• Age 18 (or age of legal consent per local regulations, whichever is older) to 85 years, inclusive.
• Documented diagnosis of ATTR amyloidosis with cardiomyopathy, classified as either hATTR amyloidosis with cardiomyopathy or wtATTR amyloidosis with cardiomyopathy:
  • Hereditary ATTR (hATTR) amyloidosis with cardiomyopathy diagnosed based on meeting all of the following criteria:
  • Documentation of a TTR pathogenic mutation consistent with hATTR amyloidosis;
  • Evidence of cardiac involvement by echocardiography with an end-diastolic interventricular septal wall thickness > 12 mm (based on central echocardiogram reading at Screening);
  • Amyloid deposits in cardiac or noncardiac tissue (e.g., fat pad aspirate, salivary gland, median nerve connective sheath) confirmed by Congo Red (or equivalent) staining OR technetium (99mTc) scintigraphy (99mTc-3,3-diphosphono-1,2- propanodicarboxylic acid [DPD-Tc], 99mTc-pyrophosphate [PYP-Tc] or 99Tchydroxymethylene diphosphonate [HMDP]) with Grade 2 or 3 cardiac uptake, if monoclonal gammopathy of undetermined significance (MGUS) has been excluded;
  • If the patient has evidence of a MGUS based on serum and urine protein electrophoresis and serum free light chains,  documentation of TTR protein in tissue with immunohistochemistry or mass spectrometry is required.
  • Wild-type ATTR (wtATTR) amyloidosis with cardiomyopathy diagnosed based on meeting all of the following criteria:
    • Documentation of absence of pathogenic TTR mutation;
    • Evidence of cardiac involvement by echocardiography with an end-diastolic interventricular septal wall thickness > 12mm (based on central echocardiogram reading at Screening);
    • Amyloid deposits in cardiac tissue with TTR protein identification by IHC, mass spectrometry, OR technetium (99mTc) scintigraphy (99mTc-3,3-diphosphono-1,2- propanodicarboxylic acid [DPD-Tc], 99mTc-pyrophosphate [PYP-Tc], or 99Tchydroxymethylene diphosphonate [HMDP]) with Grade 2 or 3 cardiac uptake, if MGUS has been excluded;
    • If the patient has evidence of a MGUS based on serum and urine protein electrophoresis and serum free light chains, the following is required: documentation of TTR protein in cardiac tissue with immunohistochemistry or mass spectrometry OR documentation of TTR protein in noncardiac tissue (e.g., fat pad aspirate, salivary gland, median nerve connective sheath) with immunohistochemistry or mass spectrometry; AND Grade 2 or 3 cardiac uptake on technetium scintigraphy.
• Medical history of HF with at least 1 prior hospitalization for HF (not due to arrhythmia or a conduction system disturbance treated with a permanent pacemaker) OR clinical evidence of HF (with or without hospitalization) manifested by signs and symptoms of volume overload or elevated intracardiac pressures (e.g., elevated jugular venous pressure, shortness of breath or signs of pulmonary congestion on x-ray or auscultation, peripheral edema) that currently requires treatment with a diuretic.
• Patient meets one of the following criteria: a. Tafamidis-naïve and not actively planning to commence treatment with tafamidis during the first 12 months following randomization.
  • Note: in addition to patients who have never taken tafamidis, those who have previously been on tafamidis and have not received any tafamidis for at least 30 days before the Screening Visit will be considered tafamidis-naïve for purposes of this study); or
  • On tafamidis.  Note: must be on-label use of commercial tafamidis per an approved cardiomyopathy indication and dose in the country of use.
• Patient is clinically stable, with no CV-related hospitalizations within 6 weeks prior to randomization, as assessed by the Investigator.
• Screening NT-proBNP > 300 ng/L and 600 ng/L and < 8500 ng/L.
• Able to complete ≥ 150 meters on the 6-MWT at Screening.
• Have a Karnofsky performance status of ≥ 60%

• Has known primary amyloidosis (AL amyloidosis) or leptomeningeal amyloidosis.
• NYHA Class IV heart failure; or NYHA Class III heart failure AND ATTR Amyloidosis Disease Stage 3 (defined as NT-proBNP > 3000 ng/L and eGFR < 45 ml/min).[Gillmore 2018].
• Has a polyneuropathy disability (PND) Score IIIa, IIIb, or IV (requires cane or stick to walk due to polyneuropathy, or is wheelchair bound) at the Screening visit.
• Has any of the following laboratory parameter assessments at Screening:
  • AST or ALT levels > 2.0 × ULN;
  • Total bilirubin > 2.0 × ULN;
  • International normalized ratio (INR) > 1.5 (unless patients were on anticoagulant therapy in which case excluded if INR ˃ 3.5).
• Has eGFR < 30 mL/min/1.73 m^2 (using the modification of diet in renal disease [MDRD] formula) at Screening.
• Has known human immunodeficiency virus infection; or evidence of current or chronic hepatitis C virus or hepatitis B virus infection.
• Tafamidis-naïve patients for whom the Investigator actively plans or anticipates commencing treatment with tafamidis either during the Screening Period or the first 12 months following randomization, taking into consideration clinical status, patient preference and/or commercial availability of tafamidis.
• Received prior TTR-lowering treatment (including revusiran, patisiran or inotersen) or participated in a gene therapy trial for hATTR amyloidosis.
• Is currently taking diflunisal; if previously on this agent, must have at least a 30-day wash-out prior to dosing (Day 1).
• Is currently taking doxycycline, ursodeoxycholic acid, or tauroursodeoxycholic acid; if previously on any of these agents, must have completed a 30-day wash-out prior to dosing (Day 1).
• Unwilling to avoid any concurrent treatment with diflunisal, ursodeoxycholic acid/tauroursodeoxycholate/doxycycline, or TTR lowering agents (e.g., patisiran, inotersen)
• Current or future participation in another investigational device or drug study, scheduled to occur during this study, or has received an investigational agent or device within 30 days (or 5 half-lives of the investigational drug, whichever is longer) prior to dosing (Day 1). In the case of investigational TTR stabilizer drugs, washout for 3 months prior to dosing (Day 1) is required; this does not apply to patients who are on tafamidis at baseline.
• Requires treatment with or is unwilling to avoid any concurrent treatment with nondihydropyridine calcium channel blockers (e.g., verapamil, diltiazem).
• 30 days (or 5 half-lives of the investigational drug, whichever is longer) prior to dosing (Day 1). In the case of investigational TTR stabilizer drugs, washout for 3 months prior to dosing (Day 1) is required; this does not apply to patients who are on tafamidis at baseline.
• Requires treatment with or is unwilling to avoid any concurrent treatment with nondihydropyridine calcium channel blockers (e.g., verapamil, diltiazem).
• Other non-TTR cardiomyopathy, hypertensive cardiomyopathy, cardiomyopathy due to valvular heart disease, or cardiomyopathy due to ischemic heart disease (e.g., prior myocardial infarction with documented history of cardiac enzymes and ECG changes) that the Investigator feels is a significant contributor or the predominant cause of the patient’s heart failure.
• Unstable congestive heart failure (CHF) (including patients who require adjustment of existing diuretics or addition of new diuretics at time of Screening for purposes of achieving optimal management of CHF).
• Had acute coronary syndrome or unstable angina within the past 3 months.
• Has history of sustained ventricular tachycardia or aborted ventricular fibrillation.
• Has history of atrioventricular nodal or sinoatrial nodal dysfunction for which a pacemaker is indicated but will not be placed.
• Has persistent elevation of systolic (˃ 170 mmHg) or diastolic (˃ 100 mmHg) blood pressure that is considered uncontrolled by physician.
• Has untreated hypo- or hyperthyroidism.
• Has an active infection requiring systemic antiviral, antiparasitic or antimicrobial therapy that will not be completed prior to dosing (Day 1).
• Prior or anticipated (during the first 12 months after randomization) heart, liver or other organ transplant or implantation of left-ventricular assist device.
• History of multiple drug allergies or history of allergic reaction to any component of or excipient in the study drug.
• History of intolerance to SC injection(s) or significant abdominal scarring that could potentially hinder study drug administration or evaluation of local tolerability.
• Has other medical conditions or comorbidities (e.g., malignancy, neuropsychiatric disorder etc…) which, in the opinion of the Investigator, would interfere with study compliance or data interpretation.
• Is not willing to comply with the contraceptive requirements during the study period.
• Female patient is pregnant, planning a pregnancy, or breast-feeding.
• Unwilling or unable to limit alcohol consumption throughout the course of the study. Alcohol intake of > 2 units/day is excluded during the study (unit: 1 glass of wine [approximately 125 mL] = 1 measure of spirits [approximately 1 fluid ounce] = ½ pint of beer [approximately 284 mL]).
• History of alcohol abuse, within the last 12 months before Screening, in the opinion of the Investigator.
• History of illicit drug abuse within the past 5 years that in the opinion of the Investigator would interfere with compliance with study procedures or follow-up visits.

Inclusion Criteria:

• Adult male or female ≥ 12 years of age at the time of informed consent or assent.
• Each subject and/or their parents or legal guardian (for adolescents), must read, understand and provide consent or assent together with their parent(s) or guardian signature (for adolescents) on the ICF for this study and be willing and able to adhere to study-related treatment regimens, procedures and visit schedule.
• Diagnosis or presumptive diagnosis of EoE that is confirmed during the Screening period by histology that demonstrates ≥ 15 peak eos/HPF. In order to ensure that a diagnosis can be made, at least 6 biopsies should be taken from both proximal and distal specimens (at least 3 each). Mid-esophageal biopsies are not required (optional). HPF will be defined as a standard area of 235 square microns in a microscope with 40x lens and 22mm ocular:
  • Esophagogastroduodenoscopies and biopsies are to be obtained during the Screening period;
  • Biopsies will be read by a central pathologist;
  • Esophagogastroduodenoscopies and biopsies performed outside the study will not be accepted to meet eligibility criteria;
  • Optional biopsies may be taken and processed locally for local use, only where specified in the local ICF. If serious pathology is unexpectedly encountered biopsies of such lesions must be processed locally.
• Have a subject-reported history of ≥ 6 episodes of dysphagia in the 14 days prior to baseline.
• Completion of the daily diary on at least 11 out of the 14 days during the 2-week Baseline Symptom Assessment.

