• Subjects with target disease ONFH and OA.

• ONFH and OA subjects taking the medications statins, steroids, or TZDs will be excluded. 

Inclusion Criteria

• Have disorders affecting the hematopoietic system that are inherited, acquired, or result from myeloablative treatment
• Any age and either gender
• Using a cord blood product manufactured by the National Cord Blood Program (at least one, if the graft contains more than one unit)

Exclusion Criteria

• Are only receiving licensed cord blood products
• Are only receiving unlicensed cord blood products from other banks
• Are being transplanted at non-US transplant centers
• Are receiving cord blood products that will be "manipulated" post-thaw (e.g., ex vivo expansion, incubation in vitro, etc.)

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

Eligibility last updated 10/12/22. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria
•Children:

• Ages 3-7.
• Outpatients or Inpatients.
• Any gender, race or ethnicity.
• Able to provide developmentally appropriate informed assent, and legal guardians able to provide informed consent .
• EBP Severity rated above the clinically significant range (≥120; T-score ≥ 60) (Eyberg Child Behavior Inventory- ECBI; Eyberg & Pincus, 1999).
• Need for more intensive behavioral treatments such as ER visit for behavioral dyscontrol or hospitalization will not be exclusionary or exit criteria.
• Families approached for participation will be asked to commit to complete the treatment.
• At least one primary caregiver and the identified child will have to be able to speak and understand English.   

 Exclusion Criteria
•Children:

• Formal diagnosis of Severe Intellectual disability, Autistic Spectrum Disorder Level 3, or a psychotic disorder for the child.
• Parents not consenting to the study.
• Parents or child is not able to adhere to the study protocol.
• A Child who is reasonable expected to be unable to tolerate wearing the Garmin device for at least 70% of the time during the day and night 70% of the days during the treatment (12 weeks). This is based on the principal investigator’s discretion.
• Unable to speak and understand English. 
• Refusal or withdrawal of consent, inability, or unwillingness to adhere to study procedures.
• Children in foster care.

Inclusion Criteria
•Adults:

• Agree to wear Garmin watch.
• Ages 18-99.
• Any gender, race, ethnicity.
• Able to provide informed consent.

Exclusion Criteria
•Adults:

• Unable to speak and understand English. 
• Refusal or withdrawal of consent, inability, or unwillingness to adhere to study procedures.

• Age > 18 years old.
• ECOG performance status (PS) 0, 1 or 2.
• Clinical and radiographic evidence suggesting a diagnosis of a diffuse glioma, or a prior diagnosis of a diffuse glioma.
• Diffuse gliomas include diffuse astrocytoma, anaplastic astrocytoma, glioblastoma, oligodendroglioma and anaplastic oligodendroglioma.
• Planned neurosurgical procedure for purposes of biopsy or resection of suspected or previously diagnosed brain tumor as part of routine clinical care.
• Willing to undergo neurosurgical resection or biopsy at Mayo Clinic (Rochester, MN).
• Ability to understand and the willingness to sign a written informed consent document.

• Vulnerable populations:
  • Pregnant women;
  • Prisoners;
  • Mentally handicapped.
• Patients who are not appropriate candidates for surgery due to current or past medical history or uncontrolled concurrent illness.

PRE-REGISTRATION

• Pathology from the resected brain metastasis must be consistent with a non-central nervous system primary site. Patients with or without active disease outside the nervous system are eligible (including patients with unknown primaries), as long as the pathology from the brain is consistent with a non-central nervous system primary site.
• Three or fewer (i.e., 0 to 3) unresected brain metastases (as defined on the post operative magnetic resonance imaging [MRI]) at the time of screening.
  • Note: Dural based metastases (e.g., commonly seen in breast cancer) are eligible.
• Unresected lesions must measure < 4.0 cm in maximal extent on the contrasted post-operative treatment MRI brain scan. The unresected lesions will be treated with SRS as outlined in the treatment section of the concept. 
  • Note: The metastases size restriction does not apply to the resected brain metastasis. 
• One brain metastasis must be completely (gross total resection) resected ≤ 30 days prior to pre-registration. 
  • NOTE: May not have had resection of more than one brain metastasis. 
• The resected brain metastasis must measure 2 cm or larger on the pre-operative MRI. 
• Resection cavity must measure < 5.0 cm in maximal extent and the resection must be complete (gross total resection) on the post-operative MRI obtained ≤ 30 days prior to pre-registration. 
• Karnofsky performance status of ≥ 60.
• For women of childbearing potential only, a negative urine or serum pregnancy test done ≤ 7 days prior to pre-registration is required. 
• Men and women of childbearing potential must be willing to employ adequate contraception throughout the study and for men for up to 3 months after completing treatment. 
• A female of childbearing potential is a sexually mature female who:
  • has not undergone a hysterectomy or bilateral oophorectomy; or 
  • has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months). 
• Ability to complete an MRI of the head with contrast.
• The brain metastasis must be located > 5 mm of the optic chiasm and outside the brain stem.
• Must be fluent in English, Spanish, or French.

REGISTRATION

• Completion of all baseline electronic patient-reported outcome (ePRO) quality of life measures (or booklet quality of life measures) and Montreal Cognitive Assessment (MoCA).

