, relative to the standard of care. Consolidation therapy will be administered only to those patients with MRD-positive status after induction therapy. This is a study based on adaptive design for decision making of treatment options. Duration of therapy (daratumumab cycles) will depend on individual approach, response, evidence of disease progression and tolerance.
• Participants ≥18 years of age or legal age of consent per local regulations (whichever is greater).
• Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.
• ECOG status (Appendix A) of ≤2 and able to tolerate all applicable treatments per investigator's evaluation and standard institutional criteria.
• Both transplant eligible and ineligible myeloma patients can be included in this study. If applicable, participant should be able to tolerate all treatments per investigator's evaluation, including high-dose chemotherapy and autologous stem cell transplant (ASCT) based on standard criteria at the institution where this treatment will be administered.
• Participant must have a diagnosis of active MM according to International Myeloma Working Group (IMWG) diagnostic criteria.
• Participant must also have measurable disease per protocol.
• Participant agrees to refrain from blood donations during therapy on study and for 12 weeks after therapy is completed.
• Participant must be registered in and must comply with all requirements of REMSTM program for lenalidomide.
• Female participant who:
• Is post-menopausal for at least one year prior to study enrollment, OR
• Is surgically sterile, OR
• If of childbearing potential, must have a negative urine or serum pregnancy test within 10-14 days prior to and again within 24 hours of starting lenalidomide. They must also be willing to use TWO effective forms of contraception simultaneously from the time of signing the study consent until 90 days following the administration of the last dose of lenalidomide and 7 months following the administration of the last dose of bortezomib, OR
• Agree to practice true abstinence if that is aligned with their lifestyle, which does not include periodic abstinence or withdrawal.
• Male participant, even if surgically sterilized, must agree to one of the following:
• Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of lenalidomide and 4 months following the administration of the last dose of bortezomib, OR
• Agree to practice true abstinence if that is aligned with their lifestyle, which does not include periodic abstinence or withdrawal. EXCLUSION:
• Diagnoses of smoldering MM (SMM), monoclonal gammopathy of undetermined significance (MGUS), non-secretory MM, plasma cell leukemia, AL amyloidosis, Waldenstrom's. macroglobulinemia, POEMS syndrome. History of SMM and/or MGUS is not excluded.
• Known disease involvement of the CNS.
• History of prior hematopoietic stem cell transplant of any type.
• Received more than one cycle of anti-myeloma therapy prior to enrollment. Up to one cycle of myeloma therapy is allowed. Concomitant treatment is allowed with low-dose corticosteroids and bisphosphonates. The dose of corticosteroids for myeloma treatment should not exceed the equivalent of 160 mg of dexamethasone over a two-week period before initiation of protocol. Prednisone up to but no more than 10 mg po daily or its equivalent is allowed, for symptom management and comorbid conditions.
• Significant renal insufficiency, defined as creatinine clearance <30ml/min per Cockcroft-Gault formula.
• Hepatic impairment, defined as bilirubin >1.5 x institutional upper limit of normal (ULN) or AST (SGOT), ALT (SGPT), or alkaline phosphatase > 3x institutional ULN.
• Absolute neutrophil count (ANC) < 1000 cells/mm3 within 14 days of enrollment. Growth factor may not be used to meet ANC eligibility criteria.
• Hemoglobin (Hgb) < 8g/dL within 14 days of enrollment. Transfusion may not be used to meet Hgb eligibility criteria.
• Platelet count < 75,000 cells/mm3 within 14 days of enrollment. Transfusion may not be used to meet platelet eligibility criteria.
• Any condition, including laboratory abnormalities, that in the opinion of the investigator places the subject at unacceptable risk if subject were to participate in the study.
• Major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from complications of the surgery.
• Clinically significant peripheral neuropathy not well controlled with treatment, defined as symptoms limiting activities of daily living (basic ADLs).
• Symptomatic uncontrolled cardiac disease including congestive heart failure with New York Heart Association class III-IV symptoms, arrhythmia, unstable angina or myocardial infarction within the past six months, or any other uncontrolled or severe cardiovascular condition.
• Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal.
• Clinically uncontrolled asthma of any classification or known moderate or severe persistent asthma within the past two years (see asthma guidelines. https://www.nhlbi.nih.gov/files/docs/guidelines/asthma_qrg.pdf).
• Serious intercurrent illness including but not limited to clinically relevant cerebrovascular disease, uncontrolled diabetes mellitus, cirrhosis, pulmonary disease.
• Active autoimmune process or other disease requiring systemic immunosuppressive, monoclonal antibody, small molecule, or radiation therapy.
• Participant is:
• Seropositive for HIV
• Seropositive for Hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]
• Subjects with resolved infection (i.e., subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded.
• Participants with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.
• Seropositive for Hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).
• History of additional active malignancy in the past five years (not including squamous cell or basal cell carcinoma of the skin or in situ cervical cancer). However, malignancy treated with curative intent with <5% chance of disease relapse / recurrence in the next two years is allowed.
• Known drug allergy or intolerance to study medications (including steroids) or appropriate prophylactic medications (e.g. acyclovir, aspirin, warfarin or low-molecular weight heparin).
• Women with a positive pregnancy test during the screening period prior to study initiation or who are lactating.
• Participation in other clinical trials, including those with other investigational agents not included in this trial, within 30 days of the start of this trial and throughout the duration of this trial.
• Any significant history of non-compliance to medical regimens or unwilling or unable to comply with the instructions given.
• Participants using strong CYP3A4 inducers are excluded unless the inducer can be switched to an alternative agent while receiving Bortezomib (per protocol).
A Research Study to See How Well the New Weekly Medicine IcoSema, Which is a Combination of Insulin Icodec and Semaglutide, Controls Blood Sugar Level in People With Type 2 Diabetes Compared to Weekly Insulin Icodec (COMBINE 1)
This study will compare the new medicine IcoSema, which is a combination of insulin icodec and semaglutide, taken once a week, to insulin icodec taken once a week in people with type 2 diabetes. The study will look at how well IcoSema controls blood sugar level in people with type 2 diabetes compared to insulin icodec. Participants will either get IcoSema or insulin icodec. Which treatment participants get is decided by chance. IcoSema and insulin icodec are both new medicines that doctors cannot prescribe. Participants will get IcoSema or insulin icodec, which participants must inject once a week with a pen, which has a small needle, in a skin fold in the thigh, upper arm, or stomach. The study will last for about 1 year and 1 month. Participants will have 21 clinic visits, 31 phone/video calls with the study doctor, and 4 contacts with the site that can either be clinic visits or phone/video calls At 11 clinic visits participants will have blood samples taken. At 7 clinic visits participants cannot eat or drink (except for water) for 8 hours before the visit. Women cannot take part if pregnant, breast-feeding or plan to get pregnant during the study period. Not applicable for China: Participants will be asked to wear a sensor that measures their blood sugar level all the time during a 5 week period at the end of the study.
• Male or female and age above or equal to 18 years at the time of signing informed consent.
• Diagnosed with type 2 diabetes mellitus 180 days or more before screening.
• HbA1c of 7.0 10.0% (53.0 85.8 mmol/mol) (both inclusive) as assessed by central laboratory on the day of screening.
• Treated with once daily or twice daily basal insulin (neutral protamine hagedorn insulin, insulin degludec, insulin detemir, insulin glargine 100 units/mL, or insulin glargine 300 units/mL) 20- 80 units/day for 90 days or more before screening. Short term bolus insulin treatment for a maximum of 14 days before screening is allowed, as is prior insulin treatment for gestational diabetes. The treatment can be with or without any of the following anti diabetic drugs with stable doses for 90 days or more before screening:
• Sulfonylureas (a)
• Meglitinides (glinides) (a)
• DPP 4 inhibitors (a)
• Sodium glucose co transporter 2 inhibitors
• Alpha glucosidase inhibitors
• Marketed oral combination products only including the products listed above.
• Body mass index (BMI) below or equal to 40.0 kg/m^2. (a) Sulfonylureas, meglitinides (glinides) and DPP 4 inhibitors must be discontinued at randomisation. Key exclusion criteria
• Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing potential and not using a highly effective contraceptive method.
• Anticipated initiation or change in concomitant medication (for more than 14 consecutive days) known to affect weight or glucose metabolism (e.g. treatment with orlistat, thyroid hormones, or systemic corticosteroids).
• Treatment with any medication for the indication of diabetes or obesity other than stated in the inclusion criteria within 90 days before screening.
• Any episodes (as declared by the participant or in the medical records.) of diabetic ketoacidosis within 90 days before screening.
• Presence or history of pancreatitis (acute or chronic) within 180 days before screening.
• Any of the following: Myocardial infarction, stroke, hospitalization for unstable angina pectoris or transient ischaemic attack within 180 days before screening.
• Chronic heart failure classified as being in New York Heart Association Class IV at screening.
• Recurrent severe hypoglycaemic episodes within the last year (12 months) as judged by the investigator.
• Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus examination performed within the past 90 days before screening or in the period between screening and randomisation. Pharmacological pupil dilation is a requirement unless using a digital fundus photography camera specified for non-dilated examination.
Efficacy and Safety of Inhaled Isoflurane Delivered Via the Sedaconda ACD-S Compared to Intravenous Propofol for Sedation of Mechanically Ventilated Intensive Care Unit Adult Patients (INSPiRE-ICU1) (INSPiRE-ICU1)
This is a study to compare safety and efficacy of inhaled isoflurane administered via the Sedaconda ACD-S device system versus intravenous propofol for sedation of mechanically ventilated patients in the Intensive Care Unit (ICU) setting.
• Adults ≥18 years of age;
• Patients who are anticipated to require >12 hours of invasive mechanical ventilation and continuous sedation in the ICU; and
• Receipt of continuous sedation due to clinical need for sedation to RASS <0.