• Have known contraindication, hypersensitivity, or intolerance to corticosteroids.
• Have a contraindication to, or factors that substantially increase the risk of, EGD procedure or esophageal biopsy or have narrowing of the esophagus that precludes EGD with a standard 9 mm endoscope.
• Have history of an esophageal stricture requiring dilatation within the previous 12 weeks prior to Screening.
• Bone age more than 12 months behind chronological age for adolescent subjects.
• Have any physical, mental, or social condition or history of illness or laboratory abnormality that in the Investigator’s judgment might interfere with study procedures or the ability of the subject to adhere to and complete the study or increase the safety risk to the subject such as uncontrolled diabetes or hypertension or may increase risk of corticosteroid toxicity (e.g., abnormal bone mineral density).
• History of recurrent or current oral or esophageal mucosal infection due to inhaled or nasal corticosteroids.
• Have any mouth or dental condition that prevents normal eating.
• Have any condition affecting the esophageal mucosa or altering esophageal motility other than EoE, including erosive esophagitis (grade B or higher as per the Los Angeles Classification of Gastroesophageal Reflux Disease;21, hiatus hernia longer than 3 cm, Barrett’s esophagus, and achalasia.
• Use of systemic (oral or parenteral) corticosteroids within 60 days before Screening, use of swallowed corticosteroids within 30 days before Screening.
• Initiation of either inhaled or nasal corticosteroids or high-potency dermal topical corticosteroids within 30 days before Screening
• Use of calcineurin inhibitors or purine analogues (azathioprine, 6-mercaptopurine) in the 12 weeks before Screening.
• Use of potent cytochrome P450 (CYP) 3A4 inhibitors (eg, ritonavir and ketoconazole) in the 12 weeks before Screening.
• Initiation of an elimination diet or elemental diet within 30 days before Screening (diet must remain stable after signing ICF).
• Morning (07:00 to 09:00, or as close to that window as possible) serum cortisol level ≤ 5 μg/dL (138 nmol/L) that is not responsive to ACTH stimulation: defined as a serum cortisol level < 16 μg/dL (440 nmol/L) at 60 minutes with ACTH stimulation test using 250 μg cosyntropin administered intramuscularly (i.e., an abnormal result on the ACTH stimulation test).
• Use of biologic immunomodulators in the 24 weeks before Screening (allergy desensitization injection or oral therapy is allowed as long as the course of therapy is not altered during the study period).
• Subjects who have initiated, discontinued, or changed dosage regimen of histamine H2 receptor antagonists, antacids or antihistamines, leukotriene inhibitors or sodium cromolyn within 4 weeks before qualifying endoscopy. If already receiving these drugs, the dosage must remain constant throughout the study.
• Subjects who have changed dosage regimen of PPIs within 8 weeks before qualifying endoscopy. If already receiving PPIs, the dosage must remain constant throughout the study.
• Infection with hepatitis B, hepatitis C, or human immunodeficiency virus.
• Have gastrointestinal bleeding or documented active peptic ulcer within 4 weeks prior to Screening or entering a new study period.
• Have chronic infection such as prior or active tuberculosis, active chicken pox or measles or absence of prior measles, mumps and rubella vaccine. Subjects with tuberculosis exposure or who live in high endemic areas should be assessed locally for tuberculosis before consideration for the study.
• Immunosuppression or immunodeficiency disorder.
• Current malignancy or malignancy within 3 years of Screening. Subjects in remission for at least 3 years post-treatment may be enrolled.
• Known severe bleeding disorder.
• Have a history or presence of Crohn’s disease, celiac disease, or other inflammatory disease of the gastrointestinal tract, including eosinophilic gastroenteritis.
• Have current drug abuse in the opinion of the Investigator.
• Have current alcohol abuse in the opinion of the Investigator.
• Female subjects who are pregnant, breastfeeding, or planning to become pregnant during the study.
• Sexually active females of childbearing potential who do not agree to follow highly effective contraceptive methods through the End of Study visit.
• Have received an investigational product, as part of a clinical trial within 30 days (or 5 halflives, whichever is longest) of Screening. Subjects who are currently participating in observational studies or enrolled in patient registries are allowed in this study.
• Have participated in a prior study with investigational product APT-1011.

• Subject has multiple myeloma, 18 years of age or older and subject or legally authorized representative is able to sign the informed consent form.
• Subject had a subject-specific batch of idecabtagene vicluecel manufactured intended for commercial treatment; however, the final manufactured product was nonconforming and did not meet commercial release criteria. The Sponsor has determined that the nonconforming idecabtagene vicleucel may be released for use under the Expanded Access Protocol.
• Remanufacturing is deemed not feasible or clinically inappropriate per assessment of the treating physician in discussion with the subject.
• Subject is clinically stable, has recovered from any prior toxicities prior to receiving lymphodepleting chemotherapy, and has adequate bone marrow function to receive lymphodepleting chemotherapy.
• Females of childbearing potential must:
  • Have a negative pregnancy test as verified by the treating physician within 7 days prior to the first dose of lymphodepleting chemotherapy following institutional testing methodology practices. This applies even if the subject practices true abstinence from heterosexual contact;
  • Either commit to true abstinence from heterosexual contact or agree to use, and be able to comply with, effective contraception without interruption. Contraception methods must include 1 highly effective method from screening until at least 12 months after the lymphodepleting chemotherapy;
  • Agree to abstain from breastfeeding during study participation and for at least 12 months following lymphodepleting chemotherapy;
  • There are insufficient exposure data to provide any recommendation concerning the duration of contraception and the abstaining from breastfeeding following treatment with nonconforming idecabtagene vicluecel. Any decision regarding contraception and breastfeeding after infusion should be discussed with the treating physician.
• Male subjects must:
  • Practice true abstinence or agree to use a condom;
  • There are insufficient exposure data to provide any recommendation concerning the duration of contraception following treatment with nonconforming idecabtagene vicluecel. Any decision regarding contraception after infusion should be discussed with the treating physician.
• Subject must agree to not donate blood, organs, tissue, sperm or semen and egg cells for usage in other individuals for at least 1 year following lymphodepleting chemotherapy. There are insufficient exposure data to provide any recommendation concerning the duration of refraining from tissue donation following treatment with nonconforming idecabtagene vicluecel. Therefore, participants treated with nonconforming idecabtagene vicluecel should not donate blood, organs, tissues, and cells for transplantation.

• Subject has a hypersensitivity to the active substance or to any of the excipients.
• Subject should not experience a significant worsening in clinical status that would, in the opinion of the treating physician, either increase the risk of AEs associated with lymphodepleting chemotherapy or exclude them from treatment with nonconforming idecabtagene vicluecel.
• Subject has any significant medical condition, laboratory abnormality, or psychiatric illness, sociologic or geographic condition that would prevent the subject from participating in the Expanded Access Protocol, complying with protocol requirements or confound the ability to interpret the data in the Investigator's judgement.
• Subject has any condition and/or laboratory abnormality that places the subject at unacceptable risk if he/she were to participate in the Expanded Access Protocol based on the Investigator's judgement.
• Pregnant or nursing women or has intention of becoming pregnant during the study.

Eligibility last updated 1/23/23. Questions regarding updates should be directed to the study team contact.

• Adults and children with a confirmed molecular diagnosis of cystic fibrosis.

• No confirmed diagnosis of CF.

Eligibility last updated 7/8/22. Questions regarding updates should be directed to the study team contact.

• Subjects male or female aged 2 to 17 years, inclusive, who weigh ≥ 10 kg at the time of screening and enrollment into the study.
• Subjects with moderately to severely active CD diagnosed at least 1 month before screening, defined by a PCDAI > 30 and an SES-CD > 6 (or an SES-CD ≥ 4 if disease is confined to terminal ileum).
• Subjects who have failed, lost response to, or been intolerant to treatment with at least 1 of the following agents:
  • corticosteroids, immunomodulators (eg, AZA, 6-mercaptopurine, methotrexate), and/or TNF-α antagonist therapy (e.g., infliximab, adalimumab). This includes subjects who are dependent on corticosteroids or exclusive or partial enteral nutrition to control symptoms and who are experiencing worsening of disease in the moderate-to-severe range when attempting to wean off corticosteroids or discontinue exclusive enteral nutrition.
• Subjects with extensive colitis or pancolitis of > 8 years’ duration or left-sided colitis of > 12 years’ duration must have documented evidence of a negative surveillance colonoscopy within 12 months before screening.
• Subjects with vaccinations that are up-to-date based on the countrywide accepted schedule of childhood vaccines.

• Subjects who have had previous exposure to approved or investigational anti-integrins, including but not limited to natalizumab, efalizumab, etrolizumab, or AMG 181, or mucosal addressin cell adhesion molecule-1 (MAdCAM-1) antagonists or rituximab.
• Subjects who have had prior exposure to vedolizumab.
• Subjects with hypersensitivity or allergies to any of the vedolizumab excipients.
• Subjects who have received either:
  • an investigational biologic within 60 days or 5 half-lives before screening (whichever is longer); or
  • an approved biologic or biosimilar agent within 2 weeks before the first dose of study drug or at any time during the screening period.
• Subjects with active cerebral/meningeal disease, signs/symptoms or history of progressive multifocal leukoencephalopathy (PML) or any other major neurological disorders including stroke, multiple sclerosis, brain tumor or neurodegenerative disease.
• Subjects who currently require surgical intervention or are anticipated to require surgical intervention for CD during this study.
• Subjects who have had subtotal or total colectomy or have a jejunostomy, ileostomy, colostomy, ileo-anal pouch, known fixed stenosis of the intestine, short bowel syndrome, or > 3 small intestine resections.
• Subjects with a current diagnosis of indeterminate colitis.
• Subjects with clinical features suggesting monogenic very early-onset inflammatory bowel disease.

• 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.

• Written informed consent.
• Aged 18 or above.
• Unresectable stage III or stage IV squamous or non-squamous NSCLC not amenable to curative surgery or radiation.
• Documented PD-L1 expression by PD-L1 IHC per local report.
• Confirmed progression during treatment with a CPI-including regimen.
• ECOG performance status of 0 or 1 at enrolment.
• Life expectancy of ≥ 12 weeks at enrolment.
• Adequate bone marrow, liver and kidney function.

• Sensitizing epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) fusion.
• Documented test result for any other known genomic alteration for which a targeted therapy is approved in first line per local standard of care (e.g. ROS1, NTRK fusions, BRAF, V600E mutation).
• Previous treatment with an anti-TIGIT therapy.
• Any concurrent chemotherapy, radiotherapy, investigational, biologic, or hormonal therapy for cancer treatment.
• Primary or secondary resistance after treatment with 2 or more regimens including a CPI.
• Symptomatic central nervous system (CNS) metastasis.
• Thromboembolic event within 3 months prior to enrolment.
• Other invasive malignancy within 2 years prior to screening.

