• Patient must be ≥ 2.5 years of age.
• Patient and/or authorized representative must be willing and able to give informed consent/assent and any authorizations required by local law for participation in the study.
• Patient and their caregiver must be willing and able (in the Investigator’s opinion) to comply with all protocol requirements.
• Patient must have completed dosing with STK-001 and the End of Study Visit in Study STK-001-DS-101, with an acceptable safety profile per Investigator judgment.
• Patient must have satisfactory compliance with study visits and procedures in Study STK-001-DS-101 per Investigator and Sponsor judgment.
• Patient must meet age-appropriate institutional standard practices for intrathecal (IT) drug administration procedures.
• Patient and/or family (or caretaker) must be sufficiently fluent in English or Spanish to be able to complete questionnaires relevant to this study.
• Patient must have completed Study STK-001-DS-101 within 4 weeks of the start of their participation in Study STK-001-DS-501, unless approved by the Sponsor.

• Patient has met any withdrawal criteria from Study STK-001-DS-101.
• Patient is currently being treated as maintenance therapy with an antiepileptic drug acting primarily as a sodium channel blocker including phenytoin, carbamazepine, oxcarbazepine, lamotrigine, lacosamide, or rufinamide.
• Patient has clinically significant unstable medical conditions other than epilepsy.
• Patient has had clinically relevant symptoms or a clinically significant illness (in the judgment of the Investigator) at Screening or prior to dosing on Day 1, other than epilepsy.
• Patient has a spinal deformity or other condition that may alter the free flow of CSF or has an implanted CSF drainage shunt.
• Patient has clinically significant (in the judgment of the Investigator) abnormal laboratory values at baseline or prior to dosing on Day 1.
• Patient has aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3-fold upper limit of normal (ULN), serum creatinine > ULN or platelet count < lower limit of normal at baseline and upon repeat testing.
• Patient has clinically significant abnormalities (in the judgment of the Investigator) in the 12-lead ECG measured at Screening/Baseline (This includes 12-lead ECG from STK-001-DS-101 [Visit 6 or Visit 9], if STK-001-DS-101 Visit 6 or Visit 9 and STK-001-DS-501 Visit 1 are the Same Day).
• Patient has a psychiatric or behavioral disorder which, in the opinion of the Investigator, may interfere with the patient’s participation in the study.
• Patient is currently taking, or within 4 weeks prior to Screening/Baseline has taken any anticoagulant (including but not limited to heparins, warfarin and other vitamin K antagonists, dabigatran, rivaroxaban and apixaban), or within 7 days prior to Screening/Baseline, has taken any antiplatelet (including but not limited to aspirin, non-steroidal anti-inflammatory drugs, clopidogrel, ticlopidine. and dipyridamole).
• Patient is a female of childbearing potential, or patient is a fertile male with female partner(s) of childbearing potential, unless willing to ensure that they or their partners use effective contraception throughout the duration of the study and for at least 6 months after their last dose of STK-001.
• . Patient is a female who is lactating or planning pregnancy during the duration of the study and for at least 6 months after their last dose of STK-001.
• Patient has any other significant disease or disorder which, in the opinion of the Investigator, may either put the patient at risk because of participation in the study, may influence the results of the study, or may affect the patient’s ability to participate in the study.
• Patient has been treated (or is being treated) with an investigational product (other than STK-001) since participating in Study STK-001-DS-101.
• Patient is participating in an observational study, unless approved by the Sponsor.

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

Eligibility last updated 4/25/23. Questions regarding updates should be directed to the study team contact.

• Informed consent, or consent via legally authorized representative, if institutionally required for subjects with decompensated liver cirrhosis with current HE Grade 1 or 2, prior to any study-related procedures.
• Male or female patients age ≥ 18 years old.
• Cirrhosis of the liver.
• Patient has diuretic-resistant ascites, intractable ascites, or in the opinion of the Investigator, is unsuitable for treatment with an effective dose of diuretics for other reasons.
• Patients must have required in the 60-day period from the last LVP before consent, between 3 and 9 LVPs, including the last LVP on or before the day of consent.
• Dates for all LVPs occurring within 90 days prior to consent have been recorded. The volume of ascites removed at each of the LVPs must also have been recorded for the 90 days period prior to the last LVPs before consent.
• Serum creatinine (SCr) ≤ 2.00 mg/dL determined prior to randomization with value at randomization being less than 1.5 fold higher than value obtained at the screening visit.
• Women of child-bearing potential (e.g., not post-menopausal for at least one year or surgically sterile) must be neither pregnant nor lactating and must agree to use adequate birth control or be abstinent for the duration of the study.
• If patient is treated with beta blockers, dose has been stable for at least 30 days prior to randomization and may be maintained on that dose for the trial duration.
• If patient is treated with diuretics, patient has been on a stable daily dose for at least 10 days prior to consent.
• Willing and able to comply with trial instructions.

