Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 8/19/22. Questions regarding updates should be directed to the study team contact.

Eligibility last updated 6/8/22. Questions regarding updates should be directed to the study team contact.

Key

• Completed 12 weeks of treatment in Study NBI-827104-CSWS2010.

Key Exclusuion Criteria:

• Have developed any other disorder for which the treatment takes priority over treatment of EECSWS or is likely to interfere with study treatment or impair treatment compliance.
• Body weight <10 kg at randomization Day 1.
• Clinically relevant findings related to cardiovascular or laboratory parameters at screening as determined by the investigator.
• Used any active investigational drug other than NBI-827104 in the context of a clinical study within 30 days or 5 half-lives (whichever is longer) before screening or plans to use such an investigational drug (other than NBI-827104) during the study.

Eligibility last updated 8/10/23. Questions regarding updates should be directed to the study team contact.

• Age ≥ 60 years old at time of consent.
• Concurrent enrollment in the Alzheimer’s Disease Research Center (ADRC, Mayo IRB 712-98) and/or Mayo Clinic Study of Aging (MCSA, Mayo IRB 14-004401).
  • Note: Participants may be but are not required to be concurrently enrolled in Brain Amyloid Imaging with Pittsburgh Compound B in Normal Aging, Mild Cognitive Impairment and Dementia (PiB, Mayo IRB 08-005553).  
• Normal cognition to moderate severity Alzheimer’s disease dementia (CDR ≤ 2) or vascular dementia.
• Participants with mild cognitive impairment or dementia must have a care partner or LAR to assist them with the WP setup and the questionnaires,

• History of or current non-Alzheimer’s or vascular dementia, such as dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), normal pressure hydrocephalus (NPH) dementia or undetermined cause dementia.
• Major neurological condition (i.e., non-lacunar stroke, TBI, epilepsy, tumor, CNS infection, demyelinating disease, neurodegenerative disease), severe autonomic failure (pure autonomic failure or autonomic neuropathy), major psychiatric disease (i.e., alcohol/drug abuse and schizophrenia),
• Current treatment of OSA. Diagnosed but untreated OSA is acceptable.
• Use of short-acting nitrates within 3 hours of the sleep study.
• Use of selective α1-adrenergic receptor antagonists, for example, tamsulosin (Flomax®), doxazosin (Cardura®), prazosin (Minipress®), and terazosin (Hytrin®) and nonselective α1 and α2 blockers (pentholamine and phenoxybenzamine)
• Finger deformity that precludes adequate sensor application
• Placement of a permanent pacemaker
• Persistent atrial fibrillation or other sustained non-sinus cardiac arrhythmias
• Severe peripheral vascular disease (e.g., status post stent or by-pass surgery in one of the limbs, faint/absent pulses)
• Status post bilateral cervical or thoracic sympathectomy
• Acute lung or heart disease (e.g., decompensated COPD or heart failure).

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 11/29/23.  Questions regarding updates should be directed to the study team contact.

• The patient must have signed and dated an IRB-approved consent form that conforms to federal and institutional guidelines.
• The patient must be ≥ 18 years old.
• The patient must have an ECOG performance status of 0 or 1.
• Patients must have histologically/pathologically confirmed Stage IIIA or Stage IIIB colon adenocarcinoma (T1-3, N1/N1c) with R0 resection accordingly to AJCC 8th edition criteria.
  • NOTE: Patients with pathologic stages II or IIIC colon adenocarcinoma with R0 resection who have a commercially obtained Signatera™ ctDNA+ve assay result post-operatively meeting all timelines and eligibility requirements otherwise, are eligible for enrollment and inclusion in Cohort B.
• No radiographic evidence of overt metastatic disease within 28 days prior to study entry (CT with IV contrast or MRI imaging is acceptable and must include chest, abdomen, and pelvis).
• The distal extent of the tumor must be ≥ 12 cm from the anal verge on colonoscopy or above the peritoneal reflection as documented during surgery or on pathology specimen (i.e., excluding rectal adenocarcinomas warranting treatment with chemoradiation).
• The patient must have had an en bloc complete gross resection of tumor (curative resection). Patients who have had a two-stage surgical procedure, to first provide a decompressive colostomy and then in a later procedure to have the definitive surgical resection, are eligible.
• The resected tumor specimen and a blood specimen from patients with Stage IIIA or Stage IIIB colon cancer must have central testing for ctDNA using the Signatera™ assay by Natera.
  • NOTE: Patients with stage IIIA or IIIB colon cancer who otherwise meet eligibility criteria and have had ctDNA status checked with the Signatera™ assay as routine care outside of the study, are allowed to be enrolled, and will be retested and placed in either Cohort A or Cohort B depending on the central ctDNA testing result.
  • NOTE: Patients with stage II or IIIC colon cancer who otherwise meet eligibility criteria and have had ctDNA status checked with the Signatera™ assay as routine care outside of the study AND have a ctDNA+ve result, are allowed to be enrolled. Patients will have central ctDNA testing, confirmed to be ctDNA+ve, and placed in Cohort B.
• Tumor must be documented as microsatellite stable or have intact mismatch repair proteins through CLIA-approved laboratory testing. Patients whose tumors are MSI-H or dMMR are excluded.
• The treating investigator must deem the patient a candidate for all potential agents used in this trial (5FU, LV, oxaliplatin and irinotecan).
• The interval between surgery (post-operative Day 7) and study entry must be no more than 60 days.
• Availability and provision of adequate surgical tumor tissue for molecular diagnostics and confirmatory profiling.
• Adequate hematologic function within 28 days before study entry defined as follows:
  • Absolute neutrophil count (ANC) must be ≥ 1500/mm^3;
  • Platelet count must be ≥ 100,000/mm^3; and
  • Hemoglobin must be ≥ 9 g/dL;
• Adequate hepatic function within 28 days before study entry defined as follows:
  • Total bilirubin must be ≤ ULN (upper limit of normal) for the lab; and
  • Alkaline phosphatase must be < 2.5 x ULN for the lab; and
  • AST and ALT must be < 2.5 x ULN for the lab.
• Adequate renal function within 28 days before study entry defined as serum creatinine ≤ 1.5 x ULN for the lab or measured or calculated creatinine clearance ≥ 50 mL/min using the CockroftGault formula for patients with creatinine levels > 1.5 x ULN for the lab.
• For Women Creatinine Clearance (mL/min) = (140 – age) x weight (kg) x 0.85 72 x serum creatinine (mg/dL).
• For Men Creatinine Clearance (mL/min) = (140 – age) x weight (kg) 72 x serum creatinine (mg/dL).
• HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• Pregnancy test (urine or serum according to institutional standard) done within 14 days before study entry must be negative (for women of childbearing potential only).
• Patients receiving a coumarin-derivative anticoagulant must agree to weekly monitoring of INR if they are randomized to Arm 1 or Arm 3 and receive capecitabine.