• Need for RASS -5;
• Sedation for invasive mechanical ventilation immediately prior to Baseline for >72 hours;
• Severe neurological condition before ICU admission that causes the patient to lack ability to participate in the study (ie, unable to be assessed for RASS and CPOT);
• Ventilator tidal volume <200 or >1000 mL at Baseline;
• Need for extracorporeal membrane oxygenation (ECMO), extracorporeal CO2 removal (ECCO2R), high frequency oscillation ventilation (HFOV), or high frequency percussive ventilation (HFPV) at Screening;
• Comfort care only (end of life care);
• Contraindication to propofol or isoflurane;
• Known or family history of MH;
• Severe hemodynamic compromise, defined as the need for norepinephrine ≥0.3 mcg/kg/min (or equivalent vasopressor dose) to maintain blood pressure within acceptable range, assumed to be mean arterial pressure ≥65 mmHg unless prescribed clinically;
• Allergy to isoflurane or propofol, or have propofol infusion syndrome.
• History of ventricular tachycardia/Long QT Syndrome;
• Requirement of IV benzodiazepine or barbiturate administration for seizures or dependencies, including alcohol withdrawal
• Neuromuscular disease that impairs spontaneous ventilation (eg, C5 or higher spinal cord injury, amyotrophic lateral sclerosis, etc);
• Concurrent enrollment in another study that, in the Investigator's opinion, would impact the patient's safety or assessments of this study;
• Participation in other study involving investigational drug(s) or devices(s) within 30 days prior to Randomization;
• Anticipated requirement of treatment with continuous infusion of a neuromuscular blocking agent for >4 hours;
• Female patients who are pregnant or breast-feeding;
• Imperative need for continuous active humidification through mechanical ventilation circuit;
• Attending physician's refusal to include the patient; or
• Inability to obtain informed consent.
A Study of HMBD-002, a Monoclonal Antibody Targeting VISTA, as Monotherapy and Combined With Pembrolizumab
This is a phase 1/2, open-label, multi-center, first-in-human, two-stage (Part 1: dose escalation and Part 2: dose expansion) study evaluating multiple doses and schedules of intravenously (IV) administered HMBD-002, with or without pembrolizumab, in patients with advanced solid tumors (i.e., locally advanced and unresectable, or metastatic).
• Histologic or cytologic evidence of a malignant solid cancer (any histology) with advanced or metastatic disease and no available therapies known to confer clinical benefit.
• Tumor tissue, or paraffin block, ideally from the patient's most recent biopsy. A fresh tumor biopsy will be obtained if archival samples are not available.
• Measurable by Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.
• At least 18 years old.
• An Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1.
• Adequate hematopoietic, kidney, and liver functions.
• A left ventricular ejection fraction (LVEF) ≥ 45%.
• Women of childbearing potential (WOCBP) must not be pregnant or breastfeeding. A WOCBP must agree to follow contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment.
• Male subjects must agree to follow contraceptive guidance during the study period and for at least 120 days after the last dose of study treatment.
• Patient must give informed written consent for the study. Inclusion Criteria for HMBD-002 Phase 2 Stage Triple Negative Breast Cancer (TNBC)
• Histologic or cytologic evidence of TNBC that is advanced or metastatic.
• Will be requested to undergo a tumor biopsy before treatment and after 6 weeks of treatment.
• Must have received appropriate treatment with at least one prior regimen for TNBC and there are no available therapies known to confer clinical benefit. Non-Small Cell Lung Cancer (Monotherapy and Combination)
• Histologic or cytologic evidence of NSCLC that is advanced or metastatic.
• Will be requested to undergo a tumor biopsy before treatment and after 6 weeks of treatment.
• Absence of an activating mutation of the EGFR or ALK.
• Must have received treatment with an approved therapy if there are other genomic aberrations for which targeted therapies are approved and available.
• Must have had disease progression on at least one approved or comparable standard therapy for NSCLC.
• Must have received appropriate prior treatment with a mAb to PD-1 or PD-L1. Multiple Other Cancers (Combination Therapy Baskets)
• Histologic or cytologic evidence of an advanced or metastatic cancer aside from TNBC and NSCLC with no available therapies known to confer clinical benefit.
• Will be requested to undergo a tumor biopsy before treatment and after 6 weeks of treatment.
• Must have had appropriate treatment for their specific cancer and there is an absence of available therapy with a reasonable likelihood of conferring clinical benefit. Exclusion Criteria
• If the patient received prior therapy with an anti-PD-1 or anti-PD-L1 mAb or with an agent targeting stimulatory or co-inhibitory T-cell receptor and was discontinued from that treatment due to a Grade 3 or higher immune related adverse event.
• Received radiotherapy within 2 weeks of treatment.
• Received radiotherapy exceeding 30 Gray (Gy) to the lung within 6 months of the first dose of study medication.
• Received an allogeneic tissue/solid organ transplant.
• Received a live or live-attenuated vaccine within 30 days prior to the first dose of study medication.
• Received a VISTA targeting agent.
• The patient must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline.
• The patient has an active autoimmune disease that required systemic treatment in the past.
• Presence of an uncontrolled endocrine disorder.
• Presence of clinically significant cardiovascular disease.
• History of (non-infectious) pneumonitis or interstitial pulmonary disease that required steroids or has current pneumonitis or interstitial pulmonary disease.
• Presence of uncontrolled, clinically significant pulmonary disease.
• A previous a severe hypersensitivity reaction (≥ Grade 3) to pembrolizumab and/or any of its excipients.
• A diagnosis of immunodeficiency or is receiving chronic systemic corticosteroids at a dose that exceeds 10 mg daily of prednisone equivalent or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug. Inhaled or topical steroids are permitted in the absence of active autoimmune disease.
• An uncontrolled intercurrent illness that would limit compliance with the study.
• A positive status for human immunodeficiency virus (HIV).
• A known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C viral (defined as HCV RNA detected) infection.
• A medical condition which, in the opinion of the Investigator, places the patient at an unacceptably high risk for toxicity.
• A positive COVID test within one week of study treatment if not fully vaccinated.
• Another active malignancy that is progressing or has required active treatment within the past 3 years.
• Known active central nervous system metastases and/or carcinomatous meningitis.
Study to Evaluate the Efficacy & Safety of the INTERCEPT Blood System for RBCs in Complex Cardiac Surgery Patients (ReCePI)
The objective of this study is to evaluate the efficacy and safety of RBC transfusion for support of acute anemia in cardiovascular surgery patients based on the clinical outcome of renal impairment following transfusion of red blood cells (RBCs) treated with the INTERCEPT Blood System (IBS) for Red Blood Cells compared to patients transfused with conventional RBCs.
• Age ≥ 11 years of age
• Weight ≥ 40 kg
• Scheduled complex cardiac surgery or thoracic aorta surgery. The procedure may be performed either on or off cardiopulmonary bypass machine (CBP or "pump"). For the purposes of this protocol "Repeat procedure" means that the subject had a previous cardiac surgery. Procedures that qualify as complex cardiac surgery include but are not limited to, the following:
• Single Vessel Coronary Artery Bypass Graft, first or repeat procedure
• Multiple Coronary Artery Bypass Grafts, first or repeat procedure
• Single Valve Repair or Replacement, first or repeat procedure
• Multiple Valve Repair or Replacement, first or repeat procedure
• Surgery involving both Coronary Artery Bypass Graft(s) and Valve Repair(s), first or repeat procedure
• One or more of the following procedures, with or without Coronary Bypass Graft(s):
• left ventricular aneurysm repair
• ventricular and/or atrial septal defect repairs
• Batista procedure (surgical ventricular remodeling)
• surgical ventricular restoration
• congenital cardiac defect repair
• aortic procedures
• other cardiac surgery or thoracic aorta surgery types with a high probability of bleeding
• TRUST probability score (Alghamdi, Davis et al. 2006) ≥ 3, or currently on a regimen of aspirin (any dose), clopidogrel (or analogs) and/or GPIIb/IIIa inhibitors or at a high probability for need of a transfusion during or after surgery at the discretion of the Investigator
• Female subjects of child-bearing potential must meet the 2 criteria below at screening:
• Negative serum or urine pregnancy test
• Use at least one method of birth control that results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomized partner
• Signed and dated informed consent/assent form
• Confirmed positive baseline serum/plasma antibody specific to INTERCEPT RBCs (S-303 specific antibody) screening panel prior to randomization.
• Pregnant or breast feeding
• Refusal of blood products or other inability to comply with the protocol in the opinion of the Investigator or the treating physician
• Treatment with any medication that is known to adversely affect RBC viability, such as, but not limited to dapsone, levodopa, methyldopa, nitrofurantoin, and its derivatives, phenazopyridine and quinidine.
• Planned cardiac transplantation
• Active autoimmune hemolytic anemia
• Left ventricular assist device (LVAD) or extracorporeal membrane oxygenation (ECMO) support pre operatively or planned need post-operatively
• Cardiogenic shock requiring pre-operative placement of an intra-aortic balloon pump (IABP) (NOTE: IABP done for unstable angina or prophylactically for low ejection fraction is not excluded).
• Planned use of autologous or directed donations.
• RBC transfusion during current hospitalization prior to enrollment and randomization (within 7 days).
• Participation in an interventional clinical study concurrently or within the previous 28 days. This includes investigational blood products, pharmacologic agents, imaging materials (including dyes), surgical techniques, or devices. Observational studies of FDA cleared or approved products or nutrition, psychology, or socioeconomic issues are not grounds for exclusion
• Patients with a current diagnosis of either chronic kidney disease or acute kidney injury and with sCr ≥1.8 mg/dL at screening and patients requiring RRT. (NOTE: If sCr at screening is <1.8 mg/dL, a patient with a diagnosis of chronic or acute kidney injury alone is not excluded).