• Ascites with causes other than cirrhosis; such as cardiac or nephrogenic ascites or malignant ascites due to peritoneal carcinomatosis.
• Urinary sodium excretion > 100 mmol/day between day of consent and randomization.
• Total bilirubin > 5 mg/dL.
• Blood clotting International normalized ratio (INR) > 2.5.
• Platelet count ≤ 100,000/µL for the first eight patients enrolled. Eligibility of patients with a platelet count > 65,000 but < 100,000/µL should be confirmed with the Medical Monitor.
• Current or recent (within 3 months of consent) renal dialysis.
• Current or recent (within 1 month of consent) hepatic encephalopathy Grade 3 or 4 (WestHaven criteria).
• Superimposed acute liver failure/injury due to factors including acute alcoholic hepatitis, acute viral hepatitis, drugs, medications (e.g., acetaminophen), or other toxins (e.g., mushroom [Amanita] poisoning).
• History or presence of hepatic hydrothorax that has required a thoracentesis in the 7 days prior to randomization, or anticipated to require one within 7 days post-randomization, known pulmonary hypertension or a history of hepatopulmonary syndrome.
• Current or recent treatment (within 7 days of randomization) with octreotide, midodrine, vasopressin, dopamine or other vasopressors.
• Treatment with ACE inhibitors or ARBs 30 days prior to randomization.
• Current or recent (in the previous 60 days from consent) episode of respiratory failure requiring positive airway pressure (PAP) devices or intubation.
• Sepsis episode in the previous 28 days from consent.
• Episode of SBP within 14 days prior to consent. If a patient develops SBP in the pretreatment period randomization cannot occur for a minimum of 10 days and documented resolution of SBP.
• SBP at baseline visit (LVP -1).
• Episode of gastrointestinal hemorrhage (non-variceal) within 28 days prior to consent.
• Episode of bleeding esophageal varices within one week prior to consent.
• Ongoing documented or suspected infection.
• Severe cardiovascular disease that is a contraindication to terlipressin therapy such as a history of myocardial infarction, angina pectoris, advanced arteriosclerosis, uncontrolled cardiac arrhythmia, severe coronary insufficiency or uncontrolled hypertension.
• Findings suggestive of severe organic renal disease (severe proteinuria/hematuria, or abnormal renal ultrasound suggestive of obstructive renal pathology).
• Use of nephrotoxic drugs (e.g., aminoglycosides) in the 2 weeks before randomization
• Severe comorbidity that in the opinion of the Investigator would affect short-term prognosis and/or disallow safe participation in the trial (such as for example, severe anemia or pancytopenia, advanced progressive neoplasia such as hepatocellular carcinoma, unless eligible for transplant).
• Patients, who in the judgement of the Investigator, have been excessive alcohol drinkers in the past 12 weeks.
• Patient is in the opinion of the investigator, despite previous education on sodium restriction, anticipated to remain grossly non-compliant of sodium restricted diet.
• Recipient of renal or liver transplant.
• Implanted alfapump or previous recipient of alfapump that had pump removed within past 3 months
• Planned elective surgery related to cirrhosis complications, for example for hernia repair.
• Known allergy or hypersensitivity to terlipressin.
• Participation in other clinical research studies involving the treatment with other investigational drugs or evaluation with implantable devices within 30 days of consent.

Eligibility last updated 4/14/22.  Questions regarding updates should be directed to the study team contact.

• Men and women above 18 years of age.
• Diagnosed with POEMS syndrome (newly diagnosed or in remission) or with newly diagnosed multiple myeloma (MM) or with monoclonal gammopathy of undetermined significance (MGUS) or amyloid light-chain (AL) amyloidosis or healthy controls from their households.

• Age under 18 years
• Pregnancy
• Substance abuse
• Antibiotics use or gastrointestinal endoscopy in the 3 months prior to the study participation
• Chronic gastrointestinal disorder
• Gastrointestinal surgeries in the past 2 years  
• Chemotherapy (including anti-plasma cell treatment and steroids) or radiation treatment for cancer within the last 2 years or active cancer (other than plasma cell disorder)

Eligibility last updated6/9/22. Questions regarding updates should be directed to the study team contact.

• English-speaking patient (aged 18 or older).
• Has received dexamethasone either intravenously or as a prescription in the past 2 weeks. 
• Patients do not have to be experiencing hiccups at the time of contact, but it is anticipated that these patients will likely have recurrent symptoms based on further or episodic dexamethasone treatment. 
• Patients must currently be in an outpatient setting, as it is unlikely that an educational session would be relevant or of value to an inpatient.

• Individuals under 18 years of age.

• Ages 18 years of age or older.
• Patients with bleeding secondary to HHT, GAVE, SBA and OGIB.
• Age and sex matched patients without bleeding (controls).
• Patients willing to provide written informed consent.

• Unwillingness/unable to provide informed consent.

• Age ≥ 1 year(s) old (no maximum age).
• Radiologic appearance of diffuse midline glioma of the pons, including diffuse infiltration of ≥ 50% of the pons on MRI, with or without extension to the midbrain and/or medulla oblongata with at least 1 of the 3 brainstem symptoms (cranial nerve deficit, long tract sign, or cerebellar sign).
• If all features of this clinicoradiologic criteria are met, then patients can continue on protocol with or without a biopsy.
• If all features of this clinicoradiologic criteria are not met, patients must receive a brainstem lesion biopsy to be treated on protocol. If this cannot be completed, patients will be withdrawn from the study.
• If biopsy has already been completed at an outside institution, pathology must be reviewed at Mayo Clinic for trial enrollment.
• Able to undergo MRI Brain.
• Negative urine pregnancy test completed ≤ 7 days prior to registration, for women of childbearing potential only.
• Primary language of English or Spanish for patients and their caregiver.
• Patient or caregiver willing and able to provide written informed consent.
• Caregiver able to complete questionnaires by themselves or with assistance.
• Willing to return to enrolling institution for follow-up during the active monitoring phase of the study.

• Any patient who has received previous radiation to the brain.
• Any patient who has received previous chemotherapy.
• Any patient with a diagnosis of neurofibromatosis type 1 or 2 (NF1 or NF2).
• Any of the following:
  • Pregnant women;
  • Nursing women;
  • Women of childbearing potential who are unwilling to employ adequate contraception.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Other active malignancy ≤ 5 years prior to registration.
  • EXCEPTIONS: Non-melanotic skin cancer, breast cancer, prostate cancer, well-differentiated thyroid cancer, carcinoma-in-situ of the cervix.
  • NOTE: If there is a history or prior malignancy, they must not be receiving other specific treatment for their cancer.
• Patients > 16 years with an Eastern Cooperative Oncology Group (ECOG) score ≥ 4 and patients ≤ 16 years with a Lansky play scale ≤ 20.

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

• Adults ≥ 18 years old.
• DLMP employees who work on-site at SDSC.
• Plan to complete the two dose SARS-CoV-2 vaccination schedule.

• Children < 18 years old.
• Subjects who have previously been diagnosed with SARS-CoV-2 infection.
• Subjects who test SARS-CoV-2 antibody positive on the pre-vaccination sample indicating prior infection.

