• 18 years or older.
• Diagnosis of Myhre Syndrome.

• Individuals < 18 years of age.

Eligibility last updated 1/18/22. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria
•RISK Primary

• New onset refractory status epilepticus with or without fever.
• Failure to respond to 2 or more first-line anti-seizure drugs.
• Age 0 to 18 years.
• Etiology for status epilepticus unknown:
  • No history of pre-existing epilepsy;
  • No pre-existing major developmental impairment;
  • No evidence of prodromal dyskinesia, hallucinations, or psychiatric symptoms;
  • No evidence of structural, cerebrovascular, neoplastic, metabolic, traumatic, or toxic etiology.

Inclusion Criteria
•RISK Primary

• Epileptiform abnormality on EEG.
• Seizure frequency at least weekly.
• Failure to respond to 2 or more first-line anti-seizure drugs.
• Age 0 to 18 years.
• Clinical and electrophysiological profile not consistent with:
  • self-limited focal epilepsy syndrome;
  • unifocal epilepsy.
• Normal 3T epilepsy protocol MRI (if available).
• Normal epilepsy panel or no evidence of known epilepsy mutations by whole exome sequencing (if available).
• No evidence of autoimmune, cerebrovascular, neoplastic, metabolic, traumatic, or toxic etiology.

Inclusion Criteria
•RISK Retrospective Recruitment Inclusion Criteria (~100 patients):

• Prior diagnosis consistent with NORSE or DRE.
• No evidence of autoimmune, infectious, structural, cerebrovascular, neoplastic, metabolic, or toxic etiology.
• Negative genetic epilepsy panel.
  • Note: No exclusions based on disease-modifying therapies, including immunomodulatory or immunosuppressive treatments (e.g., IV corticosteroids, plasma exchange, intravenous immunoglobulin, and anti-cytokine drugs such as anakinra or tocilizumab).

• Validated autoimmune disorder.
• Smoker.
• Pregnant.
• Weight < 9 kg.

Eligibility last updated 1/21/22. Questions regarding updates should be directed to the study team contact.

• Adult patients age ≥ 18.
• Undergoing either primary total knee or total hip arthroplasty for a primary underlying diagnosis of osteoarthritis.

• Individuals < 18 years of age.

Eligibility last updated 1/21/22. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria:

• Age ≥ 18 years.
• Ability to read and write in English.
• Women with newly diagnosed with ovarian, primary peritoneal, or fallopian tube cancer.
• Treatment plan includes chemotherapy.
• Able to provide written voluntary consent before performance of any study related procedure.
• Aim 1 only: after completion of initial chemotherapy.
• Aim 2 only: prior to starting chemotherapy.

• Inability to provide informed consent.
• Exposure to chemotherapy prior to ovarian cancer diagnosis.
• Life expectancy < 3 months or in hospice care or nursing home.

Inclusion Criteria:

• Age ≥ 18 years.
• Ability to read and write in English.
• Women with newly diagnosed with ovarian, primary peritoneal, or fallopian tube cancer.
• Treatment plan includes chemotherapy.
• Able to provide written voluntary consent before performance of any study related procedure.
• Aim 1 only: after completion of initial chemotherapy.
• Aim 2 only: prior to starting chemotherapy.

• Inability to provide informed consent.
• Exposure to chemotherapy prior to ovarian cancer diagnosis.
• Life expectancy < 3 months or in hospice care or nursing home.

• Age ≥ 18 years.
• Primary total knee arthroplasty.
• Patients staying at least one night in the hospital after surgery.

• Individuals < 18 years.
• Same day discharge.
• Revision or partial total knee arthroplasty.
• Corticosteroid use within 3 months prior to surgery.
• Inflammatory arthritis
• Current systemic fungal infection.
• Renal or liver failure.
• Prior adverse reaction to corticosteroid.
• Primary TKA requiring hardware removal.

• Patients with TOF or TOF-related variants.
• Age ≥ 18 years.
• Planned transcatheter valve placement in native RVOT.

• Individuals < 18 years.
• Non-TOF related variants (i.e., pulmonary stenosis, PA-IVS, etc.).
• Prior catheter or surgical ablation of ventricular tachycardia (VT).

Eligibility last updated 1/24/22. Questions regarding updates should be directed to the study team contact.

• Presence of an external traumatic event that results in a spinal cord injury, including surgical procedures, radiation, and medical complications.
• Temporary or permanent loss of sensory and/or motor function as a result of the traumatic event.
•  Admission to the system within one year of injury.
• Discharge from the System Rehab as:
  • Having completed inpatient acute rehabilitation;
  • Deceased.
• Signed informed consent and HIPAA authorization forms.
• Reside in the geographic catchment area of the system at the time of the injury.  Patients may be injured outside of the catchment area.
• A US citizen or non-US citizen who is expected to stay in the catchment area.

• Must not have previously been treated at another model system for the injury.
  • Ensures that patients are enrolled into the database by only one model system.
• Must not have completed an organized rehabilitation program prior to the admission to the system.

Eligibility last updated 1/24/22. Questions regarding updates should be directed to the study team contact.