• Colon cancer histology other than adenocarcinoma (i.e., neuroendocrine carcinoma, sarcoma, lymphoma, squamous cell carcinoma, etc.).
• Pathologic, clinical, or radiologic overt evidence of metastatic disease. This includes isolated, distant, or non-contiguous intra-abdominal metastases, even if resected.
• Tumor-related bowel perforation.
• History of prior invasive colon malignancy, regardless of disease-free interval.
• History of bone marrow or solid organ transplantation (regardless of current immunosuppressive therapy needs). Bone grafts, skin grafts, corneal transplants and organ/tissue donation are not exclusionary.
• Any prior systemic chemotherapy, targeted therapy, or immunotherapy; or radiation therapy administered as treatment for colorectal cancer (e.g., primary colon adenocarcinomas for which treatment with neoadjuvant chemotherapy and/or radiation is warranted are not permitted).
• Other invasive malignancy within 5 years before study entry. Exceptions are colonic polyps, non-melanoma skin cancer or any carcinoma-in-situ.
• Synchronous primary rectal and/ or colon cancers.
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.
• Sensory or motor neuropathy ≥ grade 2, according to CTCAE v5.0.
• Blood transfusion within two weeks before collection of blood for central ctDNA testing.
• Active seizure disorder uncontrolled by medication.
• Active or chronic infection requiring systemic therapy.
• Known homozygous DPD (dihydropyrimidine dehydrogenase) deficiency.
• Patients known to have Gilbert's Syndrome or homozygosity for UGT1A1*28 polymorphism.
• Pregnancy or lactation at the time of study entry.
• Co-morbid illnesses or other concurrent disease that would make the patient inappropriate for entry into this study (i.e., unable to tolerate 6 months of combination chemotherapy or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens or prevent required follow-up).

Inclusion Criteria for Cohort A
•Arm 2 Patients on Second Randomization:

• Patient must have developed a ctDNA +ve assay during serial monitoring.
• Patient's willingness to be re-randomized affirmed.
• The patient must continue to have an ECOG performance status of 0 or 1.
• No radiographic evidence of overt metastatic disease.
• Pregnancy test (urine or serum according to institutional standard) done within 14 days before second randomization must be negative (for women of childbearing potential only).
• Adequate hematologic function within 28 days before second randomization defined as follows:
  • Absolute neutrophil count (ANC) must be ≥ 1500/mm^3;
  • Platelet count must be ≥ 100,000/mm^3; and
  • Hemoglobin must be ≥ 9 g/dL.
• Adequate hepatic function within 28 days before second randomization defined as follows:
  • Total bilirubin must be ≤ ULN (upper limit of normal) for the lab; and
  • Alkaline phosphatase must be < 2.5 x ULN for the lab; and
  • AST and ALT must be < 2.5 x ULN for the lab.
• Adequate renal function within 28 days before second randomization defined as serum creatinine ≤ 1.5 x ULN for the lab or measured or calculated creatinine clearance ≥ 50 mL/min using the Cockroft-Gault formula for patients with creatinine levels > 1.5 x ULN for the lab. For Women Creatinine Clearance (mL/min) = (140 – age) x weight (kg) x 0.85 72 x serum creatinine (mg/dL) For Men Creatinine Clearance (mL/min) = (140 – age) x weight (kg) 72 x serum creatinine (mg/dL).

Exclusion Criteria for Cohort A
•Arm 2 patients on Second Randomization:

• Pregnancy or lactation at the time of second randomization.
• No longer a candidate for systemic chemotherapy (FOLFOX, CAPOX, and mFOLFIRINOX) in the opinion of the treating investigator.

Eligibility last updated 5/26/22. Questions regarding updates should be directed to the study team contact.

• Adults 18 years of age and older.
• Healthy subjects without known cardiovascular disease and thyroid disease.
• Subjects who are on no medications (except oral contraceptive pill).
• Nonsmokers.
• No prior history of caffeine sensitivity or allergy.

• Subjects with known cardiovascular or thyroid disease.
• Subjects currently taking medications other than oral contraceptive pill.
• Smokers.
• Prior history of caffeine sensitivity or allergy.
• Pregnancy.
• • •  
• Subjects who regularly consume energy drinks.
• Subjects who typically go to sleep after midnight.
• Subjects who traveled across 2 time zones in the last 7 days.
• Shift workers.
• Subjects who have or are suspected to have sleep apnea.
• Subjects who have a body mass index > 35kg/m^2.

Eligibility last updated 3/7/22. Questions regarding updates should be directed to the study team contact.

• Adult patient ≥ 18 years old.
• Undergoing elective cardiac surgery. 
• Muscle relaxation administration by rocuronium. 

• Patient refusal. 
• Pediatric patients. 
• Patients less than 18 years old. 
• Emergency procedure. 
• Patients with known or suspected carotid or cerebrovascular disease. 
• Patients with prior stroke. 
• Skin condition or anatomy preventing proper sensor placement. 
• Patients who receive ketamine during the study timeframe. 