• Patients with a current diagnosis of either chronic or acute hepatic insufficiency and with a total serum bilirubin ≥ 2.0 mg/dL (≥34.2 µmol/L). (NOTE: If total serum bilirubin at screening is <2.0 mg/dL, a patient with a diagnosis of chronic or acute hepatic failure alone is not excluded).
• Pre-existing antibody(ies) to RBC antigens that may make the provision of compatible study RBC components difficult.
• History of TRs requiring washed RBCs, volume reduced RBC, or RBCs with additive solution removed.
• Patients with documented IgA deficiency or a history of severe allergic reactions to blood products.
• Patients who require gamma-irradiated RBC blood components.
• Positive DAT as defined below: A polyspecific DAT reaction strength > 2+, or A polyspecific DAT (any strength) in conjunction with pan-reactivity with a commercial IAT antibody screening panel that precludes the identification of underlying alloantibodies or indicates the presence of autoantibody
Groningen International Study on Sentinel Nodes in Vulvar Cancer-III (GROINSS-VIII)
Vulvar cancer patients with SN-metastasis > 2mm will receive chemoradiation instead of an inguinofemoral lymphadenectomy.
• Histological confirmed primary SCC of the vulva
• T1 tumor, not encroaching urethra/vagina/anus
• Depth of invasion > 1mm
• Tumor diameter < 4cm
• Unifocal tumor
• No enlarged (>1.5cm) or suspicious inguinofemoral lymph nodes at imaging (CT/MRI/ultrasound)
• Possibility to obtain informed consent
• Metastatic sentinel lymph node; size of metastasis > 2mm and / or extracapsular extension, or
• Metastatic sentinel lymph node: more than 1 SN with metastasis ≤ 2mm
• Patients are able to understand requirements of study, provide written informed consent and comply with the study and follow-up procedures
• Adequate bone marrow, renal and liver function:
• Absolute neutrophil count ≥ 1.5 x 109 /L
• Platelet count ≥ 100 x 109 /L
• Creatinine clearance ≥ 40 ml/min measured by the Cockroft Gault formula
• Total bilirubin < 1.25 x ULN Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN
• Performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG) Scale (Appendix A)
• Age 18 years or older
• Life expectancy of ≥ 12 weeks
• Written informed consent
• Inoperable tumors and tumors > 4cm
• Multifocal tumors
• Tumors with other pathology than squamous cell carcinoma
• Patients with enlarged / suspicious lymph nodes which are proven metastatic after fine needle aspiration cytology
• No other carcinomas, other than basal cell carcinomas, within last 5 years
• History of pelvic radiotherapy
• History of any infection requiring hospitalization or antibiotics within 2 weeks before enrollment
• Pregnant female or nursing mother
• Desire to become pregnant
• Known brain or spinal cord metastases unless adequately treated (surgery or radiotherapy) with no evidence of progression and neurologically stable off anticonvulsants and steroids
• Unstable angina, myocardial infarction, cerebrovascular accident, > Class II congestive heart failure according to the New York Heart Association Classification for Congestive Heart Failure (see Appendix B) within 6 months before enrollment
Study to Assess the Effect of Ofatumumab in Treatment Naïve, Very Early RRMS Patients Benchmarked Against Healthy Controls. (AGNOS)
This study will evaluate the impact of ofatumumab in Relapsing Remitting Multiple Sclerosis (RRMS) participants that are very early in the course of their disease using clinical and magnetic resonance imaging (MRI) outcomes. The study will also assess changes in disease using monitoring techniques including digital biometric device use, biomarker analysis and non-conventional MRI. Select outcomes in the ofatumumab treated group will be compared to a group of Healthy participants to determine if there are similarities between the groups after the patients with MS undergo treatment with ofatumumab.
• Signed informed consent must be obtained prior to participation in the study
• Age 18-35 years Patients in the healthy control arm eligible for inclusion must fulfill the following criteria:
• Able to obtain MRI (HC with abnormal MRI at Screening will be excluded) and use wearable device
• Able to provide blood sample (no CSF will be collected in HC) Patients in the ofatumumab-treated arm eligible for inclusion must fulfill the following criteria:
• Diagnosis of RRMS per McDonald Criteria (2010/2017)
• Within 6 months of diagnosis of clinically definite MS (CDMS)
• EDSS 0-3.0 (Inclusive)
• Treatment-naïve to MS DMT
• Able to obtain MRI and attend study visits at sites
• Able to use wearable device
• Able to provide blood sample (and CSF for sub-group n=15) Key
• Confounding medical condition as determined by the investigator RRMS patients fulfilling any of the following exclusion criteria are not eligible for inclusion in this study:
• Diseases other than multiple sclerosis responsible for the clinical or MRI presentation
• Patients with neuromyelitis optica, Radiologic/ Clinically Isolated Syndrome, Secondary Progressive or Primary Progressive MS diagnosis
• Use of experimental or investigational drugs for MS
• Previous use of Disease Modifying Therapy (DMT) or chemotherapeutic medications for MS
• Relapse between screening and Baseline visits
• Known sensitivity to gadolinium; patients with chronic, severe kidney disease
• Known history of hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes
• CNS anomalies that are better accounted for by another disease process or MRI anomalies causing clinically apparent impairments
• Known active malignancies
• Pregnant or nursing (lactating) women
• Females of childbearing potential (all women physiologically capable of becoming pregnant) should use effective contraception while receiving ofatumumab and for 6 months after the last treatment of ofatumumab
• Patients with an active chronic disease (or stable but treated with immune therapy) of the immune system other than MS or with immunodeficiency syndrome
• Patients with active infections including systemic bacterial, viral (including SARS-CoV-2/COVID-19) or fungal infections, or known to have AIDS or to test positive for HIV antibody at Screening
• Patients with neurological findings consistent with Progressive Multifocal Leukoencephalopathy (PML), or confirmed PML
• Patients with IgG or IgM levels below LLN at Screening
• Patients that have received any live or live-attenuated vaccines within 4 weeks prior to first dose of study drug administration
• Patients at risk of developing or having reactivation of hepatitis
Radiofrequency Ablation and Steroid Versus Steroid Alone for Relief of Pain in Patients With Advanced Knee and Hip Osteoarthritis
The purpose of this trial is to determine if radiofrequency ablation plus steroid perineural injections at the knee or hip provide longer pain relief and better function to patients than the current standard of care, perineural steroid injections alone. This pilot study is a prospective two arm randomized trail, all participants will be recruited from the University of Texas Southwestern Medical Center (UTSW) outpatient orthopedic clinic. 40 participants (20 hip and 20 knee OA) will be enrolled into the standard of care arm (treated with steroid injections alone) and 40 participants (20 hip and 20 knee OA) will be enrolled into the investigational arm (treatment with a combination of radiofrequency ablation (RFA) plus steroid injections) for a total of 80 enrolled participants. All subjects will complete a function and pain assessment at the time of injection and three additional time points: 2 weeks, 3 months, and 6 months post injection. This study will use the same knee function questionnaire and frequency currently used in clinic per standard of care. In addition, all participant's surgical history and prior injection history will be reviewed via the Electronic Medical Record (EMR).
• Males or females age 18 to 100 years
• Osteoarthritis of the knee Kellgren-Lawrence grade 3-4 OR
• Osteoarthritis of the hip Tonnis grades 2 or higher
• History of knee or hip replacement
• History of intra-articular steroid injections within the past 6 weeks
• Active infection
Prospective Treatment Efficacy in IPF Using Genotype for Nac Selection (PRECISIONS) Trial (PRECISIONS)
The purpose of this study is to compare the effect of n-acetylcysteine (NAC) plus standard care with matched placebo plus standard of care in patients diagnosed with idiopathic pulmonary fibrosis (IPF) who have the TOLLIP rs3750920 TT genotype. The study will compare the time to a composite endpoint of relative decline in lung function [10% relative decline in forced vital capacity (FVC), first respiratory hospitalization, lung transplantation, or all-cause mortality] The secondary objectives will be to examine the effect of NAC on the components of the primary composite endpoint, the rates of clinical events, change in physiology, change in health status, and change in respiratory symptoms.
• ≥ 40 years of age
• Diagnosed with IPF according to 2018 ATS/ERS/JRS/ALAT, confirmed by enrolling investigator
• Signed informed consent
• If taking pirfenidone or nintedanib, must be on stable dose for at least 6 weeks prior to enrollment visit
• Confirmed rs3570920 TT TOLLIP genotype
• Pregnancy or planning to become pregnant
• Women of childbearing potential not willing to remain abstinent (refrain from heterosexual intercourse) or use two adequate methods of contraception, including at least one method with a failure rate of <1% per year during study participation
• Significant medical, surgical or psychiatric illness that in the opinion of the investigator would affect subject safety, including liver and renal failure
• Receipt of an investigational drug or biological agent within the previous 4 weeks of the screening visit or 5 times the half-life, if longer
• Supplemental or prescribed NAC therapy within 60 days of enrollment
• Listed for lung transplantation at the time of screening
• History of lung cancer
• Inability to perform spirometry
• Forced vital capacity (FVC) less than 45% predicted, using the global lung function index (GLI) equation at Visit 1
• Active respiratory infection requiring treatment with antibiotics within 4 weeks of Visit 1
Study to Assess the Efficacy and Safety of Adjunctive NBI-1065845 in Adults With Major Depressive Disorder (MDD) (SAVITRI)
The purpose of this study is to evaluate the efficacy of NBI-1065845 compared with placebo used in addition to oral antidepressants in adults with MDD on improving symptoms of depression.
• The subject has completed written informed consent.
• At the time of signing the informed consent, subject must be 18 to 65 years of age, inclusive.
• The subject has a primary diagnosis of Major Depressive Disorder (MDD), without psychotic features, meeting the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria.
• Subject must have had inadequate response to antidepressant treatment.
• Subject is currently on stable pharmacological treatment for depression.