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

Inclusion Criteria
•Main Phase 0:

• Histologically (if prior biopsy) or radiologically diagnosed glioblastoma.
• Neurosurgical tumor resection is indicated and planned, according to the assessment of the treating physician.
• Patients must be at least 18 years old.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
• Adequate organ function.
• Life expectancy ≥ 3 months at the start of treatment in the opinion of the investigator.

Inclusion Criteria
•Main Phase Ia:

• Histologically demonstrated diagnosis of TP53 wild type glioblastoma harboring unmethylated MGMT promoters (Glioblastoma definition according to 2021 WHO Classification of CNS tumors; i.e., IDH-wild type only).
• Patient has undergone neurosurgical tumor resection and is eligible for standard radiotherapy.
• Formalin-fixed paraffin-embedded tumor blocks or representative H/E (haematoxylin/eosin) slides (preferably both) must be available for retrospective histopathological central review. Locally performed histopathological diagnosis will be accepted for entry into this trial.
• Patients must be at least 18 years old.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
• Adequate organ function.
• Life expectancy ≥ 3 months at the start of treatment in the opinion of the investigator.

Exclusion Criteria
•Main Phase 0:

• Known TP53 mutant glioblastoma (Note: testing is not mandatory for inclusion).
• Known IDH mutant grade IV astrocytoma.
  • Note: testing is not mandatory for inclusion.
• Patients with pacemakers or other metallic implants that can interfere with the magnetic field during MRI investigations.
• Inability to undergo contrast-enhanced MRI (GFR < 30 mL/min).

Exclusion Criteria
•Main Phase Ia:

• Patients who have received previous systemic therapy (with the exception of patients who participated in Phase 0) or radiotherapy for glioblastoma.
• Patients with pacemakers or other metallic implants that can interfere with the magnetic field during MRI investigations.
• Inability to undergo contrast-enhanced MRI (GFR < 30 mL/min).

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

Eligibility last updated 12/26/23. Questions regarding updates should be directed to the study team contact

• Critically ill adult (>18 years old) patients and expected to have >48-hour ICU stay.
• Functional GI tract (able to tolerate oral diet or tube feeding).

• Premorbid known immunosuppression over 1 month duration (due to medications including chronic steroids, TNF-alpha inhibitors, monoclonal antibodies, immunosuppressive antimetabolites, etc.).
• Compromised gut integrity (bowel resection, GI malignancy, GI bleed, inflammatory bowel disease, intestinal obstruction, intra-abdominal hypertension, intestinal ischemia/reperfusion injury or secondary ileus).
• Dairy intolerance or milk allergy.
• Extremely poor prognosis and not expected to survive the treatment period.
• Goals of care change to comfort care.
• Pregnant patients.

• Male or female and at least 18 years of age at screening.
• Has a history of UC for at least 3 months prior to screening (with involvement beyond the rectum to at least 15 cm from the anal verge).
• Has moderate-to-severely active UC, as defined by a Mayo endoscopic subscore of ≥ 2 points and an adapted Mayo score between 4
  •9 points, inclusive.
• Is corticosteroid-dependent or has demonstrated inadequate response, or intolerance to conventional therapy (aminosalicylates, corticosteroids, immunomodulators) or biologics.
• If subject is currently receiving oral aminosalicylate (e.g., mesalamine products, balsalazide, or sulfasalazine):
• Subject is eligible provided the subject has been on it at a stable dose for ≥ 4 weeks prior to Day 1.
• During the Study and for 7 days after receiving the last dose of the Study drug, females of childbearing potential or men capable of fathering children must agree to use highly effective birth control measures (failure rate < 1% when used consistently and correctly) or agree to abstain from sexual intercourse. Females of childbearing potential must test negative for pregnancy at screening and at Day 1.
• All male subjects must agree to refrain from semen donation during the Study and for 7 days after the last dose of Study drug.
• Must be able and willing to adhere to the Study visit schedule and comply with other protocol requirements.
• Are capable of providing informed consent, which must be obtained prior to any Study-related procedures.

Inclusion Criteria for Extended Induction (additional 8 weeks):

• Did not meet criteria for clinical response by adapted Mayo score using centrally read endoscopic subscore at Week 8a.

Inclusion Criteria for Maintenance Study:

• Must have met the criteria for a clinical response by adapted Mayo score using centrally read endoscopic subscore during Induction at Week 8a or during Extended Induction Study at Week 16.

• Has symptoms suggestive of fulminant colitis, megacolon or intestinal perforation.
• Has primary sclerosing cholangitis (PSC).
• Likely to require surgery for UC or other major surgeries.
• Has had a clinically significant, as deemed by the investigator, prior intestinal resection for UC or for other gastrointestinal diseases (e.g., that may have resulted in chronic diarrhea)
• Has previously received / is currently receiving prohibited medications within specified timeframe.
• Is refractory to 3 biologics with ≥ 2 mechanisms of action.
• Has a current bacterial, parasitic, fungal, or viral infection.
• Has clinically significant abnormalities in laboratory evaluations.
• Has had any prior exposure to an approved Janus kinase (JAK) inhibitor or potential exposure to an investigational JAK inhibitor that was stopped due to intolerance or lack of efficacy.
• Are pregnant, lactating, breastfeeding or planning to become pregnant during the Study or within 7 days after the last dose of Study Drug.
• Has known moderate or severe hepatic impairment (e.g., Child-Pugh Class B or C).
• Has clinically significant abnormalities in the results of laboratory evaluations at screening visit as determined by the investigator, including:
  • AST, ALT, or alkaline phosphatase ≥ 2 x the upper limit of normal (ULN);
  • Total bilirubin > 2 x ULN (unless diagnosis of Gilbert’s syndrome);
  • Creatinine clearance as calculated by the Cockcroft-Gault formula < 30 mL/min;
  • Total white blood cell count (WBC) < 3 x 10^9 /L;
  • Absolute neutrophil count < 1.5 x 10^9 /L;
  • Absolute lymphocyte count < 0.8 x 10^9 /L;
  • Hemoglobin < 8 g/dL; or
  • Platelet count < 100 x 10^9 /L.
• Has a clinically significant abnormal electrocardiogram (ECG) at screening, including QTcF > 450 msec for males and > 470 msec for females.
• Has unstable or uncontrolled and clinically significant condition/disease that would compromise subject safety or confound Study safety assessment as determined by the investigator at screening and Day 1.
• Has known hypersensitivity to excipients or contents of the Study drug.
• Has participated in another clinical trial of an investigational drug (or medical device) within 30 days prior to Screening or 5 x the half-life of the investigational drug, whichever is longer, or is currently participating in another trial of an investigational drug (or medical device).
• Have or has a history of alcohol or drug abuse within 1 year of screening, per the judgment of the investigator.
• Has a current, or history of, malignancy requiring radiation or pharmacologic treatment within 5 years prior to screening, except for completely resected basal cell carcinoma or squamous cell carcinoma of the skin without recurrence for ≥ 1 year, cervical carcinoma in situ that has been adequately treated and without recurrence for ≥ 5 years.
• Is deemed by the investigator to be inappropriate for this Study; or has any condition which would confound or interfere with the evaluation of the safety, tolerability, or PK of the investigational drug; or is unable or unwilling to comply with the Study protocol.

• Patients over the age of 18 years old.

• Children.

• Symptomatic, moderate-to-severe or severe mitral regurgitation (MR ≥ Grade III per American Society of Echocardiography criteria), or severe mitral annular calcification (MAC), where a transcatheter therapy is deemed more appropriate than conventional mitral valve surgery by the local site heart team.
  • Note: MR severity must be determined by assessment of a qualifying transesophageal echocardiogram (TEE) and transthoracic echocardiogram (TTE), obtained within 120 days prior to subject consent, and must be confirmed by the Echocardiography Core Laboratory.
  • Note: Patients with severe MAC must have symptomatic mitral valve disease associated with MR ≥ Grade III, or severe mitral stenosis (MS), or both moderate MR and moderate MS as assessed by the Echocardiography Core Laboratory.
• NYHA Functional Classification ≥ II (if Class IV, patient must be ambulatory).
• The local site heart team determines that the subject has been adequately treated per applicable standards for coronary artery disease (e.g., revascularization), left ventricular dysfunction (e.g., cardiac resynchronization therapy) and heart failure (e.g., GDMT). The Subject Eligibility Committee must concur that the subject has been adequately treated.
• The local site heart team and the Subject Eligibility Committee concur on the intended study cohort for the subject.
  • Randomized Cohort: Eligibility for this cohort is limited to subjects where the local site heart team deems the mitral valve anatomy is amenable to transcatheter edge-to-edge repair within approved MitraClip indications. Subjects with primary MR must be at prohibitive surgical risk, while subjects with secondary MR must be symptomatic despite maximally-tolerated guideline- directed medical therapy.
  • Non-repairable Cohort: Eligibility for this cohort is limited to subjects where the local site heart team deems the mitral valve anatomy is not amenable for transcatheter repair with MitraClip or does not meet MitraClip indications.
  • Severe MAC Cohort: Eligibility for this cohort is limited to subjects where the local site heart team deems the degree of MAC renders the subject unsuitable for mitral valve surgery.
• Age 18 years or older at time of consent.
• Subject has been informed of the nature of the trial and agrees to its provisions, including the possibility of randomization to the Control group, complying with trial required testing, medications, and follow-up visits, and has provided written informed consent.