Eligibility last updated 2/15/22. Questions regarding updates should be directed to the study team contact.

• Aged ≥ 55 years.
• Able and willing to give consent to study participation.
• Presence of unilateral or bilateral GA, secondary to AMD.

• History or evidence of choroidal neovascularisation (for example, wet AMD) in both eyes.  Subjects with CNV in only one eye may be included after approval from Gyroscope.
• Currently receiving active treatment for CNV in either eye.
• Presence of severe non-proliferative diabetic retinopathy or worse in either eye.
• Have received any investigational product for the treatment of GA within the past 6 months, or 5 half-lives (whichever is longer) other than nutritional supplements such as the age-related eye disease study formula.
• Received gene/cell therapy at any time previously.
• Have any other significant ocular or non-ocular medical or psychiatric condition which,in the opinion of the Investigator, may either put the Subject at risk or may influence the results of the study.

Eligibility last updated 10/22/21. Questions regarding updates should be directed to the study team contact.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 2/21/23. Questions regarding updates should be directed to the study team contact.

• Histologically confirmed diagnosis of peripheral T-cell lymphoma (PTCL) with < 10% CD30 expression by immunohistochemistry in the following subtypes (by local review): nodal T-cell lymphoma with T-follicular helper (TFH) phenotype (TFH-PTCL), follicular T-cell lymphoma, PTCL-not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), enteropathy associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma.
• Patients will be stratified by presence or absence of TFH phenotype (i.e., diagnosis of AITL, TFH-PTCL, follicular T-cell lymphoma) based on local review of pathology. Determination of TFH phenotype can be defined by expression of two or more of the following markers CD10, BCL6, CXCL13, ICOS, and PD1 by immunohistochemistry.
• Measurable disease as defined by the Lugano criteria.
• No prior systemic therapy for lymphoma (excluding corticosteroids).
• Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for women of childbearing potential only, a negative urine or serum pregnancy test done ≤ 7 days prior to registration is required.
• Age ≥ 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• Platelet count ≥ 75,000/mm^3 (≥ 50,000/mm^3 if secondary to bone marrow involvement from lymphoma per investigator assessment; the first 12 patients on each arm of the study must have platelets ≥ 75,000/mm^3 regardless of bone marrow involvement).
• Absolute neutrophil count (ANC) ≥ 1,000/mm^3.
• Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) ≤ 3.0 x upper limit of normal (ULN) * Except in subjects with documented liver involvement by lymphoma.
• Calculated creatinine clearance ≥ 30 mL/min by Cockcroft-Gault formula.
• Total bilirubin ≤ 2.0 x ULN * Except in cases of Gilbert's Syndrome or documented liver or pancreatic involvement by lymphoma.
• Archival tissue must be available for submission.
• No active viral infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C. Those who are seropositive (e.g., hepatitis B core antibody [Ab] positive) are permitted if they are negative by polymerase chain reaction (PCR). Those who are seropositive for hepatitis B and are negative for hepatitis B virus (HBV) deoxyribonucleic acid (DNA) by PCR must receive concomitant hepatitis B directed antiviral therapy. Those who have hepatitis C Ab positivity who have completed curative therapy for hepatitis C with negative hepatitis C PCR are eligible.
• Patients with history of HIV are eligible if they have an undetectable viral load for at least 6 months.
• No active uncontrolled systemic fungal, bacterial or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy and/or other treatment).
• Patients with Epstein-Barr virus (EBV) viremia related to their lymphoma are permitted.
• Patients must have documented left ventricular ejection fraction of ≥ 45%.
• No significant active cardiac disease within the previous 6 months including: 
  • New York Heart Association (NYHA) class III or IV congestive heart failure;
  • Unstable angina or angina requiring surgical or medical intervention; and/or
  • Myocardial infarction.

• Patients with expression of CD30 in ≥ 10% of the tumor (based on local immunohistochemistry review) regardless of histology will not be permitted.
• Patients with a diagnosis of other PTCL subtype histologies other than those specified in the inclusion criteria are excluded including large cell transformation of mycosis fungoides.
• Patients known to have HTLV 1/2.
• Patients with known central nervous system involvement.
• No concurrent malignancy requiring active therapy within the last 3 years with the exception of basal cell carcinoma limited to the skin, squamous cell carcinoma limited to the skin, carcinoma in situ of the cervix, breast or localized prostate cancer. Adjuvant hormonal therapy for cancer previously treated for curative intent is permitted.
• No contraindication to any drug in the chemotherapy regimen, including neuropathy ≥ grade 2.
• Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration on the study. Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment.

Eligibility last updated 9/30/21. Questions regarding updates should be directed to the study team contact.

• Subject must be ≥ 18 years of age.
• Subject meets indications for TAVR using approved devices.
• The study patient has been informed of the nature of the study, agrees to its provisions, and has provided written informed consent as approved by the Institutional Review Board (IRB) of the respective clinical site.
• Subject is willing to comply with specified follow-up evaluations.
• Subject meets the legal minimum age to provide Informed Consent based on local regulatory requirements.

• Patient with any implanted or have an indication for treatment with rhythm management device (i.e., pacemaker, Cardiac Resynchronization Therapy (CRT) or Cardiac Resynchronization Therapy with cardioverter-defibrillator (CRT-D) at baseline.
• Any contraindication to the TAVR procedure according to the instructions for use.
• Subject is less than the legal age of consent, legally incompetent, or otherwise vulnerable.
• Patients who have a planned treatment with any other investigational device, drug or procedure (excluding registries) during the study period.

Eligibility last updated 6/24/22.   Questions regarding updates should be directed to the study team contact.

• Male or female patients, aged 18 years and older.
• Scheduled to undergo gastric surgery for obesity.
• Able to provide written informed consent before participating in the study.
• Able to communicate adequately with the investigator and to comply with the requirements for the entire study.