• Subject must have a total Hamilton Depression Rating Scale-17 Item (HAMD17) score ≥ 22 at screening.
• Subjects must have been taking current antidepressant medication(s) for ≥ 8 weeks.
• Subjects must be willing to comply with all study procedures and restrictions.
• Subject is pregnant or breastfeeding.
• Subject has an unstable medical condition or chronic disease.
• Subject has a history of neurological abnormalities.
• Subject is currently diagnosed with or prior diagnoses of psychiatric disorder which was the primary focus of treatment other than MDD.
• The subject's depressive symptoms have previously demonstrated nonresponse to an adequate course of treatment with electroconvulsive therapy (ECT).
• The subject has an alcohol or substance use disorder.
• In the Investigator's opinion, the subject is not capable of adhering to the protocol requirements.
A Study to Assess the Efficacy, Safety, and Tolerability of Oral LPCN 1148 in Male Subjects With Cirrhosis of the Liver and Sarcopenia
This is a randomized, double-blind, placebo-controlled study to assess the efficacy, safety, and tolerability of LPCN 1148 in men with cirrhosis of the liver and sarcopenia.
• Male ≥ 18 years old
• Currently listed, on the liver transplant waitlist for cirrhosis secondary to Hepatitis B or C infection, Alcoholic Liver Disease (ALD), or Non-Alcoholic Steatohepatitis (NASH)
• Evidence of sarcopenia with appropriate cutoff recommended by clinical guidance
• Suspected or proven hepatocellular carcinoma (HCC)
• History of current or suspected prostate or breast cancer
• History of malignancies other than prostate, breast, or HCC, unless successfully treated with curative intent and believed to be cured (defined as complete remission lasting at least 5 years)
• History of uncontrolled or recurrent portal hypertensive bleeding, including uncontrolled or recurrent bleeding from varices, gastropathy, colopathy, or hemorrhoidal bleeding.
• History or current thrombosis (including portal vein thrombosis), thromboembolism, or treatment for portal vein thrombosis
• History of hemochromatosis
• History of hypercoagulable state (e.g. Factor V Leiden deficiency, protein C deficiency, protein S deficiency, anti-thrombin III deficiency, or the presence of lupus anticoagulant)
• Prior history of complications of ascites including:
• Spontaneous bacterial peritonitis
• Hepatic hydrothorax
• MELD score > 25
• Abnormal lab value in serum chemistry, hematology, or urinalysis that the PI considers clinically significant, including but not limited to:
• PSA > 4 ng/mL
• Polycythemia (Hematocrit >54%) or history of polycythemia
• ALT or AST > 5x ULN
• ALP > 1.5x ULN
• Platelet count < 30,000/mL
• EGFR < 60 mL/min/1.73 m2
• Total bilirubin > 3.0 mg/dL
• Serum albumin < 2.8 g/dL
• INR > 2.3 or PT prolongation > 6.0 seconds
• Subjects with PSA between 2.5 ng/mL and 4 ng/mL are excluded only if any of the below criteria are met at baseline:
• Hematocrit > 48%
• I-PSS > 19
• Any irregularity found on digital rectal examination of the prostate
• Subjects with PSA > 3 ng/mL are excluded only if any of the below criteria are met at baseline:
• Subject is African American
• Subject has a first-degree relative who has a history of prostate cancer
• Hematocrit > 48%
• I-PSS > 19
• Any irregularity found on digital rectal examination of the prostate
• Clinically significant abnormal prostate digital rectal examination (DRE) in the opinion of the PI, with DRE screening initiated at International Prostate Symptom Score (I-PSS) > 19
• History of bariatric surgery
• History of stroke or myocardial infarction within the past 5 years
• Known positivity for Human Immunodeficiency Virus (HIV) infection
• Acute liver failure as the indication for addition to the liver transplant waitlist
• Estimated life expectancy less than 3 months or expected to undergo liver transplant within 3 months
• Known heart failure of New York Heart Association class III or IV
• Evidence of severe encephalopathy or encephalopathy that is not controlled despite adequate medical therapy
• History of prior organ transplant
• History of Fontan physiology
• History of pulmonary embolus
• Porto-pulmonary hypertension
• Hepatopulmonary syndrome
• Uncontrolled epilepsy or migraine
• Active substance abuse or dependency extending to within the previous 6 months
• History of significant sensitivity or allergy to testosterone, or product excipients.
• Use of known strong inhibitors (e.g., ketoconazole) or inducers (e.g., dexamethasone, phenytoin, rifampin, carbamazepine) of cytochrome P450 3A (CYP3A) within 30 days prior to study drug administration and through the end of the study
• Subjects who are currently receiving any androgens (testosterone or other androgens or androgen-containing supplements) and are unwilling to washout prior to screening a. Washout: 12 weeks following long-acting intramuscular androgen injections; 4 weeks following topical or buccal androgens; 3 weeks following oral androgens
• Uncontrolled hypertension (>160/90 mmHg despite treatment)
• Uncontrolled obstructive sleep apnea
• Use of any investigational drug within 5 half-lives of the last dose or in the past 6 months prior to Study Day -2 without medical monitor and/or Sponsor approval
• Subject who is not willing to use adequate contraception for the duration of the study
• Any other condition, which in the opinion of the investigator would impede compliance to the study protocol (including diet, exercise, and alcohol abstinence) or hinder completion of the study
• Failure to give informed consent
A Study to Evaluate the Safety and Efficacy of JCAR017 in Pediatric Subjects With Relapsed/Refractory (r/r) B-cell Acute Lymphoblastic Leukemia (B-ALL) and B-cell Non-Hodgkin Lymphoma (B-NHL)
This is a Phase 1/2, open-label, single arm, multicohort study to evaluate the safety and efficacy of JCAR017 in pediatric subjects aged ≤ 25 years with CD19+ r/r B-ALL and B-NHL. Phase 1 will identify a recommended Phase 2 dose (RP2D). Phase 2 will evaluate the efficacy of JCAR017 RP2D in the following three disease cohorts: Cohort 1 (r/r B-ALL), Cohort 2 (MRD+ B-ALL) and Cohort 3 (r/r B-NHL, [DLBCL, BL, or PMBCL]). A Simon's Optimal two-stage study design will be applied to Cohort 1 and 2 in Phase 2.
• Phase 1: Subject < 18 years of age and weighs ≥ 6 kg at the time of signing the informed consent form (ICF)/informed assent form (IAF). Phase 2: Subject ≤ 25 years of age and weighs ≥ 6 kg at the time of signing the ICF/IAF.
• Subject (when applicable, parental/legal representative) must understand and voluntarily provide permission to the ICF/IAF prior to conducting any study-related assessments/procedures.
• Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
• Investigator considers the subject is appropriate for adoptive T cell therapy.
• Evidence of CD19 expression via flow cytometry (peripheral blood or bone marrow) or immunohistochemistry (bone marrow biopsy)
• Subject has a Karnofsky score of ≥ 50 (subjects ≥ 16 years of age) or a Lansky score ≥ 50 (subjects < 16 years of age).
• Diagnosis of B-cell ALL or B-cell NHL as defined below: Phase 1: Subjects with r/r B-ALL, defined as morphological evidence of disease in BM (5% or greater lymphoblast by morphology) and either of the following:
• First or greater marrow relapse, or
• Any marrow relapse after allogeneic HSCT, or
• Primary refractory defined as not achieving a CR or a CRi after 2 or more separate induction regimens (or chemo-refractory as not achieving CR/CRi after 1 cycle of standard chemotherapy for relapsed leukemia), or
• Ineligible for allogeneic HSCT Note: Subjects will be included regardless of MRD status. Phase 2: Subjects with one of the following:
• Cohort 1: r/r B-ALL, defined as morphological evidence of disease in BM (5% or greater lymphoblast by morphology) and either:
• First or greater marrow relapse, or
• Any marrow relapse after allogeneic HSCT, or
• Primary refractory defined as not achieving a CR or a CRi after 2 or more separate induction regimens (or chemo-refractory as not achieving CR/CRi after 1 cycle of standard chemotherapy for relapsed leukemia), or
• Ineligible for allogeneic HSCT.
• Cohort 2: MRD+ B-ALL, defined as:
• < 5% lymphoblasts by morphology with,
• MRD detected by a validated assay at a frequency of 1 x10-4 or greater in BM cells. Subjects eligible for enrollment in Cohort 2 are those with MRD positive morphologic CR2 after re-induction when these subjects had previously experienced an early relapse (< 36 months) after first-line chemotherapy. Subjects who are in MRD+ morphologic CR3 and later, regardless of time to relapse in earlier lines, are also eligible. Subjects who are in morphologic relapse at screening (r/r B-ALL) and become MRD+ after bridging chemotherapy are also eligible for treatment in Cohort 2.
• Cohort 3: r/r B-NHL (DLBCL, BL or PMBCL), defined as measurable disease after 1 or more lines of chemotherapy and/or having failed HSCT or being ineligible for HSCT. Note: B-NHL subjects with secondary CNS lymphoma involvement are eligible however subject selection must consider clinical risk factors for severe neurological AEs and alternative treatment options. Subjects should only be enrolled if the Investigator considers the potential benefit outweighs the risk for the subject.
• Subjects with Philadelphia chromosome positive ALL are eligible if they are intolerant to or have failed one or more lines of tyrosine-kinase inhibitor (TKI) therapy or if TKI therapy is contraindicated.
• Adequate organ function, defined as:
• Adequate BM function to receive LD chemotherapy as assessed by the Investigator.
• Subject with adequate renal function, which is defined as: Serum creatinine based on age/gender as described below. Subjects that do not meet the criteria but who have a creatinine clearance or radioisotope glomerular filtration rate (GFR) > 70 mL/min/1.73 m2 are eligible.• Alanine aminotransferase (ALT) ≤ 5 x upper limit of normal (ULN) and total bilirubin < 2.0 mg/dL (or < 3.0 mg/dL for subjects with Gilbert's syndrome or leukemic/lymphomatous infiltration of the liver).