• Mitral valvular vegetation or mass.
• Left Ventricle (LV) or Left Atrium (LA) thrombus.
• Chest condition that prevents transapical access.
• Left Ventricular Ejection Fraction (LVEF) less than 25% assessed by the site based on a TTE obtained within 120 days prior to subject consent.
  • Note: LVEF will be principally based on TTE and must be confirmed by the Echocardiography Core Laboratory.
• Left Ventricular End Diastolic Diameter (LVEDD) > 7.0 cm assessed by the site based on a TTE obtained within 120 days prior to subject consent.
  • Note: A qualifying LVEDD must be confirmed by the Echocardiography Core Laboratory.
• Prior surgical or interventional treatment of mitral valve involving implantation of prosthetic material (e.g. valve repair or replacement, or MitraClip).
• Mitral pathoanatomy and Left Ventricular Outflow Tract (LVOT) anatomy deemed not suitable for Tendyne mitral valve implantation.
• Aortic valve disease requiring surgery or transcatheter intervention.
• Tricuspid valve disease requiring surgery or transcatheter intervention.
• Severe tricuspid regurgitation or severe right ventricular dysfunction.
• Any surgical or interventional procedure within the period of 60 days prior to or planned procedure 60 days following subject registration.
• Implant or revision of Cardiac Resynchronization Therapy (CRT) device within 90 days prior to intended subject registration.
• Myocardial Infarction (MI) within 30 days prior to intended subject registration.
• Symptomatic, unresolved multi-vessel or unprotected left main coronary artery disease (e.g., active ischemia) requiring stenting or Coronary Artery Bypass Grafting (CABG).
• Cerebrovascular accident (CVA) within 6 months prior to intended subject registration.
• Unresolved severe symptomatic carotid stenosis (> 70% by ultrasound).
• Cardiogenic shock or hemodynamic instability requiring inotropes or mechanical support devices at the time of planned implant procedure.
• Hypertrophic or restrictive cardiomyopathy, or constrictive pericarditis.
• Any of the following: leukopenia, acute anemia, thrombocytopenia, history of bleeding diathesis, or coagulopathy if cannot be adequately treated.
• History of endocarditis within 6 months of planned implant procedure.
• Active systemic infection requiring antibiotic therapy.
• Known hypersensitivity or contraindication to procedural or post- procedural medications (e.g., contrast solution, anti-coagulation and antiplatelet therapy) that cannot be adequately managed medically.
• Subjects in whom TEE is contraindicated or high risk.
• Known hypersensitivity to nickel or titanium.
• Subject is undergoing hemodialysis due to chronic renal failure.
• Subject has pulmonary arterial hypertension (fixed PAS > 70mmHg).
  • Note: If PAS > 70mmHg, site must provide documentation PAS is not fixed in order to be eligible.
• Subject has Chronic Obstructive Pulmonary Disease (COPD) requiring continuous home oxygen therapy or chronic outpatient oral steroid use.
• Subjects with non-cardiac comorbidities that are likely to result in a life expectancy of less than 12 months.
• Modified Rankin Scale ≥ 4 disability.
• Status 1 heart transplant or prior orthotopic heart transplantation.
• Pregnant, lactating, or planning pregnancy during the clinical investigation follow-up period.
  • Note: Female subjects of childbearing age should be instructed to use safe contraception (e.g. intrauterine devices, hormonal contraceptives: contraceptive pills, implants, transdermal patches hormonal vaginal devices, injections with prolonged release).
• Currently participating in an investigational drug or another device trial that has not reached its primary endpoint.
  • Note: Trials requiring extended follow-up for products that were investigational, but have since become commercially available, are not considered investigational trials.
• Presence of other anatomic or comorbid conditions, or other medical, social, or psychological conditions that, in the investigator’s opinion, could limit the subject’s ability to participate in the clinical investigation or to comply with follow- up requirements, or impact the scientific soundness of the clinical investigation results.

Eligibility last updated 4/28/22. Questions regarding updates should be directed to the study team contact.

STEP 1 REGISTRATION

• If this will be the first patient from a registering site to receive a given RT modality (3DCRT vs. IMRT), the site must first submit pre-RT planning documents within 3 days of Step 1 registration and receive approval from Imaging and Radiation Oncology Core (IROC) before randomizing the patient to Step 2. If this will not be the first patient to receive a specific RT modality, the patient should be immediately randomized to Step 2 on the same day. 

STEP 2 RANDOMIZATION

• If patient required review of pre-RT planning, randomization must occur within 14 days of initial registration. 
• Patients must have histologically proven, T2-T4a N0M0 urothelial carcinoma of the bladder within 70 days prior to randomization. Patients with mixed urothelial carcinoma will be eligible for the trial, but the presence of small cell carcinoma will make a patient ineligible. Patients with lymph nodes ≥ 1.0 cm in shortest cross-sectional diameter on imaging (computed tomography [CT]/magnetic resonance imaging [MRI]) must have a biopsy of the enlarged lymph node showing no tumor involvement within 70 days prior to randomization. These patients may be suitable for neoadjuvant chemotherapy and radical cystectomy and are eligible for this trial if they seek out a bladder sparing treatment strategy, however patients who have received prior systemic chemotherapy for bladder cancer are not eligible for the trial. 
• Patients must undergo a transurethral resection of bladder tumor (TURBT) within 70 days prior to randomization. In a situation where a patient is referred from outside to the enrolling institution, patient must have a repeat cystoscopy by the urologist who will be following the patient on the clinical trial to assess the adequacy of the prior TURBT. Patient may then undergo repeat TURBT if deemed necessary as standard of care by the treating urologist. Patients may have either completely or partially resected tumors as long as the treating urologist attempted maximal resection. Patient must not have T4b disease. 
• Patients must undergo radiological staging within 70 days prior to randomization. Imaging of chest, abdomen, and pelvis must be performed using CT or MRI. Patients must not have evidence of T4bN1-3 disease. Eligibility is based on the local radiology report. 
• Patients with hydronephrosis are eligible if they have unilateral hydronephrosis and kidney function meets criteria specified. 
• Patients must not have had urothelial carcinoma or histological variant at any site outside of the urinary bladder within the previous 24 months except Ta/T1/carcinoma in situ (CIS) of the upper urinary tract including renal pelvis and ureter if the patient had undergone complete nephroureterectomy. 
• Patients must not have diffuse CIS based on cystoscopy and biopsy. 
• Patient must be planning to receive one of the protocol specified chemotherapy regimens.
• All adverse events associated with any prior surgery and intravesical therapy must have resolved to Common Terminology Criteria for Adverse Events (CTCAE) grade ≤ 2 prior to randomization. 
• Patient must not have received any systemic chemotherapy for their bladder cancer. 
• Patient must not have had prior pelvic radiation. 
• Patients must not have received prior treatment for muscle invasive bladder cancer including neoadjuvant chemotherapy for the current tumor. 
• Patients must not have received any systemic therapy (including, but not limited to, interferon alfa-2b, high dose IL-2, pegylated interferon [PEG-IFN], anti-PD-1, anti-PD-L1), for non-muscle invasive bladder cancer. Prior intravesical BCG, interferon, and intravesical chemotherapy are allowed. 
• Patients must not have received any of the following prohibited therapies within 28 days prior to randomization or be planning to receive any of the following prohibited therapies during protocol treatment: 
  • Anti-cancer systemic chemotherapy or biological therapy not specified in the protocol
  • Immunotherapy not specified in this protocol;
  • Systemic or intravesical use of any non-study anti-cancer agent (investigational or non-investigational);
  • Investigational agents other than atezolizumab;
  • Live vaccines: Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, shingles, yellow fever, rabies, bacillus Calmette-Guerin (BCG), and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed. Prior administration of intravesical BCG is allowed;
  • Glucocorticoids for any purpose other than to modulate symptoms from an event of suspected immunologic etiology. The use of physiologic doses of corticosteroids (defined as 10 mg prednisone) are acceptable, however site investigators should consult with the study chair for any dose higher than 10 mg prednisone. Dexamethasone 4 mg iv with chemotherapy to prevent nausea is allowed;
  • RANKL infusion: Concurrent denosumab (which binds the cytokine RANKL) for any known indication is prohibited due to interaction with study medication. 
• Patients must not have a major surgical procedure within 28 days prior to randomization. If patient had any surgical procedure then they should have recovered to full presurgical performance status and surgical adverse events should have resolved to grade ≤ 2. TURBT is not considered a major surgical procedure. 
• Patients must not have received treatment with systemic immunosuppressive medications (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 14 days prior to randomization. Exceptions: 
  • Patients may have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea);
  • The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed. Physiological doses equivalent of 10 mg prednisone daily are allowed. Short term steroids given as antiemetic therapy; e.g., 4 mg dexamethasone or equivalent once a week, is allowed. 
• Patients must not have received a live, attenuated vaccine within 4 weeks prior to randomization or anticipate that such a live, attenuated vaccine will be required while on protocol treatment and up to 5 months after the last dose of protocol treatment. 
  • Inactivated influenza vaccination should be given during influenza season only (approximately October to March). Patients must not receive live, attenuated influenza vaccine within 4 weeks prior to randomization or while on protocol treatment and up to 5 months after the last dose of protocol treatment. 
• Patients must not have undergone prior allogeneic bone marrow transplantation or prior solid organ transplantation. 
• Patient may or may not be radical cystectomy candidates.
• Absolute neutrophil count (ANC) ≥ 1,500/microliter (mcL) (within 28 days prior to randomization). 
• Platelets ≥ 100,000/mcL (within 28 days prior to randomization).
• Hemoglobin ≥ 9 g/dL (within 28 days prior to randomization).
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (IULN) (except patients with Gilbert's syndrome, who must have a total bilirubin < 3.0 mg/dL) (within 28 days prior to randomization). 
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2.5 x IULN (within 28 days prior to randomization). 
• Patients must not have clinically significant liver disease that precludes patient from treatment regimens prescribed on the study (including, but not limited to, active viral, alcoholic or other autoimmune hepatitis, cirrhosis or inherited liver disease). 
• Patients must have adequate renal function as evidenced by calculated creatinine clearance ≥ 25 mL/min. The creatinine used to calculate the clearance result must have been obtained within 28 days prior to randomization. 
• Patients must have Zubrod performance status ≤ 2. 
• Patients must have a baseline electrocardiography (ECG) performed within 30 days prior to randomization. 
• Patient must not have history of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis. 
• Patients must not have an active infection requiring oral or IV antibiotics within 14 days prior to randomization. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are not eligible. If patient develops urinary tract infection after TURBT they must have recovered from the infection prior to registration.
• Patients must not have active autoimmune disease that has required systemic treatment in past two years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Autoimmune diseases include, but are not limited to, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Bell's palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, Graves' disease treated with methimazole or glomerulonephritis. 
• Patient must not have a history of active tuberculosis. 
• If patient has a known history of hepatitis B virus (HBV) or hepatitis C virus (HCV), they must meet the following criteria within 28 days prior to randomization. 
  • Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible;
  • Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA). 
• Patients who are known to be positive for human immunodeficiency virus (HIV) are eligible only if they have all of the following: 
  • A stable regimen of highly active anti-retroviral therapy (HAART);
  • No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections;
  • A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard PCR-based tests within 28 days prior to randomization.
• No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for two years. Patients with localized prostate cancer who are being followed by an active surveillance program are also eligible. 
• Female patients of childbearing potential must have a serum pregnancy test prior to randomization. Patients must not be pregnant or nursing due to the potential teratogenic side effects of the protocol treatment. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of protocol treatment, and for 5 months (150 days) after the last dose of all study drugs. A woman is considered to be of "reproductive potential" if she has had a menses at any time in the preceding 12 consecutive months. 
• Patients must not be known to be allergic to Chinese hamster egg or ovary cell products and must not have any known major allergic reactions to any study drug. 
• Patients must be offered the opportunity to participate in specimen banking for future studies. 
• Patients who can complete Patient-Reported Outcome instruments in English or Spanish must agree to complete the EORTC QLQ-C30, the EORTC QLQ-BLM30, the EPIC-26 (bowel domain only), and the EQ-5D-5L per protocol schedule of assessment. 
• As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system.