• Adult participants (≥ 25 years of age).
• PLS diagnosis is based on the new PLS diagnostic criteria.
• Symptom onset was no more than 15 years prior to baseline.
• Ability to independently walk with or without an assistive device (e.g., walker) at the baseline evaluation.
• In cases where a molecular test has been done prior to enrollment in this study, HSP or HSP- related mutations are negative.
• Expected to have at least some bulbar symptoms (dysarthria, dysphagia, drooling or pseudobulbar affect); however, the absence of these symptoms will not exclude participants when molecular testing is negative for known HSP.
• UMN symptoms and signs in a region other than the legs.
• Normal brain and spinal cord neuroimaging except for changes expected for PLS.
• No active major neurological diseases other than PLS and no history of major neurological diseases.
• No major unstable medical diseases that require treatment (e.g., active cancer, dialysis) in the past 6 months.
• Participant is residing within a commutable distance to the study site and is willing to visit the study site as required.
• No history of ALS or PLS in immediate family and no family history of hereditary spastic paraplegia (HSP).
• gia (HSP) If disease duration is less than 5 years, no significant lower motor neuron (LMN) degeneration upon the EMG examination within 12 months before enrollment (evident entrapment neuropathy or radiculopathy are acceptable). If EMG tests were not done in this period, an EMG test should be obtained through regular patient care (through insurance) in order to make a diagnosis of PLS (this cost will not be covered by this research study). If disease duration is more than 5 years and at least one EMG was performed post-diagnosis, an EMG examination 12 months prior to enrollment is not required.
• Participant understands the study’s purpose, has capacity to consent, and is willing to sign the informed consent form.

• Unwilling or unable to give informed consent.
• UMN symptoms and signs only in the legs.
• Unwilling or unable to visit the study site as required.
• Clinically obvious cognitive impairment that precludes obtaining informed consent, as determined by the site PI.
• Participating in clinical treatment trials.

Eligibility last updated 5/3/22. Questions regarding updates should be directed to the study team contact.

• Subject is female.
• Subject has a BMI ≤ 29.
• Subject is between 18 and 80 years of age.
• Subject is a candidate for a unilateral or bilateral nipple sparing mastectomy procedure with mmediate reconstruction.
• Subject is at increased risk for breast cancer and is seeking prophylactic NSM surgery.
• Subject has no presence of occult cancer as confirmed by physical exam and by preoperative imaging per institution’s guidelines.  Known carriers of pathogenic BRCA1/2 mutations should have negative breast MRI.
• Subject has breast ptosis ≤ Grade 2.
• Subject has cup size ≤ C.
• Subject is at low to moderate risk for anesthesia (ASA class I, II or III).
• Subject is willing and able to provide written informed consent.
• Subject is willing and able to comply with the study protocol requirements including follow up examinations up to 5 years (+/- 90 days) post operatively.

• Subject has current or prior history of ipsilateral in-situ or invasive breast carcinoma.
• Subject has had previous breast surgery of the ipsilateral breast (excluding needle or core biopsies).
• Subject has an inflammatory and/or infectious skin condition and/or unhealed wounds on the ipsilateral breast.
• Subject has had chemotherapy for contralateral breast cancer within 3 weeks.
• Subject has had previous radiation treatment to the ipsilateral breast/chest area.
• Subject is planned to have other concomitant procedures (oophorectomy, hysterectomy, etc.).
• Subject has a current history of smoking or has smoked within 1 month of screening.
• Subject has hemoglobin A1C levels ≥ 8.
• Subject has a high risk for anesthesia (ASA class ≥ IV) or significant medical comorbidities (i.e., cardiac, pulmonary and neurologic) that preclude longer anesthesia times.
• Subject is contraindicated for general anesthesia or surgery.
• Subject has a known bleeding or clotting disorder.
• Subject is pregnant or suspected to be pregnant or is lactating.

• Unimpaired APOE e4/4 homozygotes age 65-75 and APOE e3/4 heterozygotes age 75-85 for the preclinical AD subset and age, sex, and education matched APOE e4 noncarriers for the unaffected controls. 
• Biomarker confirmation for preclinical diagnosis will be utilized to the extent possible (a subset of 130 members of our cohort have undergone amyloid-PET resulting in approximately 45 who are amyloid positive).

Exclusion Criteria:

• Previous stroke.
• Severe head injury.
• Craniotomy.
• Any other potentially confounding neurologic illness (typically anything that causes structural brain damage). 
• Psychoactive medication use will not be an absolute exclusionary criterion in patients with moderate to severe dementia but patients who are relatively drug-free will be prioritized to the extent they are available within the study period. 
• Psychoactive drug use will be exclusionary in the prospectively obtained clinical patients.

• Provide written informed consent from subjects, an impartial witness (for a subject who is physically unable to sign the informed consent form, but able to provide his/her consent by some other means [e.g., speaking, nodding, blinking]), or the subject’s legally authorized representative (LAR) (for a subject who lacks capacity to consent for him/herself [e.g., a subject without mental capacity to consent]), prior to beginning any study procedures.
• Cervical spinal cord injury who meet either of the following criteria:
  • AIS A with ISNCSCI neurological level of injury between C4 and C7 (for C4, the subject must have at least 1 point of motor activity within the ZPP inclusive of C5 to T1);
  • AIS B or C with ISNCSCI neurological level of injury between C4 and C7, and UEMS ≤ 28.
• Male and female subjects, age between 18 and 70 years at time of consent.
• Body mass index (BMI) < 40 kg/m^2.
• Acute traumatic spinal cord injury subjects who can receive MT-3921 as soon as possible after the injury, at least within 48 hours from the time of the injury.
• Willing and able to participate in all aspects of the study, including completion of subjective evaluations, attendance at scheduled clinic visits, and compliance with all protocol requirements as evidenced by providing informed consent.
• Both female and male subjects of childbearing potential must agree to use of contraception or abstinence during the study.

• Any concomitant injury that, in the judgement of the Investigator, interferes with the performance, interpretation or validity of neurological examinations (including fractures requiring casts), such as but not limited to multiple spinal cord lesions, brachial/lumbar plexus injury, cauda equina injury or traumatic brain injury defined by a Glasgow Coma Scale (GCS) <14 at time of examination.
• Poly-traumatic Injury as defined by Injury Severity Score (ISS) values > 25 at time of Screening.
• Penetrating spinal cord injuries.
• Complete transection of the spinal cord or spinal cord contusion size > 3 cm determined by MRI.
• Subjects who are highly anticipated to be dependent on long-term mechanical ventilation (e.g., beyond 10-14 days), which would interfere with study procedures including neurological exams.
• Any other significant pre-existing medical conditions prior to spinal cord injury or current conditions that, in the judgement of the Investigator, may increase the risks associated with study participation, and would preclude successful participation in the study.
• Subjects with history of active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV), except for adequately treated hepatitis B (HBV) and hepatitis C virus (HCV) with documentation of sustained virologic response defined as undetectable HCV RNA at least 12 weeks after the end of treatment.
• History of anaphylaxis or significant allergy to any food and medications.
• History or presence of malignancy within the last 3 years prior to screening, except subjects who have been treated successfully with no recurrence for >1 year of basal cell or squamous cell carcinoma of the skin or in-situ cervical cancer.
• Subjects with hereditary fructose intolerance.
• Psychoactive substance use disorder at any time during the 3 months preceding study entry (as defined by Diagnostic and Statistical Manual of Mental Disorders [DSM-5]).
• Participation in any clinical trial of a new chemical entity within 12 weeks prior to Screening.
• Pregnant or nursing women.