• Adequate pulmonary function, defined as ≤ Grade 1 dyspnea according to Common Toxicity Criteria for Adverse Events (CTCAE) and oxygen saturation (SaO2) ≥ 92% on room air.
• Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) ≥ 40% as assessed by echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) within 4 weeks prior to leukapheresis.
• Adequate vascular access for leukapheresis procedure.
• Participants must agree to use effective contraception
• Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
• Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
• Subject has any condition that confounds the ability to interpret data from the study.
• Subject with a history of another primary malignancy that has not been in remission for at least 2 years prior to enrollment.
• Subjects who have received previous CD19-targeted therapy must have CD19-positive disease confirmed since completing the prior CD19-targeted therapy.
• Prior CAR T cell or other genetically-modified T cell therapy.
• Subject with a previous history of or active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection.
• Subjects with uncontrolled systemic fungal, bacterial, viral or other infection (including tuberculosis) despite appropriate antibiotics or other treatment at the time of leukapheresis or JCAR017 infusion.
• Subject has presence of acute or chronic graft-versus-host disease (GVHD).
• Subject with active autoimmune disease requiring immunosuppressive therapy.
• Subject has cardiac disorders (CTCAE version 4.03 Grade 3 or 4) within the past 6 months.
• Subject with a concomitant genetic syndrome, with the exception of Down's syndrome.
• Subject with active CNS disease and significant neurological deterioration. Subjects with CNS-2 or CNS-3 involvement are eligible provided they are asymptomatic and do not have significant neurological deterioration and, in the opinion of the study investigator, the CNS disease burden can be controlled until JCAR017 infusion.
• Subject with a history or presence of clinically relevant CNS pathology such as epilepsy, seizure, paresis, aphasia, stroke, cerebral edema, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis.
• Subject is pregnant or nursing.
• Subject has used the following:
• Therapeutic doses of corticosteroids (defined as > 0.4 mg/kg maximum 20 mg/day prednisone or equivalent) within 7 days prior to leukapheresis or 72 hours prior to JCAR017 infusion. Physiologic replacement, topical, and inhaled steroids are permitted.
• Low-dose chemotherapy (eg, vincristine, rituximab, cyclophosphamide ≤ 300 mg/m2) given after leukapheresis to maintain disease control must be stopped ≥ 7 days prior to LD chemotherapy.
• Cytotoxic chemotherapeutic agents that are not considered lymphotoxic within 1 week prior to leukapheresis. Oral anticancer agents are allowed if at least 3 half-lives have elapsed prior to leukapheresis.
• Lymphotoxic chemotherapeutic agents (eg, cyclophosphamide, ifosfamide, bendamustine) within 2 weeks prior to leukapheresis.
• Experimental agents within 4 weeks prior to leukapheresis unless no response or PD is documented on the experimental therapy and at least 3 half-lives have elapsed prior to leukapheresis.
• Immunosuppressive therapies within 4 weeks prior to leukapheresis and JCAR017 infusion (eg, calcineurin inhibitors, methotrexate or other chemotherapeutics, mycophenolate, rapamycin, thalidomide, immunosuppressive antibodies such as antitumor necrosis factor [TNF], anti-IL-6, or anti-IL-6R).
• Donor lymphocyte infusions (DLI) within 6 weeks prior to JCAR017 infusion.
• Radiation within 6 weeks prior to leukapheresis. Subjects must have PD in irradiated lesions or have additional non-irradiated lesions to be eligible. Radiation to a single lesion, if additional non-irradiated, measurable lesions are present, is allowed up to 2 weeks prior to leukapheresis.
• Allogeneic HSCT within 90 days prior to leukapheresis.
• Tumor invasion of venous or arterial vessels (B-NHL subjects only).
• Deep Venous Thrombosis (DVT) or Pulmonary Embolism (PE) within 3 months prior to leukapheresis. Subjects with DVT or PE that occurred longer than 3 months prior to leukapheresis, who still require ongoing therapeutic levels of anti-coagulation therapy, are also excluded.
• Existence of CD19-negative clone(s) of leukemia cells
A Prospective, Multi-center, Randomized Controlled Blinded Trial Demonstrating the Safety and Effectiveness of VNS Therapy® System as Adjunctive Therapy Versus a No Stimulation Control in Subjects With Treatment-Resistant Depression (RECOVER)
Objectives of this study are to determine whether active VNS Therapy treatment is superior to a no stimulation control in producing a reduction in baseline depressive symptom severity, based on multiple depression scale assessment tools at 12 months from randomization.
A Study to Evaluate the Safety and Efficacy of CNTX-6970 in Subjects With Knee Osteoarthritis Pain.
The primary objective of this study is to evaluate the safety and efficacy of two doses of CNTX-6970 for the treatment of pain related to OA of the knee compared to placebo. CNTX-6970 is being developed as a new treatment for chronic pain, including painful osteoarthritis of the knee.
• Individuals between 40 and 90 years of age (inclusive) at the time of the Screening Visit.
• Willing to use a mobile smart device during the study period. Individuals who do not have access to a mobile device will be provided with one for the duration of the study and trained in its use.
• Can understand the nature of the study and protocol requirements and is willing to comply with study drug administration requirements and discontinue prohibited concomitant medications.
• Radiography of both knees with a posterior-anterior, fixed-flexion view taken during the Screening visit. The Index knee must show evidence of chronic OA with a K-L Grading Scale of 1, 2, 3, or 4. Such evidence will be provided by a central reading of the radiography of both knees from an expert radiologist of the CCC of EPPIC-Net.
• Moderate to severe pain in the Index knee associated with OA and stable for a minimum of 6 months prior to Screening in the opinion of the investigator.
• Confirmation of OA of the index knee: American College of Rheumatology (ACR) diagnostic criteria.
• Subjects must have failed 2 or more prior therapies. Failure is deemed to be inadequate relief in the opinion of the investigator.
• Body mass index (BMI) of ≤ 40 kg/m2.
• Willing to refrain from illicit drug use during the study, and to have illicit drug testing at screening and at later time points. A subject will be excluded from the study if they meet any of the following criteria:
• Any form of joint replacement surgery, open surgery, or arthroscopic surgery of the index knee/knee joint with 12 months of Screening.
• Any painful condition(s) of the index knee due to disease other than OA. For example, periarticular or referred pain involving the index knee, or from joint disease other than OA associated with the index knee.
• Other chronic pain anywhere in the lower extremities (e.g. hips, legs, feet) that is equal or greater in intensity or impairment than index knee pain or that requires the use of analgesic medications. This includes radicular low back pain with radiation to the knee.
• Documented history of neuropathic arthropathy in the knee.
• Significant instability (e.g., cruciate ligament tear or rupture or previous repair) within the past 5 years or current misalignment (>10 degrees varus or valgus) of the index knee.
• Plans to have surgery, invasive procedures, or intra-articular (IA) injections of the index knee or procedure or surgery otherwise contraindicated for study participation while in the study. a. Concomitant Medications for Pain - i. Continuous use of one of the following medications prescribed for pain: tramadol, gabapentin, duloxetine, pregabalin, milnacipran, or tricyclic antidepressants that is:
• chronic for at least 12 weeks; and
• at a stable dose for at least 4 weeks before Screening ii. Intermittent use of opioids that is:
• ongoing for at least 4 weeks before Screening;
• at a frequency no more than 4 days/week; and
• not be taken within 24 hours of a study visit iii. As needed use of acetaminophen b. Concomitant Medications for Non-Pain Indications That May Impact Pain - i. Continuous use of medication for non-pain indications that are known to potentially impact pain, e.g. duloxetine for depression, that is at a stable dose for at least 12 weeks prior to Screening.
• Corticosteroid injection in the index knee within 90 days of Screening or during study participation.
• Received IA viscosupplementation (e.g., Synvisc®, Hyalgan®) within 90 days of Screening or any time during study participation.
• History of clearly documented allergic reaction to celecoxib (Celebrex®), or to sulfa drugs.
• Use of an investigational medication within 30 days of Screening, or 5 pharmacokinetic or pharmacodynamic half-lives (whichever is longer) or scheduled to receive such an agent while participating in the current study.
• Current therapy with any immunosuppressive therapy, including corticosteroids (>5 mg/day of prednisone).
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:
• 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
• 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
A Research Study to Look Into How Well Semaglutide Medicine Works at Different Doses in People With Type 2 Diabetes and Overweight
This study compares how three doses of semaglutide work in participants with type 2 diabetes (T2D) and overweight who are taking metformin. The study will look mainly at how well participant's blood sugar and participant's body weight are controlled when they are taking the study medicine at different doses. Participants will either get semaglutide [2 milligrams (mg), 8 mg, or 16 mg] or semaglutide placebo (a dummy medicine). Participants will take the study medicine with an injection pen called NovoPen®4. The injection pen is a medical tool with a needle used to inject the study medicine under the skin. The study will last for about 52 weeks. Participants will have 13 clinic visits and 4 phone calls.
• Male or female.
• Aged 18-64 years (both inclusive) at the time of signing informed consent.
• Diagnosed with type 2 diabetes mellitus greater than equal to (≥) 180 days prior to the day of screening.
• Glycosylated haemoglobin (HbA1c) of 7.0 - 10.5 percentage (%) [53 - 91 millimoles per mole (mmol/mol)] (both inclusive).
• Body Mass Index (BMI) ≥ 27.0 kilograms per meter square (kg/m^2).
• Stable daily dose(s) ≥ 90 days prior to the day of screening of any metformin formulations.
• Treatment with any medication for the indication of diabetes or obesity other than stated in the inclusion criteria within 90 days before screening. However, short term insulin treatment for a maximum of 14 days prior to the day of screening is allowed, as is prior insulin treatment for gestational diabetes.
• Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus examination performed within the past 90 days prior to day of screening or in the period between screening and randomisation. Pharmacological pupil-dilation is a requirement unless using a digital fundus photography camera specified for non-dilated examination.
• Renal impairment measured as estimated glomerular filtration rate (eGFR) value of less than (<) 30 milliliters per minute (mL/min)/1.73 meter square (m^2) at screening.
Tofacitinib in Recurrent GBM Patients
The purpose of this study is to examine the effects of Tofacitinib in patients with recurrent Glioblastoma.
• 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.
• 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.
• Karnofsky Performance Status (KPS) ≥ 60%.
• Patients must be willing and able to provide written informed consent and to comply with the study protocol as judged by the investigator.
• Age ≥ 18 years.
• Patients must be able to swallow oral medications.
• 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.
• 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).
• Patients who have undergone recent surgery for recurrent or progressive tumor are eligible provided that:
• 1 Surgery must have confirmed the recurrence.
• 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.
• 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.
• 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:
• 1 Greater than or equal to 28 days elapsed from the administration of any investigational agent.
• 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.
• GBMs of the study patients must have EGFR gene amplification, which will be detected by next generation sequencing of tumor tissue from resected sample.
• Prior use of bevacizumab is allowed, however patient must be off of this medication for 180 days.
• 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
• Prior treatment with an EGFR or JAK inhibitor.
• Subjects may not be receiving any other investigational agents for the treatment of the cancer under study.
• Patients unable to undergo brain MRI scans with IV gadolinium contrast.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to Tofacitinib
• 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.
• Subjects must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.
• 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).
• 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.
• 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.
• Concurrent use of Bevacizumab.
Efficacy and Safety of QGE031 (Ligelizumab) in Patients With Peanut Allergy
This is a 52-week, Phase 3 multi-center, randomized, double-blind and placebo-controlled study to assess the safety and clinical efficacy of two dosing regimens of ligelizumab (240 mg and 120 mg) subcutaneous injection every 4 weeks (SCq4w) in participants with a medically confirmed diagnosis of IgE-mediated peanut allergy.
• Male or female participants who are ≥ 6 and ≤ 55 years of age at the time of signing informed consent/assent.
• Documented medical history of allergy to peanuts or peanut-containing foods.
• Positive peanut-specific immunoglobulin E (peanut sIgE), ≥ 0.35 kUA/L at Screening visit 1 (Screening 1).
• Positive skin prick test (SPT) for peanut allergen at Screening 1 defined as an average diameter (Longest diameter and mid-point orthogonal diameter) ≥ 4 mm wheal compared to saline control.
• A positive peanut DBPCFC at baseline (Screening Visit 2, Part 1 and Part 2 DBPCFC) defined as the occurrence of dose-limiting symptoms at a single dose ≤ 100 mg of peanut protein. Eligibility to proceed with the DBPCFC requires fulfillment of all other eligibility criteria.
• Participants must weigh ≥ 20 kg at Screening 1.
• Total IgE >2000 IU/mL at Screening 1.
• History of severe or life-threatening hypersensitivity event needing an ICU admission or intubation within 60 days prior to baseline DBPCFC (Screening visit 2).
• Participants with uncontrolled asthma (according to GINA guidelines, GINA 2020) who meet any of the following criteria:
• FEV1 <80% of subject's predicted normal value at Screening visit 1
• One hospitalization for asthma within 12 months prior to Screening visit 1 Other protocol-defined inclusion/exclusion criteria may apply.
Nemvaleukin Alfa (ALKS 4230) Monotherapy in Patients With Advanced Cutaneous Melanoma or Advanced Mucosal Melanoma - ARTISTRY-6 (ARTISTRY-6)
This study observes the antitumor activity, safety, tolerability, PK, and pharmacodynamics in patients with inoperable and/or metastatic melanoma following prior anti-PD-[L]-1 therapy
• The patient must have advanced cutaneous melanoma or acral melanoma; no more than 5 patients with acral melanoma may enroll in this cohort (Cohort 1). Or, the patient must have unresectable and/or metastatic mucosal melanoma (Cohort 2).
• The patient must have received previous treatment as follows:
• Patient has received anti-PD-[L]1 therapy with or without anti-CTLA-4 therapy, and no more than one other prior regimen of systemic anti-neoplastic therapy (eg, targeted therapy, chemotherapy). Previous adjuvant and/or neoadjuvant therapy counts as one prior regimen.
• Patients have experienced objective response (partial response [PR] or CR; by RECIST 1.1 or iRECIST) or stable disease (SD; by RECIST 1.1 or iRECIST) as best overall response (BOR) to anti-PD-[L]1 therapy. Patients with confirmed progressive disease (by RECIST 1.1 or iRECIST) as best response may be included, if they received anti-PD-[L]1 therapy for a minimum of 12 weeks (eg, 4 doses of pembrolizumab every 3 weeks).
• Patients with BRAF mutations may or may not have received prior targeted therapy.
• Patients must have disease that is measurable based on RECIST 1.1., that has not recently been irradiated or used to collect a biopsy.
• Patient is willing to undergo a pretreatment tumor biopsy or provide qualifying archival tumor tissue.
• Patient has an Eastern Cooperative Oncology Group (ECOG) status of 0 or 1 and an estimated life expectancy of ≥3 months.
• Additional criteria may apply.
• Patient has uveal melanoma.
• Patient has received prior IL-2-based or IL-15-based cytokine therapy; patient has had exposure, including intralesional, to IL-12 or analogs thereof.
• Patient requires systemic corticosteroids (>10 mg of prednisone daily, or equivalent) however, replacement doses, topical, ophthalmologic, and inhalational steroids are permitted.
• Patient has undergone prior solid organ and/or non-autologous hematopoietic stem cell or bone marrow transplant.
• Patient is currently pregnant, breastfeeding, or is planning to become pregnant or to begin breastfeeding during the study period or within 30 days after last study drug administration.
• Patients with active or symptomatic central nervous system metastases unless the metastases have been treated by surgery and/or radiation therapy and/or gamma knife, the subject has been tapered to a dose of 10 mg of prednisone (or equivalent) or less of corticosteroids for at least 2 weeks before the first dose, and the subject is neurologically stable. Patients with leptomeningeal disease are excluded.
• Patient has known or suspected hypersensitivity to any components of nemvaleukin.
• Patients with an uncontrollable bleeding disorder.
• Patient has QT interval corrected by the Fridericia Correction Formula values of >470 msec (in females) or >450 msec (in males); patient who is known to have congenital prolonged QT syndromes; or patient who is on medications known to cause prolonged QT interval on ECG.
• Patient has developed Grade ≥3 immune-related AEs (irAEs) while on prior immunotherapy, (eg, pneumonitis, nephritis, and neuropathy).
• Additional criteria may apply.
Late Onset Alzheimer's Disease (LOAD)
The goal of this study is to is to focus on the genetic influences on Alzheimer's Disease (AD) risk. The investigators are looking for families and/or individuals (affected or unaffected) of any ethic background (African American, Caucasian, and Hispanics) with a family history of AD and willing to participate.
• Established diagnosis of definite or probable AD or have a diagnosis of a related neurodegenerative disorder such as Frontotemporal Dementia (FTD) or Lewy Body Dementia (LBD) (will also recruit sporadic FTD and LBD) cases.
• a living sibling with probable or possible AD;
• a third living relative affected with AD (onset age 50 or older) or unaffected (60 or older);
• participants in the proband's generation with an identified companion serving as an informant;
• participants who have capacity to consent or participants lacking capacity to consent with a surrogate/proxy in place to provide consent.
• failure to identify an appropriate informant;
• uncertainty of the clinical diagnosis of Alzheimer's disease or other related disorder;
• discovery of additional diagnosis that could account for the clinical manifestations;
• unwillingness to participate;
• failure to identify a living sibling with AD or other related disorder (except in the cases of sporadic FTD and sporadic LBD);
• participants lacking the capacity to consent who do not have a surrogate or proxy or next of kin to provide consent.
Two-Part Study for Dose Determination of SRP-5051 (Vesleteplirsen) (Part A), Then Dose Expansion (Part B) in Participants With Duchenne Muscular Dystrophy Amenable to Exon 51-Skipping Treatment (MOMENTUM)
This study will be comprised of 2 parts: 1) Part A (Multiple Ascending Dose [MAD]) will be conducted to evaluate the safety and tolerability of SRP-5051 (vesleteplirsen) at MAD levels to determine doses to be administered in Part B, and 2) Part B will be conducted to further evaluate the SRP-5051 doses selected in Part A. Participants enrolling in Part B will be those who completed Part A or Study 5051-102 and meet applicable eligibility criteria for Part B, as well as additional participants who meet applicable eligibility criteria for enrollment at the beginning of Part B.
• Has received prior SRP-5051 treatment in Part A of this study or in Study 5051-102 Exclusion Criteria for participants previously treated with SRP-5051 and new participants enrolling into Part B:
• Presence of other clinically significant illness, including cardiac, pulmonary, hepatic, renal, hematologic, immunologic, or behavioral disease, or infection or malignancy or any other condition that, in the Investigator's opinion, could interfere with participation in the trial. Inclusion Criteria for treatment-naïve participants enrolling into Part B:
• Has a genetic diagnosis of Duchenne muscular dystrophy (DMD) and an out-of-frame deletion mutation of the DMD gene amenable to exon 51-skipping treatment.
• Has been on a stable dose of oral corticosteroids for at least 12 weeks prior to study drug administration and the dose is expected to remain constant throughout the study (except for modifications to accommodate changes in weight), or has not received corticosteroids for at least 12 weeks prior to study drug administration.
• Has stable pulmonary function (forced vital capacity [FVC] ≥40% of predicted and no requirement for nocturnal ventilation). Exclusion Criteria for treatment-naive participants enrolling into Part B:
• History of hypomagnesemia within 12 weeks prior to Screening.