Note: Participants aged 16 or 17 may enroll in M14-234 or M14-675 where locally permissible.

• Participant has not achieved clinical response at the end of the induction period (Week 8) in Study M14-234 Substudy 1, has had loss of response during the maintenance period of Study M14-234 Substudy 3, or has successfully completed Study M14-234 Substudy 3.
• If female, participant must meet the criteria for Contraception Recommendations.
• Women of childbearing potential must have a negative urine pregnancy test at Week 0 visit.
• Participant is judged to be in otherwise good health as determined by the principal investigator based upon clinical evaluations performed during the preceding study (Study M14-234).
• Must be able and willing to give written informed consent and to comply with the requirements of this study protocol.

• For any reason participant is considered by the investigator to be an unsuitable candidate.
• Female participant with a positive pregnancy test at the final visit of Study M14-234 or who is considering becoming pregnant during the study or within 30 days after the last dose of study drug.
• Participant with an active or recurrent infection that based on the investigator's clinical assessment makes the participant an unsuitable candidate for the study. Participants with ongoing infections undergoing treatment may be enrolled BUT NOT dosed until the infection has been successfully treated.
• Current evidence of active or untreated latent tuberculosis.
• Participant with a poorly controlled medical condition, such as uncontrolled diabetes, unstable ischemic heart disease, moderate or severe congestive heart failure (New York Heart Association class III or IV), recent cerebrovascular accidents and any other condition which, in the opinion of the investigator or sponsor, would put the subject at risk by participation in this study.
• Participants have malignancy, high-grade dysplasia, un-removed low-grade dysplasia of the gastrointestinal tract diagnosed at the endoscopy performed at the final visit of Study M14-234.
• History of any malignancy except for successfully treated nonmelanoma skin cancer (NMSC) or localized carcinoma in situ of the cervix from evaluations performed in Study M14-234.

• Patient must be 18 years of age or older, at the time of signing the informed consent.
• Anti-aquaporin-4 antibody-positive and a diagnosis of NMOSD as defined by the 2015 international consensus diagnostic criteria.
• At least 1 attack or relapse in the last 12 months prior to the Screening Period.
  • NOTE: Patients with a single life-time attack will be considered to satisfy inclusion criterion #3 if the attack occurred in the last 12 months.
• Expanded Disability Status Scale score ≤ 7.
• Patients who enter the trial receiving supportive IST (eg, corticosteroids, azathioprine [AZA], mycophenolate mofetil [MMF], methotrexate [MTX], and tacrolimus [TAC]) for the prevention of relapse, either in combination or monotherapy, must be on a stable dosing regimen of adequate duration prior to Screening with no plan to change the dose during the study period (defined as from the screening visit through the end of the study) as follows: a. If patients who enter the study are receiving AZA, they must have been on AZA for ≥ 6 months and have been on a stable dose for ≥ 2 months prior to Screening. b. If patients who enter the study are receiving other ISTs (eg, MMF, MTX, or TAC), they must have been on the IST for ≥ 3 months and have been on a stable dose for ≥ 4 weeks prior to Screening. c. If patients who enter the study are receiving oral corticosteroids, they must have been on a stable dose for ≥ 4 weeks prior to Screening. d. If a patient enters the trial receiving oral corticosteroid(s) with or without other IST(s), the daily corticosteroid dose must be no more than prednisone 20 mg/day (or equivalent) prior to Screening.
• Vaccinated against N. meningitidis within 3 years prior to, or at the time of, initiating ravulizumab. Patients who initiate study drug treatment less than 2 weeks after receiving a meningococcal vaccine must receive appropriate prophylactic antibiotics until 2 weeks after the vaccination.
• Body weight ≥40 kilograms.
• Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
  • Male patients must agree to use contraception as detailed in the protocol during the treatment period and for at least 8 months after last dose of study drug and refrain from donating sperm during this period;
  • Not a woman of childbearing potential (WOCBP) OR • Is a WOCBP and using a highly effective or acceptable contraceptive method as described in Section 10.4 during the treatment period and for a minimum of 8 months after the last dose of study drug. − The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study drug. A WOCBP must have a negative serum pregnancy test at screening and a negative urine pregnancy test before the first dose of study drug. Additional requirements for pregnancy testing during and after study drug. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

• History of N. meningitidis infection.
• Human immunodeficiency virus (HIV) infection (evidenced by HIV-1 or HIV-2 antibody titer).
• History of unexplained infections.
• Active systemic bacterial, viral, or fungal infection within 14 days prior to study drug administration on Day 1.
• Presence of fever ≥ 38°C (100.4°F) within 7 days prior to study drug administration on Day 1.
• Hypersensitivity to murine proteins or to 1 of the excipients of ravulizumab.
• Any medical condition that, in the opinion of the Investigator, might interfere with the patient’s participation in the trial, poses any added risk for the patient, or confounds the assessment of the patient.
• Previously or currently treated with a complement inhibitor.
• Use of rituximab within 3 months prior to Screening.
• Use of mitoxantrone within 3 months prior to Screening.
• Use of Intravenous Immunoglobulin (IVIg) within 3 weeks prior to Screening.
• Participation in any other investigational drug study or exposure to an investigational drug or device within 30 days of Screening or 5 half-lives of the investigational drug, whichever is greater.
• Pregnant, breastfeeding, or intending to conceive during the course of the study.
• Patient is currently treated with a biologic medication that may affect immune system functioning, or has stopped treatment with a biologic medication that may affect immune system functioning, and 5 half-lives of the medication have not elapsed by the time of the Screening visit, unless otherwise specified in the protocol.
• Participation in the PREVENT study (ECU-NMO-301), regardless of the study drug received (eculizumab or placebo).

• Subject must have completed protocol AVTX-803-LAD-301.
• Subject must be between 6 months and 75 years old.
• Subject or parent (for subjects under legal age for consent) has provided written informed consent for this study. Additionally, written informed assent has been provided, as appropriate, for minors of older age, per local institutional review board (IRB)/ethics committee (EC) policy and requirements.
• Subject has biochemically and genetically proven LAD II (SLC35C1-CDG).
• Subject is willing and able to comply with the protocol.
• Women of childbearing potential (WOCBP) meeting the criteria below:
  • Non-lactating and has a negative pregnancy test at screening; AND
  • Uses an acceptable double-barrier method of contraception as determined by the investigator or sub-investigator for the duration of the study and 30 days following the last dose of study drug.
• Male subjects must agree to use an acceptable double-barrier method of contraception with their partner as determined by the investigator or sub-investigator for the duration of the study and 30 days following the last dose of study drug.  

• Subject has severe anemia defined as hemoglobin < 8.0 g/dL (< 4.9 mmol/L).
• Subject has impaired renal function as defined by an eGFR < 90 mL/min.
• Subject has known or suspected intolerance or hypersensitivity to fucose or any ingredients of the investigational product.
• In the investigator’s opinion, subject has a history of failure to respond to fucose at adequate dosing.
• In the investigator’s opinion, subject is not able or not willing to comply with the study requirements.
• Subject is pregnant.

Eligibility last updated 7/13/22. Questions regarding updates should be directed to the study team contact.

• Able to provide written informed consent. Adult patients under guardianship may participate if permitted by local regulations with the consent of their legally authorized guardian. All local regulations concerning patients under guardianship must be followed.
• Age ≥ 18 years at the time of informed consent.
• Histologically confirmed diagnosis of cutaneous melanoma with metastases to the brain.
• Presence of BRAFV600 mutation in tumor tissue previously determined by a local PCR or NGS-based assay at any time prior to Screening or by a central laboratory during Screening.
• Patients are required to submit archival or fresh tumor tissue and a blood sample prior to enrollment. Tissue samples will be used to determine BRAFV600-mutation status by central laboratory.
• Must have at least 1 parenchymal brain lesion ≥ 0.5 cm and ≤ 4 cm, defined as an MRI contrast-enhancing lesion that may be accurately measured in at least 1 dimension. Note: Measurable intracranial lesions that have been previously irradiated and have not been shown to be progressing following irradiation should not be considered as target lesions.
• Patients may have received the following prior therapies.

Safety Lead-in, Phase 2 Randomized, Phase 2 Arm A Cohort 1:

• May have received prior local therapy for brain metastases including but not restricted to brain surgery, whole brain radiotherapy (WBRT), stereotactic radiotherapy or stereotactic radiosurgery (e.g., gamma knife, linear-accelerated-based radiosurgery, charged particles, and CyberKnife). Multiple local (brain) therapies or combinations of local therapies are allowed. For patients receiving local therapy to all brain lesions (including WBRT), progression of pre-existing lesions based on RECIST 1.1 (> 20% increase in longest diameter on baseline scan) or new measurable lesions are required. For patients receiving local therapy for some but not all lesions, disease progression based on RECIST 1.1 is not required as long as there are remaining brain lesions that are measurable and not previously treated.

Phase 2 Arm A Cohort 2:

• Received no prior local therapy (e.g., brain surgery, craniotomy, SRS or SRT) for brain metastases;
• All patients (Safety Lead-In and Phase 2): May have received prior immunotherapy;
• All patients (Safety Lead-In and Phase 2): If receiving concomitant corticosteroids must be on a stable or decreasing dose (up to a total daily dose of 4 mg of dexamethasone or equivalent) for at least 2 weeks prior to first dose of study treatment.
• An ECOG PS of 0 or 1 and Karnofsky score ≥ 80 (see Section 7.2.5).
• Adequate bone marrow, organ function and laboratory parameters:
  • ANC ≥ 1.5 × 10^9 /L;
  • Hemoglobin ≥ 9 g/dL with or without transfusions;
  • Platelets ≥ 100 × 10^9 /L;
  • AST and ALT ≤ 2.5 × ULN; in patients with liver metastases ≤ 5 × ULN;
  • Total bilirubin ≤ 1.5 × ULN.
    • Note: Patients with documented Gilbert syndrome or hyperbilirubinemia due to non-hepatic cause (e.g., hemolysis, hematoma) may be enrolled following discussion and agreement with the Sponsor Medical Monitor.
    • Serum creatinine ≤ 1.5 × ULN; OR calculated creatinine clearance > 50 mL/min by Cockcroft-Gault formula; OR estimated glomerular filtration rate > 50 mL/min/1.73m^2.
• Female patients of childbearing potential must have a negative serum β-HCG test result.
• Female patients of childbearing potential must agree to protocol-approved methods of contraception and to not donate ova from Screening until 30 days after the last dose of study drug.
• Male patients must agree to use methods of contraception that are highly effective or acceptable and to not donate sperm from Screening until 90 days after the last dose of study drug.
• The patient is deemed by the Investigator to have the initiative and means to comply with scheduled visits, treatment plan and study procedures.