• Must not have any prior whole brain radiation therapy.  Past radiosurgery to other lesions is allowed. 
  • NOTE: The surgically resected lesion cannot be the same location treated in the past with radiosurgery (i.e., repeat radiosurgery to the same location/lesion is not allowed on this protocol). 
• May not have primary germ cell tumor, small cell carcinoma, or lymphoma. 
• No evidence of leptomeningeal metastasis (LMD). 
  • NOTE: For the purposes of exclusion, LMD is a clinical diagnosis, defined as positive cerebrospinal fluid (CSF) cytology and/or equivocal radiologic or clinical evidence of leptomeningeal involvement. Patients with leptomeningeal symptoms in the setting of leptomeningeal enhancement by imaging (MRI) would be considered to have LMD even in the absence of positive CSF cytology, unless a parenchymal lesion can adequately explain the neurologic symptoms and/or signs. In contrast, an asymptomatic or minimally symptomatic patient with mild or nonspecific leptomeningeal enhancement (MRI) would not be considered to have LMD. In that patient, CSF sampling is not required to formally exclude LMD, but can be performed at the investigator's discretion based on level of clinical suspicion.

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

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

Key

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

Eligibility last updated 7/11/23. Questions regarding updates should be directed to the study team contact.

Key Inclusion Criteria:

• Patients that receive brain stimulation for evaluation or treatment of neurological diseases including intractable epilepsy, chronic pain syndromes and brain tumors.

Key Exclusion Criteria: 

• Patients that do not receive brain stimulation for evaluation or treatment of neurological diseases including intractable epilepsy, chronic pain syndromes, and brain tumors.

   

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

Eligibility last updated12/22/22. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 9/8/23. Questions regarding updates should be directed to the study team contact.

• Subjects over the age of 18 able to provide consent or have a legally authorized consent in the event the subject is unable to consent due to a transient clinical condition.
• Subject scheduled to undergo a TIPS procedure.

• Minors under the age of 18 at the time of enrollment.
• Prisoners.
• Pregnant women.
• Subjects undergoing TIPS placement as part of an investigational study outside of usual clinical care.

• Patients must be women age 45 or older and under age 75 at the time of study entry.
• Women of childbearing potential must not be known to be pregnant or lactating.
• Patients must be scheduled for, or have intent to schedule, a screening mammogram.
• Patients must be able to tolerate digital breast tomosynthesis and full-field digital mammographic imaging required by protocol, to be performed at an American College of Radiology Imaging Network (ACRIN)-qualified facility.
• Patients must be willing and able to provide a written informed consent.
• Patients must not have new symptoms or signs of benign or malignant breast disease (e.g., bloody or clear nipple discharge, breast lump) based on physician physical exam or self breast exam that have not been previously worked up with imaging. Patients with physiologic nipple discharge or breast pain are eligible as long as other criteria are met.
• Patients must not have had a screening mammogram within the last 11 months prior to date of randomization.
• Patients must not have previous personal history of breast cancer including ductal carcinoma in situ.
• Patients must not have breast enhancements (e.g., implants or radiopaque injections).

ANNUAL SCREENING REGIMEN ELIGIBILITY CHECK 

To be eligible for inclusion in the annual screening regimen one of the following three conditions must be met in addition to the eligibility criteria above:

• Patients are pre-menopausal; or
• Post-menopausal aged 45-69 with any of the following four risks factors:
  • Dense Breasts (BIRADS density categories c-heterogeneously dense or d-extremely dense), or
  • At least one benign breast biopsy with a diagnosis of Lobular Carcinoma in Situ (LCIS) or atypia of any kind (atypical ductal hyperplasia, atypical lobular hyperplasia, atypical hyperplasia NOS, or intraductal papilloma with atypia), or
  • Family history of breast cancer (first degree relative with breast cancer) or family history of breast cancer is not known, or, participant positive genetic testing for any deleterious genes that indicate an increased risk for breast cancer, or
  • Currently on hormone therapy¹; or
• Post-menopausal ages 70-74 with either of the following three risk factors:
  • Dense Breasts (BIRADS density categories c-heterogeneously dense or d-extremely dense); or
  • At least one benign breast biopsy with a diagnosis of LCIS or atypia of any kind (atypical ductal hyperplasia, atypical lobular hyperplasia, atypical hyperplasia NOS, or intraductal papilloma with atypia); or
  • Currently on hormone therapy¹.
• Postmenopausal women are defined as those with their last menstrual period more than 12 months prior to study entry. For the purpose of defining menopausal status for women who have had surgical cessation of their periods, women who no longer have menses due to bilateral oophorectomy with either hysterectomy or endometrial ablation will be considered postmenopausal. Women who no longer have menses due to either hysterectomy or endometrial ablation, and who have at least one ovary will be considered premenopausal until age 52 and postmenopausal thereafter.
• All other postmenopausal women are eligible for inclusion in the biennial screening regimen.
• For those women who cannot be assigned to annual or biennial screening at the time of study entry and randomization because they are postmenopausal, have no family history or known deleterious breast cancer mutation, are not on hormone therapy1 AND for whom a prior mammogram interpretation is not available, breast density will be determined by the radiologist’s recording of it at the time of interpretation of the first study screening examination, either DM or TM. For those who are randomized to TM, radiologists will assign BI-RADS density through review of the DM or synthetic 2D portion of the TM examination. Such women cannot be part of the planned stratification by screening frequency and are expected to represent far less than 1% of the TMIST population.
• ¹ For this study we define hormone therapies as those that increase breast cancer risk, including: estrogen, progesterone, estrogen/progesterone analogs, or hormonal birth control prescribed by a doctor, and include hormones in oral contraceptives, patch, gel, etc. BUT, for this study, Soy use is not considered hormone therapy.
• Breast density will be determined by prior mammography reports, when available, or by radiologist review of prior imaging.
  • NOTE: If the latter method is used, a signed, dated attestation by the radiologist indicating the resulting determination must be kept as a record and made available for monitoring/auditing.
• All other risk factors used to determine patient eligibility for annual or biennial screening will be determined by subject self-report.