• Individuals < 18 years old.
• Clinical evidence of significant cardiovascular, respiratory, renal, hepatic, gastrointestinal, hematological, neurological, psychiatric or other disease that may interfere with the objectives of the study.
• Medications. Opiates and high doses of anticholinergic agents (e.g., amitriptyline greater than 50 mg daily).
• Any other condition or prior therapy that, in the opinion of the investigator, would make the patient unsuitable for the study.

Eligibility last updated 9/1/21. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years.
• Stage 3 acute kidney injury according to the KDIGO criteria.
• Started or intending to start CKRT for volume management.
• Attending intensivist or nephrologist intending to remove fluid using CKRT for at least 48 hours.

• Respiratory distress due to pulmonary edema or fluid overload.
• Massive volume infusion (i.e., > 200 mL/h for > 6 hours of continuous infusion).
• No intention to remove fluid as determined by attending intensivist or nephrologist.
• Attending intensivist or nephrologist believes that the protocol will not be followed.
• Continuous fluid removal for > 24 hours prior to study enrollment.
• Actual or estimated premorbid body weight > 120 kilograms.
• Patients treated with intermittent hemodialysis during the current admission.
• Patients on chronic outpatient hemodialysis. 
• Patients with history of, or current admission for kidney transplantation.
• Do not resuscitate, intubate, or comfort measures only orders (i.e., DNR/DNI/CMO).
• Moribund not expected to survive > 24 hours.
• Confirmed pregnancy.
• Patients treated with extracorporeal membrane oxygenation (ECMO), ventricular assist device (VAD), or intra-aortic balloon pump (IABP).
• Organ donors with neurological determination of death (i.e., brain dead donors).
• Drug overdose requiring CKRT.
• Enrollment in a concurrent interventional clinical trial with direct impact on fluid balance (e.g., > 500 mL study drug administration).

Eligibility last updated 3/9/22. Questions regarding updates should be directed to the study team contact.

• Age: 18 years old or older, male or female.
• Patients must have histologically or cytologically confirmed tumors of the following types.
• Dose Escalation Phase:
  • Patients with PMF, PV/ET-MF;
  • Intermediate or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythaemia myelofibrosis which failed standard treatment;
  • Symptomatic splenomegaly;
  • Not undergone splenectomy or splenic radiation therapy within 6 months prior to screening.
• Dose expansion phase:
  • Patients with PMF, PV/ET-MF who relapsed or are intolerant to standard treatment, and relapsed/refractory AML.
• Platelet count ≥ 100 × 10e^9/L within 14 days before study drug administration.
• Absolute neutrophil count (ANC) ≥ 1.5 × 10e^9/L within 14 days before study drug administration.
• Women of childbearing potential negative pregnancy test at screening. Female patients of childbearing potential, or male patients and their partners should agree to effective contraception from signing ICF until 6 months after the last dose of study drug.

• Allergic to any component of LNK01002.
• Serum total bilirubin greater than 1.5 times the upper limit of the normal (ULN) reference range, except patients diagnosed as Gilbert's disease.
• ALT or AST higher than 3 times the ULN reference range without hepatic involvement by leukemia, which are excluded if higher than 5 times the ULN.
• Glomerular filtration rate or estimated creatinine clearance < 50 mL/min according to the Cockcroft-Gault formula.
• Serum amylase or lipase levels higher than the ULN and considered clinically significant.
• International normalized ratio (INR) or partial activated prothrombin time (aPTT) above 1.5 times the ULN reference range.
• Known history of clinically significant liver disease, including viral or other hepatitis:
  • Patients with hepatitis B or hepatitis C may be enrolled if they have a negative polymerase chain reaction (PCR);
  • Known human immunodeficiency virus (HIV) infection.
• Clinically significant cardiovascular diseases, including acute myocardial infarction, unstable angina, coronary artery bypass surgery within 6 months before enrollment, congestive heart failure with New York Heart Association (NYHA) classification of III or above, left ventricular ejection fraction (LVEF) < 50%, or uncontrolled hypertension, cardiac arrhythmia.
• Patients with history or presence of clinically relevant non-malignant CNS disease requiring treatment.
• Patients who have received systemic antineoplastic therapy or radiotherapy within 2 weeks prior to start of study treatment.
• Patients who have received hematopoietic stem cell transplantation (HSCT) within 60 days prior to the start of study treatment, or are receiving immunosuppressive therapy after HSCT at screening, or have graft-versus-host disease (GVHD) requiring drug control.
• Received anti-tumor Chinese herbal medicine treatment within 1 week before the start of study treatment.
• Received CYP3A substrates, CYP2B6 substrates, CYP2C substrates, OATP1B3 substrates, UGT1A1 inhibitors, or UGT1A3 inhibitors less than one week or 5 half-lives (whichever is longer) prior to the start of study treatment.
• Uncontrolled, active infections requiring intravenous antibiotic treatment.

Eligibility last updated 10/14/21. Questions regarding updates should be directed to the study team contact.

