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

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

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

Eligibility last updated 3/14/23. Questions regarding updates should be directed to the study team contact.

• Confirmed anhydramnios before 22 weeks GA for patients with FRF or confirmed diagnosis of CoBRA.
  • Anhydramnios in the absence of ruptured membranes (ROM) on ultrasound.
  • No significant bladder filling on ultrasound.
• Consent is signed and first therapeutic amnioinfusion can and does occur before 26 weeks and 0 days gestational age.
• Confirmation that the expectant mother does not wish to undergo termination of the pregnancy.
• Age ≥ 18 years of age for expectant mothers.
• Willingness to be followed and deliver at a RAFT center.
• Willingness for postnatal care to be performed at a RAFT center until discharge.
• Completed consults with Pediatric Nephrology, Neonatology, Transplant Surgery, Pediatric surgery, Maternal-Fetal Medicine Specialist, and Licensed Clinical Social Worker and a Genetic Counselor.

• Cervix less than 2.5 cm in length.
• No significant pathogenic or likely significant pathogenic findings on Karyotype or Microarray.
• Other significant congenital anomalies in the fetus.
• Evidence of chorioamnionitis or abruptio placentae.
• Evidence of rupture of membranes or chorioamniotic separation.
• Evidence of preterm labor.
• Multiple gestation.
• Severe maternal medical condition in pregnancy.
• Maternal depression as assessed by a Beck Depression Inventory score equal to or greater than 17 that is refractory to treatment.
• Technical limitations precluding amnioinfusion.

• Patients must be ≥ 2 years and ≤ 25 years of age at the time of enrollment on Step 0.
• All patients > 21 years of age at the time of enrollment must have had initial diagnosis of low-grade glioma by 21 years of age. 
• Patient is suspected of having progressive or recurrent low-grade glioma (LGG).
• Patient does not have a known diagnosis of neurofibromatosis type 1 (NF1) or tuberous sclerosis complex (TSC).
• Patient and/or their parents or legal guardians have signed informed consent for eligibility screening on APEC14B1 Part A.

• Prior therapy with vinblastine and/or a MEK inhibitor is permitted, with the following exceptions:
  • Patients must not have had progressive disease while on therapy with vinblastine or a MEK inhibitor;
  • Patients must not have discontinued vinblastine or selumetinib due to toxicity.
• Patients with a concurrent malignancy or history of treatment (other than surgery) for another tumor within the last year.
• Patients with diffuse intrinsic pontine tumors as seen on MRI (> 2/3 of pons involvement on imaging) are not eligible even if biopsy reveals Grade I/II histology.
• Patients may not be receiving any other investigational agents.
• Patients must not have known hypersensitivity to selumetinib, vinblastine, or similar compounds.
• CYP3A4 Agents: Patients must not have received fluconazole or drugs that are strong inducers or inhibitors of CYP3A4 within 7 days prior to study enrollment.
• Patients with any serious medical or psychiatric illness/condition, including substance use disorders or ophthalmological conditions, likely in the judgment of the investigator to interfere or limit compliance with study requirements/treatment.
• Patients who, in the opinion of the investigator, are not able to comply with the study procedures.
• Surgery within 2 weeks prior to enrollment, with the exception of a surgical biopsy, placement of a vascular access device or CSF diverting procedure such as endoscopic third ventriculostomy (ETV) and ventriculoperitoneal (VP) shunt.
  • Note: Patients must have healed from any prior surgery.
• Patients who have an uncontrolled infection.
• Female patients who are pregnant are not eligible since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential.
• Lactating females who plan to breastfeed their infants.
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation and for 12 weeks after stopping study therapy.
  • Note: Women of child-bearing potential and males with sexual partners who are pregnant or who could become pregnant (i.e., women of child-bearing potential) should use effective methods of contraception for the duration of the study and for 12 weeks after stopping study therapy to avoid pregnancy and/or potential adverse effects on the developing embryo.

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

Eligibility last updated 8/2/23. Questions regarding updates should be directed to the study team contact.

• Adults, ≥ 18 years of age.
• Waitlist active, temporarily inactive, and deferred adult lung transplant candidates from Mayo Clinic Florida; Mayo Clinic Rochester; or UW Medicine.

• Children < 18 years old.
• Patients who are non-verbal, non-English speakers, or extremely hard-of-hearing.

• Pediatric patients age to 17 years old, inclusive.
• Parental or LAR informed consent for patients ages 6 years and younger.
• Parental or LAR informed consent and subject assent for subjects ages to 17.

• Any condition that, in the opinion of the Investigator, would make the subject inappropriate for the evaluation.