• Initiation or change of dosing (except for modifications to accommodate changes in weight or changes in standard of care) within 12 weeks prior to Screening for any of the following: angiotensin-converting enzyme inhibitors, angiotensin receptor-blocking agents, β-blockers, or potassium.
• Initiation or change of dosing within 12 weeks prior to Screening for over-the-counter preparations, such as herbal/nonherbal supplements, vitamins, minerals, and homeopathic preparations.
• Has a left ventricular ejection fraction (LVEF) <40.0% based on an echocardiogram (ECHO) performed within 12 weeks prior to Screening or at the Screening Visit.
• Treatment with any exon 51-skipping therapy within 4 weeks prior to Screening, or with any experimental gene therapy for the treatment of DMD at any time. Other inclusion/exclusion criteria apply.
A Study to Assess the Efficacy and Safety of Namilumab in Participants With Chronic Pulmonary Sarcoidosis (RESOLVE-Lung)
This is a randomized, double-blind, placebo-controlled study with an open-label extension (OLE).
• 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.
Posoleucel (ALVR105) for the Treatment of Adenovirus Infection in Pediatric and Adult Participants Receiving Standard of Care Following Allogeneic Hematopoietic Cell Transplantation
This study will assess the safety and efficacy of Posoleucel for the treatment of adenovirus (AdV) infection in pediatric and adult allo-HCT recipients receiving standard of care (SoC).
• Male or female >1 year of age.
• Has undergone allogeneic cell transplantation ≥21 days prior to randomization and demonstrated engraftment with an absolute neutrophil count >500/mm^3, AND has one of the following:
• AdV viremia DNA ≥10,000 copies/mL at screening, OR
• Two consecutive and rising AdV viremia DNA results of ≥1,000 copies/mL at screening, AND
• has absolute lymphocyte count <180/mm3, OR
• has received T cell depletion.
• Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies and refrain from donating sperm or eggs for at least 90 days after treatment completion.
• Willing and able to provide signed informed consent.
• Has an HLA type matching with at least 1 suitably matched and available posoleucel VST line for infusion.
• Grade >2 acute GVHD
• Ongoing therapy with high-dose systemic corticosteroids
• Grade 4 diarrhea
• Uncontrolled viral (other than AdV), bacterial, or fungal infection(s)
• Requirement for fraction of inspired oxygen >0.5 to maintain arterial oxygen saturation >90% (via pulse oximetry) or need for mechanical ventilation.
• Prior therapy with anti-thymocyte globulin, alemtuzumab (Campath®), or other immunosuppressive T cell monoclonal antibodies within 28 days prior to randomization.
• Prior donor lymphocyte infusion or CD34+ stem cell infusion within 21 days prior to randomization.
• Use of vasopressors within 7 days prior to randomization.
• Use of any investigational antiviral agent, including brincidofovir, within 7 days prior to randomization.
• Lactating female unwilling to discontinue nursing prior to randomization.
• Severe allergy to any component of posoleucel or history of severe prior reactions to blood product transfusions.
• Positive for SARS-CoV-2 virus at screening.
Developing an Intervention to Promote Lethal Means Safety in Suicidal Adolescents
Study Objective: to develop a phone-based intervention to aid parents of suicidal adolescents to adhere to lethal means safety. Lethal means counseling is the practice of educating patients and their families about limiting access to items that can be used to attempt suicide. Though lethal means counseling is standard practice in treating suicidal patients, there is little experimental literature related to its utilization across different providers and its efficacy. Further, there is a significant gap in the literature on lethal means counseling as it relates to adolescents. The proposed project will investigate a novel text message-based intervention aimed to promote lethal means safety.
• Proficiency in spoken and written English
• Own cell phone that has internet capabilities
• Adolescent participants are patient's at Children's Health SPARC IOP (ages 12-17)
• Adult participants are parents and/or legal guardians of adolescent participants (ages 18+)
• Non-English speaking
Neoadjuvant Lenvatinib and Pembrolizumab for IVC Tumor Thrombus
This study will be evaluating safety and efficacy of the combination of lenvatinib and pembolizumab neoaadjuvant therapy prior to surgical resection of locally advanced renal cell carcinoma with IVC tumor thrombus.
• Male/female participants who are at least 18 years of age
• Have histologically confirmed cT3-4,N0-1,M0-1 (clinical stage III-IV) diagnosis of renal cell carcinoma (any subtype) with level II-IV inferior vena cava tumor thrombus
• The primary tumor and thrombus may be assessed to be resectable or unresectable at the time of enrollment
• Male participants: A male participant must agree to use a protocol-approved contraception during the 120 day neoadjuvant treatment period and for at least 90 days after the last dose of study treatment and refrain from donating sperm during this period.
• Female participants: A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
• Not a woman of childbearing potential (WOCBP) OR
• A WOCBP who agrees to follow the protocol-approved contraceptive guidance during the treatment period and for at least 30 days after the last dose of study treatment.
• The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
• Have measurable disease based on RECIST 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
• Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention.
• Have adequate organ function as defined in the following table. Specimens must be collected within 10 days prior to the start of study intervention.
• Absolute neutrophil count (ANC): ≥1500/µL
• Platelets: ≥100 000/µL
• Hemoglobin: ≥9.0 g/dL or ≥ 5.6 mmol/La
• Creatinine OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl): ≤1.5 × ULN OR ≥30 mL/min for participant with creatinine levels >1.5 × institutional ULN
• Total bilirubin: ≤1.5 ×ULN OR direct bilirubin ≤ ULN for participants with total bilirubin levels >1.5 × ULN
• AST (SGOT) and ALT (SGPT): ≤2.5 × ULN (≤5 × ULN for participants with liver metastases)
• International normalized ratio (INR) OR prothrombin time (PT) OR Activated partial thromboplastin time (aPTT): ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
• ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal.
• Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks.
• Creatinine clearance (CrCl) should be calculated per institutional standard.
• Note: This includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for the administration of specific chemotherapies.
• A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137).
• Has received prior systemic anti-cancer therapy including investigational agents prior to allocation.
• Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
• Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. COVID-19 vaccines are permitted provided they are not live attenuated vaccines.
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
• Has a known additional malignancy that is progressing or has required active treatment within the past year. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ (eg, breast carcinoma, cervical cancer, bladder in situ) that have undergone potentially curative therapy are not excluded.
• Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.
• Has more than three different sites of metastatic renal cell carcinoma.
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab and lenvatinib and/or any of its excipients.
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• Has an active infection requiring systemic therapy.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.
• Has had an allogenic tissue/solid organ transplant.
• Has prolongation of QTcF interval to >480 ms.
• Has a left ventricular ejection fraction (LVEF) below the institutional (or local laboratory) normal range, as determined by multigated acquisition (MUGA) or echocardiogram (ECHO)
• Has clinically significant cardiovascular disease within 12 months from first dose of study intervention, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability. Note: Medically controlled arrhythmia would be permitted
• Has urine protein ≥1 g/24 hours. Note: Participants with proteinuria ≥2+>1+ (≥100 mg/dL) on urine dipstick testing (urinalysis) will undergo 24-hour urine collection for quantitative assessment of proteinuria.
• Uncontrolled blood pressure (Systolic BP>140 mmHg or diastolic BP >90 mmHg) in spite of an optimized regimen of antihypertensive medication.
An Open-Label, Phase 2 Trial of Nanatinostat in Combination With Valganciclovir in Patients With Epstein-Barr Virus-Positive (EBV+) Relapsed/Refractory Lymphomas (NAVAL-1)
A Phase 2 study to evaluate the efficacy of nanatinostat in combination with valganciclovir in patients with relapsed/refractory EBV-positive lymphomas
• EBV+ relapsed/refractory lymphoma following 2 or more prior systemic therapies
• EBV+ DLBCL, NOS: Must have received at least one course of an anti-CD20 immunotherapy, and at least one course of anthracycline-based chemotherapy
• PTLD: Must have received immunotherapy with an anti-CD20 agent.
• Hodgkin lymphoma: Must have received at least one course of anthracycline-based chemotherapy. Patients with classical Hodgkin lymphoma should have failed or be ineligible for an anti-PD-1 agent and CD30-directed therapy.
• For ENKTL and PTCL patients only: Relapsed/refractory disease following 1 or more prior systemic therapies. ENKTL patients must have failed an asparaginase-containing regimen.
• No available therapies in the opinion of the Investigator
• Not eligible for high-dose chemotherapy with allogeneic/autologous stem cell transplantation or CAR-T therapy
• Measurable disease per Lugano 2007
• ECOG performance status 0, 1, 2
• Adequate bone marrow function Key
• Presence or history of CNS involvement by lymphoma
• Systemic anticancer therapy or CAR-T within 21 days
• Antibody (anticancer) agents within 28 days
• Less than 60 days from prior autologous hematopoietic stem cell or solid organ transplant
• Less than 90 days from prior allogeneic transplant.
• Daily corticosteroids (≥20 mg of prednisone or equivalent) within week prior to Cycle 1 Day 1
• Inability to take oral medication, malabsorption syndrome or any other gastrointestinal condition (nausea, diarrhea, vomiting) that may impact the absorption of nanatinostat and valganciclovir.
• Active infection requiring systemic therapy (excluding viral upper respiratory tract infections).
Open-label Extension Study of GB002 in Adult Subjects With Pulmonary Arterial Hypertension (PAH)
This open-label extension study will evaluate the long-term effects of GB002 (seralutinib) in subjects who previously participated in a GB002 PAH study.
• Subjects must have completed a prior GB002 PAH study and, in the opinion of the Investigator and Sponsor, have been compliant with study procedures and have completed treatment with IP through parent study end-of-treatment (EOT) visit.