• Is 18 years old or older.
• Self-identifies as a member of the LGBTQ community or self-identified as such at the time of their admission or is the spouse, partner, or family member who identifies as a member of the LGBTQ community.
• Has been on a ventilator in the intensive care unit or is the spouse, partner, or family member of a patient on a ventilator in the intensive care unit between 1/2016 and 2/2022.

• Does not meet the above criteria for age, LGBTQ identity, relationship to an LGBTQ identifying individual, and past mechanical ventilation.

Eligibility last updated 3/2/22. Questions regarding updates should be directed to the study team contact.

- Sedation for invasive mechanical ventilation immediately prior to Baseline for > 72 hours (patients who have been extubated for at least 24 hours and subsequently re-intubated will have sedation for invasive mechanical ventilation starting from when they were re-intubated); 

- Severe neurological condition that causes the patient to lack ability to participate in the study (i.e., unable to be assessed for RASS and Critical Care Pain Observation Tool), including, but not restricted to, patients with acute stroke, severe head trauma, suspected of having elevated intracranial pressure (ICP), or the need for ICP monitoring;

- Ventilator tidal volume 1000 mL at Baseline;

- Need for extracorporeal membrane oxygenation, extracorporeal carbon dioxide removal, high frequency oscillation ventilation, or high frequency percussive ventilation at Screening;

- Comfort care only (end of life care);

Contraindication to propofol or isoflurane, including:

a. Known or suspected personal or family history of malignant hyperthermia (MH) or high risk for MH or acute drug-induced muscle injury (e.g., muscular dystrophies);

b. Severe hemodynamic compromise, defined as the need for norepinephrine ≥ 0.3 mcg/kg/min (or equivalent vasopressor dose) to maintain blood pressure within acceptable range, assumed to be mean arterial pressure ≥ 65 mmHg unless prescribed clinically; or

c. Allergy to isoflurane or propofol, or have propofol infusion syndrome.

-  History of ventricular tachycardia/Long QT Syndrome;

-  Requirement of intravenous (IV) benzodiazepine or barbiturate administration for seizures or dependencies, including alcohol withdrawal;

- Neuromuscular disease that impairs spontaneous ventilation (eg, C5 or higher spinal cord injury, amyotrophic lateral sclerosis, etc);

- Concurrent enrollment in another study that, in the Investigator’s opinion, would impact the patient’s safety or assessments of this study;

- Participation in other study involving investigational drug(s) or devices(s) within 30 days prior to Randomization;

- Previous randomization or receipt of treatment in this study or in SED004;

- Anticipated requirement of treatment with continuous infusion of a neuromuscular blocking agent for > 4 hours;

- Female patients who are pregnant or breast-feeding;

- Imperative need for continuous active humidification through mechanical ventilation circuit;

- Attending physician’s refusal to include the patient; or

- Inability to obtain informed consent.

Eligibility last updated 8/22/23. Questions regarding updates should be directed to the study team contact.

Patient

• Adults ≥ 18 years with biopsy proven resected NSCLC.
• Appointment to discuss adjuvant treatment of resected NSCLC.

Patient

• Major barriers to providing informed consent (i.e. dementia, severe hearing or visual impairment).

Clinician

• Clinicians who meet with patients to discuss adjuvant treatment of resected NSCLC.

Clinician

• None.

PAG Member

• Adults ≥ 18 years.
• Member of the KER Unit PAG.

PAG Member

• None.

Eligibility last updated 1/28/22. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years old.
• Presence of fatigue and post exertional malaise.
• Presence of headache
• Clinical diagnosis of post COVID syndrome.
• They have consented to participate in the study
• They have the ability to participate in all aspects of the study.

• Age < 18 years old.
• Pregnant.
• Prior adverse reaction to 14FDG.
• Active implantable medical device e.g. pacemaker, hearing aid implant
• Metallic device e.g. stent, orthopedic hardware in neck
• Using another electronic device at the same time e.g. TENS, mobile phone. 
• Any other condition deemed exclusionary by the study principal investigator

Eligibility last updated 1/26/22. Questions regarding updates should be directed to the study team contact.

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

• Any patient undergoing surgery for intralesional resection of neoplasm such as tumors of the spine/extremities or metastatic disease.

• Patients undergoing surgery with an expected blood loss of less than 135cc.
• Provisions for inclusion of minorities: 
  • Subjects will be enrolled prospectively irrespective of their sex/gender, race, and ethnicity in order to improve generalizability.        

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

• Age 21-65.
• BMI ≥ 30 and ≤ 40 kg/m² .
• Willingness to comply with the substantial lifelong dietary restrictions required by the procedure.
• History of failure with non-surgical weight-loss methods.
• Willingness to follow protocol requirements, including signed informed consent, routine follow-up schedule, completing laboratory tests, and completing diet counseling. 
• Residing within a reasonable distance from the investigator’s office and able to travel to the investigator to complete all routine follow- up visits.
• Ability to give informed consent.
• Women of childbearing potential (i.e., not post-menopausal or surgically sterilized) must agree to use adequate birth control methods. 