• Patients with newly diagnosed stages 2
  •4 diffuse anaplastic Wilms tumor must be enrolled on AREN03B2 and have risk assignment or final pathology classification (if at delayed nephrectomy) results available prior to enrollment on AREN1921. Enrollment on AREN03B2 is not applicable for patients with relapsed favorable histology Wilms tumor.
• Patients must be ≤ 30 years old at study enrollment.
• Patients with the following diagnoses are eligible for this study:
  • Newly diagnosed stages 2
    •4 diffuse anaplastic Wilms tumor as confirmed by central review;
  • Favorable histology Wilms tumor at first relapse. Relapsed FHWT patients must have previously achieved remission for their initial FHWT diagnosis to be eligible for this study. The relapse risk groups are defined as follows, regardless of radiation therapy:
  • Standard-Risk relapse: Patients who received two chemotherapy agents for frontline therapy; primarily actinomycin D and vincristine;
  • High-Risk relapse: Patients who received three chemotherapy agents for frontline therapy; primarily vincristine, actinomycin D and doxorubicin or vincristine, actinomycin D and irinotecan;
  • Very High-Risk relapse: Patients who received four or more chemotherapy agents as part of initial therapy; primarily Regimen M or its variations.
• Patients with newly diagnosed DAWT must have had histologic verification of the malignancy. For relapsed FHWT patients, biopsy to prove recurrence is encouraged, but not required.
  • Note: for relapsed FHWT patients, an institutional pathology report confirming favorable histology Wilms tumor (from relapse, if available, or from original diagnosis) must be available for upload prior to initiation of protocol therapy
• Patients with newly diagnosed stages 2
  •4 diffuse anaplastic Wilms tumor must be enrolled on AREN1921 within 2 weeks of the first tumor-directed surgery or biopsy procedure (surgery/biopsy is day 0), except for patients who received prior therapy for presumed favorable histology Wilms tumor, later confirmed to have diffuse anaplastic Wilms tumor at subsequent review
• Patients with newly diagnosed DAWT who undergo upfront nephrectomy must have at least 1 lymph node sampled prior to study enrollment
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 years of age
• Patients must have a life expectancy of ≥ 8 weeks
• Histology must have had no prior systemic therapy, except in the following situations:
  • Patients with diffuse anaplastic Wilms tumor who received no more than 12 weeks of pre nephrectomy chemotherapy for what was originally presumed to be favorable histology Wilms tumor, subsequently confirmed to be diffuse anaplastic Wilms tumor at delayed nephrectomy;
  • Patients with diffuse anaplastic Wilms tumor who received no more than 6 weeks of chemotherapy following upfront nephrectomy or biopsy for presumed favorable histology Wilms tumor based on institutional review, but subsequently corrected to diffuse anaplastic Wilms tumor based on the AREN03B2 initial risk assignment results;
  • Treatment consisting of vincristine/doxorubicin/ cyclophosphamide initiated on an emergent basis and within allowed timing as described.
• Patients who received prior therapy for presumed favorable histology Wilms tumor, later identified to have diffuse anaplastic Wilms tumor as per above, must begin study treatment starting at cycle 3 (week 7) of regimen UH 3. For treatment details specific to this group of patients.
• Patients who received emergency radiation to preserve organ function are eligible as noted.
• Relapsed Favorable Histology Wilms Tumor:
  • Patients must not have received prior chemotherapy for their relapsed favorable histology Wilms tumor diagnosis. In addition, patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
  • Myelosuppressive chemotherapy;
  • Must not have received within 2 weeks of entry onto this study.
  • Radiation therapy (RT):  2 weeks (wks) must have elapsed for local palliative RT (small port); ≥ 6 months must have elapsed if prior craniospinal RT or if ≥ 50% radiation of pelvis; ≥ 6 wks must have elapsed if other substantial BM radiation. Patients with relapsed favorable histology Wilms tumor who received emergency radiation to preserve organ function are eligible and do not need to washout with the above criteria.
• Patients may not be receiving any other investigational agents (within 4 weeks prior to study enrollment).
• Peripheral absolute neutrophil count (ANC) ≥ 750/uL (performed within 7 days prior to enrollment).
• Platelet count ≥ 75,000/uL (transfusion independent) (performed within 7 days prior to enrollment).
• Hemoglobin ≥ 8.0 g/dL (may receive red blood cell [RBC] transfusions) (performed within 7 days prior to enrollment).
• Patients with high-risk or very high-risk relapsed FHWT who will be treated with Regimen ICE/Cyclo/Topo, must have renal function assessed by creatinine clearance or radioisotope glomerular filtration rate (GFR) and meet the following requirement:
  • Creatinine clearance or radioisotope GFR ≥ 60 mL/min/1.73 m^2 (performed within 7 days prior to enrollment).
• Patients diagnosed with stage 2-4 DAWT or standard risk relapsed FHWT, who will be treated with Regimen UH 3, may either obtain a creatinine clearance, radioisotope GFR (meeting the above criteria of GFR ≥ 60 mL/min/1.73 m^2), or an adequate serum creatinine as per the following table:
  • Age: Maximum Serum Creatinine (mg/dL);
  • 1 month to < 6 months: 0.4 (male and female);
  • 6 months to < 1 year: 0.5 (male and female);
  • 1 to < 2 years: 0.6 (male and female);
  • 2 to < 6 years: 0.8 (male and female);
  • 6 to < 10 years: 1 (male and female);
  • 10 to < 13 years: 1.2 (male and female);
  • 13 to < 16 years: 1.5 (male), 1.4 (female);
  • ≥ 16 years: 1.7 (male), 1.4 (female).
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age or direct bilirubin ≤ ULN for patients whose total bilirubin > 1.5 x ULN (performed within 7 days prior to enrollment).
• Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x upper limit of normal (ULN) for age or ≤ 5 x ULN for patients with liver metastases (performed within 7 days prior to enrollment);
• Shortening fraction of ≥ 27% by echocardiogram, or ejection fraction of ≥ 50% by radionuclide angiogram (performed within 7 days prior to enrollment).