• Treatment with standard of care PAH disease-specific background therapies (stable dose). Informed Consent
• Review and signature of an IRB-approved informed consent form.
• Persistent and clinically significant systemic hypertension or hypotension.
• Interval history of newly developed left-sided heart disease.
• Potentially life-threatening cardiac arrhythmia with an ongoing risk.
• Uncontrolled bacterial, viral, or fungal infections which require systemic therapy.
• Other severe acute or chronic medical or laboratory abnormality that may increase the risk associated with study participation or GB002 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.
• History of portopulmonary hypertension or portal hypertension due to cirrhosis classified as Child-Pugh Class A or higher.
• Subjects with a history of severe milk protein allergy. In addition, subjects with known intolerance or hypersensitivity to lactose who, in the opinion of the investigator, may experience severe symptoms following the ingestion of lactose.
• Current use of inhaled tobacco and/or inhaled marijuana. Ingestible or topical marijuana is allowed, per local restrictions and regulations.
• Current alcohol use disorder as defined by DSM-5, and/or history of current utilization of drugs of abuse (amphetamines, methamphetamines, cocaine, phencyclidine [PCP]).
• Have any other condition or reason that, in the opinion of the Investigator and/or the Sponsor's Medical Monitor (or designee), would prohibit the subject from participating in the study. Diagnostic Assessments
• Chronic renal insufficiency
• Hemoglobin (Hgb) concentration <8.5 g/dL.
• Absolute neutrophil count (ANC) < 1x 10^9/L.
• Platelet count <50 x 10^9/L. Prior Therapy
• Use of inhaled prostanoids.
• Chronic use of oral anticoagulants (ie, vitamin K antagonist such as warfarin or novel oral anticoagulant [NOAC]/direct oral anticoagulant [DOAC]).
• Chronic use of any prohibited medication. NOTE: Additional inclusion/exclusion criteria may apply, per protocol.
UroLift System With SAbR for Prostate Cancer and BPH
Confirming safety of combining UroLift System prior to SAbR for patients with newly diagnosed prostate cancer and a history of BPH, by measuring the acute complication rate of UroLift System implant in patients with BPH undergoing SAbR (within 90 days of treatment completion)
• AJCC 8th edition clinical stage T1 (a, b, or c) or T2 (a, b, or c) adenocarcinoma of the prostate gland, Gleason 3+3 = 6 or 3+4 = 7, with no direct evidence of regional or distant metastases following appropriate staging studies. See Appendix I for details on AJCC 8th Edition staging criteria. T-staging may be assessed by multi-parametric imaging alone if digital rectal examination was deferred
• Histologic confirmation of prostate cancer is required by biopsy performed within 18 months of registration.
• Age > 45 years.
• Eastern Cooperative Oncology Group (ECOG) Performance status 0-1.
• American Society of Anesthesia (ASA) physical status score of 1-3
• Baseline AUA symptom score ≥ 17 regardless of medical therapy
• The serum PSA should be < 20 ng/ml within 120 days of registration
• Study entry PSA must not be obtained during the following time frames: (1) 10-day period following prostate biopsy; (2) following initiation of ADT or anti-androgen therapy; (3) within 30 days after discontinuation of finasteride; (4) within 90 days after discontinuation of dutasteride; (5) within 5 days of a digital rectal examination
• Ultrasound or MRI based volume estimation of prostate gland < 100 grams, regardless of cytoreduction with pharmacotherapy
• Ability to undergo general anesthesia for <60 minutes
• Ability to understand and the willingness to sign a written informed consent.
• All men must agree to use adequate contraception (barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy.
• Contraindications to UroLift System placement including:
• Prostate volume >100 cc based on imaging-based estimation
• Urethral conditions (e.g. urethral strictures and neoplams) that may prevent insertion of UroLift System delivery system into the bladder
• Urinary incontinence due to incompetent sphincter
• An active urinary tract infection
• Current gross hematuria
• In addition to the contraindications if there is a known allergy to nickel, titanium, or stainless steel these patients should be excluded
• Prior transurethral resection of the prostate (TURP), median lobe manipulation, simple prostatectomy, or other ablative procedures for benign prostatic hyperplasia.
• Foley / self-catheterization in the last 12 months.
• Patients with all three intermediate risk factors (PSA >10 and ≤ 20, Gleason 7, clinical stage T2b-T2c) who ALSO have ≥50% of the number of their template biopsy cores positive for cancer are ineligible.
• Prior pelvic radiotherapy, chemotherapy, or surgery for prostate cancer.
• Current active androgen deprivation therapy
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.
• 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.
Exploratory Ph 2A, Double-Blind, Placebo-Controlled Dose Escalation Study of Safety, Tolerability, PD, & PK of HU6 for Subjects With Obese HFpEF (HFpEF)
This is a Phase 2A, randomized, parallel-group, placebo-controlled, double-blind, within subject dose escalation trial with 3 dose levels of HU6 and placebo. Subjects will be randomized (1:1) either to HU6 or placebo. Two dose levels will be administered in sequential order (150 mg daily followed by 300 mg daily), each for 20 days, to reach the third and highest dose of 450 mg daily if safety and tolerability are demonstrated at the lower 2 preceding doses. Administration of the 450 mg high dose will continue for a total of 94 days, with a safety follow-up visit within ~14 days of the last dose.
• Adult male or female, ≥40 years of age.
• Competent to understand the information given in the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved Informed Consent Form (ICF) and must sign the form prior to the initiation of any study procedures.
• Body mass index (BMI) ≥30 kg/m2;
• Signs and symptoms of HF in the judgement of the Investigator, and meets the following disease severity criteria: a. KCCQ OSS ≤80; b. NYHA Classification Class II-III; c. Baseline peak VO2 ≤18 mL/kg/min for females or ≤20 mL/kg/min for males; d. Respiratory exchange ratio (respiratory quotient) (RER [RQ]) at baseline of >1.0; e. Left ventricular ejection fraction (EF) ≥50%; f. At least 1 of the following objective criteria for HF: i. Documented hospitalization with HF as primary cause within in last year, or if greater than the past year, then with addition of structural heart disease on echocardiography (increased left atrial volume size or left ventricular hypertrophy, with sex-specific cut-points as per Lang, 2015) as follows:
• Left ventricular hypertrophy (LVH):
• Men: Either septal wall thickness (cm) either ≥1.1 or posterior wall thickness ≥1.1;
• Women: Either septal wall thickness (cm) either ≥ 1.0 or posterior wall thickness ≥1.0;
• Left atrial dilation (LAD): AP dimension (cm): ≥4.0 in men; >3.8 in women; ii. Pulmonary capillary wedge pressure (PCWP) at rest >15 mmHg (or left ventricular end-diastolic pressure [LVEDP] ≥18 mmHg) or >25 mmHg (or 2.0 mmHg/L/min) with exercise in the last year; iii. E/e' ratio ≥14 at septal annulus at rest on Doppler and tissue Doppler imaging in the last year; or iv. Currently elevated NT-proBNP defined as >125 pg/mL without atrial fibrillation and >350 pg/mL for subjects with chronic controlled atrial fibrillation.
• Participants should maintain their stable level of physical activity throughout the duration of the study and must agree to not enroll in an exercise training program during the study.
• Participants should maintain their stable diet and no plan to enter into a weight loss program prior to or during the course of the study.
• Euthyroid as assessed by a thyroid profile utilizing thyroid stimulating hormone (TSH) and free thyroxine (T4) testing at screening. Subjects with a stable history of thyroid disease and who have been on stable doses of thyroid medications for a minimum of 4 months can be enrolled.
• Ambulatory (not wheelchair- or scooter-dependent) and able to perform upright exercise testing including a 6 MWT.
• Stable doses of medications (defined as no new medication or change in existing dose of medication ≥50%) for 30 days prior to screening, with additional specific criteria for the diuretics:
• If treated with a loop or thiazide diuretic, must be on stable regimen, which dose permits a flexible diuretic dosing schedule.
• Life expectancy <1 year due to non-cardiovascular reasons, in the judgement of the Investigator.
• History of malignancy within 5 years (except non-high-grade skin cancers, carcinoma-in-situ, or low-grade prostate cancer).
• Weight change (gain or loss) of ≥10 pounds either by self-reporting or documented weight loss within the past 90 days.
• Bariatric surgery prior to screening or planned bariatric surgery during the course of the study.
• Treatment with GLP-1 receptor antagonist begun within 1 year of screening.
• Treatment with SGLT2 inhibitors begun within 6 months of screening.
• Intolerance to MRI or with conditions contraindicated for MRI procedures including but not limited to:
• Having surgical clips/metallic implants/shrapnel/internal electric implants; or
• Inability to fit into MRI scanner due to subject habitus or exceeding weight tolerance limit of the scanner (generally, 350 or 400 lbs, dependent on manufacturer); or
• Claustrophobia: history of severe claustrophobia that would lead to inability to conduct MRI.
• Current acute decompensated HF requiring intravenous (IV) diuretics or recent (<1 month before screening) hospitalization for HF.
• Primary cardiomyopathy (e.g., constrictive, restrictive, infiltrative, toxic, hypertrophic [congenital], congenital, or any other primary cardiomyopathy, in the judgement of the Investigator.
• Active myocarditis (COVID-induced or otherwise).
• Active collagen vascular disease.
• Current greater than moderate left- or right sided valve disease, in the opinion of the Investigator.
• Planned cardiac surgery or catheter intervention during the time of trial participation.
• Prior documented EF <40% within the last 3 years.
• Tachycardia (>110 beats/minute) at screening.
• Atrial fibrillation or atrial flutter with an uncontrolled heart rate response or with a resting heart rate greater than 110 bpm by ECG at screening. Subjects may rescreen after appropriate adjustment of medication to manage the atrial fibrillation. A maximum of 16 subjects with this condition can be enrolled in this study.
• Untreated, life-threatening dysrhythmia.