• History of foregut or gastrointestinal (GI) surgery (except uncomplicated cholecystectomy or appendectomy).
• Prior gastrointestinal surgery with sequelae; i.e., obstruction, and/or adhesive peritonitis or known abdominal adhesions.  
• Prior open or laparoscopic bariatric surgery.  
• Prior surgery of any kind on the esophagus, stomach or any type of hiatal hernia surgery. 
• Any inflammatory disease of the gastrointestinal tract including severe (LA Grade C or D) esophagitis, Barrett’s esophagus, gastric ulceration, duodenal ulceration, cancer or specific inflammation such as Crohn’s disease.  
• Potential upper gastrointestinal bleeding conditions such as esophageal or gastric varices, congenital or acquired intestinal telangiectasis, or other congenital anomalies of the gastrointestinal tract such as atresias or stenoses. 
• Gastrointestinal stromal tumors, history of premalignant gastric lesions (intestinal metaplasia), history of familial and nan-familial adenomatous syndromes.  
• A gastric mass or gastric polyps > 1 cm in size.  
• A hiatal hernia > 4cm of axial displacement of the z-line above the diaphragm or severe or intractable gastro-esophageal reflux symptoms.  
• A structural abnormality in the esophagus or pharynx such as a stricture or diverticulum that could impede passage of the endoscope.  
• Achalasia or any other severe esophageal motility disorder.
• Severe coagulopathy. 
• Insulin-dependent diabetes (either Type 1 or Type 2) or a significant likelihood of requiring insulin treatment in the following 12 months or a HgbA1C ≥ 9. 
• Subjects with any serious health condition unrelated to their weight that would increase the risk of endoscopy.
• Chronic abdominal pain.
• Motility disorders of the GI tract such as gross esophageal motility disorders, gastroparesis or intractable constipation. 
• Hepatic insufficiency or cirrhosis.
• Use of an intragastric device prior to this study due to the increased thickness of the stomach wall preventing effective suturing.  
• Active psychological issues preventing participation in a life-style modification program as determined by a psychologist.
• Patients unwilling to participate in an established medically supervised diet and behavior modification program, with routine medical follow-up.  
• Patients receiving daily prescribed treatment with high dose aspirin (> 80 mg daily), anti-inflammatory agents, anticoagulants or other gastric irritants.  
• Patients who are unable or unwilling to take prescribed proton pump inhibitor medication.
• Patients who are pregnant or breast-feeding.  
• Patients currently taking weight-loss medications or other therapies for weight loss within the prior 6 months. 
• Subjects with severe cardiopulmonary disease or other serious organic disease which might include known history of coronary artery disease, myocardial infarction within the past 6 months, poorly controlled hypertension, required use of NSAIDs.
• Subjects taking medications on specified hourly intervals that may be affected by changes to gastric emptying, such as anti-seizure or anti-arrhythmic medications.
• Subjects who are taking corticosteroids, immunosuppressants, and narcotics.
• Symptomatic congestive heart failure, cardiac arrhythmia or unstable coronary artery disease.  
• Pre-existing respiratory disease such as moderate or severe chronic obstructive pulmonary disease (COPD) requiring steroids, pneumonia or cancer.  
• Diagnosis of autoimmune connective tissue disorder (e.g. lupus, erythematous, scleroderma) or immunocompromised.  
• Specific diagnosed genetic disorder such as Prader Willi syndrome. 
• Eating disorders including night eating syndrome (NES), bulimia, binge eating disorder, or compulsive overeating. 
• Known history of endocrine disorders affecting weight such as uncontrolled hypothyroidism. 
• If deemed medically inappropriate or ineligible by investigator. 

Eligibility last updated 2/1/22. Questions regarding updates should be directed to the study team contact.

• Patients referred to the Mayo Clinic HF Clinic with a diagnosis of heart failure who have a clinical blood draw scheduled.
• Adults ≥ 18 years old.

• Individuals < 18 years old.
• Any history of Hemoglobin less than 9 mg/dL during the past 3 months.
• Active cancer.

Eligibility last updated 1/28/22. Questions regarding updates should be directed to the study team contact.

• Esophageal cancer any stage.
• Age ≥ 18 years old.
• Willing and able to provide consent.
• No prior history of neoadjuvant therapy for the esophageal cancer.

• Age < 18 years old.
• Unable to provide consent.

Eligibility last updated 2/11/22. Questions regarding updates should be directed to the study team contact.

• Adult males and females over the age of 18.
• Subjects living at Acacia Creek Retirement Community who use a Sleep Number® bed.

• Individuals under the age of 18.
• Subjects who do not have a Sleep Number® bed.
• Subjects without an internet connection to transmit nightly SleepIQ® data.

Eligibility last updated 1/31/22. Questions regarding updates should be directed to the study team contact.

Subjects must satisfy all following criteria at the Screening visit unless otherwise stated:

• Male or female aged 18 years or older.
• Able to provide written informed consent.
• Active and consistent cortisol excess:
  This is defined as having a consistently elevated UFC in patients newly diagnosed
  with Cushing’s or in patients with recurrent or refractory Cushing’s disease having
  high-normal UFCs or both of the other guideline-recommended tests (overnight
  dexamethasone suppression or late-night/bedtime salivary cortisol) being consistent
  with cortisol excess:
  • Urinary free cortisol (UFC) > upper limit of normal (ULN) based on at least 2
    valid (i.e., complete) 24-hour urine samples collected during Screening. The subjects will be provided collection devices for three 24--hour collections to ensure 2 complete collections are received, particularly if a subject requires washout of other cortisol -suppressing agents. If more than 2 valid collections
    are received; the mean of all valid completed collections collected after completion of the washout period (if applicable), and available at Day 1 must
    be > ULN, as confirmed by the central laboratory. Should an additional, otherwise disqualifying, UFC value become available only after Day 1
    randomization, the subject will be allowed to continue planned treatment and a sensitivity, per-protocol analysis will be conducted.
• Overnight dexamethasone suppression testing to minimally include a non-suppressed morning serum cortisol ≥ 1.8 mcg/dL (50 nmol/L) after 1 mg ONDST within the last year. Testing should be confirmed by concurrent dexamethasone level adequate to provide suppression. Individuals using estrogen should meet further criteria accounting for potential increased
  corticosteroid binding globulin (CBG); e.g., free cortisol > 80 ng/dL (2.2 nmol/L), total serum cortisol ≥ 5 mcg/dL (138 nmol/L), or correction based on CBG measurement. If ONDST dates or results are not available for
  tests performed within the past year, ONDST with dexamethasone level should be repeated to confirm eligibility and should use local laboratory results.
• Late-night/bedtime salivary cortisol above ULN based on at least 2 adequate samples collected during Screening using local laboratory results.
• Documented diagnosis of ACTH-dependent Cushing’s syndrome:
  • This includes Cushing’s disease, ectopic ACTH secretion, and ectopic CRH secretion.
    Subjects may include newly diagnosed subjects who have declined or are not considered candidates for surgery or subjects with residual or recurrent disease after 
    surgery in whom surgery or radiation are not planned within the next 6 months.
  • Previous medical records will be used to support the diagnosis. At least 1 of the following will be considered satisfactory to establish the diagnosis:
  • History of positive ACTH-staining pathology;
  • History of documented, transient, AI after tumor removal requiring
    glucocorticoid replacement;
  • ACTH level > 20 pg/mL with positive ACTH or cortisol response to CRH or desmopressin (DDAVP) stimulation in the presence of hypercortisolemia;
  • Inferior petrosal sinus sampling with ACTH central: plasma gradient ≥ 2 before CRH or DDAVP or ≥ 3 after CRH or DDAVP;
  • Presumptive Cushing’s disease based on presence of a pituitary tumor ≥ 6 mm along with positive ACTH or cortisol response to CRH or DDAVP stimulation
    or an overnight or high-dose (8 mg) dexamethasone suppression of cortisol, performed and interpreted according to locally recognized standards of
    diagnosis;
  • In the absence of any of the above, an individual might be eligible if ectopic ACTH-dependent Cushing’s syndrome was otherwise confirmed via adequate testing consistent with the local standards of care. Such cases must be discussed with and explicitly approved by the Medical Monitor and Sponsor,
    and the specific diagnostic criteria used to establish the diagnosis of ACTH-dependent Cushing’s syndrome must be documented. 
• Willing to comply with reproductive precautions: Females will not be pregnant or lactating, and females of childbearing potential and males will agree to use contraception.
• Current evidence of Cushing’s comorbidities of hyperglycemia, dyslipidemia, hypertension, or osteopenia:
  • Defined by having at least 1 of the below criteria, ideally including both or either of “a” and “b”, but including any of “a”, “b”, “c”, or “d”;
  • Diagnosis of insulin-resistance/pre-diabetes or type 2 diabetes:
  • Including subjects on stable diabetic treatment but excluding those ethically requiring further or frequent therapy adjustments. Type 2 diabetes is defined as a current HbA1c ≥ 6.5% but ≤ 9.5% (otherwise excluded), fasting blood glucose (FBG) > 126 mg/dL, or 2-hour OGTT ≥ 200 mg/dL. Pre-diabetes is defined as current HbA1c < 6.5% but > 5.7%, FBG > 100 to 125 mg/dL, or 2-hour OGTT 140 to 199 mg/dL. Insulin-resistance may also be defined by abnormal HOMA-IR > 2.5 or by CGM data (e.g., mean glucose, glycemic variability, time in range, estimated HbA1c).
  • Diagnosis of dyslipidemia:This is evidenced by history of total cholesterol level of ≥ 6.2 mmol/L (240 mg/dL) or triglycerides of ≥ 5.2 mmol/L (200 mg/dL). Current total cholesterol may be < 6.2 mmol/L, and current triglycerides may be < 5.2 mmol/L, if controlled with allowed lipid-lowering therapy;
  • Diagnosis of hypertension: 
  • Incident hypertension should be brought under control and stabilized prior to randomization at Day 1. Subjects with hypertension, which is reasonably, but sub-optimally managed by standard therapy at baseline (systolic blood pressure [SBP] >140 but < 180 or DBP > 90 but < 120 mmHg) qualify;
  • Diagnosis of osteoporosis or osteopenia:
  • Osteopenia (T-score ≤ -1.0 or Z-score ≤ -2.0) or osteoporosis as determined previously, during the site’s local Baseline DEXA reading, or history or evidence of minimal-traumatic or osteoporotic fracture treated with lifestyle modification with mineral or vitamin supplementation or stable approved osteoporosis therapies. 