• Patients with a history of bilateral Wilms tumor (synchronous or metachronous).
• Patients with any uncontrolled, intercurrent illness including, but not limited to, ongoing or active infection, or symptomatic congestive heart failure (defined as grade 2 or higher heart failure per Common Terminology Criteria for Adverse Events [CTCAE] version 5.0).
• Relapsed FHWT patients who did not receive frontline chemotherapy (e.g., very low risk FHWT initially observed without chemotherapy) or received only one chemotherapy agent for frontline therapy.
• For patients with high-risk or very high-risk relapsed FHWT:
  • Patients with renal tubular acidosis (RTA) as evidenced by serum bicarbonate < 16 mmol/L and serum phosphate =< 2 mg/dL (or < 0.8 mmol/L) without supplementation.
• For stages 2-4 DAWT and standard-risk relapsed FHWT patients:
  • Chronic inflammatory bowel disease and/or bowel obstruction;
  • Concomitant use of St. John's wort, which cannot be stopped prior to the start of trial treatment.
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential.
• Lactating females who plan to breastfeed their infants.
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation.

• Admission to PICU or SDU at any point during illness due to severity (not due to bed availability).
• ≤ 21 years old on admission.
• Influenza-associated LRTI:
  • Positive influenza test (rapid antigen, DFA or PCR); and
  • > 1 sign of acute respiratory illness: cough, shortness of breath, tachypnea or retractions, invasive or non-invasive mechanical ventilation, need for FiO2 to maintain SpO2 > 92%, pulmonary infiltrate or hyperinflation on chest imaging.
• At least 1 parent or legal guardian able and willing to provide permission.

• Previous enrollment in this study during the current season.
• Hospital acquired influenza infection as determined by site hospital infection control experts.
• Pre-existing conditions that are known risk factors for severe influenza infection (with the exception of asthma or reactive airways disease (RAD).  Exclusions include:
  • Chronic pulmonary (except asthma/RAD) or upper airway disorders;
  • History of prematurity in patients < 1 year of age;
  • Known immune disorders;
  • Cardiac disease with compromise requiring medications or alterations in activities;
  • Neurologic disorders impairing respiratory muscle strength or secretion management;
  • Sickle cell disease;
  • Complex genetic disorders impairing multiple organ systems; AND
  • Metabolic disorders that may be worsened by infection including diabetes mellitus.

• Age ≥ 18 years.
• Cirrhosis or chronic liver disease (defined as FIB-4 > 1.45 or other non-invasive markers that show > F3 fibrosis on outpatient values).
• Admitted for non-elective reasons.
• Able to consent or have a legal representative who can consent.

• Individuals < 18 years of age.
• Acute liver failure.
• Unable to consent.
• Admitted electively.
• Life expectancy < 48 hours.
• Prisoners.
• HCC without loco-regional control for > 6 months or patients on systemic therapy for Hepatocellular Carcinoma (HCC) currently.
• COVID-19 diagnosis confirmed during the current admission.
• Post-TIPS if TIPS is > 6 months prior.
• Known recent MI (< 6 months) or stroke with residual defects.