• Age ≥ 18 years.
• Documented diagnostic right heart catheterization (RHC) at any time prior to screening confirming the diagnosis of WHO pulmonary arterial hypertension (PAH) Group .1 in any of the following subtypes:
  • Idiopathic PAH;
  • Heritable PAH;
  • Drug/toxin-induced PAH;
  • PAH associated with connective tissue disease;
  • PAH associated with simple, congenital systemic-to-pulmonary shunts at least 1 year following repair.
• Symptomatic PAH classified as WHO Functional Class II or III.
• Baseline RHC performed during the Screening Period documenting a minimum pulmonary vascular resistance (PVR) of 2: 5 Wood units (WU).
• On stable doses of background PAH therapy and diuretics (i.e., patient-specific dose goal for each therapy already achieved) for at least 90 days prior to screening; for infusion prostacyclins, dose adjustment within 10% of optimal dose is allowed per medical practice. 
• 6MWD 2: 150 and :S 500 m repeated twice at screening (measured at least 4 hours apart, but no longer than 1 week), and both values are within 15% of each other (calculated from the highest value).
• Females of childbearing potential must:
  • Have 2 negative urine or serum pregnancy tests as verified by the investigator prior to starting study therapy; she must agree to ongoing urine or serum pregnancy testing during the study and until 8 weeks after the last dose of the study drug;
  • If sexually active, have used, and agree to use, highly effective contraception without interruption, for at least 28 days prior to starting the investigational product, during the study (including dose interruptions), and for 16 weeks (112 days) after discontinuation of study treatment;
  • Refrain from breastfeeding a child or donating blood, eggs, or ovum for the duration of the study and for at least 16 weeks (112 days) after the last dose of study treatment.
• Male participants must:
  • Agree to use a condom, defined as a male latex condom or nonlatex condom NOT made out of natural (animal) membrane (e.g., polyurethane), during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 16 weeks (112 days) following investigational product discontinuation, even if he has undergone a successful vasectomy;
  • Refrain from donating blood or sperm for the duration of the study and for 16 weeks (112 days) after the last dose of study treatment.
• Ability to adhere to study visit schedule and understand and comply with all protocol requirements.
• Ability to understand and provide written informed consent.

• Diagnosis of pulmonary hypertension WHO Groups 2, 3, 4, or 5.
• Diagnosis of the following PAH Group 1 subtypes: human immunodeficiency virus (HIV)-associated PAH and PAH associated with portal hypertension. Exclusions in PAH Group I should also include schistosomiasis APAH and pulmonary veno-occlusive disease.
• Hemoglobin (Hgb) at screening above gender-specific upper limit of normal (ULN), per local laboratory test.
• Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure> 160 mmHg or sitting diastolic blood pressure > 100 mmHg during screening visit after a period of rest.
• Baseline systolic BP < 90 mmHg at screening.
• Pregnant or breastfeeding women.
• Any of the following clinical laboratory values at the screening visit:
  • Estimated glomerular filtration rate (eGFR) < 30 mL/min/m^2 (as defined by MDRD equation);
  • Serum alanine aminotransferase or aspartate aminotransferase levels > 3 x ULN or total bilirubin > 1.5 x ULN.
• Currently enrolled in or have completed any other investigational product study within 30 days for small-molecule drugs or within 5 half-lives for biologics prior to the date of signed informed consent.
• Prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536) and/or excipients or known allergic reaction to either one.
• Have full or partial pneumonectomy.
• Pulmonary function test (PFT) values of forced vital capacity (FVC) < 60% predicted at the screening visit or within 6 months prior to the screening visit. If PFT is not available, a chest CT scan showing no more than mild interstitial lung disease (ILD) perfonned at the screening visit or 1 year to it.
• Initiation of an exercise program for cardiopulmonary rehabilitation within 90 days prior to the screening visit or planned initiation during the study (participants who are stable in the maintenance phase of a program and who will continue for the duration of the study are eligible).
• History of more than mild obstructive sleep apnea that is untreated.
• Known history of portal hypertension or chronic liver disease, including hepatitis B and/or hepatitis C (with evidence of recent infection and/or active virus replication) defined as mild to severe hepatic impairment (Child-Pugh Class A-C).
• History of restrictive, constrictive or congestive cardiomyopathy.
• History of atrial septostomy within 180 days prior to the screening visit.
• Electrocardiogram (ECG) with Fridericia's corrected QT interval (QTcF) > 500 ms during the screening period.
• Personal or family history oflong QT syndrome (LQTS) or sudden cardiac death.
• Left ventricular ejection fraction < 45% on historical echocardiogram within 6 months prior to the screening visit or pulmonary capillary wedge pressure > 15 mmHg as determined in the Screening Period RHC.
• Any symptomatic coronary disease events within 6 months (prior myocardial infarction, percutaneous coronary interventi on, coronary artery bypass graft surgery, or cardiac anginal chest pain) within 6 months of the screening visit.
  • Note: Anginal pain can be ignored as an exclusion criterion if coronary angiography shows no obstructions.
• Cerebrovascular accident within 3 months prior to the screening visit.
• Acutely decompensated heart failure within 30 days prior to the screening visit, as per investigator assessment.
• Significant (2: 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular disease, mitral stenosis and more than mild aortic valve stenosis.
• Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine, vasopressin) within 30 days prior to the screening visit.