• Patients over the age of 18 years.
• Ability to provide informed consent.
• Patients scheduled for gastrointestinal endoscopy and clinically indicated resection through our advanced endoscopy practice at Mayo Clinic Saint Mary Hospital, Alfred 6 Endoscopy Unit; or
• Patients undergoing clinically indicated surgical resection of the gastrointestinal tract (esophagus, stomach, small bowel, colon).

• Patients in who endoscopic or surgical resection is contraindicated.
• Patients who are pregnant.

Eligibility last updated 8/25/21. Questions regarding updates should be directed to the study team contact.

• Women ≥ 25 years of age.
• Women who had previously undergone salpingectomy or salpingo oophorectomy for any indication, including risk reduction, independent of final pathology including:
  • Morphologically unremarkable FTs;
  • STIC, pure (isolated) or concurrent with:
  • Histologic diagnosis of STIC has been confirmed by the GYN pathologist.
  • OHGSC.
• FFPE block is available for research.
• IRB approved informed consent for banking remnant tissue (taken during the course of routine care) for future use in research or waivers of consent and HIPAA Authorization for the release of information and biospecimens.
• Assessment of risk for ovarian cancer will be based on criteria derived from the inclusion criteria for the United Kingdom Familial Ovarian Cancer Screening Study (UKFOCSS).

• Patients who don’t satisfy the inclusion criteria listed above.
• Subjects with history of other malignancies, except:
  • Adequately treated non-melanoma skin cancer;
  • Curatively treated in-situ cancer of the cervix;
  • Other solid tumors curatively treated with no evidence of disease for > 5 years.

Eligibility last updated 7/17/23. Questions regarding updates should be directed to the study team contact.

• Participants from an existing IRB approved protocol (#18-008476, #14-004401, #712-98)

• Unable to complete study activities.
• Unable to read and speak English.

Pre-Registration
•

• Age ≥ 18 years.
• Currently have or have had in the past the diagnosis of any type of lymphoma.
• If previously treated, the patient must be off myelosuppressive chemotherapy with no planned chemotherapy for ≥2 months. Patients with lymphoproliferative disorders being observed (i.e., never treated) or those on rituximab (or equivalent) maintenance or chronic oral therapies such as BTK inhibitors, venetoclax, tazemetostat, or corticosteroids are also eligible.
• Able to eat a full range of solid food and liquids and tolerate seeds/nuts.
• ECOG Performance Status (PS) 0, 1, or 2).
• Provide written informed consent.
• Able to recollect dietary intake for the prior 24 hours in order to complete a one-day food record with assistance from a dietitian at each study visit.
• Willing to be seen at the enrolling institution at baseline, and at 4 weeks and 8 weeks (end of treatment) in person or by video/phone.
• Willing to have a blood magnesium checked every 2 weeks x 4 at any Mayo Clinic site.
• Ability to complete questionnaire(s) by themselves or with assistance.

Pre-Registration
•

• Cannot eat normal table food by mouth. 
  • Note: Patients with any form of feeding tube or a swallowing disorder are not eligible.
• Have taken dedicated magnesium supplements (i.e., magnesium oxide) or IV magnesium ≤ 28 days prior to pre-registration.
  • Note: If patient is already on a multivitamin containing -magnesium, they may be enrolled, but the brand should not be changed during the 8 weeks on study.
• Co-morbid systemic illnesses such as active infection or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Patients with significant gut malabsorptive conditions (such as inflammatory bowel disease or others at the discretion of the investigator) will be excluded as well as patients with chronic kidney disease stage 3b or greater (eGFR < 45).
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Receiving any other investigational agent for lymphoma or any other disease.
• Active other malignancy requiring treatment that would interfere with the assessments of this study.
• Major surgery other than diagnostic surgery ≤ 4 weeks prior to pre-registration.
• Have an allergy to nuts.
• Patients with active skin lymphoma or rashes that would preclude lotion testing.
• Have taken antibiotics ≤ 7 days prior to pre-registration.

Registration -

• The following laboratory value obtained ≤ 5 days prior to registration:
  • Magnesium level of 1.5 – 1.9 mg/dL.

Registration
•

• None.

Eligibility last updated 11/16/21. Questions regarding updates should be directed to the study team contact.

Eligibility last updated 12/23/22. Questions regarding updates should be directed to the study team contact.

Eligibility last updated 12/23/22. Questions regarding updates should be directed to the study team contact.

Eligibility last updated 12/23/22. Questions regarding updates should be directed to the study team contact.

• Age 16-55 years old.
• Medial, lateral, vertical longitutdinal, oblique, or radial meniscal tear.
• Complex tears may be included (investigator discetion) if the patient has one of the tear patterns listed in incluse as the predominant finding.
• No other concomitant procedures unless (one of the following):
  • Chondroplasty;
  • Synovectomy;
  • Loose body removal;
  • “Contralateral” menisectomy (i.e., medial meniscus repair with a lateral menisectomy or lateral meniscus repair with a medial menisectomy) would be permitted for inclusion;
  • Any other procedure that does not include drilling, requires prior approval of the study sponsor for each procedure.