• Mayo Clinic patients with a previously confirmed infection with the novel SARS-CoV-2 virus who have been seen in the PCCOC, CARP, Pulmonary for post COVID clinic, Neurology, or approval by MAGPIES research group.
• Aged 5 years and older.
• All racial and ethnic groups are eligible.

• Lacking the capacity to consent.
• Prisoners and institutionalized individuals.

Eligibility last updated 9/8/21. Questions regarding updates should be directed to the study team contact.

.

• Physicians, Nurse Practitioners, and Physician Assistants.
• No prior training in pharmacogenomics.

• Any reported prior training in pharmacogenomics.

• Male or female, ≥  18
  •40 years of age.
• A healthy volunteer will be defined as an otherwise healthy person who does not have a medical condition that affects brain function or have problems with concentration, memory, balance, or coordination.

• Subjects with non-MRI compatible devices, required sedation (claustrophobia or unable to remain still for exam), or women who are pregnant will be excluded.

Eligibility last updated to match clinicaltrials.gov on 2/10/23. Questions regarding updates should be directed to the study team contact.

• Age 18 or over.
• Diagnosis of alcohol-associated liver disease and alcohol use disorder:
  • The diagnosis of ALD will be determined by a hepatologist based on history of regular and excessive alcohol consumption in the absence of other causes of liver cirrhosis or acute hepatitis, compatible clinical, imaging, and laboratory findings and typical histology on liver biopsy, if performed;
  • The diagnosis of AUD will be determined by a hepatologist and/or addiction psychiatrist based on history obtained that is consistent with DSM-5 diagnostic criteria for AUD (all categories of mild, moderate, and severe considered eligible).
• Capacity to provide consent.
• Access to a smartphone, cellular data, and wireless internet connection through the smartphone device.

• Inability to respond to smartphone-delivered questionnaires.
• Inability to send and receive text messages.
• Moderate to severe hepatic encephalopathy, defined by West-Haven score of 3 or higher.
• Severe psychiatric comorbidity, not controlled on pharmacological or non-pharmacological therapy.

Eligibility last updated 2/23/22. Questions regarding updates should be directed to the study team contact.

• Able to read and write English fluently.
• Can sign consent for themselves.
• Age 18 years or older.
• Diagnosis of sporadic Vestibular Schwannoma (VS) (also called acoustic neuroma).

• Age less than 18 years old.
• Diagnosis of VS secondary to neurofibromatosis type 2 (NF2).
• Lack of capacity to consent.
• Unable to read/write English fluently.

Inclusion Criteria
•All Groups:

• All participants must sign an informed consent indicating that they are aware of the investigational nature of this study and willing to undergo study interventions, and authorizing the use of their protected health information for research purposes.
• Meet one set of group-specific inclusion criteria listed below.
• All participants must be ≥ 18 years old and ≤ 75 years at the time of enrollment.

Inclusion Criteria
•No Pancreas Disease Controls:

• No personal history or symptoms of pancreatic disease.
• No upper abdominal symptoms
• *Participant will answer “No” and “None” to below questions to meet this criterion:
  • Have you had a stomach ache or pain more than SIX times in the past year?
  • □ YES            □ NO
• How many times have you had a feeling of WANTING TO THROW UP (nausea) in the last year?
  • □ NONE        □ ANY
• No family history of pancreatic disorders, celiac disease, cystic fibrosis.
• No history of acute infectious or inflammatory conditions requiring medical treatment or evaluation in the preceding 6 months (per provider clinical judgment).
• No history of cancer, except for non-melanoma skin cancers.
• No known pregnancy at the time of enrollment.
• No solid organ transplant or history of HIV/AIDS.
• Able to provide an informed consent.
• Not currently incarcerated.
• ASA 1-2.

Inclusion Criteria - Chronic Upper Abdominal Pain of Suspected Pancreatic Origin:

• Referred to a pancreas or GI clinic or admitted to the hospital for evaluation of unexplained upper abdominal pain of at least 3 months in duration for which a pancreatic origin is clinically considered in the differential diagnosis.*

* Pancreatic type pain is defined as epigastric pain that is often constant, often worsens post-prandially, and may radiate to the back. This can often be associated with lipase/amylase elevations that do not meet the threshold for diagnosis of AP (i.e. <3-fold upper limit of normal).