• Male or female age ≥ 18 years.
• Is able and willing to provide written informed consent, which includes compliance with study requirements and restrictions listed in the consent form.
• Have a ≥ 6-month history of documented sarcoidosis including histological confirmation in the subject’s medical records.
• Have high-resolution computed tomography (HRCT) and PET scan consistent with active pulmonary sarcoidosis of the lung parenchyma confirmed by central read.
• Have FVCp ≥ 50% to ≤ 90% and DLCO ≥ 50%.
• If receiving prednisone (or equivalent), dose must have been ≤25 mg, and dose must have been stable for at least 4 weeks prior to randomization.
• Symptomatic as indicated by mMRC Dyspnea scale >1 (i.e., Grade 2 or more) in the prior year.
• If receiving methotrexate and/or other immunosuppressive therapy (IST) dose must have been stable for ≥ 3 months prior to randomization.
• Female subjects must agree to use an approved highly effective birth control (BC) method (< 1% failure rate per year) throughout the study, unless documented to have a reproductive status of non-childbearing potential or is postmenopausal:
  • Non-childbearing potential defined as pre-menopausal female with medical history of bilateral tubal ligation, bilateral oophorectomy (removal of the ovaries), or hysterectomy; hysteroscopic sterilization;
  • Postmenopausal defined as 12 months of spontaneous amenorrhea; otherwise, a follicle stimulating hormone (FSH) confirmation will be required. For females with questionable menopausal history (e.g., irregular menstrual periods and age > 40 years) a documented serum FSH level must be ≥ 30 mIU/mL;
  • Woman of childbearing potential (WCBP) who is already using an established method of highly effective contraception or agrees to use one of the allowed BC methods, for at least 28 days prior to the start of dosing, throughout the study, and for 4 months following the last dose of study drug.
• Males who are sexually active must agree to use one of the allowed BC methods. Male subjects must also agree to sufficiently minimize the risk of pregnancy throughout study participation (and for 4 months following the last dose of study drug).
• Body Mass Index (BMI) 18 to 40 kg/m^2 at screening.
• Subjects must agree to steroid taper, and cessation of their IST therapy at randomization.
• Completion of vaccination for COVID-19 at least 2 weeks prior to randomization.

Exlusion Criteria:

• Hospitalized for any respiratory illness ≤ 30 days prior to screening.
• Prednisone dose > 25 mg/day at any time in the previous 4 weeks.
• ≥ 20% fibrosis as indicated on CT-scan that has been confirmed by central read prior to randomization.
• eGFR ≤30 mL/min/1.73 m^2 (MDRD equation) or requiring hemofiltration or dialysis.
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 3 × upper limit of normal range (ULN).
• Platelet count <100,000 per mm^3.
• Hemoglobin ≤ 9.5 g/dL.
• Absolute neutrophil count < 1,000 per mm^3.
• History of known anti-GM-CSF autoAb or tests positive at screening, or history of pulmonary alveolar proteinosis (PAP).
• Use of biologic — approved or investigational agents (e.g., anti-TNFα, anti-IL-1, anti-IL-6, anti-IL-17, anti-IL-12/23 or specific anti-IL-23 inhibitors, anti CD20, anti-IL-18) within the 6 months prior to screening.
• Prior use of immunoglobulin within 6 months prior to screening.
• Prior use of any investigational immunomodulator (e.g., NRP2 modulator) within 6 months of screening.
• Prior use of any JAK inhibitor within 3 months of screening.
• Participation in another interventional clinical trial within 6 months prior to screening.
• Known left ventricular ejection fraction (LVEF) ≤30% or NYHA class III or IV heart failure.
• ECG abnormalities that warrant further investigation, in the opinion of the Investigator.
• Pulmonary hypertension requiring therapy.
• Systolic blood pressure (SBP)  < 90 or > 180 mm Hg; Diastolic blood pressure (DBP) < 60 or > 110 mm Hg.
• Known COVID-19 infection within 3 months prior to screening.
• Have received any live virus or bacterial vaccinations < 3 months of screening. Age-appropriate non-live vaccinations may be administered during screening so long as the last vaccine dose is administered at least 2 weeks prior to planned randomization.
• Any infection requiring antibiotics or pulse of OCS where completion of treatment has been < 30 days prior to screening.
• History of 3 or more lower respiratory tract infections requiring anti-microbial therapy in the past year.
• Any history of mycetoma or fungal respiratory infection.
• Requirement for supplemental oxygen at rest.
• Prior history of, or likely to have any organ transplantation during study including OLE.
• History of smoking (or vaping) in the prior year or current use. Occasional use (defined as less frequently than once per month) is allowable, though subjects should be counseled to remain abstinent during the study including OLE.
• Other significant pulmonary disease likely to interfere with the primary endpoint, in the opinion of the Investigator.
• Other autoimmune disease likely to require therapy during the study.
• Symptoms and features of extra-PS that may warrant treatment in addition to that required for lung involvement.
• Significant ischemic heart disease (i.e., myocardial infarction within 6 months, unstable angina or PCTA/stent within 1 month or planned intervention during study).
• Known or suspected active and untreated/inadequately treated tuberculosis (TB), human immunodeficiency virus (HIV), hepatitis B or C infection. Subjects with latent TB may be enrolled if anti-TB therapy is commenced prior to randomization.
• For women: pregnant or planning to become pregnant during the study or currently breastfeeding.
• Prior history of any malignancy or lymphoproliferative disorder (not including fully resected basal cell carcinoma of the skin, fully resected intra-epithelial neoplasia or carcinoma in situ) within the past 5 years.

Eligibility last updated 12/23/21. Questions regarding updates should be directed to the study team contact.

• Adult patients, ≥ 18 years old.
• Patients diagnosed for benign thyroid nodule and scheduled for RFA procedure.

• Patients < 18 years old.
• Patients without established IV access.

Eligibility last updated 6/27/22. Questions regarding updates should be directed to the study team contact.

• ≥ 18 and ≤ 90 years of age.
• Patient undergoing elective intestinal resection surgery including open, laparoscopic, robotic, or hand-assist technique for:
  • Segmental ileocolic resection with or without diversion;
  • Segmental colon resection with or without diversion;
  • Segmental coloproctectomy with or without diversion;
  • Low anterior resection with or without diversion;
  • Abdominoperineal resection;
  • Total abdominal colectomy with or without diversion;
  • Proctocolectomy with or without end ileostomy or diversion;
  • Closure of end colostomy (Hartmann’s reversal).

• Allergies to any of the device components (i.e., adhesive).
• Inability to have prototype device applied to their abdominal wall due to disease conditions or surgical alterations (e.g., fistulas, stomas, drains, etc.).
• Patients undergoing:
  • Small bowel resection without colonic resection;
  • Transanal proctectomy without transabdominal approach;
  • Perineal proctosigmoidectomy;
  • Closure of loop colostomy or ileostomy.
• Patients with preoperative evidence of an anastomotic leak, deep wound infection, organ space infection, or urinary tract infection.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 6/6/23. Questions regarding updates should be directed to the study team contact.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 9/20/22. Questions regarding updates should be directed to the study team contact.