• Patients requiring cartilage restorative or repair procedures (i.e., OCD fixation, micro-fracture repair, or others).
• Patients with meniscus root tears.
• Patients undergoing repair for horizontal cleavage tears.
• Kellgren-Lawrence scale > 2.
• Patients undergoing lateral release.
• Ipsilateral chondral lesion with Outerbridge classification of 3-4.
• Use of prednisone or other steroids, any immunosuppressant, or chemotherapy 1-week before surgery or expected use within six weeks after surgery.
• Cortisone use within the six weeks prior to surgery.
• Utilizing worker’s compensation at the time of screening.
• Any previous ligament surgery on the index limb. Any previous meniscal surgery on the index meniscus.
• Concomitant ligamentous insufficiency.
• Inflammatory rheumatic disease or other rheumatic disease.
• Immune compromised patients (hepatitis, HIV, etc.).
• Any nicotine based products within the three months prior to surgery (including cigarettes, cigars, vaping, nicotaine patch, etc.).
• History of distal femur, proximal tibia, or patellar fracture that was treated operatively.
• Non English-speaking patients.

• Scholars and former scholars of the Mayo Clinic Cancer Center’s “Paul Calabresi Clinical Oncology (K12) Training Program.”

• None.

• Adult patients with brain metastases, for whom gamma knife radiosurgery recommended.

• Patients unable to tolerate/obtain MRI brain.

• Adults, age ≥ 18 years old.
• of Home Enteral Nutrition (HEN) patient receiving at least 90% of energy needs from enteral nutrition.
• BMI > 30.
• History of stroke.
• Weight stable over the past month.

• Diagnosis of cancer undergoing active treatment (chemotherapy, radiation, immunotherapy).
• Life expectancy of less than 6 months.
• Stage IV or higher kidney disease (GFR < 30).

Healthy Adults

• Healthy women (≥ 18 years of age).
• Participants will be categorized by menopausal status using the STRAW+10 guidelines36:
  • Premenopausal women will be experiencing regular menstrual cycles; 
  • Perimenopausal women will be experiencing irregular cycles (i.e., early perimenopause) or 2-11 mo of amenorrhea (i.e., late perimenopause). Postmenopausal women will have been > 5 years without menstruation and have undergone natural menopause.
• No history of cardiovascular, pulmonary, neurologic, orthopedic, or other diseases affecting the neuromuscular system.
• Undergoing treatment for menopausal symptoms (e.g., hormone replacement therapy).
• Having taken oral contraceptives in the past > 6 months.
• BMI ≤ 35kg/m^2.
• Current non-smokers with smoking history < 15 pack years.
• Able to engage in exercise (i.e., without significant orthopedic limitations or musculoskeletal disorders limiting their ability to exercise).

Patients with Hypertension

• (≥ 18 years).
• No history of dangerous arrhythmias.
• Not pacemaker dependent.
• Undergoing treatment for menopausal symptoms (e.g., hormone replacement therapy).
• Having taken oral contraceptives in the past > 6 months.
• Body mass index ≤ 35 kg/m^2.
• Currently non-smokers with < 15 pack year history.
• Able to exercise (i.e., without significant orthopedic limitations or musculoskeletal disorders limiting their ability to exercise).
• Patients will be tested while receiving optimized standard pharmacologic optimized therapy.
• All patients will be managed by their primary care physician or cardiologist with additional review by Dr. Borlaug (Co-Investigator) prior to enrollment to ensure inclusion and exclusion criteria have been satisfied and participation in exercise testing is safe.

• History of dangerous arrhythmias.
• Undergoing treatment for menopausal symptoms (e.g., hormone replacement therapy.
• Having taken oral contraceptives in the past > 6 months.
• Body mass index > 35 kg/m^2.
• Current smokers and/or smoking history > 15 pack years.
• Pregnant women.
• Uremia, history of allergy to iodides.
• Impaired renal function.
• Creatinine value than or equal to 1.3 mg/dL (via clinical record within the past 6 months).
• Diagnosis of liver disease.
• Individuals who are not able to engage in exercise.
• For individuals agreeing to undergo dual energy x-ray absorptiometry (DEXA) scanning for measurement of body composition as part of their study visit, additional exclusion criteria apply:
• Recently administered gastrointestinal contrast or radionuclides;
• Severe degenerative changes or fracture deformity in measurement areas; or
• Inability to attain correct position and/or remain motionless for the measurement period.

• Have worked in the outpatient PPT setting at Mayo Clinic within the last 8 years (5 years for recent recall, plus 3 years to account for decreased patient population of interest during Covid-19 pandemic).
• Have worked with at least 1 Arabic speaking patient/family with interpreter services.
• Report ability to discuss experience with this patient population.

• Have not met inclusion criteria.

Eligibility last updated 10/17/22. Questions regarding updates should be directed to the study team contact.

• Written informed consent.
• Male or female between the ages of 18 and 75 years, inclusive, at Screening.
• Meets the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria for SSc with a total score of ≥ 9 (Van den Hoogen et al., 2013).
• Classified as having skin involvement proximal to the elbow and knee (diffuse cutaneous SSc subset by LeRoy and Medsger, 2001).
• At the time of enrollment, less than 36 months since the onset of the first SSc manifestation, other than Raynaud's phenomenon.
• Based on data available through medical history and/or medical records, the subject should have at least 1 of the following:
  • disease duration ≤ 18 months;
  • increase ≥ 3 in mRSS units compared with the last visit within the previous 1 month to 6 months;
  • involvement of 1 new body area with ≥ 2 mRSS units or 2 new body areas with ≥1 mRSS unit;
  • documentation of worsening skin thickening for subjects who did not have mRSS performed during the previous visit;
  • presence of tendon friction rub at Screening.
• Presence of at least 1 of the following features of elevated acute phase reactants at Screening:
  • high-sensitivity C-reactive protein (hsCRP) ≥0.6 mg/dL (≥ 6 mg/L);
  • erythrocyte sedimentation rate (ESR) ≥ 28 mm/hr;
  • platelet count ≥ 330 × 10^9/L (330,000/μL).
• Skin thickening from SSc in the forearm suitable for repeat biopsy.
• mRSS units ≥ 15 at Screening.
• FVC ≥ 45% predicted at Screening, as determined by spirometry.
• Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the trial.