Subjects will be excluded from the study if they satisfy any of the following criteria at the Screening visit unless otherwise stated:

• Recent or planned Cushing’s surgery:
• Surgery for Cushing’s within the past 6 weeks or planned within 6 months after randomization.
• Use of medications for Cushing’s syndrome within the washout periods prior to randomization.
• Recent Cushing’s radiotherapy:
• A history of radiation therapy for Cushing’s within a period prior to plateau of efficacy (typically within the past 2 years of intensive targeted therapy [e.g., stereotactic radiation] or within 4 years of more conventional radiation therapy).
• History of bilateral adrenalectomy.
• History of pseudo-Cushing’s syndrome.
• History of cyclic Cushing’s syndrome.
• Exogenous hypercortisolism or factitious Cushing’s syndrome.
• History of non-ACTH-dependent hypercortisolism:
• This includes disease caused by a known inherited syndrome (e.g., McCune Albright syndrome, Carney complex) but not including multiple endocrine neoplasia type 1 where diagnostic testing has led to a diagnosis of Cushing’s disease (79%) while excluding autonomous adrenal Cushing’s syndrome (21%).
• High risk of acute morbidity from corticotroph adenoma growth: (similar to that which occurs with Nelson’s syndrome) defined as:
• Current evidence of macroadenoma with, or at risk of impingement on vital structures. For example, tumor showing aggressive growth abutting or compressing the optic chiasm or with evidence of blood-vessel encroachment, encirclement, invasion, or compression.
• Uncontrolled Cushing’s comorbidities of hyperglycemia, dyslipidemia, hypertension, or osteopenia:
• Including evidence of chronic, poor glycemic control (HbA1c > 9.5%), symptomatic dyslipidemia (e.g., hypercholesterolemia with recent (< 1 year) cerebro- orcardiova scular events, hypertriglyceridemia with pancreatitis), persistent uncontrolled hypertension (systolic blood pressure > 180 mmHg or DBP > 120 mmHg), or recent (< 1 year) osteoporotic fracture ethically requiring additional medical intervention.
• Use of drugs likely to interfere with study assessments:
• These include chronic systemic corticosteroids, thiazolidinediones, drugs that may alter the metabolism and clearance of corticosteroids (e.g., 5-alpha-reductase inhibitors), supplements or traditional medicines that contain a HSD-1 inhibitor, within 12 weeks prior to the first dose of study drug. 
• Uncontrolled hypothyroidism or hyperthyroidism:
• For patients with a history of, or treatment for, abnormal thyroid function, free thyroxine (T4) should be in normal range and stable, whether endogenous or on levothyroxine replacement [> 8 weeks]. Thyroid-stimulating hormone (TSH) will often not be reliable in post-operative patients, but if measured, should not be significantly elevated. Locally obtained recent, (within 3 months of screening) T4 and TSH results may be used for screening evaluation. If central laboratory data are not available, or delayed, these labs may be obtained locally during the screening period.
• Moderate or severe renal impairment:
• Defined by an estimated glomerular filtration rate (GFR) repeatedly < 60 mL/min/1.73 m^2  or confirmed by measured GFR < 60 mL/min/1.73 m^2.
• In the long-term phase of study, patients having function decline to < 45 mL/min/1.73 m^2 should be withdrawn from the study unless formal renal-impairment studies support safe continuation.
• Medically significant liver disease Including cirrhosis, chronic active hepatitis, chronic persistent hepatitis, or subjects with serum total bilirubin > 1.5 × ULN (unless previously diagnosed with benign Gilbert’s disease) or serum ALT or AST > 3 × ULN.
• Medically significant cardiovascular or ECG abnormalities: 
• This includes subjects with recent (< 1 year) myocardial infarction or stroke, orthostatic or vasovagal syncope, QT interval corrected (QTc) intervals > 500 msec, or evidence of significant, life-threatening arrhythmia or bradycardia (HR < 45 bpm).
• History of idiopathic thrombocytopenic purpura.
• History of adrenal carcinoma.
• Recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection:
• Positive test for infection within the past 4 weeks or hospitalization for coronavirus disease 2019 (COVID-19) within the past 6 months.
• History of cancer within 3 years other than ectopic ACTH from an unidentified source, with plans for therapy, intervention (e.g., biopsy), or likelihood for recurrence is likely to interfere with or confound the results of this trial. If stable and requiring hormone-suppressive therapy, subjects with breast, prostate, bone, or other endocrine cancer may be included at Medical Monitor discretion, however their data may be excluded in assessment of SPI-62 effects on HPA and HPG axis biomarkers).
• Any major surgery, or significant post-operative sequelae, within 1 month prior to informed consent or planned during the trial.
• Pregnant, lactating, or planning fertility in the next 6 months and unwilling to adhere to approved contraceptive use or abstinence.
• Participation in any clinical trial within 30 days or 5 half-lives, whichever is longer, prior to informed consent (or longer for biologic and long-lasting experimental therapies).
• Receipt of blood products within 2 months prior to Screening.
• Donation of blood from 3 months prior to Screening, plasma from 2 weeks prior to Screening, or platelets from 6 weeks prior to Screening. Subjects are not to donate blood, plasma, or platelets during the study.
• Poor peripheral venous access.
• Any other current or prior medical condition expected to interfere with the conduct of the study or the evaluation of its results. 