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

Eligibility last updated 0/6/23. Questions regarding updates should be directed to the study team contact.

REGISTRATION ELIGIBILITY CRITERIA (STEP 1)

• Newly diagnosed patients with CD-22 positive B-cell acute lymphoblastic leukemia (WHO criteria) are eligible.
• Patients with Burkitt type ALL are NOT eligible.
• Patients who have BCR-ABL fusion transcript determined by fluorescence in situ hybridization (FISH) or real time-polymerase chain reaction (RT-PCR) or t(9;22)(q34;q11) by cytogenetics are not eligible and should be considered for enrollment on studies that incorporate imatinib during induction; please note: flow cytometry is to be performed at the local reference lab and must include assessment of CD20 and CD22 positivity, as well as CD29 and CD22 anti-positivity.
• No prior therapy except for limited treatment (< 7 days) with corticosteroids or hydroxyurea and a single dose of intrathecal cytarabine.
• No prior therapy for acute leukemia except emergency therapy (corticosteroids or hydroxyurea) for blast cell crisis, superior vena cava syndrome, or renal failure due to leukemic infiltration of the kidneys; when indicated, leukapheresis or exchange transfusion is recommended to reduce the WBC.
• Single-dose intrathecal cytarabine is allowed prior to registration or prior to initiation of systematic therapy for patient convenience; systemic chemotherapy must begin within 72 hours of this intrathecal therapy.
• Patients receiving prior steroid therapy are eligible for study; the dose and duration of previous steroid therapy should be carefully documented on case report forms.
• Not pregnant and not nursing; for women of childbearing potential only, a negative urine or serum pregnancy test done =< 7 days prior to registration is required.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  •Patients with down syndrome are excluded from this study.
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN), unless suspected leukemic involvement of the liver.
• Direct bilirubin =< 3 x upper limit of normal (ULN), unless suspected leukemic involvement of the liver.
• Calculated (calc.) creatinine clearance >= 50 mL/min by Cockcroft-Gault.

RANDOMIZATION ELIGIBILITY CRITERIA (STEP 2) 

• Completion of remission induction therapy.
• Patients with M2 marrow or better are eligible; patients with M3 or M4 marrow (greater than 25% lymphoblasts) will not be eligible to be randomized:
  • Rating: M0, M1; Blast Cells (%): 0-5.0;
  • Rating: M2; Blast Cells (%): 5.1-25.0;
  • Rating: M3; Blast Cells (%): > 25-50;
  • Rating: M4; Blast Cells (%): > 50.0; 
  • The term "blast cell" includes any cell that cannot be classified as a more mature normal element, and includes "leukemic cells," pathologic lymphocytes, and stem cells.
• No ascites, effusions or significant edema.
• Absolute neutrophil count (ANC) >= 1,000/mm^3.
• Platelet count >= 100,000/mm^3.
• Total bilirubin =< 1.5 x upper limit of normal (ULN), except for patients with known Gilbert's syndrome.
• Aspartate aminotransferase (AST) =< 8 x upper limit of normal (ULN).
• Completion of first 12 weeks (12+ weeks) of maintenance therapy (Course V).
• Patient has at least 24 weeks (24+ weeks) remaining before end of maintenance therapy (Course V).
• Patient is in complete continuous first remission at entry into A041501-HO1.
• Patient is receiving oral anti-metabolite chemotherapy during the maintenance phase of therapy; treatment plan must call for the following doses of antimetabolites: 6MP 75 mg/m2/day orally; methotrexate (MTX) 20 mg/m2/week orally (modification of 6 MP or MTX dosing based on laboratory or clinical parameters is acceptable).
• Patient is able and willing to use the Medication Event Monitoring System (MEMS) TrackCap (e.g. not using a pillbox).

Newly-Diagnosed

• Age ≥ 18 years.
• Histologically confirmed Grade IV GBM, inclusive of gliosarcoma (WHO criteria; IDH wild-type by immunohistochemistry [IHC] or sequencing for IDH) established following either a surgical resection or biopsy. An MRI scan with the required imaging sequences performed within 21 days prior to randomization preferably. The post-operative MRI scan performed within 96 hours of surgery or the MRI scan performed for radiation therapy planning may serve as the MRI scan performed during screening if all required imaging sequences were obtained.
• Karnofsky performance status ≥ 60%. performed within a 14-day window prior to randomization.
• Availability of tumor tissue representative of GBM from definitive surgery or biopsy.

Recurrent

• Age ≥ 18 years.
• Histologically confirmed Grade IV GBM, inclusive of gliosarcoma (WHO criteria; IDH wild-type by immunohistochemistry [IHC] or sequencing for IDH) at first or second recurrence after initial standard, control or experimental therapy that includes at a minimum radiation therapy (RT).
• Evidence of recurrent disease demonstrated by disease progression using slightly modified Response Assessment in Neuro-Oncology (RANO) criteria.
• Two scans to confirm progression are required: at least 1 scan at the time of progression and 1 scan prior to the time of progression.
• Karnofsky performance status ≥ 70% performed within a 14-day window prior to randomization.
• Availability of tumor tissue representative of GBM from initial definitive surgery and/or, recurrent surgery, if performed.