• Positive for anti-centromere antibodies.
• Diagnosed with sine scleroderma or limited cutaneous SSc.
• Diagnosed with other autoimmune connective tissue diseases, except for fibromyalgia, scleroderma-associated myopathy and secondary Sjogren's syndrome.
• Scleroderma renal crisis diagnosed within 6 months of the Screening Visit.
• Any of the following cardiovascular diseases:
  • uncontrolled, severe hypertension (≥ 160/100 mmHg) or persistent low blood pressure (systolic blood pressure < 90 mmHg) within 6 months of Screening,
  •  myocardial infarction within 6 months of Screening,
  •  unstable cardiac angina within 6 months of Screening.
• DLCO < 40% predicted (corrected for hemoglobin). If severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure is of clinical concern for any subject, consider using a DLCO up to 6 months before the Screening Visit.
• Pulmonary arterial hypertension (PAH) by right heart catheterization requiring treatment with more than 1 oral PAH-approved therapy or any parenteral therapy. Treatment is allowed for erectile dysfunction and/or Raynaud's phenomenon/digital ulcers.
• Corticosteroid use for conditions other than SSc within 4 weeks prior to Screening (topical steroids for dermatological conditions and inhaled/intranasal/intra-articular steroids are allowed).
• Use of any other non-steroid immunosuppressive agent, small biologic molecule, cytotoxic or anti-fibrotic drug within 4 weeks of Screening, including cyclophosphamide, azathioprine (Imuran®) or other immunosuppressive or cytotoxic medication. Exceptions include mycophenolate mofetil (CellCept®), mycophenolic acid (Myfortic®), methotrexate and low-dose prednisone, as follows: use of CellCept ≤ 3 g/day, Myfortic ≤ 2.14 g/day, methotrexate ≤ 15 mg/week and prednisone ≤ 10 mg/day (or equivalent dosing of glucocorticoids) is allowed. Subjects taking CellCept, Myfortic or methotrexate must have been doing so for ≥ 6 months and the dose must have been stable for ≥ 16 weeks prior to the Day 1 Visit. Prednisone must have been at a stable dose for ≥ 8 weeks prior to the Day 1 Visit. It is acceptable to be on background low-dose prednisone and anti-malarial drug along with CellCept, Myfortic or methotrexate. Rituximab must not have been used within 6 months of the Day 1 Visit.
• Known active bacterial, viral, fungal, mycobacterial or other infection, including tuberculosis or atypical mycobacterial disease (fungal infections of nail beds are allowed).
• Use of a United States Food and Drug Administration-approved agent for SSc or an investigational agent for any condition within 90 days or 5 half-lives, whichever is longer, prior to Screening or anticipated use during the course of the trial. 12. Malignant condition in the past 5 years (except successfully treated basal/squamous cell carcinoma of the skin or cervical cancer in situ).
•  Women of childbearing potential or male subjects not agreeing to use highly effective method(s) of birth control throughout the trial and for 1 month after last dose of trial drug. Male subjects must refrain from sperm donation and females from egg/ova donation for this same time period.
• Pregnant or lactating women.
• Current drug or alcohol abuse or history of either within the previous 2 years, in the opinion of the Investigator or as reported by the subject.
• Previous enrollment in this trial or participation in a prior HZN-825 or SAR100842 clinical trial.
• Known history of positive test for human immunodeficiency virus.
• Active hepatitis (hepatitis B: positive hepatitis B surface antigen and positive anti-hepatitis B core antibody [anti-HBcAb] and negative hepatitis B surface antibody [HBsAb] or positive for HBcAb with a positive test for HBsAb and with presence of hepatitis B virus DNA at Screening; hepatitis C: positive anti-hepatitis C virus [anti-HCV] and positive RNA HCV).
• Current alcoholic liver disease, primary biliary cirrhosis or primary sclerosing cholangitis.
• Previous organ transplant (including allogeneic and autologous marrow transplant).
• International normalized ratio > 2, prolonged prothrombin time > 1.5 × the upper limit of normal (ULN) or partial thromboplastin time > 1.5 × ULN at Screening.
• Alanine aminotransferase or aspartate aminotransferase > 2 × ULN.
• Estimated glomerular filtration rate < 30 mL/min/1.73 m^2 at Screening.
• Total bilirubin > 2 × ULN. Subjects with documented diagnosis of Gilbert's syndrome may be enrolled if their total bilirubin is ≤ 3.0 mg/dL.
• Any other condition that, in the opinion of the Investigator, would preclude enrollment in the trial.

• All patients ≥ 16 years old.
• Scheduled for a primary Hip Arthroscopy at Mayo Clinic (Rochester, MN), and Mayo Clinic Orthopedics and Sports Medicine (Minneapolis, MN). 

• Patients with a medical history of known allergies or intolerance to allergies or intolerance to Motrin, Gabapentin, Tylenol, dexamethasone, tramadol, or Robaxin.
• Substantial alcohol or drug abuse.
• History of narcotics within 6 months of surgery.
• Pregnancy.
• Renal impairment.
• Peptic ulcer disease.
• GI bleeding.

• All patients ≥ 16 years old.
• Scheduled for a primary Hip Arthroscopy at Mayo Clinic (Rochester, MN), and Mayo Clinic Orthopedics and Sports Medicine (Minneapolis, MN). 

• Patients with a medical history of known allergies or intolerance to allergies or intolerance to Motrin, Gabapentin, Tylenol, dexamethasone, tramadol, or Robaxin.
• Substantial alcohol or drug abuse.
• History of narcotics within 6 months of surgery.
• Pregnancy.
• Renal impairment.
• Peptic ulcer disease.
• GI bleeding.