• Signed Informed Consent Form.
• Age 18-75 years at time of signing Informed Consent Form.
• Ability to comply with the study protocol, in the investigator's judgment.
• Active or active/chronic ISN/RPS 2003 Class III or IV proliferative LN by renal biopsy performed in the 6 months prior to screening or during screening:
  • One or more active glomerular lesions must be present;
  • Class V disease may be present in addition to Class III or IV;
  • The local biopsy report will be used to determine eligibility.
• SLE according to the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) Classification Criteria, which are met by the presence of Class III or IV LN (above) and current or past positive antinuclear antibody (ANA) Positive ANA is defined by ANA at a titer of ≥ 1:80 on HEp-2 cells or an equivalent positive ANA test at least once. UPCR ≥ 1 on a 24-hour collection at screening
• Receipt of at least one dose of pulse methylprednisolone IV (≥ 250 mg) or equivalent for treatment of the current episode of active LN during the 6 months prior to screening or during screening, or to be given on Day 1 prior to the first infusion.
  • A maximum of 3 g methylprednisolone IV or equivalent during the 4 weeks prior to screening or during screening is allowed.
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use highly effective contraception, as defined below: Women must remain abstinent or use two reliable methods of contraception, including at least one method with a failure rate of < 1% per year, during study treatment and for 18 months after the final dose of obinutuzumab or placebo and 6 weeks after the final dose of MMF. A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations. Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation; male sterilization; established, proper use of hormonal contraceptives that inhibit ovulation; hormone-releasing intrauterine devices; and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form.
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating sperm, as defined below: With a female partner of childbearing potential, men who are not surgically sterile must remain abstinent or use a condom plus an additional contraceptive method used by the female partner that together result in a failure rate of < 1% per year during the treatment period and for 90 days after the final dose of MMF. Men must refrain from donating sperm during this same period. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception.

• Pregnant or breastfeeding, or intending to become pregnant during the study or within 18 months after the final dose of obinutuzumab or placebo or within 6 weeks after the final dose of MMF.
• Women of childbearing potential, including those who have had a tubal ligation, must have a negative urine pregnancy test at screening. Positive test results will be confirmed with a serum pregnancy test. Severe renal impairment, as defined by eGFR < 30 mL/min/1.73 m^2 (as estimated using the CKD-EPI equation) or the need for dialysis or renal transplantation.
• Sclerosis in > 50% of glomeruli on renal biopsy.
• Presence of rapidly progressive glomerulonephritis, defined by any of the following:
  • Crescent formation in ≥ 50% of glomeruli assessed on renal biopsy;
  • Sustained doubling of serum creatinine during the 2 months prior to screening;
  • The investigator’s opinion that the patient has rapidly progressive glomerulonephritis.
• Receipt of any of the following excluded therapies:
  • Any anti-CD20 therapy such as rituximab, ocrelizumab, or ofatumumab less than 9 months prior to screening or during screening;
  • If an anti-CD20 therapy has been received between 9 and 12 months prior to screening, the peripheral CD19+ B-cell count must be ≥ 25 cells/µL;
  • Cyclophosphamide, tacrolimus, ciclosporin, or voclosporin during the 2 months prior to screening or during screening;
  • Any biologic therapy (other than anti-CD20) such as, but not limited to, belimumab, ustekinumab, anifrolumab, secukinumab, or atacicept during the 2 months prior to screening or during screening;
  • Oral inhibitors of Janus-associated kinase (JAK), Bruton’s tyrosine kinase (BTK), or tyrosine kinase 2 (TYK2), including baricitinib, tofacitinib, upadacitinib, filgotinib, ibrutinib, or fenebrutinib or any investigational agent during the 2 months prior to screening or during screening;
  • Any live vaccine during the 28 days prior to screening or during screening.
• Severe, active central nervous system SLE, including retinitis, poorly controlled seizure disorder, acute confusional state, myelitis, stroke, cerebellar ataxia, or dementia.
• High risk for clinically significant bleeding or any condition requiring plasmapheresis, intravenous immunoglobulin, or acute blood product transfusions.
• Significant or uncontrolled medical disease which, in the investigator’s opinion, would preclude patient participation.
• HIV infection:
  • For patients with unknown HIV status, HIV testing will be performed at screening if required by local regulations.
• Tuberculosis (TB) infection:
  • Testing for latent TB will be performed at screening if required by local regulations or in accordance with local clinical practice;
  • Latent TB after completion of appropriate treatment is not exclusionary.
• Active infection of any kind, excluding fungal infection of the nail beds.
• Any major episode of infection that also fulfills any of the following criteria:
  • Requires hospitalization during the 8 weeks prior to screening or during screening;
  • Requires treatment with IV antibiotics or anti-infectives during the 8 weeks prior to screening or during screening;
  • Requires treatment with oral antibiotics or anti-infectives during the 2 weeks prior to screening or during screening:
    • Antibiotics or anti-infectives given in the absence of a major episode of infection are not exclusionary.
• History of serious recurrent or chronic infection.
• History of progressive multifocal leukoencephalopathy (PML).
• History of cancer, including solid tumors, hematological malignancies, and carcinoma in situ, within the past 5 years:
  • Patients with non-melanomatous carcinomas of the skin that have been treated or excised and have resolved are eligible.
• Major surgery requiring hospitalization during the 4 weeks prior to screening or during screening.
• Current alcohol or drug abuse or history of alcohol or drug abuse within 12 months prior to screening or during screening.
• Intolerance or contraindication to study therapies, including any of the following:
  • History of severe allergic or anaphylactic reactions to monoclonal antibodies or known hypersensitivity to any component of the obinutuzumab infusion;
  • Intolerance or contraindication to oral or IV corticosteroids;
  • Intolerance to MMF;
  • Lack of peripheral venous access.
• Any of the following laboratory parameters:
  • AST or ALT > 2.5 x ULN;
  • Amylase or lipase > 2 x ULN;
  • Neutrophils < 1.5 x10^3 /µL;
  • Positive hepatitis B surface antigen (HBsAg);
  • Patients who are HBsAg negative and hepatitis B core antibody (HBcAb) positive with no detectable hepatitis B virus (HBV) DNA are eligible but will require monthly HBV DNA monitoring until 12 months after the last dose of obinutuzumab or placebo.
• Positive hepatitis C serology Patients with positive hepatitis C antibody test result with no detectable hepatitis C virus (HCV) RNA at least 6 months after completion of antiviral therapy are eligible but will require monthly HCV RNA monitoring until 12 months after the last dose of obinutuzumab or placebo.
• Hemoglobin < 7 g/dL, unless caused by autoimmune hemolytic anemia resulting from SLE.
• Platelet count < 25,000/µL.
• Positive serum human chorionic gonadotropin measured at screening.