• ​​​​​​​Patients with symptomatic brain metastasis (e.g., have neurologic symptoms related to brain metastases).
• Prophylactic or preventive anti-epileptic therapy.
  • Note: Anti-epileptic therapy indicated in order to prevent neurologic symptoms caused by a preexisting condition and not related to brain metastasis is allowed.
• Known hypersensitivity or contraindication to any component of study treatment or their excipients.
• Inability to swallow and retain study treatment.
• Uveal or mucosal melanoma.
• History of or current leptomeningeal metastases.
• Treatment with SRS or craniotomy within 14 days prior to start of study treatment, or treatment with whole-brain radiation within 28 days prior to study treatment. Patients who received local therapy should have complete recovery with no neurological sequelae.
• Either of the following:
  • Radiation therapy to non-brain visceral metastasis within 2 weeks prior to start of study treatment;
  • Continuous or intermittent small-molecule therapeutics or investigational agents within 5 half-lives of the agent (or within 4 weeks prior to start of study treatment, when half-life is unknown).
• Patients treated in the adjuvant setting with BRAF or MEK inhibitor(s) < 6 months prior to enrollment. Patients who received BRAF or MEK inhibitors in the metastatic setting are excluded.
• Is currently participating in a study and receiving an investigational agent; has received an investigational agent or used an investigational device within 14 days prior to start of study treatment.
• Patients who have undergone major surgery (e.g., inpatient procedure with regional or general anesthesia) ≤ 6 weeks prior to start of study treatment. For minor surgical procedures ≤ 6 weeks prior to start of study treatment, consult the Sponsor Medical Monitor.
• Patient has not recovered to ≤ Grade 1 from toxic effects of prior therapy before starting study treatment. Note: Stable chronic conditions (≤ Grade 2) that are not expected to resolve (such as neuropathy, myalgia, alopecia, prior therapy-related endocrinopathies) are exceptions and patients with these may enroll.
• Impaired cardiovascular function or clinically significant cardiovascular disease including, but not limited to, the following:
  • History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty or stenting) < 6 months prior to Screening;
  • Congestive heart failure requiring treatment (New York Heart Association Grade ≥ 2);
  • An LVEF < 50% as determined by MUGA or ECHO; d. Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy;
  • History or presence of clinically significant cardiac arrhythmias (including resting bradycardia, uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia); f. Triplicate average baseline QTcF interval ≥ 480 msec.
• Continuous or intermittent small-molecule therapeutics or investigational agents within 5 half-lives of the agent (or within 4 weeks prior to start of study treatment, when half-life is unknown). 9. Patients treated in the adjuvant setting with BRAF or MEK inhibitor(s) < 6 months prior to enrollment. Patients who received BRAF or MEK inhibitors in the metastatic setting are excluded.
• Is currently participating in a study and receiving an investigational agent; has received an investigational agent or used an investigational device within 14 days prior to start of study treatment.
• Patients who have undergone major surgery (e.g., inpatient procedure with regional or general anesthesia) ≤ 6 weeks prior to start of study treatment. For minor surgical procedures ≤ 6 weeks prior to start of study treatment, consult the Sponsor Medical Monitor.
• Patient has not recovered to ≤ Grade 1 from toxic effects of prior therapy before starting study treatment. Note: Stable chronic conditions (≤ Grade 2) that are not expected to resolve (such as neuropathy, myalgia, alopecia, prior therapy-related endocrinopathies) are exceptions and patients with these may enroll.
• Impaired cardiovascular function or clinically significant cardiovascular disease including, but not limited to, the following:
  • History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty or stenting) < 6 months prior to Screening;
  • Congestive heart failure requiring treatment (New York Heart Association Grade ≥ 2);
  • An LVEF < 50% as determined by MUGA or ECHO;
  • Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy;
  • History or presence of clinically significant cardiac arrhythmias (including resting bradycardia, uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia);
  • Triplicate average baseline QTcF interval ≥ 480 msec.
• Other severe, acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study treatment administration or that may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient an inappropriate candidate for the study.

• Pathologically (histologically or cytologically) proven diagnosis of limited stage small cell lung cancer (Stage Tx, T1-T4, N0-3, M0, American Joint Committee on Cancer [AJCC] staging, 8th edition [Ed.]), within 60 days prior to registration.
• Patients must have received one pre-registration cycle of platinum/etoposide chemotherapy prior to study entry, with study registration required within 21 days from day 1 of the pre-registration cycle of chemotherapy and protocol treatment designed to begin 21 days after. If patient has not recovered from pre-registration cycle chemotherapy toxicities, then an additional 14 days is permitted.
• Patients must have had measurable disease (per Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1) prior to the required cycle of platinum/etoposide chemotherapy.
• Minimal staging requirements include:
  • History/physical examination within 30 days prior to registration;
  • Positron emission tomography (PET)/computed tomography (CT) scan for staging within 45 days prior to registration;
  • CT chest/abdomen with IV contrast (unless contraindicated based on kidney function) within 45 days prior to registration
    •this can be obtained as part of PET/CT if CT imaging is of diagnostic quality.
    • Note: If contrast allergy exists, premedication per institutional guidelines should be performed prior to obtaining CT with contrast. The only exception to this is a documented life-threatening allergy.
  • Magnetic resonance imaging (MRI) scan of the brain with contrast (preferred) or CT scan of the brain with contrast (allowable if there is a contraindication with MRI with contrast) within 30 days prior to registration. 
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 within 30 days prior to registration.
  • Absolute neutrophil count (ANC) ≥ 1, 500/cells/mm^3 (pre-registration cycle)
  • Platelet count ≥ 100,000 cells/mm^3 (pre-registration cycle).
  • Hemoglobin ≥ 9 g/dL (pre-registration cycle).
  • Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (pre-registration cycle).
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.0 x ULN (pre-registration cycle).
  • Glomerular filtration rate (GFR) ≥ 50 mL/min/1.73 m^2 (within 30 days prior to registration).
  • Patients presenting with a pleural effusion will be eligible if thoracentesis is cytologically negative and non-bloody or if pleural fluid is too small a volume to effectively sample by thoracentesis and does not show increased metabolic activity on CT/PET imaging.
  • Negative serum pregnancy test within 14 days of registration for pre-menopausal women of childbearing potential.
  • The patient or a legally authorized representative must provide study-specific informed consent prior to study entry.

• Definitive clinical or radiologic evidence of metastatic disease.
• Definitive surgical resection of small cell lung cancer.
• Prior invasive malignancy (except non-melanomatous skin cancer, localized prostate cancer, or any early stage cancer treated with curative intent resection) unless disease free for a minimum of 2 years (carcinoma in situ of the breast, oral cavity, or cervix are all permissible).
• More than 1 cycle of prior platinum-based chemotherapy for SCLC prior to enrollment; note that prior chemotherapy for a different cancer is allowable.
• Any prior atezolizumab or other immunotherapy agent.
• Prior radiotherapy to the lungs or mediastinum that would result in clinically significant overlap of radiation therapy fields; prior tangent fields for breast cancer with minimal overlap with target volumes are allowed per approval of study principal investigators (PIs).
• Patients with cytologically positive pleural or pericardial fluid are not eligible. 
• An active, known or suspected autoimmune disease. Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
• Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).
• History of allogeneic organ transplant
• History of primary immunodeficiency.
• Severe, active co-morbidity defined as follows: 
  • Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, fatty liver, and inherited liver disease;
  • Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications;
  • Active tuberculosis;
  • Active hepatitis B (chronic or acute) or hepatitis C infection.
    • Note that if hepatitis status is unknown, hepatitis B/C testing is required:
      • Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg]) test, a positive anti-HBc (antibody to hepatitis B core antigen), and a negative viral deoxyribonucleic acid (DNA) test (only obtained if HBsAg is found positive) are eligible.  Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA). (The HCV RNA test must be performed for patients who have a positive HCV antibody test).
  • Known immunosuppressive disease, for example history of bone marrow transplant or chronic lymphocytic leukemia (CLL):
    • CD4 count < 200 cells/microliter.
      • Note that patients who are human immunodeficiency virus (HIV) positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count ≥ 200 cells/microliter within 30 days prior to registration. Note also that HIV testing is not required for eligibility for this protocol.
  • Chronic obstructive pulmonary disease (COPD) requiring chronic oral steroid therapy of > 10 mg prednisone daily or equivalent at the time of registration. Inhaled corticosteroids are not exclusionary. 
  • Unstable angina and/or congestive heart failure requiring hospitalization within the last 3 months. 
  • Transmural myocardial infarction within the last 3 months.
  • Clinically significant interstitial lung disease. 
• A condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception for the duration of study treatment and for 150 days after the last dose of study drug (Arm 2); this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.

• Pathologically (histologically or cytologically) proven diagnosis of limited stage small cell lung cancer (Stage Tx, T1-T4, N0-3, M0, American Joint Committee on Cancer [AJCC] staging, 8th edition [Ed.]), within 60 days prior to registration.
• Patients must have received one pre-registration cycle of platinum/etoposide chemotherapy prior to study entry, with study registration required within 21 days from day 1 of the pre-registration cycle of chemotherapy and protocol treatment designed to begin 21 days after. If patient has not recovered from pre-registration cycle chemotherapy toxicities, then an additional 14 days is permitted.
• Patients must have had measurable disease (per Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1) prior to the required cycle of platinum/etoposide chemotherapy.
• Minimal staging requirements include:
  • History/physical examination within 30 days prior to registration;
  • Positron emission tomography (PET)/computed tomography (CT) scan for staging within 45 days prior to registration;
  • CT chest/abdomen with IV contrast (unless contraindicated based on kidney function) within 45 days prior to registration
    •this can be obtained as part of PET/CT if CT imaging is of diagnostic quality.
    • Note: If contrast allergy exists, premedication per institutional guidelines should be performed prior to obtaining CT with contrast. The only exception to this is a documented life-threatening allergy.
  • Magnetic resonance imaging (MRI) scan of the brain with contrast (preferred) or CT scan of the brain with contrast (allowable if there is a contraindication with MRI with contrast) within 30 days prior to registration. 
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 within 30 days prior to registration.
  • Absolute neutrophil count (ANC) ≥ 1, 500/cells/mm^3 (pre-registration cycle)
  • Platelet count ≥ 100,000 cells/mm^3 (pre-registration cycle).
  • Hemoglobin ≥ 9 g/dL (pre-registration cycle).
  • Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (pre-registration cycle).
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.0 x ULN (pre-registration cycle).
  • Glomerular filtration rate (GFR) ≥ 50 mL/min/1.73 m^2 (within 30 days prior to registration).
  • Patients presenting with a pleural effusion will be eligible if thoracentesis is cytologically negative and non-bloody or if pleural fluid is too small a volume to effectively sample by thoracentesis and does not show increased metabolic activity on CT/PET imaging.
  • Negative serum pregnancy test within 14 days of registration for pre-menopausal women of childbearing potential.
  • The patient or a legally authorized representative must provide study-specific informed consent prior to study entry.