Newly-Diagnosed

• Received any prior treatment for glioma including:
  • Prior prolifeprospan 20 with carmustine wafer;
  • Prior intracerebral, intratumoral, or cerebral spinal fluid (CSF) agent;
  • Prior radiation treatment for GBM or lower-grade glioma;
  • Prior chemotherapy or immunotherapy for GBM or lower-grade glioma. Receiving additional, concurrent, active therapy for GBM outside of the trial.
• Extensive leptomeningeal disease.
• QTc > 450 msec if male and QTc > 470 msec if female.
• History of another malignancy in the previous 2 years, with a disease-free interval of < 2 years. Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible.

Recurrent

• Early disease progression prior to 3 months (12 weeks) from the completion of RT.
• More than 2 prior lines for chemotherapy administration. (NOTE: In the 1st line adjuvant setting, combination of temozolomide (TMZ) with an experimental agent, is considered one line of chemotherapy).
• Received any prior treatment with lomustine, agents part of any of the experimental arms, and bevacizumab or other vascular endothelial growth factor (VEGF) or VEGF receptor-mediated targeted agent.
• Any prior treatment with prolifeprospan 20 with carmustine wafer.
• Any prior treatment with an intracerebral agent.
• Receiving additional, concurrent, active therapy for GBM outside of the trial.
• Extensive leptomeningeal disease.
• QTc > 450 msec if male and QTc > 470 msec if female.
• History of another malignancy in the previous 2 years, with a disease-free interval of < 2 years. Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible.

Eligibility last updated 2/16/22. Questions regarding updates should be directed to the study team contact.

• Subjects scheduled to elective and/or urgent median sternotomy for cardiac surgery, who are preoperative hemodynamically stable. 
• Males and females. 
• Subjects of age 18 years and older. 
• Subjects with both Diabetes Mellitus AND BMI ≥ 30 OR Diabetes Mellitus/BMI ≥ 30 AND at least one of the following: 
  • Current/Previous smoking history ≥ 30 pack year;
  • Chronic Obstructive Pulmonary Disease (COPD).
• Female of childbearing potential should have a negative serum pregnancy test prior to index procedure.
  • Note: All female of childbearing potential must agree to use a highly effective method of contraception (such as double barrier, oral or parenteral hormonal, intrauterine device and spermicide) consistently and correctly for the duration of the study. 
• Subject is willing and able to provide a signed Informed Consent Form and is willing and able to comply with study's procedures including follow-up visits.

• Subjects undergoing partial sternotomy. 
• Subjects with any preoperative active significant infection. 
• Subjects that received oral or IV doxycycline during the last 4 weeks prior to screening. 
• Subjects with sensitivity to doxycycline and/or to tetracycline family of drugs and/or other study drug ingredients. 
• Subjects with known allergies to more than 3 substances (an allergy questionnaire will be filled during the screening process). 
• Subjects with history of allergic/hypersensitivity reaction to any substance having required hospitalization and/or treatment with intra-venous steroids/epinephrine or in the opinion of the investigator the patient is at high risk of developing severe allergic/hypersensitivity reactions. 
• Subjects with uncontrolled Asthma (GINA III-IV). 
• Subjects with chronic urticaria. 
• Immunocompromised subjects from any reason, at screening. 
• Subjects with renal failure requiring dialysis. 
• Subjects scheduled to major organ transplantation and/or to other significant concomitant surgical procedure. 
• Subjects scheduled for mechanical assist device. 
• Subjects scheduled to be treated with preventive negative pressure devices.
• Subjects undergone Cerebro-Vascular Accident (CVA)/Transient Ischemic Attack (TIA) within the past 3 months prior to randomization. 
• Subjects that have undergone previously, any cardiac surgery through sternotomy. 
• Subjects with active or previous malignancy in the chest area. 
• Any subject with active malignancy or with malignancy that has not been in complete remission for at least 5 years. Subjects who have had carcinoma in situ of the cervix, squamous cell carcinoma of the skin and basal cell carcinoma of the skin, are eligible. 
• Pregnant or breast-feeding women or women of childbearing age not protected by an effective contraceptive method of birth control (such as double barrier, oral or parenteral hormonal, intrauterine device and spermicide). 
• Subjects enrolled in any intervention study with an investigational medicinal product and/or received any investigational medicinal product within 30 days or 5½ half-lives of the product prior to enrollment (whichever is longer). 
• In the opinion of investigator, subject is not eligible to participate in the study and/or to comply with protocol requirements (e.g., due to a cognitive, medical condition or residency distanced from site that may jeopardize Follow-Up visits attendance etc.).