Eligibility last updated 9/9/21. Questions regarding updates should be directed to the study team contact.

• Age 7-80 years at time of screening.
• Has a clinical diagnosis of type 1 diabetes:
• 14-80 years of age: A clinical diagnosis of type 1 diabetes for 2 years or more as determined via medical record or source documentation by an individual qualified to make a medical diagnosis.
• 7-13 years of age: A clinical diagnosis of type 1 diabetes for 1 year or more as determined via medical record or source documentation by an individual qualified to make a medical diagnosis.
• Does not require a legally authorized representative to consent on their behalf due to mental or intellectual disability.
• Subject or parent/caregiver is literate and able to read the language offered in the
• pump or pump materials.
• Subject and/or legally authorized representative is willing to provide informed consent for participation.
• Is willing to perform fingerstick blood glucose measurements as needed.
• Is willing to wear the system continuously throughout the study.
• Must have a minimum daily insulin requirement (Total Daily Dose) of greater than or equal to 8 units and a maximum total daily dose of 250 units or less.
• Has a Glycosylated hemoglobin (HbA1c) less than 10% (as processed by Central Lab) at time of screening visit.
  • Note: All HbA1c blood specimens will be sent to and tested by a National Glycohemoglobin Standardization Program (NGSP) certified Central Laboratory. HbA1c testing must follow NGSP standards.
• Has thyroid-stimulating hormone (TSH) in the normal range OR if the TSH is out of normal reference range, the Free T3 is below or within the lab's reference range and Free T4 is within the normal reference range.
• Uses pump therapy for greater than 6 months (with or without CGM experience) prior to screening.
• Is willing to upload data from the study pump, must have Internet access, and a computer system, or compatible smartphone that meets the requirements for uploading the study pump.
• Is willing to take one of the following insulins and can financially support the use of insulin preparations as required during the run-in period:
  • Humalog (insulin lispro injection);
  • NovoLog (insulin aspart injection);
  • Admelog(insulin lispro injection).
• Is willing to take Lyumjev insulin during the study period (supplied via Sponsor).

• Has hypersensitivity to insulin lispro or one of the excipients in Lyumjev®.
• Has a history of 2 or more episodes of severe hypoglycemia, which resulted in any the following during the 6 months prior to screening:
  • Medical assistance (i.e., Paramedics, Emergency Room [ER] or Hospitalization);
  • Coma;
  • Seizures.
• Has been hospitalized or has visited the ER in the 6 months prior to screening resulting in a primary diagnosis of uncontrolled diabetes.
• Has had DKA in the last 6 months prior to screening visit.
• Will not tolerate tape adhesive in the area of sensor placement as assessed by a qualified individual.
• Has any unresolved adverse skin condition in the area of sensor placement (e.g., psoriasis, dermatitis herpetiformis, rash, Staphylococcus infection).
• Is female of child-bearing potential and result of pregnancy test is positive at screening.
• Is sexually active female of child-bearing potential and is not using a form of contraception deemed reliable by the investigator.
• Is female and plans to become pregnant during the course of the study.
• Is being treated for hyperthyroidism at time of screening.
• Has diagnosis of adrenal insufficiency.
• Has taken any oral, injectable, or intravenous (IV) glucocorticoids within 8 weeks
• from time of screening visit, or plans to take any oral, injectable, or IV glucocorticoid during the course of the study.
• Is using hydroxyurea at time of screening or plans to use it during the study.
• Is actively participating in an investigational study (drug or device) wherein he/she has received treatment from an investigational study drug or investigational study device in the last 2 weeks.
• Is currently abusing illicit drugs.
• Is currently abusing marijuana.
• Is currently abusing prescription drugs.
• Is currently abusing alcohol.
• Using pramlintide (Symlin), DPP-4 inhibitor, liraglutide (Victoza or other GLP-1 agonists), metformin, canagliflozin (Invokana or other SGLT2 inhibitors) at time of screening.
• Has a history of visual impairment which would not allow subject to participate in the study and perform all study procedures safely, as determined by the investigator.
• Has elective surgery planned that requires general anesthesia during the course of the study.
• Has sickle cell disease, hemoglobinopathy; or has received red blood cell transfusion or erythropoietin within 3 months prior to time of screening.
• Plans to receive red blood cell transfusion or erythropoietin over the course of study participation.
• Is diagnosed with current eating disorder such as anorexia or bulimia.
• Has been diagnosed with chronic kidney disease that results in chronic anemia.
• Has a hematocrit that is below the normal reference range of lab used.
• Is on dialysis.
• Has serum creatinine of >2 mg/dL.
• Has celiac disease that is not adequately treated as determined by the investigator.
• Has had any of the following cardiovascular events within 1 year of screening:
  • myocardial infarction, unstable angina, coronary artery bypass surgery, coronary artery stenting, transient ischemic attack, cerebrovascular accident, angina, congestive heart failure, or ventricular rhythm disturbances.
• Has had history of cardiovascular event 1 year or more from the time of screening without:
  • a normal EKG and stress test within 6 months prior to screening or during screening; or
  • clearance from a qualified physician prior to receiving the study devices if there is an abnormal EKG or stress test.
• Has 3 or more cardiovascular risk factors listed below without a normal EKG within 6 months prior to screening or during screening or clearance from a qualified physician if there is an abnormal EKG:
  • Age >35 years;
  • Type 1 diabetes of > 15 years' duration;
  • Presence of any additional risk factor for coronary artery disease;
  • Presence of microvascular disease (proliferative retinopathy or nephropathy, including microalbuminuria);
  • Presence of peripheral vascular disease;
  • Presence of autonomic neuropathy.
• Is a member of the research staff involved with the study.
• Has used a MiniMed 780G pump prior to screening.