PRIOR TO STEP 1 REGISTRATION

• Pathologically proven diagnosis of adenocarcinoma of prostate cancer within 180 days prior to registration.
• High-risk disease defined as having at least one or more of the following:
  • PSA > 20 ng/mL prior to starting ADT;
  • cT3a-T4 by digital exam or imaging (American Joint Committee on Cancer [AJCC] 8th edition [Ed.]);
  • Gleason score of 8-10;
  • Node positive by conventional imaging with a short axis of at least 1.0 cm;
  • Appropriate stage for study entry based on the following diagnostic workup:
    • History/physical examination within 120 days prior to registration;
    • Bone imaging within 120 days prior to registration;
      • Note: To be eligible, patient must have no definitive evidence of bone metastases (M0) on bone scan or sodium fluoride (NaF) PET within 120 days prior to registration (negative Na F PET/CT or negative axumin or choline PET or negative fluciclovine, choline or prostate-specific membrane antigen (PSMA) PET within 120 days prior to registration is an acceptable substitute if they have been performed).
  • Patients who have bone metastases established only fluciclovine, choline, or PSMA PET but not definitive on bone scan or Na F PET will still be eligible.
  • CT or MRI of the pelvis within 120 days prior to registration (negative fluciclovine, choline, or PSMA PET within 120 days prior to registration is an acceptable substitute). As with bone staging, nodal staging for trial purposes will be based off of conventional imaging findings only.
  • Patients with confirmed N1 metastases on conventional imaging (CT/MRI) as defined by > 10 mm on short axis are eligible but will be automatically assigned to the intensification study. Patients who are positive by fluciclovine, choline, or PSMA PET (i.e., N1), but whose nodes do not meet traditional size criteria for positivity (i.e., they measure ≤ 10 mm on either the CT or MRI portion of the PET or on a dedicated CT or MRI) will not be considered N1 for the trial and will not automatically be assigned to the intensification study.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 within 120 days prior to registration.
  • Hemoglobin ≥ 9.0 g/dL, independent of transfusion and/or growth factors (within 120 days prior to registration).
  • Platelet count ≥ 100,000 x 10^9/uL independent of transfusion and/or growth factors (within 120 days prior to registration).
  • Creatinine clearance (CrCl) ≥ 30 mL/min estimated by Cockcroft-Gault equation (within 120 days prior to registration).
  • For Black patients whose renal function is not considered adequate by Cockcroft-Gault formula, an alternative formula that takes race into account (Chronic Kidney Disease Epidemiology Collaboration CKD-EPI formula) may be used for calculating creatinine clearance for trial eligibility.
  • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) within 120 days prior to registration.
    • Note: In subjects with Gilbert's syndrome, if total bilirubin is > 1.5 x ULN, measure direct and indirect bilirubin and if direct bilirubin is ≤ 1.5 x ULN, subject is eligible.
    • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.5 x institutional ULN (within 120 days prior to registration).
    • Serum albumin ≥ 3.0 g/dL (within 120 days prior to registration).
• The patient must agree to use a condom (even men with vasectomies) and another effective method of birth control if he is having sex with a woman of childbearing potential or agree to use a condom if he is having sex with a woman who is pregnant while on study drug and for 3 months following the last dose of study drug.
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy (didanosine [DDI] is not permitted) with undetectable viral load within 6 months are eligible for this trial and have a CD4 count ≥ 200 cells/microliter within 60 days prior to registration. Note: HIV testing is not required for eligibility for this protocol. Of note, for patients with HIV in the intensification trial randomized to abiraterone acetate and apalutamide, highly active antiretroviral therapy (HAART) may need to be adjusted to medications that do not interact with abiraterone acetate and apalutamide.
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable after or on suppressive therapy within 60 days prior to registration, if indicated.
  • Note: HBV viral testing is not required for eligibility for this protocol.
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
  • Note: Any patient with a cancer (other than keratinocyte carcinoma or carcinoma in situ or low-grade non-muscle invasive bladder cancer) who has been disease-free for less than 3 years must contact the principal investigator.
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry.

PRIOR TO STEP 2 RANDOMIZATION

• Confirmation of Decipher score.
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load within 60 days prior. Note: Apalutamide may interfere with HCV drugs.
• Patients on HCV medications should alert their infectious diseases physician if they get randomized to apalutamide due to the possibility that apalutamide can affect the bioavailability of some HCV medications. HCV viral testing is not required for eligibility for this protocol.

For patients entering the Intensification Cohort ONLY:

• Patients must discontinue or substitute concomitant medications known to lower the seizure threshold at least 30 days prior to Step 2 randomization.

For patients entering the Intensification Cohort ONLY:

• Serum potassium ≥ 3.5 mmol/L prior to Step 2 randomization.

PRIOR TO STEP 1 REGISTRATION

• Definitive radiologic evidence of metastatic disease outside of the pelvic nodes (M1a, M1b or M1c) on conventional imaging (i.e., bone scan, CT scan, MRI).
• Prior systemic chemotherapy within ≤ 3 years prior to registration; note that prior chemotherapy for a different cancer is allowed (completed > 3 years prior to registration.
• Prior radical prostatectomy.
• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields.
• Current use of 5-alpha reductase inhibitor.
  • Note: If the alpha reductase inhibitor is stopped prior to randomization the patient is eligible.
• Didanosine (DDI) antiretroviral therapy is not permitted.
• History of any of the following:
  • Seizure disorder;
  • Current severe or unstable angina;
  • New York Heart Association Functional Classification III/IV;
    • Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification.
  • History of any condition that in the opinion of the investigator, would preclude participation in this study.
• Evidence of any of the following at registration:
  • Active uncontrolled infection requiring IV antibiotics;
  • Baseline moderate and severe hepatic impairment (Child-Pugh class B & C);
  • Inability to swallow oral pills;
  • Any current condition that in the opinion of the investigator, would preclude participation in this study.
• Prior pharmacologic androgen ablation for prostate cancer is allowed only if the onset of androgen ablation (both luteinizing hormone-releasing hormone [LHRH] agonist and oral anti-androgen) is ≤ 60 days prior to registration; Please note: baseline PSA and testosterone must be obtained prior to the start of any ADT.

PRIOR TO STEP 2 RANDOMIZATION

• Evidence of known gastrointestinal disorder affecting absorption of oral medications at registration.

For patients entering the Intensification Cohort ONLY:

• Any chronic medical condition requiring a higher dose of corticosteroid than 10 mg prednisone/prednisolone once daily.

For patients entering the Intensification Cohort ONLY:

• Presence of uncontrolled hypertension (persistent systolic blood pressure [BP] ≥ 160 mmHg or diastolic BP ≥ 100 mmHg);
• Subjects with a history of hypertension are allowed, provided that BP is controlled to within these limits by anti-hypertensive treatment.