• Male or female ≥ 16 and ≤ 75 years of age at Baseline.
  • Adolescent subjects at the age of 16 and 17 years old will be enrolled if approved by the country or regulatory/health authority. If these approvals have not been granted, only subjects ≥ 18 years old will be enrolled.
  • Adolescent subjects at the age of 16 and 17 years old must weigh ≥ 40 kg and meet the definition of Tanner Stage 5 at the screening visit.
• Diagnosis of ulcerative colitis for 90 days or greater prior to Baseline, confirmed by colonoscopy during the Screening Period, with exclusion of current infection, colonic dysplasia and/or malignancy. Appropriate documentation of biopsy results consistent with the diagnosis of UC, in the assessment of the Investigator, must be available.
• Active ulcerative colitis with an Adapted Mayo score of 5 to 9 points and endoscopic sub score of 2 to 3 (confirmed by central reader).
• Demonstrated an inadequate response to, loss of response to, or intolerance to at least one of the following treatments including, oral aminosalicylates, corticosteroids, immunosuppressants and/or biologic therapies, in the opinion of the investigator as defined below:
  • Note: An inadequate response, loss of response, or intolerance to Oral Aminosalicylates will NOT count towards eligibility for the following countries:
    • Austria, Czechia, Finland, Ireland, Italy, Latvia, Lithuania, Norway, Poland, Portugal, Spain, Sweden and United Kingdom.
  • Oral aminosalicylates (e.g., mesalamine, sulfasalazine, olsalazine, balsalazide):
    • Signs and symptoms of persistently active disease, in the opinion of the investigator, during a current or prior course of at least 4 weeks of treatment with 2.4 g/day mesalamine, 4 g/day sulfasalazine, 1 g/day olsalazine, or 6.75 g/day balsalazide.
  • Corticosteroids:
    • Signs and symptoms of persistently active disease despite a history of at least one induction regimen that included a dose equivalent to prednisone ≥ 40 mg/day orally for at least 3 weeks or intravenously for 1 week, OR
    • Unable to taper corticosteroids to below a dose equivalent to prednisone 10 mg daily orally without recurrent active disease, OR
    • Signs and symptoms of persistently active disease during or after a course of at least 4 weeks of treatment with 9 mg/day budesonide or 5 mg/day beclomethasone, OR
    • Unable to taper oral budesonide to at or below 6 mg/day without recurrent active disease, OR
    • History of intolerance to corticosteroids (including, but not limited to Cushing's syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, infection).
  • Immunosuppressants:
    • Signs and symptoms of persistently active disease despite a history of at least one 90 day regimen of oral azathioprine (≥ 1.5 mg/kg/day; for subjects in Japan, China, and Taiwan only: ≥ 1.0 mg/kg/day), 6-MP (≥ 1 mg/kg/day; [for subjects in Japan, China, and Taiwan only: ≥ 0.6 mg/kg/day, rounded to the nearest available tablet of half tablet formulation] or a documented 6-TGN level of 230 –450 pmol/8 × 108 RBC or higher on the current dosing regimen), injectable MTX (≥ 15 mg/week subcutaneous [SC] or intramuscular), or tacrolimus (for subjects in Japan and Taiwan only: documented trough level of 5 –10 ng/mL); OR
    • History of intolerance to at least one immunosuppressant (including, but not limited to nausea/vomiting, abdominal pain, pancreatitis, liver enzyme abnormalities, lymphopenia, infection).
      • Note: Oral MTX use is allowed during the study, however prior or current use of oral MTX is not sufficient for inclusion into the study unless these subjects were previously treated with aminosalicylates, corticosteroids or immunosuppressants (azathioprine or 6-MP) and have inadequate response to, loss of response to or intolerance to the therapy as defined above.
  • Biologic Agents for UC:
    • Signs and symptoms of persistently active disease despite a history of any of the following:
      • at least one 6-week induction regimen of infliximab (≥ 5 mg/kg IV at 0, 2, and 6 weeks);
      • at least one 4-week induction regimen of adalimumab (one 160 mg subcutaneous (SC) dose followed by one 80 mg SC dose [or one 80 mg SC dose, in countries where this dosing regimen is allowed] followed by one 40 mg SC dose at least 2 weeks apart);
      • at least one 2-week induction regimen of golimumab (one 200 mg SC dose followed by one 100 mg SC dose at least 2 weeks apart);
      • at least one 6-week induction regimen of vedolizumab (300 mg IV at 0, 2 and 6 weeks); OR
    • Recurrence of symptoms during scheduled maintenance dosing following prior clinical benefit (discontinuation despite clinical benefit does not qualify); OR
    • History of intolerance to at least one biologic agent (including, but not limited to infusion-related reaction, demyelination, congestive heart failure, infection).
      • Note: Non-bio-IR subjects who have received a prior biologic for up to 1 year may be enrolled, however, subjects must have discontinued the biologic for reasons other than inadequate response or intolerance (e.g., change of insurance, well controlled disease), and must meet the criteria for inadequate response, loss of response or intolerance to aminosalicylates, corticorsteroids and/or immunosuppressants as defined above.
• Female subjects of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at the Baseline Visit prior to study drug dosing.
  • Note: subjects with borderline serum pregnancy test at Screening must have a serum pregnancy test ≥ 3 days later to document continued lack of positive result.
  • For subjects in Ireland, a repeat serum pregnancy test ≥ 3 days later that is still borderline will result in screen failure.
  • If female, subject must meet the contraception criteria.
• Subject is judged to be in otherwise good health as determined by the Investigator based upon the results of medical history, laboratory profile, physical examination and a 12-lead electrocardiogram (ECG) performed during Screening.
• Subject must be able and willing to give written informed consent and to comply with the requirements of this study protocol. In Japan, if the subject is < 20 years old, a subject's parent or legal guardian must be willing to give written informed consent.