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

Eligibility last updated 8/28/23. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 12/21/22]. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 7/27/22. Questions regarding updates should be directed to the study team contact

• Male patients.
• Age 45-80 years, with > 10 years life expectancy.
• Biopsy-confirmed, NCCN (favorable GG2 and unfavorable GG3) intermediate-risk prostate cancer.
• Stage ≤ T2c, N0, M0.
• ISUP Grade Group 2 or 3 disease on TRUS-guided biopsy (minimum 8 cores, combination of systematic and MRI fusion-guided) or in-bore biopsy (minimum 3 cores from each PI-RADS v2 category ≥ 3 lesion). Biopsy reported within 12 months of baseline visit, with minimum 6-week interval between biopsy and baseline.
• PSA ≤ 20 ng/mL reported within 3 months of baseline.
• Treatment naïve.
• Planned ablation volume < 3.0 cm axial radius from the urethra on mpMRI acquired within 6 months of baseline.  

• Inability to undergo MRI or general anaesthesia.
• Suspected tumour > 30 mm from the prostatic urethra.
• Prostate calcifications > 3 mm in maximum extent obstructing ablation of tumour on low-dose pelvic CT:                
  • Criteria subject to additional review and approval by sponsor. Alternatively, prospective TRUS to query calcifications or susceptibility-weighted MRI if available may be used to assess calcifications. Imaging for calcification screening must be dated within 1 year of baseline visit.
• Unresolved urinary tract infection or prostatitis.
• History of proctitis, bladder stones, hematuria, history of acute urinary retention, severe neurogenic bladder.
• Artificial urinary sphincter, penile implant or intraprostatic implant.
• Less than 10 years life expectancy.
• Patients who are otherwise not deemed candidates for RP.
• Inability or unwillingness to provide informed consent.
• History of anal or rectal fibrosis or stenosis, or urethral stenosis, or other abnormality challenging insertion of devices.

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

• Male and female patients aged ≥ 18 years at the time of informed consent form (ICF) signature.
• Received allogeneic HSCT from a related or unrelated, human leukocyte antigen-matched or mismatched donor. Patients having received any of the following stem cell sources are eligible: granulocyte colony stimulating factor mobilized peripheral blood stem cells, bone marrow, umbilical cord blood.
• Diagnosis of TA-TMA established by histologic evidence of microangiopathy in any biopsied organ OR, as per the laboratory markers below, indicating TMA:
  • De novo or progressing thrombocytopenia (platelet count < 50 x 10^9/L or > 50 % decrease in platelet count from the highest value achieved after transplantation); AND
  • Elevated LDH (> 1.5 x ULN); AND
  • At least 1 additional laboratory criteria among the following:
  • Schistocytes on the peripheral blood smear (≥ 2 per hpf); OR
  • De novo anemia (hemoglobin < LLN or anemia requiring PRBC transfusion support as per local institutional standard); OR
  • Proteinuria (rUPCR ≥ 2 mg/mg); OR
  • Elevated plasma concentration of sC5b-9 above ULN.
• Have a diagnosis of TA-TMA that persists despite initial management of any triggering condition.
• Have at least 1 sign/symptom of organ dysfunction:
  • Kidney: doubling of serum creatinine compared with pre-HSCT level or patient receiving renal replacement therapy or proteinuria ≥ 30 mg/dL AND rUPCR ≥ 2 mg/mg;
  • Lungs: hypoxemia or any need for noninvasive or invasive positive pressure ventilation;
  • Cardiovascular: pulmonary hypertension diagnosed by a cardiologist using cardiac catheterization, or pulmonary hypertension criteria on echocardiography or arterial hypertension, defined by systolic blood pressure (BP) ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg at baseline or hypertension requiring > 2 medications (excluding diuretics);
  • Serositis: clinically significant pleural effusion or pericardial effusion requiring surgical therapy (e.g., pericardiocentesis/ thoracocentesis);
  • CNS: seizures attributable to posterior reversible encephalopathy syndrome;
  • GI tract: presence of biopsy-proven GI TA-TMA. Patients with GI bleeding (hematemesis or hematochezia) will be excluded.
• Women of childbearing potential, defined as any women who have experienced menarche and who are NOT permanently sterile or postmenopausal, must have a negative serum pregnancy test at screening and agree to use protocol-defined methods of contraception for the duration of the study and 8 weeks after their last IMP dose.
  • Note: Postmenopausal is defined as having had 12 consecutive months with no menses without an alternative medical cause.
• Men must agree to the following for the duration of the study and 8 weeks after their last dose of IMP:
  • Avoid fathering a child;
  • Use protocol-defined methods of contraception;
  • Refrain from donating sperm.
• Patient and/or legally authorized representative must be capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF.

• Positive direct Coombs test.
• Known familial or acquired ADAMTS13 deficiency.
• Known Shiga toxin‐related hemolytic uremic syndrome.
• Known bone marrow or graft failure.
• Diagnosis of disseminated intravascular coagulation.
• Diagnosis of VOD.
• Active GI bleeding (hematemesis or hematochezia) at baseline.
• Body weight < 30 kg and > 100 kg.
• Uncontrolled systemic bacterial or fungal infection, presence or suspicion of sepsis.
• Previously or currently treated with a complement inhibitor (approved or investigational).
• Pregnancy or breastfeeding.
• Positive human immunodeficiency virus antibody at screening or documented in pre-HSCT medical record.
• Hepatitis C virus detectable by polymerase chain reaction at screening or documented in pre-HSCT medical record.
• Chronic inactive hepatitis B virus with viral loads > 1000 IU/mL (> 5000 copies/mL) at screening or documented in pre-HSCT medical record. Eligible patients who are chronic active carriers (≤ 1000 IU/mL) must receive prophylactic antiviral treatment (e.g., entecavir, tenofovir, lamivudine) according to local country guidelines.
• Inability to cooperate with study procedures or any condition that, in the opinion of the investigator, could increase the patient’s risk by participating in the study or confound the outcome of the study.