• No history of AP or CP.
• No prior endoscopic sphincterotomy or pancreatic surgery.
• Normal cross-sectional abdominal imaging (CT and MRI/MRCP).**

** CT and MRI/MRCP must be performed ≤24 months prior to enrollment OR within 6 months after study enrollment. CT and MRI scans must be intravenous contrast-enhanced and MRCP with secretin (a non-contrast MRI and MRCP without secretin prior to enrollment is acceptable at baseline to be used for enrollment). If the patient has had only one imaging study, the patient is eligible for enrollment as “Chronic Abdominal Pain – Undifferentiated”. The second imaging study can be performed in this situation after the enrollment and the final assignment into the appropriate subgroup can be done after review of the imaging results.

• If the second study was planned within 6 months after enrollment but could not be completed, it will not be considered as eligibility violation and attempts will be made to complete this during follow-up as feasible. If the second study could not be performed, the subject will be assigned to Chronic upper abdominal pain group if the available study was normal or as Indeterminate CP if the available study shows Cambridge 1-2 findings.

Inclusion Criteria - Indeterminate CP with no history of AP:

• Referred to a pancreas or GI clinic or admitted to the hospital for evaluation of unexplained upper abdominal pain of at least 3 months in duration for which a pancreatic origin is clinically considered in the differential diagnosis*

* Pancreatic type pain is defined as epigastric pain that is often constant, often worsens post-prandially, and may radiate to the back. This can often be associated with lipase/amylase elevations that do not meet the threshold for diagnosis of AP (i.e. <3-fold upper limit of normal).

• No history of AP or CP.**

**AP is defined as compatible symptoms (upper abdominal pain) together with A) ≥ 3-fold elevation of serum amylase and/or lipase above upper limit of normal, AND/OR B) features of AP on cross-sectional imaging (CT and/or MR).

• Cambridge grade I-II changes of CP# on cross-sectional imaging (CT or MRI/MRCP).***

*** CT and MRI/MRCP must be performed ≤24 months prior to enrollment OR within 6 months after study enrollment.  CT and MRI scans must be intravenous contrast-enhanced and MRCP with secretin (a non-contrast MRI and MRCP without secretin prior to enrollment is acceptable at baseline to be used for enrollment). If the patient has had only one imaging study, the patient is eligible for enrollment as “Chronic Abdominal Pain – Undifferentiated”. The second imaging study can be performed in this situation after the enrollment and the final assignment into the appropriate subgroup can be done after review of the imaging results.

• If the second study was planned within 6 months after enrollment but could not be completed, it will not be considered as eligibility violation and attempts will be made to complete this during follow-up as feasible. If the second study could not be performed by month 6 after enrollment, the subject will be assigned to Chronic upper abdominal pain group if the available study was normal or as Indeterminate CP if the available study shows Cambridge 1-2 findings. 
• No prior endoscopic sphincterotomy or pancreatic surgery.

Inclusion Criteria - Acute Pancreatitis (AP):

•  History of one documented attack of AP in the preceding 18 months.*

* AP is defined as compatible symptoms (upper abdominal pain) together with A) ≥ 3-fold elevation of serum amylase and/or lipase above upper limit of normal, AND/OR B) features of AP on cross-sectional imaging (CT and/or MR). Patient should not have had an attack of AP in the month prior to enrollment.

• Patients should not have had an ERCP prior to the episode of AP.
• Pancreatitis episode is not attributable to gallstones (i.e., suspected or definite biliary etiology), medications, trauma or autoimmune pancreatitis.
• Pancreatic necrosis, if present, is <50% (to be verified by a CPDPC site radiologist).
• Cambridge grade < III changes of CP# on cross-sectional imaging (CT or MRI/MRCP).***

*** CT and MRI/MRCP must be performed ≤ 24 months prior to enrollment OR within 6 months after study enrollment. CT and MRI scans must be intravenous contrast-enhanced and MRCP with secretin (a non-contrast MRI and MRCP without secretin prior to enrollment is acceptable at baseline to be used for enrollment). If the patient has had only one imaging study, the patient is eligible for enrollment. The second study  can be performed in this situation after the enrollment.

• If the second study was planned within 6 months after enrollment but could not be completed, it will not be considered as eligibility violation. Final group assignment in this situation will be based on the available study.   
• No prior pancreatic surgery.

Inclusion Criteria - Recurrent Acute Pancreatitis (RAP):

• Two or more documented attacks of AP* separated by at least 1 month, with complete symptom resolution between the attacks.

* AP is defined as compatible symptoms (epigastric pain with nausea or vomiting) together with A) ≥ 3-fold elevation of serum amylase and/or lipase above upper limit of normal, AND/OR B) features of AP on cross-sectional imaging (CT and/or MR).