• Definitive clinical or radiologic evidence of metastatic disease.
• Definitive surgical resection of small cell lung cancer.
• Prior invasive malignancy (except non-melanomatous skin cancer, localized prostate cancer, or any early stage cancer treated with curative intent resection) unless disease free for a minimum of 2 years (carcinoma in situ of the breast, oral cavity, or cervix are all permissible).
• More than 1 cycle of prior platinum-based chemotherapy for SCLC prior to enrollment; note that prior chemotherapy for a different cancer is allowable.
• Any prior atezolizumab or other immunotherapy agent.
• Prior radiotherapy to the lungs or mediastinum that would result in clinically significant overlap of radiation therapy fields; prior tangent fields for breast cancer with minimal overlap with target volumes are allowed per approval of study principal investigators (PIs).
• Patients with cytologically positive pleural or pericardial fluid are not eligible. 
• An active, known or suspected autoimmune disease. Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
• Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).
• History of allogeneic organ transplant
• History of primary immunodeficiency.
• Severe, active co-morbidity defined as follows: 
  • Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, fatty liver, and inherited liver disease;
  • Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications;
  • Active tuberculosis;
  • Active hepatitis B (chronic or acute) or hepatitis C infection.
    • Note that if hepatitis status is unknown, hepatitis B/C testing is required:
      • Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg]) test, a positive anti-HBc (antibody to hepatitis B core antigen), and a negative viral deoxyribonucleic acid (DNA) test (only obtained if HBsAg is found positive) are eligible.  Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA). (The HCV RNA test must be performed for patients who have a positive HCV antibody test).
  • Known immunosuppressive disease, for example history of bone marrow transplant or chronic lymphocytic leukemia (CLL):
    • CD4 count < 200 cells/microliter.
      • Note that patients who are human immunodeficiency virus (HIV) positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count ≥ 200 cells/microliter within 30 days prior to registration. Note also that HIV testing is not required for eligibility for this protocol.
  • Chronic obstructive pulmonary disease (COPD) requiring chronic oral steroid therapy of > 10 mg prednisone daily or equivalent at the time of registration. Inhaled corticosteroids are not exclusionary. 
  • Unstable angina and/or congestive heart failure requiring hospitalization within the last 3 months. 
  • Transmural myocardial infarction within the last 3 months.
  • Clinically significant interstitial lung disease. 
• A condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception for the duration of study treatment and for 150 days after the last dose of study drug (Arm 2); this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.

• Pathologically (histologically or cytologically) proven diagnosis of limited stage small cell lung cancer (Stage Tx, T1-T4, N0-3, M0, American Joint Committee on Cancer [AJCC] staging, 8th edition [Ed.]), within 60 days prior to registration.
• Patients must have received one pre-registration cycle of platinum/etoposide chemotherapy prior to study entry, with study registration required within 21 days from day 1 of the pre-registration cycle of chemotherapy and protocol treatment designed to begin 21 days after. If patient has not recovered from pre-registration cycle chemotherapy toxicities, then an additional 14 days is permitted.
• Patients must have had measurable disease (per Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1) prior to the required cycle of platinum/etoposide chemotherapy.
• Minimal staging requirements include:
  • History/physical examination within 30 days prior to registration;
  • Positron emission tomography (PET)/computed tomography (CT) scan for staging within 45 days prior to registration;
  • CT chest/abdomen with IV contrast (unless contraindicated based on kidney function) within 45 days prior to registration
    •this can be obtained as part of PET/CT if CT imaging is of diagnostic quality.
    • Note: If contrast allergy exists, premedication per institutional guidelines should be performed prior to obtaining CT with contrast. The only exception to this is a documented life-threatening allergy.
  • Magnetic resonance imaging (MRI) scan of the brain with contrast (preferred) or CT scan of the brain with contrast (allowable if there is a contraindication with MRI with contrast) within 30 days prior to registration. 
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 within 30 days prior to registration.
  • Absolute neutrophil count (ANC) ≥ 1, 500/cells/mm^3 (pre-registration cycle)
  • Platelet count ≥ 100,000 cells/mm^3 (pre-registration cycle).
  • Hemoglobin ≥ 9 g/dL (pre-registration cycle).
  • Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (pre-registration cycle).
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.0 x ULN (pre-registration cycle).
  • Glomerular filtration rate (GFR) ≥ 50 mL/min/1.73 m^2 (within 30 days prior to registration).
  • Patients presenting with a pleural effusion will be eligible if thoracentesis is cytologically negative and non-bloody or if pleural fluid is too small a volume to effectively sample by thoracentesis and does not show increased metabolic activity on CT/PET imaging.
  • Negative serum pregnancy test within 14 days of registration for pre-menopausal women of childbearing potential.
  • The patient or a legally authorized representative must provide study-specific informed consent prior to study entry.

• Definitive clinical or radiologic evidence of metastatic disease.
• Definitive surgical resection of small cell lung cancer.
• Prior invasive malignancy (except non-melanomatous skin cancer, localized prostate cancer, or any early stage cancer treated with curative intent resection) unless disease free for a minimum of 2 years (carcinoma in situ of the breast, oral cavity, or cervix are all permissible).
• More than 1 cycle of prior platinum-based chemotherapy for SCLC prior to enrollment; note that prior chemotherapy for a different cancer is allowable.
• Any prior atezolizumab or other immunotherapy agent.
• Prior radiotherapy to the lungs or mediastinum that would result in clinically significant overlap of radiation therapy fields; prior tangent fields for breast cancer with minimal overlap with target volumes are allowed per approval of study principal investigators (PIs).
• Patients with cytologically positive pleural or pericardial fluid are not eligible. 
• An active, known or suspected autoimmune disease. Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
• Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).
• History of allogeneic organ transplant
• History of primary immunodeficiency.
• Severe, active co-morbidity defined as follows: 
  • Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, fatty liver, and inherited liver disease;
  • Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications;
  • Active tuberculosis;
  • Active hepatitis B (chronic or acute) or hepatitis C infection.
    • Note that if hepatitis status is unknown, hepatitis B/C testing is required:
      • Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg]) test, a positive anti-HBc (antibody to hepatitis B core antigen), and a negative viral deoxyribonucleic acid (DNA) test (only obtained if HBsAg is found positive) are eligible.  Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA). (The HCV RNA test must be performed for patients who have a positive HCV antibody test).
  • Known immunosuppressive disease, for example history of bone marrow transplant or chronic lymphocytic leukemia (CLL):
    • CD4 count < 200 cells/microliter.
      • Note that patients who are human immunodeficiency virus (HIV) positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count ≥ 200 cells/microliter within 30 days prior to registration. Note also that HIV testing is not required for eligibility for this protocol.
  • Chronic obstructive pulmonary disease (COPD) requiring chronic oral steroid therapy of > 10 mg prednisone daily or equivalent at the time of registration. Inhaled corticosteroids are not exclusionary. 
  • Unstable angina and/or congestive heart failure requiring hospitalization within the last 3 months. 
  • Transmural myocardial infarction within the last 3 months.
  • Clinically significant interstitial lung disease. 
• A condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception for the duration of study treatment and for 150 days after the last dose of study drug (Arm 2); this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.

• Have completed a Corcept-sponsored study of relacorilant in endogenous Cushing syndrome with at least 80% compliance with the dosing schedule.
• According to the Investigator's opinion, will benefit from continuing treatment with relacorilant.

• Premature discontinuation from a relacorilant parent study.
• Has uncontrolled, clinically significant hypothyroidism or hyperthyroidism.
• Has poorly controlled hypertension.
• Has Stage ≥ 4 renal failure.

Eligibility last updated 2/8/22. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years of age.
• Renal biopsy read at Mayo Clinic confirming the diagnosis of PGNMID.
• Proteinuria ≥ 1000 mg over 24 hours.
• Creatinine clearance ≥ 20 mL/min/SA.
• Subjects able and willing to give informed consent.
• For female subjects of reproductive childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously during the Treatment Period, during any dose interruptions, and for 3 months after the last dose of any component of the treatment regimen. Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drug. This birth control method must include one highly effective form of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, injections, hormonal patches, vaginal rings, or implants] or partner’s vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to dosing. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy:
  • A woman of childbearing potential must have 2 negative serum or urine pregnancy tests at Screening, first within 10 to 14 days prior to dosing and the second within 24 hours prior to dosing;
  • A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for a period of 3 months after receiving the last dose of any component of the treatment regimen.
• For male subjects of reproductive potential who are sexually active with females ofreproductive potential must always use a latex or synthetic condom during the study and for 3 months after discontinuing study treatment (even after a successful vasectomy):
• • Male subjects of reproductive potential must not donate sperm during the study or for 3 months after the last dose of study treatment;
  • Must sign an informed consent form (ICF) or their legally acceptable representative must sign indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study.