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

• Over 18 years old.
• Fusion of the MCP joint at Mayo Clinic between January 01, 1990- December 31, 2020.

• ​​​​​​​Individuals under 18 years old.

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

• Women who will give birth at Mayo Clinic by caesarean-section at term following an uncomplicated pregnancy.

• Multiple pregnancy.
• Known presence of clinical infections (e.g., chorioamnionitis), congenital anomalies or maternal pathologies (i.e., diabetes, hypertension, preeclampsia).
• Intrauterine growth retardation or fetal macrosomia.
• Maternal age under 18 or over 50.
• Maternal body mass index (BMI) of less than 18 and more than 40.
• Pregnancy less than 37 weeks of completed gestation.

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

• Age 22
  •65 years.
• BMI ≥ 35 and < 40 kg/m^2 or BMI of 30 to 34.9 kg/m^2 with one or more major obesity-related comorbid conditions.
• Willingness to comply with the substantial lifelong dietary restrictions required by the procedure.
• History of obesity (BMI ≥ 30) for at least 2 years.
• History of failure with non-surgical weight loss methods.
• Willingness to follow protocol requirements, including signed informed consent, routine follow-up schedule, completing laboratory tests, completing diet counseling.
• Residing within a reasonable distance from the investigator’s office and able to travel to the investigator to complete all routine follow-up visits.
• Ability to give informed consent.
• Women of childbearing potential (i.e., not post-menopausal or surgically sterilized) must agree to use adequate birth control methods.  Acceptable birth control methods are limited to hormonal contraceptives (oral, flexible vaginal ring, skin patch, injection), diaphragms, IUDs, condoms with or without spermicide, and voluntary abstinence.  Should a treatment arm subject become pregnant during the implantation period, the balloon will be extracted during the second trimester
  •the timing of which will be determined via consultation with the subject’s obstetrician.

• Prior surgery involving the esophagus, stomach, and duodenum or bariatric surgery.
• Prior open or laparoscopic bariatric surgery.
• Prior surgery of any kind on the esophagus, stomach, duodenum or any type of hiatal hernia surgery.
• Any inflammatory disease of the gastrointestinal tract including esophagitis, Barrett’s esophagus, gastric ulceration, duodenal ulceration, cancer or specific inflammation such as Crohn’s disease
• Potential upper gastrointestinal bleeding conditions such as esophageal or gastric varices, congenital or acquired intestinal telangiectasis, or other congenital anomalies of the gastrointestinal tract such as atresias or stenoses.
• A gastric mass.
• A hiatal hernia > 2cm or severe or intractable gastro-esophageal reflux symptoms.
• Acid reflux symptoms to any degree that require more than one medication for symptom control.
• A structural abnormality in the esophagus or pharynx such as a stricture or diverticulum that could impede passage of the balloon alongside the endoscope.
• Achalasia or any other severe esophageal motility disorder that may pose a safety risk during the removal of the device.
• Severe coagulopathy.
• Insulin-dependent diabetes (either Type 1 or Type 2) or a significant likelihood of requiring insulin treatment in the following 12 months.
• Subjects with any serious health condition unrelated to their weight that would increase the risk of endoscopy.
• Chronic abdominal pain.
• Motility disorders of the GI tract such as gross esophageal motility disorders, gastroparesis or intractable constipation.
• Hepatic insufficiency or cirrhosis.
• Serious or uncontrolled psychiatric illness or disorder that could compromise patient understanding of or compliance with follow up visits and removal of the device after 8 months.
• Alcoholism or drug addiction.
• Patients unwilling to participate in an established medically-supervised diet and behavior modification program, with routine medical follow-up.
• Patients receiving daily prescribed treatment with aspirin, anti-inflammatory agents, anticoagulants or other gastric irritants.
• Patients who are unable or unwilling to take prescribed proton pump inhibitor medication for the duration of the device implant.
• Patients who are known to have, or suspected to have, an allergic reaction to materials contained in the system.
• Patients who have BOTH:
  • A previous history of a serotonin syndrome; AND
• • currently taking any drug known to affect the levels of serotonin in the body [e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs)].
• Patients who are pregnant or breast-feeding.
• Subjects with severe cardiopulmonary disease or other serious organic disease which might include known history of coronary artery disease, myocardial infarction within the past 6 months, poorly controlled hypertension, required use of NSAIDs.
• Subjects who have tested positive for H. Pylori, and who have not yet been treated.

Eligibility last updated 2/3/22. Questions regarding updates should be directed to the study team contact.