PRIOR TO STEP 1 REGISTRATION

• Pathologically proven diagnosis of adenocarcinoma of prostate cancer within 180 days prior to registration.
• High-risk disease defined as having at least one or more of the following:
  • PSA > 20 ng/mL prior to starting ADT;
  • cT3a-T4 by digital exam or imaging (American Joint Committee on Cancer [AJCC] 8th edition [Ed.]);
  • Gleason score of 8-10;
  • Node positive by conventional imaging with a short axis of at least 1.0 cm;
  • Appropriate stage for study entry based on the following diagnostic workup:
    • History/physical examination within 120 days prior to registration;
    • Bone imaging within 120 days prior to registration;
      • Note: To be eligible, patient must have no definitive evidence of bone metastases (M0) on bone scan or sodium fluoride (NaF) PET within 120 days prior to registration (negative Na F PET/CT or negative axumin or choline PET or negative fluciclovine, choline or prostate-specific membrane antigen (PSMA) PET within 120 days prior to registration is an acceptable substitute if they have been performed).
  • Patients who have bone metastases established only fluciclovine, choline, or PSMA PET but not definitive on bone scan or Na F PET will still be eligible.
  • CT or MRI of the pelvis within 120 days prior to registration (negative fluciclovine, choline, or PSMA PET within 120 days prior to registration is an acceptable substitute). As with bone staging, nodal staging for trial purposes will be based off of conventional imaging findings only.
  • Patients with confirmed N1 metastases on conventional imaging (CT/MRI) as defined by > 10 mm on short axis are eligible but will be automatically assigned to the intensification study. Patients who are positive by fluciclovine, choline, or PSMA PET (i.e., N1), but whose nodes do not meet traditional size criteria for positivity (i.e., they measure ≤ 10 mm on either the CT or MRI portion of the PET or on a dedicated CT or MRI) will not be considered N1 for the trial and will not automatically be assigned to the intensification study.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 within 120 days prior to registration.
  • Hemoglobin ≥ 9.0 g/dL, independent of transfusion and/or growth factors (within 120 days prior to registration).
  • Platelet count ≥ 100,000 x 10^9/uL independent of transfusion and/or growth factors (within 120 days prior to registration).
  • Creatinine clearance (CrCl) ≥ 30 mL/min estimated by Cockcroft-Gault equation (within 120 days prior to registration).
  • For Black patients whose renal function is not considered adequate by Cockcroft-Gault formula, an alternative formula that takes race into account (Chronic Kidney Disease Epidemiology Collaboration CKD-EPI formula) may be used for calculating creatinine clearance for trial eligibility.
  • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) within 120 days prior to registration.
    • Note: In subjects with Gilbert's syndrome, if total bilirubin is > 1.5 x ULN, measure direct and indirect bilirubin and if direct bilirubin is ≤ 1.5 x ULN, subject is eligible.
    • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.5 x institutional ULN (within 120 days prior to registration).
    • Serum albumin ≥ 3.0 g/dL (within 120 days prior to registration).
• The patient must agree to use a condom (even men with vasectomies) and another effective method of birth control if he is having sex with a woman of childbearing potential or agree to use a condom if he is having sex with a woman who is pregnant while on study drug and for 3 months following the last dose of study drug.
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy (didanosine [DDI] is not permitted) with undetectable viral load within 6 months are eligible for this trial and have a CD4 count ≥ 200 cells/microliter within 60 days prior to registration. Note: HIV testing is not required for eligibility for this protocol. Of note, for patients with HIV in the intensification trial randomized to abiraterone acetate and apalutamide, highly active antiretroviral therapy (HAART) may need to be adjusted to medications that do not interact with abiraterone acetate and apalutamide.
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable after or on suppressive therapy within 60 days prior to registration, if indicated.
  • Note: HBV viral testing is not required for eligibility for this protocol.
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
  • Note: Any patient with a cancer (other than keratinocyte carcinoma or carcinoma in situ or low-grade non-muscle invasive bladder cancer) who has been disease-free for less than 3 years must contact the principal investigator.
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry.

PRIOR TO STEP 2 RANDOMIZATION

• Confirmation of Decipher score.
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load within 60 days prior. Note: Apalutamide may interfere with HCV drugs.
• Patients on HCV medications should alert their infectious diseases physician if they get randomized to apalutamide due to the possibility that apalutamide can affect the bioavailability of some HCV medications. HCV viral testing is not required for eligibility for this protocol.

For patients entering the Intensification Cohort ONLY:

• Patients must discontinue or substitute concomitant medications known to lower the seizure threshold at least 30 days prior to Step 2 randomization.

For patients entering the Intensification Cohort ONLY:

• Serum potassium ≥ 3.5 mmol/L prior to Step 2 randomization.

PRIOR TO STEP 1 REGISTRATION

• Definitive radiologic evidence of metastatic disease outside of the pelvic nodes (M1a, M1b or M1c) on conventional imaging (i.e., bone scan, CT scan, MRI).
• Prior systemic chemotherapy within ≤ 3 years prior to registration; note that prior chemotherapy for a different cancer is allowed (completed > 3 years prior to registration.
• Prior radical prostatectomy.
• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields.
• Current use of 5-alpha reductase inhibitor.
  • Note: If the alpha reductase inhibitor is stopped prior to randomization the patient is eligible.
• Didanosine (DDI) antiretroviral therapy is not permitted.
• History of any of the following:
  • Seizure disorder;
  • Current severe or unstable angina;
  • New York Heart Association Functional Classification III/IV;
    • Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification.
  • History of any condition that in the opinion of the investigator, would preclude participation in this study.
• Evidence of any of the following at registration:
  • Active uncontrolled infection requiring IV antibiotics;
  • Baseline moderate and severe hepatic impairment (Child-Pugh class B & C);
  • Inability to swallow oral pills;
  • Any current condition that in the opinion of the investigator, would preclude participation in this study.
• Prior pharmacologic androgen ablation for prostate cancer is allowed only if the onset of androgen ablation (both luteinizing hormone-releasing hormone [LHRH] agonist and oral anti-androgen) is ≤ 60 days prior to registration; Please note: baseline PSA and testosterone must be obtained prior to the start of any ADT.

PRIOR TO STEP 2 RANDOMIZATION

• Evidence of known gastrointestinal disorder affecting absorption of oral medications at registration.

For patients entering the Intensification Cohort ONLY:

• Any chronic medical condition requiring a higher dose of corticosteroid than 10 mg prednisone/prednisolone once daily.

For patients entering the Intensification Cohort ONLY:

• Presence of uncontrolled hypertension (persistent systolic blood pressure [BP] ≥ 160 mmHg or diastolic BP ≥ 100 mmHg);
• Subjects with a history of hypertension are allowed, provided that BP is controlled to within these limits by anti-hypertensive treatment.

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

Eligibility last updated 10/12/23. Questions regarding updates should be directed to the study team contact.