• Patient should not have had an ERCP prior to having first documented attack of pancreatitis.
• Cambridge grade < III changes of CP# on cross-sectional imaging (CT or MRI/MRCP)**

**CT and MRI/MRCP must be performed ≤24 months prior to enrollment OR within 6 months after study enrollment. CT and MRI scans must be intravenous contrast-enhanced and MRCP with secretin (a non-contrast MRI and MRCP without secretin prior to enrollment is acceptable at baseline to be used for enrollment). If the patient has had only one imaging study, the patient is eligible for enrollment. The second study can be performed in this situation after the enrollment.

• Cambridge grade < III changes of CP# on cross-sectional imaging (CT or MRI/MRCP).**

**CT and MRI/MRCP must be performed ≤24 months prior to enrollment OR within 6 months after study enrollment. CT and MRI scans must be intravenous contrast-enhanced and MRCP with secretin (a non-contrast MRI and MRCP without secretin prior to enrollment is acceptable at baseline to be used for enrollment). If the patient has had only one imaging study, the patient is eligible for enrollment. The second study can be performed in this situation after the enrollment.

• If the second study was planned within 6 months after enrollment but could not be completed, it will not be considered as eligibility violation. Final assignment in this situation will be based on the available study.
• In a rare circumstance, the last imaging patient had was >24 months prior to enrollment. In this circumstance, the patient is still eligible for enrollment, and can undergo CT scan first, and if there is no evidence of Cambridge 3-4 findings, undergo an MRI/MRCP to fulfill entry criteria. If the planned studies could not be completed within 6 months after enrollment, the final group assignment will be in this situation will be based on the available study.
• Pancreatitis episodes are not attributable to gallstones, medications, trauma or autoimmune pancreatitis.
• No prior pancreatic surgery.

Inclusion Criteria - Definite Chronic Pancreatitis

• Presence of unequivocal CP (i.e., Cambridge grade ≥ 3) and/or parenchymal and/or ductal calcifications by cross-sectional imaging (IV contrast-enhanced MRI/MRCP or CT) verified by the CPDPC site radiologist.*

* Must exclude the possibility that calcifications are vascular. Calcifications noted by EUS only (and not correlated with CT) are not included as definite CP. A non-contrast CT scan or MRI/MRCP documenting definite CP as per criteria is acceptable for enrollment.

• Pancreatic histology diagnostic of CP (including findings of fibrosis [Ammann’s ≥ 6], chronic inflammation, and acinar loss) as verified by a CPDPC site pathologist, if pathology slides are available for review.

• History of autoimmune or traumatic pancreatitis, or sentinel attack of acute necrotizing pancreatitis which   results in suspected disconnected duct syndrome.
• Primary pancreatic tumors
  •pancreatic ductal adenocarcinoma, suspected cystic neoplasm (> 1 cms in size or main duct involvement), neuroendocrine tumors, and other uncommon tumors. 
• Pancreatic metastasis from other malignancies.
• History of solid organ transplant, HIV/AIDS.
• Known isolated pancreatic exocrine insufficiency (e.g., in the absence of any eligible inclusion criteria).
• Participants must not have medical or psychiatric illnesses or ongoing substance abuse that in the investigator’s opinion would compromise their ability to tolerate study interventions or participate in longitudinal follow up.
• Patients with known abnormal creatinine (GFR < 30) or renal failure (applies to patients with chronic upper abdominal pain of suspected pancreatic origin and suspected CP (yellow) subgroups).
• Failure to agree for longitudinal follow-up.
• Known Pregnancy. All participants of childbearing potential, except if post-menopausal [i.e., no menses for ≥ 2 years] or had a hysterectomy, bilateral tubal ligation/clip (surgical sterilization) or surgical removal of both the ovaries), must have a negative urine or serum B-HCG pregnancy test documented within 2 days prior to any endoscopic or radiologic procedures done for research purposes. Any standard of care tests will follow institutional policies regarding pregnancy test.
• Currently incarcerated.
• Inability to get MRI/MRCP in patients with chronic abdominal pain of suspected pancreatic origin (Green II) or Suspected CP (Yellow groups) at baseline (e.g., metal object in the body which precludes performance of MRI).

• Age greater than 28 days and less than 85 years.
• Planned complex cardiac surgery with planned use of cardiopulmonary bypass.

• Expected order for washed or volume reduced platelets.
• Patient with known anti-platelet antibodies.
• Platelet transfusion refractoriness due to anti-HLA antibodies.
• Known or suspected pregnancy.
• Previously randomized in this study.
• Conscious objection or unwillingness to receive blood products.
• Known IgA deficiency.
• Known congenital platelet disorder.
• Known congenital bleeding disorder.
• Planned post-operative extracorporeal membrane oxygenation (ECMO), ventricular assist device (VAD), and/or continuous renal replacement therapy (CRRT)/ hemodialysis.
• Patients intended to receive whole blood either intra-operative or post-operative for bleeding.
• Platelet transfusion (of any type) within 24 hours prior to receiving study platelets.
• Pre-operative thrombocytopenia.