• Patient ≥ 18 years of age.
• Patient is a candidate for elective, primary total hip arthroplasties (THA) or total knee arthroplasties (TKA).
• Patient is considered high-risk for developing Periprosthetic joint infections (PJI) based on having at least one of the following criteria:
  • Body mass index (BMI) > 35 kg/m^2;
  • Diagnosis of diabetes mellitus;
  • Active tobacco smoker;
  • Chronic kidney disease;
  • Autoimmune disease;
  • Nasal colonization with methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-sensitive Staphylococcus aureus (MSSA).

• < 18 years of age.
• Inability to consume oral antibiotics.
• Allergy to antibiotic alternatives in the protocol.
• History of clostridium difficile colitis.
• Revision hip or knee arthroplasty procedure.
• Non-elective surgery.
• Hemiarthroplasty.
• Unicompartmental knee arthroplasty.
• Simultaneous bilateral THA or TKA.
• Will have subsequent THA or TKA within 12 weeks of the index study procedure.
• Pregnant.

• Deceased children with partial ornithine transcarbamylase (OTC) deficiency who were under strict treatment and died unexpectedly, and their parents.

• Lack of quality or significant volume of DNA from all submitted specimens.

Eligibility last updated 2/3/22. Questions regarding updates should be directed to the study team contact.

• Informed consent/assent:
  • For adult participants (≥ 18 years of age), ability to comprehend and willingness to sign an ICF;
  • For adolescent participants (≥ 12 to < 18 years of age), written informed consent of the parent(s) or legal guardian and written assent from the adolescent participant.
    • Note: Adolescents who during the course of the study become legal adults will be asked for their consent to participate in the study.
• Female and male adults and adolescents ≥ 12 years of age.
• Clinical diagnosis of FOP (based on findings of congenital malformation of the great toes, episodic soft-tissue swelling, and/or progressive HO).
• Participant-reported FOP disease activity within 1 year of the screening visit. This is defined as pain, swelling, and other signs and symptoms associated with FOP flare-ups or wosening of joint function or radiographic progression of HO (increase in site or number of HO lesions) with or without an association with flare-up episodes.
• Ability to swallow and retain orally administered tablets, either whole or crushed and dispersed in foods or liquids.
• Willingness to avoid pregnancy or fathering children based on the criteria below.
  • Male participants with reproductive potential must agree to take appropriate precautions to avoid fathering children from screening through 90 days after the last dose of study drug and must refrain from donating sperm during this period. Permitted methods in preventing pregnancy (see Appendix A) should be communicated to the participants and their understanding confirmed.
  • Female participants of childbearing potential must have a negative pregnancy test at screening (serum) and before the first dose on Day 1 (urine). Female participants of childbearing potential must agree to take appropriate precautions to avoid pregnancy from screening through 190 days after the last dose of study drug and must refrain from donating oocytes during this period. Permitted methods in preventing pregnancy should be communicated to the participants and their understanding confirmed.
  • Women without childbearing potential (ie, surgically sterile with a hysterectomy and/or bilateral oophorectomy OR ≥ 12 months of amenorrhea and at least 50 years of age) are eligible.
• Willing and able to undergo low-dose WBCT (excluding the head) imaging without requiring intubation.
• Willing and able to comply with study procedures and requirements and attend all study visits as defined in this Protocol.

• Pregnant or breast-feeding.
• CAJIS score ≥ 24.
• FOP disease severity that in the investigator's opinion precludes participation (e.g., ankyloses of most or all joints, symptomatic thoracic insufficiency syndrome, or recurrent respiratory infections).
• History of uncontrolled or unstable cardiovascular, respiratory, renal, gastrointestinal, endocrine, hematopoietic, psychiatric, and/or neurological disease within 6 months of screening.
• Any clinically significant medical condition other than FOP that would, in the investigator's judgment, interfere with full participation in the study, pose a significant risk to the participant, or interfere with interpretation of study data.
• Presence of a clinically significant finding on echocardiogram (as assessed by the investigator).
• Presence of an abnormal finding on ECG at screening that in the investigator's opinion is clinically significant and/or the following ECG parameters: QTcF interval > 450 milliseconds, QRS interval > 120 milliseconds, PR interval > 220 milliseconds, ECG evidence of Brugada syndrome, atrial fibrillation or atrial flutter, or Mobitz II or higher grade atrioventricular block.
• Current treatment with a potent/strong inhibitor or inducer of CYP3A4 within 5 half-lives before the first dose of study treatment or expected to receive such treatment during the study.
  • Note: Topical ketoconazole is allowed.
• Use of the following medications:
  • Imatinib 30 days prior to baseline (Day 1 visit);
  • Any medication that might interfere with HO formation in the 90 days before baseline (Day 1 visit);
  • Bisphosphonates within 1 year of screening.
• Participation in an investigational drug study for the treatment of FOP or any other indication within 30 days or 5 half-lives (whichever is longer) before baseline (Day 1 visit).
• Planning to receive a live vaccine during the course of the study or within 6 weeks after the last dose of study drug.
• Known or suspected allergy to INCB000928 or any component of the study drug.
• Known history of clinically significant drug or alcohol abuse as defined by the investigator in the l year before baseline (Day 1 visit).
• Chronic or current active infectious disease requiring systemic antibiotic, antifungal, or antiviral treatment.
• HIV, HBV, or HCV infection.

Note: Successfully treated HCV is allowed.

• Participants with laboratory values at screening defined in Table 7.

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