• Subject with current diagnosis of Crohn's disease (CD) or diagnosis of indeterminate colitis (IC).
• Current diagnosis of fulminant colitis and/or toxic megacolon.
• Subject with disease limited to the rectum (ulcerative proctitis) during the screening endoscopy.
• History of colectomy (total or subtotal) with ileoanal pouch, Kock pouch, or ileostomy for UC or is planning bowel surgery.
• Received treatment with rectal aminosalicylates or corticosteroids, other enemas/suppositories (other than required for endoscopy), within 14 days prior to the Screening endoscopy and during the remainder of the Screening Period.
• Received cyclosporine, tacrolimus, mycophenolate mofetil or thalidomide within 30 days prior to Baseline.
• Subjects who received azathioprine or 6-mercaptopurine within 10 days of Baseline.
• Received intravenous corticosteroids within 14 days prior to Screening or during the Screening Period.
• Subject on MTX or oral aminosalicylates who:
  • has not been on the current course of MTX for at least 42 days prior to Baseline, and has not been on stable doses for at least 28 days prior to Baseline;
  • has not been on stable doses of oral aminosalicylates for at least 14 days prior to Baseline;
  • has discontinued use of aminosalicylates within 14 days of Baseline.
• Subject on treatment with corticosteroids who meet the following:
  • Oral corticosteroid dose > 30 mg/day (prednisone or equivalent) or has not been on the current course for at least 14 days prior to baseline and on a stable dose for at least 7 days prior to Baseline;
  • Oral budesonide dose > 9 mg/day or has not been on the current course for at least 14 days prior to Baseline and on a stable dose for at least 7 days prior to Baseline;
  • Oral beclomethasone dose > 5 mg/day or has not been on the current course for at least 14 days prior to baseline and on a stable dose for at least 7 days prior to Baseline.
  • Subject has been taking both oral budesonide (or oral beclomethasone) and oral prednisone (or equivalent) simultaneously, with the exception of topical or inhalers within 14 days prior to Screening or during the Screening Period.
• Subject has active TB or meets TB exclusionary parameters.
• Subject who received fecal microbial transplantation within 30 days prior to Baseline.
• Subject on UC-related antibiotics who has not been on stable doses for at least 14 days prior to Baseline or has discontinued these medications within 14 days of Baseline.
• Subjects who received any of the following biologic therapy:
  • infliximab, certolizumab, adalimumab, golimumab, vedolizumab, natalizumab, within 8 weeks prior to Baseline; OR
  • ustekinumab within 12 weeks prior to Baseline.
  • Note: If there is proper documentation of undetectable drug level measured by a commercially available assay for any of the approved biologics above, there is no minimum washout prior to Baseline.
• Subject with previous exposure to JAK inhibitor (e.g., tofacitinib, baricitinib, filgotinib, upadacitinib).
• Subject who received non-steroidal anti-inflammatory drugs (NSAIDs) (except topical NSAIDs and the use of low dose aspirin for cardiovascular [CV] protection) within 7 days prior to Baseline.
• Subject received traditional Chinese medicine within 30 days prior to baseline.
• Subject received live vaccine(s) within 30 days (8 weeks for Japan) prior to Baseline, or who is expected to need live vaccination during study participation including at least 30 days (8 weeks for Japan) after the last dose of study drug.
• Systemic use of known strong cytochrome P450 (CYP)3A inhibitors or strong CYP3A inducers during the Screening Period and through the end of the study.
• Subject currently receiving total parenteral nutrition (TPN) or plan to receive TPN at any time during study treatment.
• Subject who received any investigational agent or procedure within 30 days or 5 half-lives prior to Baseline, whichever is longer or is currently enrolled in an interventional study.
• Subject with positive C. difficile toxin stool assay during Screening.
• Infection(s) requiring treatment with intravenous anti-infectives within 30 days prior to the Baseline Visit or oral/intramuscular anti-infectives within 14 days prior to the Baseline Visit.
• Chronic recurring infection and/or active viral infection that, based on the investigator's clinical assessment, makes the subject an unsuitable candidate for the study.
• Subject has current or past history of recurrent or disseminated (even a single episode) herpes zoster.
• Subject has current or past history of disseminated (even a single episode) herpes simplex.
• Subject has HBV, HCV, or human immunodeficiency virus (HIV) infection defined as:
  • HBV: hepatitis B surface antigen (HBs Ag) positive (+) or detected sensitivity on the HBV deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) qualitative test for subjects who are hepatitis B core antibody (HBc Ab) positive (+) subjects (and for Hepatitis B surface antibody positive (+) subjects where mandated by local requirements);
  • HCV: HCV ribonucleic acid (RNA) detectable in any subject with anti-HCV antibody (HCV Ab);
  • HIV: confirmed positive anti-HIV antibody (HIV Ab).
• Prior or current gastrointestinal (GI) dysplasia, other than completely removed lowgrade dysplastic lesion in any biopsy performed during or before the Screening endoscopy.
• History of any malignancy, except for successfully treated nonmelanoma skin cancer (NMSC) or localized carcinoma in situ of the cervix.
• History of gastrointestinal (GI) perforation (other than appendicitis or penetrating injury), diverticulitis or significantly increased risk of GI perforation per investigator's judgment.
• Screening laboratory and other analyses show any of the following abnormal results:
  • Serum Aspartate Transaminase (AST) or Alanine Transaminase (ALT) > 2 × upper limit of normal (ULN);
  • Estimated glomerular filtration rate (eGFR) by simplified 4-variable Modification of Diet in Renal Disease (MDRD) formula < 30 mL/min/1.73 m^2;
  • Total White Blood Cell (WBC) count < 2,500/μL;
  • Absolute neutrophil count (ANC) < 1,200/μL;
  • Platelet count < 100,000/μL;
  • Absolute lymphocytes count < 750/μL;
  • Hemoglobin < 9 g/dL.
• Female subject who is pregnant, breastfeeding or considering becoming pregnant during the study or within 30 days after the last dose of study drug, or has positive pregnancy test at Screening (serum) or Baseline (urine).
• History of an allergic reaction or significant sensitivity to constituents of the study drug (and its excipients) and/or other products in the same.
• History of clinically significant (per investigator's judgment) drug or alcohol abuse in the last 6 months.
• Subject who previously received stem cell transplantation.
• Subject has been a previous recipient of an organ transplant which requires continued immunosuppression.
• For Japan subjects only: positive result of beta-D-glucan or two consecutive indeterminate results of beta-D-glucan (screening for Pneumocystis jiroveci infection).
• Received cytoapheresis treatment (GCAP, LCAP etc.) within 60 days prior to Baseline.
• For Japan subjects only: received ATM treatment (antibiotic combination therapy with amoxicillin, tetracycline and metronidazole) during the Screening Period.
• Recent (within past 6 months) cerebrovascular accident, myocardial infarction, coronary stenting or Moderate to severe congestive heart failure (New York Heart Association class III or IV).
• Conditions that could interfere with drug absorption including but not limited to short bowel syndrome (e.g., history of gastric bypass surgery).
• History of clinically significant medical condition or any other reason which, in the opinion of the investigator, would interfere with the subject's participation in this study, would make the subject an unsuitable candidate to receive study drug, or would put the subject at risk by participating in the protocol.