Eligibility last updated 11/2/21. Questions regarding updates should be directed to the study team contact.

• Resident, fellow or teaching physicians participating and endoscopic sinus surgery for chronic rhinosinusitis.

• Anyone not meeting inclusion criteria or anyone not wishing to participate.

• ≥ 18 years of age.
• Biopsy proven Focal Segmental Glomerulosclerosis (FSGS) lesion
• Foot process effacement ≥ 80% on electron microscopy.
• Presence of nephrotic syndrome (proteinuria > 3.5g/24hrs and serum albumin < 3.5 g/dl) prior to initiation of immunosuppressive therapy.
• Resistant or dependent on therapy, including corticosteroids or calcineurin inhibitors or who have failed rituximab. Patient who have contraindication to or refuse to take high dose corticosteroids are allowed. 

• Genetic or secondary forms of FSGS.
• Hepatitis B, C or HIV positive.
• Pregnant or breast-feeding.
• Active infection.
• Kidney transplant.
• Anemia with Hgb < 8.0 g/dL.
• Thrombocytopenia with platelet count < 100’000.
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complication.
• Patients who have received cyclophosphamide in the last 6 months.
• Patients who received rituximab previously with CD20 count of < 5 cells/microliter  at the time of enrollment.
• For women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent or use two adequate methods of contraception, including at least one method with a failure rate of less than (<) 1 percent (%) per year, during the treatment period and for at least 18 months after the last dose of study drug.
• For men: agreement to remain abstinent or use two adequate methods for contraception, including at least one method with failure rate of less than 1% per year during the treatment period and for at least 6 months (180 days) after the last dose of drug.

​​​​​​

• Lesions must be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 1 cm with CT or MRI (or ≥ 1.5 cm for lymph nodes). Non-measurable disease includes disease smaller than these dimensions or lesions considered truly nonmeasurable including: leptomeningeal disease, ascites, pleural or pericardial effusion, lymphangitic involvement of skin or lung.
• Prior treatment with other chemotherapy, radiotherapy (including peptide radionuclide receptor therapy [PRRT]), or surgery must be completed ≥ 28 days prior to registration. Patients must have recovered from any effects of any major surgery prior to registration. Prior treatment with radiolabeled MIBG must be completed ≥ 12 weeks prior to registration and lifetime cumulative 131I-MIBG dose must be < 1000 MBq kg-1 (36 mCi kg-1 ). Prior treatment with antibiotics must be completed ≥ 7 days prior to registration. No prior treatment with temozolomide, dacarbazine, or a poly ADP ribose polymerase (PARP) inhibitor. No prior allogeneic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
• Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic, and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done ≤ 7 days prior to registration is required.
• Therapy utilized in this trial is associated with medium/high fetal risk. Women of childbearing potential and their partners, who are sexually active, must agree to use two highly effective forms of contraception in combination. This should be started from the time of registration and continue throughout the period of taking study treatment and for at least 1 month after last dose of study drug(s), or they must totally/truly abstain from any form of sexual intercourse. Male patients must use a condom during treatment and for 3 months after the last dose of study drug(s) when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential.
• Male patients should not donate sperm throughout the period of taking study drug(s) and for 3 months following the last dose of study drug(s).
• Age ≥ 18 years old.
• ECOG Performance Status: 0-2.
• Required Initial Laboratory Values:
  • Absolute Neutrophil Count ≥ 1,500/mm^3;
  • Platelet Count ≥ 100,000/mm3;
  • Hemoglobin ≥ 10 mg/dL* ;
  • Total Bilirubin ≤ 1.5 x upper limit of normal (ULN)** ;
  • AST/ALT ≤ 3.0 x ULN;
  • Creatinine < 1.5 x ULN OR Calc. Creatinine Clearance > 50 mL/min.***

*.   In the absence of transfusion within the previous 24 hours.
**   Except in the case of Gilbert’s syndrome, then Total Bilirubin must be ≤ 3.0 x ULN.
*** Calculated by Cockcroft-Gault equation.