• Pregnant or planning to become pregnant.
• Seropositive for human immunodeficiency virus (HIV).
• 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).
• Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, 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]) will also be excluded. Subjects 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 and can be included.
• Multiple myeloma defined as >10% plasma cells on bone marrow biopsy and M-spike > 3 g/dL and presence of myeloma defining event (hypercalcemia, cast nephropathy, bone disease, or anemia), or plasma cells >60% or FLC ratio of involved to uninvolved > 100.
• Abnormal clinical labs defined as: anemia with Hgb < 8.0 g/dL, thrombocytopenia with platelet count < 75,000, leukopenia with WBC < 3.5, or neutropenia with ANC < 1000 , AST/ALT > 2.5 X ULN, bilirubin > 2 X ULN.
• Chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal. Note that FEV1 testing is required for participants suspected of having COPD and participants must be excluded if FEV1 is < 50% of predicted normal.
• Moderate or severe persistent asthma withing the past 2 years or uncontrolled asthma of any classification. Note the participants who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate.
• Clinically significant cardiac disease including:
  • Myocardial infarction within 6 months before randomization, or unstable or uncontrolled disease/condition related to cardiac dysfunction (e.g. unstable angina, congestive heart failure, New York Heart Association Class III-IV);
  • Uncontrolled arrythmia.
• Prior or current exposure to any of the following:
  • To daratumumab or other anti-CD-38 therapies (unless a re-treatment study);
  • Exposure to an investigational drug (including investigational vaccine) or invasive investigational medical device for any indication within 4 weeks or 5 pharmacokinetic half-lives, whichever is longer;
  • Focal radiation therapy within 14 days prior to randomization with the exception of palliative radiotherapy for symptomatic management but not on measurable extramedullary plasmacytoma.
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complication
•  Unable to provide consent.
• Patients receiving therapy with oral prednisone or glucocorticoid equivalent in the last 4 weeks.  Patients treated with low dose oral prednisone or glucocorticoid are allowed to be included if they are taking the medication for conditions unrelated to PGNMID (e.g., asthma, gout) at a daily dose of 10mg or less.
• Patients who had received immunosuppressive therapy with MMF, cyclosporine, tacrolimus, or azathioprine in the last 3 months.
• Patients who have received cyclophosphamide or bortezomib will be allowed to participate as long as there is clear evidence of lack of response to cyclophosphamide or bortezomib defined as lack of achieving complete or partial remission (see section 3.3 regarding definition).
• Patients who received rituximab previously with CD20 count of < 20 cells/microliter at the time of enrollment.
• Have received vaccination with live attenuated vaccines within 4 weeks of first study agent administration.
• A history of malignancy (other than multiple myeloma) unless all treatment of that malignancy was completed at least 2 years before consent and the patient has no evidence of disease before the date of randomization. Exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix or breast, or other non-invasive lesion that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 3 years.

Eligibility last updated 8/4/22. Questions regarding updates should be directed to the study team contact.

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

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

• Adults between 18 and 65 years of age.
• Bipolar I or II disorder as confirmed by structured clinical interview for DSM-IV-TR.
• Major depressive episode unresponsive to steady and stable (i.e., at least 2 weeks) mood stabilization (e.g., lithium, valproate, lamotrigine, carbamazepine/oxcarbamazepine, and/or atypical antipsychotic therapy) and non-psychotropic medication.
• Antidepressant therapy is allowed in the study as long as patients are also on a mood stabilizer. Patients will be enrolled provided that any needed modifications to the antidepressant would be made at least two weeks prior to randomization.
• Patients receiving psychotherapy will be allowed to be randomized provided therapy frequency does not change during the 8-week blinded phase.  
• Symptom severity score on the Quick Inventory for Depressive Symptomatology – Clinician (QIDS-C16) ≥ 9, and the Clinical Global Impression for Bipolar Illness (CGI-BP) Depression Severity Scale ≥ 3.
• Patients on stimulants for comorbid attention deficit disorder (ADHD) and/or binge eating disorder (BED) will be enrolled provided that the stimulant can be tapered and discontinued at least one week prior to randomization; symptom severity inclusion criteria must be met again prior to randomization.
• Patients with a prescribed opiate (e.g.. hydroxicodone) or other pain intervention for acute or chronic pain management will be allowed provided they:
  • use a prescribed opiate or other pain intervention at a recommendation dose and established duration;
  • show no evidence of prescription misuse;
  • do not meet abuse or dependence criteria by SCID;
  • no known significant pharmacological interactions.
• Ability to travel for the assessment visits.  

• Inability to provide written informed consent.
• Inability to understand English.
• Score less than 86% correct (i.e., one wrong) on comprehension assessment that reviews study goals.
• Clinically significant signs of acute suicidality from any of the following assessments:
  • Response of > 2 on question #12 of QIDS-C; or
  •  Response = 3 on the SCID Module A- #A19.
• Suicide attempt within the past year.
• Concomitant treatment with monoamine oxidase inhibitors (MAOIs); also, within 14 days following discontinuation of treatment with a monoamine oxidase inhibitor.
• Baseline Young Mania Rating Scale (YMRS) score ≥ 12.
• Patients with active psychosis (measured by a score > 4 on YMRS question #8) or a diagnosis of schizophrenia, schizoaffective disorder, delusional, or schizophreniform disorder identified by structured clinical interview for DSM-IV-TR.
• Active abuse or dependence of alcohol, opiates, or cannabis (nicotine dependence will be an exception) by structured clinical interview for DSM-IV-TR; patients meeting full remission for at least 3 months can be randomized. 
• Positive toxicology screen for drugs of abuse (i.e., cocaine, methamphetamine, illegal opiates).
• Positive toxicology screen for cannabis and a cannabis use disorder by structured clinical interview for DSM-IV-TR.  Participants who use cannabis for recreational or medicinal purposes and fail the toxicology screen can potentially be included in the study only if they take the CUDIT-R and score a 12 or less.
• Known lifetime history of cocaine or methamphetamine abuse or dependence identified by structured clinical interview for DSM-IV-TR.
• Active stimulant prescription abuse or dependence by structured clinical interview for DSM-IV-TR; patients meeting full remission for at least 6 months can be randomized.
• Known lifetime history of stimulant-induced mania.
• Known hypersensitivity, such as angioedema or anaphylaxis, to amphetamines or other ingredients of MYDAYIS.
• Clinically unstable medical disease.
• Known history of a structural cardiac abnormality, cardiomyopathy, serious heart rhythm abnormality, coronary artery disease, stroke, or other serious cardiovascular problems.
• ECG with clinically significant arrhythmias, conduction abnormalities, or voltage criteria met for left ventricular hypertrophy (unless cleared by cardiology consultation).
• Uncontrolled hypertension (> 160/100) or tachycardia (heart rate > 110).
• History of grand mal seizure; history of febrile seizure as infant permitted.
• Established vasculopathy or history of Raynaud’s phenomena.
• Narrow angle glaucoma.
• Chronic kidney disease (CKD) > stage IIIa (GFR 40-59).
• Tourette syndrome.
• Women who are pregnant, lactating or of child-bearing potential not using at least one adequate contraceptive measure (i.e., hormonal contraception-birth control pills, intrauterine devices (IUD), tubal ligation or condoms during sexual intercourse).
• Current positive test for SARS-CoV-2; those with previous COVID-19 illness and those who test positive for SARS-CoV-2 any time after starting study drug or placebo will be included.
• Otherwise excluded for administrative reasons and/or clinician judgment.

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

• Adults between 18 and 65 years of age.
• Bipolar I or II disorder as confirmed by structured clinical interview for DSM-IV-TR.
• Major depressive episode unresponsive to steady and stable (i.e., at least 2 weeks) mood stabilization (e.g., lithium, valproate, lamotrigine, carbamazepine/oxcarbamazepine, and/or atypical antipsychotic therapy) and non-psychotropic medication.
• Antidepressant therapy is allowed in the study as long as patients are also on a mood stabilizer. Patients will be enrolled provided that any needed modifications to the antidepressant would be made at least two weeks prior to randomization.
• Patients receiving psychotherapy will be allowed to be randomized provided therapy frequency does not change during the 8-week blinded phase.  
• Symptom severity score on the Quick Inventory for Depressive Symptomatology – Clinician (QIDS-C16) ≥ 9, and the Clinical Global Impression for Bipolar Illness (CGI-BP) Depression Severity Scale ≥ 3.
• Patients on stimulants for comorbid attention deficit disorder (ADHD) and/or binge eating disorder (BED) will be enrolled provided that the stimulant can be tapered and discontinued at least one week prior to randomization; symptom severity inclusion criteria must be met again prior to randomization.
• Patients with a prescribed opiate (e.g.. hydroxicodone) or other pain intervention for acute or chronic pain management will be allowed provided they:
  • use a prescribed opiate or other pain intervention at a recommendation dose and established duration;
  • show no evidence of prescription misuse;
  • do not meet abuse or dependence criteria by SCID;
  • no known significant pharmacological interactions.
• Ability to travel for the assessment visits.  

• Inability to provide written informed consent.
• Inability to understand English.
• Score less than 86% correct (i.e., one wrong) on comprehension assessment that reviews study goals.
• Clinically significant signs of acute suicidality from any of the following assessments:
  • Response of > 2 on question #12 of QIDS-C; or
  •  Response = 3 on the SCID Module A- #A19.
• Suicide attempt within the past year.
• Concomitant treatment with monoamine oxidase inhibitors (MAOIs); also, within 14 days following discontinuation of treatment with a monoamine oxidase inhibitor.
• Baseline Young Mania Rating Scale (YMRS) score ≥ 12.
• Patients with active psychosis (measured by a score > 4 on YMRS question #8) or a diagnosis of schizophrenia, schizoaffective disorder, delusional, or schizophreniform disorder identified by structured clinical interview for DSM-IV-TR.
• Active abuse or dependence of alcohol, opiates, or cannabis (nicotine dependence will be an exception) by structured clinical interview for DSM-IV-TR; patients meeting full remission for at least 3 months can be randomized. 
• Positive toxicology screen for drugs of abuse (i.e., cocaine, methamphetamine, illegal opiates).
• Positive toxicology screen for cannabis and a cannabis use disorder by structured clinical interview for DSM-IV-TR.  Participants who use cannabis for recreational or medicinal purposes and fail the toxicology screen can potentially be included in the study only if they take the CUDIT-R and score a 12 or less.
• Known lifetime history of cocaine or methamphetamine abuse or dependence identified by structured clinical interview for DSM-IV-TR.
• Active stimulant prescription abuse or dependence by structured clinical interview for DSM-IV-TR; patients meeting full remission for at least 6 months can be randomized.
• Known lifetime history of stimulant-induced mania.
• Known hypersensitivity, such as angioedema or anaphylaxis, to amphetamines or other ingredients of MYDAYIS.
• Clinically unstable medical disease.
• Known history of a structural cardiac abnormality, cardiomyopathy, serious heart rhythm abnormality, coronary artery disease, stroke, or other serious cardiovascular problems.
• ECG with clinically significant arrhythmias, conduction abnormalities, or voltage criteria met for left ventricular hypertrophy (unless cleared by cardiology consultation).
• Uncontrolled hypertension (> 160/100) or tachycardia (heart rate > 110).
• History of grand mal seizure; history of febrile seizure as infant permitted.
• Established vasculopathy or history of Raynaud’s phenomena.
• Narrow angle glaucoma.
• Chronic kidney disease (CKD) > stage IIIa (GFR 40-59).
• Tourette syndrome.
• Women who are pregnant, lactating or of child-bearing potential not using at least one adequate contraceptive measure (i.e., hormonal contraception-birth control pills, intrauterine devices (IUD), tubal ligation or condoms during sexual intercourse).
• Current positive test for SARS-CoV-2; those with previous COVID-19 illness and those who test positive for SARS-CoV-2 any time after starting study drug or placebo will be included.
• Otherwise excluded for administrative reasons and/or clinician judgment.

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