Eligibility last updated 5/15/23. Questions regarding updates should be directed to the study team contact.

• Age 50 years or older.
• English speaking.
• Admitted to the intensive care unit (medical or surgical).
• Expected mechanical ventilator support for ≥ 48 hours.
• Consentable through a legally authorized representative.
• Have access to a telephone (after discharge).

• History of dementing illnesses and other neurodegenerative diseases such as Alzheimer’s disease or vascular dementia.
• Psychiatric illness which is not well controlled.
• Alcohol withdrawal symptoms/concern for withdrawal.
• Suspected or confirmed drug intoxication/overdose.
• Traumatic brain injury, ischemic or hemorrhagic cerebrovascular accident, or undergoing neurosurgery.
• Uncorrected hearing or vision impairment including legal blindness.
• Incarcerated at the time of study enrollment.
• Enrolled in another clinical trial which does not permit co-enrollment.
• Any medical condition precluding safe use of headphones such as:  skin breakdown, burns, facial or skull fractures.
• COVID-19 positive test.

• Both males and females will be enrolled and must be at least 18 years of age.
• Patients with a known history of IBD and dysplasia (low grade or high grade) undergoing surveillance.
• Only patients who undergo both WATS and standard biopsy will be included in this study.
• Institutional Review Board (IRB)-approved consent must be signed by patients to participate in this study.

• Individuals < 18 years of age.

Eligibility last updated 2/7/22. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria

• Individuals age 18 to 45 years.

• Individuals less than 18 or more than 45 years of age.
• BMI > 32 kg/m^2. 
• Cardiovascular, metabolic (type 2 diabetes, fasting plasma glucose at or above 110 mg/dL and untreated hypo- or hyperthyroidism) or renal disease.
• Orthopedic problems that would keep them from being able to perform an exercise.
• Medications that are known to impact mitochondrial function: 
  • Corticosteroids, opiates, benzodiazepines, tricyclic antidepressants, beta-blockers, sulfonylureas, insulin, In, barbiturates, insulin sensitizers, fibrates (PPAR gamma agonist). 
• Smoking.
• Pregnancy. 

Eligibility last updated 2/21/22. Questions regarding updates should be directed to the study team contact.

• Female, 18 years of age or older.
• Women treated for breast cancer with radiation with a curative intent

• Non breast cancer.
• Children under 18-years of age.
• Non curative intent.

Eligibility last updated 4/19/22.  Questions regarding updates should be directed to the study team contact.

•  ≥  18 years of age. 
• Suspected of having a H. pylori infection and are undergoing or recently have undergone a gastric biopsy.

• On a current antibiotic regimen and negative for H. pylori as tested from a gastric biopsy.

Eligibility last updated 9/8/22. Questions regarding updates should be directed to the study team contact.

• Patient is male or female and is 2 months to 24 months of age, inclusive.
• Patient has been diagnosed with IS within 6 weeks prior to Screening. Diagnostic criteria include both clinical spasms and an electroencephalogram (EEG) pattern consistent with hypsarrhythmia or significant abnormality compatible with IS.
  • NOTE: If a video EEG is performed at the clinical site within 48 hours prior to the patient's parent/guardian providing written informed consent, and it meets the criteria, this video EEG may be used as the screening/baseline EEG for the study.
• Patient has normal renal function as defined by an estimated glomerular filtration rate (eGFR).
• > 60 mL/min/1.73 m^2, calculated as eGFR = 0.413 x (height [cm]/ serum creatinine [mg/dL]).
• Patient's legally authodzed representative (i.e., parent or guardian) must provide written informed consent obtained per Institutional Review Board policy and requirements, consistent with the International Council for Harmonisation.
• Patient's parent/guardian is able to understand and willing to comply with study procedures and restrictions.

• Patient has been diagnosed with tuberous sclerosis.
• Patient has acute illness considered clinically significant by the Investigator within 30 days prior to Screening.
• Patient has a diagnosis of recent systemic fungal infection; history of ocular herpes simplex; history of or current peptic ulcer; uncontrolled hypertension or congestive heart failure; or any other condition that would be significantly impacted by the study drug.
• Patient has a preplanned surgery or procedurc(s) that would interfere with the conduct of the study.
• Patient has received any prior treatment for IS.
• Patient has been previously treated with adrenocorticotropic honnonc (ACTH), corticosteroids, or vigabatrin for seizures.
• Patient has been previously treated with a course of corticosteroids for an indication other than seizures within 30 days prior to Screening.
• Patient has a known or suspected allergy to ACTH or vigabatrin or any component of AMZ002 or vigabatrin.
• Patient has used any other investigational drug within 30 days or 5 half-lives prior to the first dose of AMZ002 or vigabatrin (whichever is longer).
• Patient's parent/guardian is unable to provide written informed consent and/or to complete the daily diary.
• Patient has any other disease, condition, or therapy that, in the opinion of the Investigator, might compromise safety or compliance, preclude the patient from successfully completing the study, or interfere with the interpretation of the results.

Eligibility last updated 9/15/21. Questions regarding updates should be directed to the study team contact.