• No indication of uncontrolled, potentially reversible cardiac condition(s) as determined by investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation > 500 msec, electrolyte disturbances, etc.) and no known congenital long QT syndrome.
• No extensive bilateral lung disease or pneumonitis.
• No abnormal organ or bone marrow function ≤ 28 days prior to registration.
• Patients with HIV positivity are allowed if CD4 Count > 250 cells/μL and they have an undetectable HIV viral load within 6 months of registration.
• No active infection.
• No history of myelodysplastic syndrome (MDS) (or any dysplastic leukocyte morphology suggestive of MDS) or acute myeloid leukemia.
• No known gastrointestinal condition(s) that might predispose for drug intolerability or poor drug absorption.
• No known medical condition causing an inability to swallow oral formulations of agents.
• No history of allergic reaction attributed to compounds of similar chemical or biologic composition to PARP inhibitors.
• Concurrent use of combination antiretroviral therapy (ART) is not permitted.
• Chronic concomitant treatment with strong or moderate CYP3A4 inducers or inhibitors is not allowed.
• Patients must discontinue the agent(s) ≥ 21 days prior to registration; enzalutamide and/or phenobarbital must be discontinued ≥ 5 weeks prior to registration. 

• Age 18-75.
• Persistent (at least 12 weeks apart) aPL-positivity within 12 months prior to the screening defined as: o aCL IgG/M/A (> 40U, medium-to-high titer, and/or greater than the 99th percentile) and/or o aβ2GPI IgG/M/A (>40U, medium-to-high titer, and/or greater than the 99th percentile) and/or o Positive LA test based on the International Society of Thrombosis & Haematosis Recommendations.

• Patient refusal.
• Inability to comply with study and follow-up procedures.

• Age 18+.
• English speaking.
• Consented for Outcomes Registry Study (15-000136).
• Undergoing radiotherapy for cancer treatment with curative intent.
• Willing to and able to give consent and participate in study.
• Willing to complete all questionnaires and surveys.
• Able to access a device (computer, smartphone, or tablet) with web access every day to complete study surveys.
• Willing to connect to a device (i.e., a smartphone, Fitbit or tablet) that can regularly link to Hugo for data transfer.
• Willing to use the Hugo health data sharing platform.
• Willing to create a Mayo Clinic Patient Portal (if not already created).

• Unable to give consent and enroll prior to administration of baseline survey.
• Partial breast RT (3 fraction), due to overlap in cadence used for all disease sites.
• SBRT to the lung, due to overlap in cadence used for all disease sites.
• Co-enrollment on another PRO related study (soft rule):
  • Coordinator would need to get source data from Adam via Hugo;
  • Response data will only be accessible by select people.

• Provision of signed and dated informed consent form.
• Adults, males and females, ages 18 -79 who have a bilateral sensorineural hearing loss with postlingual onset.
• Minimum of 30 days experience with appropriately fit binaural amplification (standardized NAL fitting method) verified with real ear measurements within 5 dB SPL of targets.
• Limited benefit from conventional amplification in the best aided condition as defined by test scores of:
  • The ear to implanted: CNC words ≤ 60% or AzBio sentences (+10, +5 dB SNR ≤ 60% correct);
  • Contralateral ear: ≤ 80% on CNC words or AzBio sentences (+10, +5 dB SNR ≤ 80% correct);
  • Low frequency Pure Tone Average (PTA- 125, 250, 500 Hz) ≤ 55 dB HL in the ear to be implanted;
  • Severe to profound mid to high-frequency sensorineural hearing loss (threshold average of 1000, 2000, 3000, and 4000 Hz ≥75 dB HL) in the ear to be implanted;
  • Low frequency PTA ≤ 55 dB HL sloping to moderately severe to profound mid-to high frequency sensorineural hearing loss (threshold average of 1000, 2000, 3000, 4000 Hz ≥ 60 dB) in the contralateral ear.
• Proficient in English.
• Undergoing implantation with a current generation cochlear implant device from either Cochlear Limited or Advanced Bionics AG.
• Cochlear Limited devices include: Nucleus CI612, CI622, CI632, CI624.
• Advanced Bionics AG devices include:  HiFocus SlimJ, Mid-Scala.
• Stated willingness and ability to complete testing and all associated study visits.

• An individual who meets any of the following criteria will be excluded from participation in this study:
  • Previous cochlear implantation;
  • Prelingual onset of hearing loss;
  • Abnormal inner ear anatomy on CT imaging;
  • Auditory neuropathy spectrum disorder;
  • Retrocochlear pathology such as a vestibular schwannoma or stroke.
• Unwillingness or inability to comply with all investigational requirements including the randomization process.
• Additional medical, or social barriers that would prevent completion of all study requirements.
• Medical condition contraindicated for surgery.
• Device selection of Med El cochlear implant (per the patient’s selection).

• 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.