• Has an adequate comprehension of a GFD assessed by completion of a knowledge test after viewing of educational materials.
• Has at least 1 CeD-related GI symptom of moderate or greater severity, as measured by the CDSD, on at least 3 days out of any consecutive 7-day period during the screening period (Week -8 visit until Week -4 visit), felt by the investigator to be related to gluten exposure. The CeD-related symptom(s) may vary day by day as long as the severity of at least 1 symptom is moderate or greater. The participants must meet symptom criteria to undergo esophagogastroduodenoscopy (EGD)/video capsule endoscopy (VCE).
• Has been attempting to maintain a GFD for at least 12 months as self-reported by the participant.
• Has small intestinal villous atrophy on duodenal biopsy defined as Vh:Cd <2.5 at Week -4.
• The participant is human leukocyte antigen (HLA)-DQ2 and/or HLA-DQ8 positive.
• The participant is in a good general state of health according to clinical history and physical examination, in the opinion of the investigator.
• Have a body mass index (BMI) between 16 and 40 kilogram per meter square (kg/m^2), inclusive.
• The participant is willing and able to continue any current dietary and/or medical regimens (including gastric acid suppression) in effect at the first visit (Visit 1).

• There should be no changes to diet, medications (prescription or over-the-counter) or supplements during study participation.

  ---

  Exclusion Criteria:

• Has the presence of other inflammatory GI disorders or systemic autoimmune diseases (including but not limited to the following: inflammatory bowel disease, eosinophilic esophagitis, gastroenteritis or colitis, microscopic colitis diagnosed at screening or requiring treatment in the 6 months before screening, scleroderma, psoriatic or rheumatoid arthritis, lupus) other than those noted below:

  • Thyroid disease that has been well-controlled for at least 6 months.
  • Well-controlled type 1 diabetes (glycosylated hemoglobin <8% and no hospitalization or emergency room visit in the last 12 months for hyperglycemia or hypoglycemia).

• Has ongoing systemic immunosuppressant, systemic corticosteroid treatment excluding medication given for the endoscopies, or treatment with systemic immunosuppressants or systemic corticosteroids in the 12 weeks before Screening.

  • The participant is receiving immunosuppressive doses of corticosteroids: 3 mg per day or more of budesonide for more than 3 consecutive days within 3 months before Screening, more than 20 mg of prednisone given daily or on alternative days for 2 weeks or more within 6 months before the first dose, any dose of oral or intravenous (IV) corticosteroids within 30 days of the first dose, or high-dose inhaled corticosteroids (>960 micrograms per day [μg/day] of beclomethasone dipropionate or equivalent), or other systemic immunosuppressive agents.

• Has ongoing use of over-the-counter digestive enzymes or digestive supplements, other than lactase, including those for gluten digestion. Probiotics are allowable if they were started before Screening and not discontinued or changed in dose or type during the study.
• Has completed the CDSD on ≤75% of the days during Week -8 until randomization.

• Has active microscopic colitis requiring treatment in the 6 months before Screening.

  • Microscopic colitis detected at screening if sigmoidoscopy is performed would exclude the participant.

• Has known or suspected type 2 refractory CeD or ulcerative jejunitis.
• Has ongoing chronic use (defined as >7 days continuous use) of a nonsteroidal anti-inflammatory drug aside from <100 mg aspirin, daily, for prophylactic use.
• Has ongoing use, or use in the 3 months before screening, of medications known to cause villous abnormalities (e.g., mycophenolate mofetil, angiotensin receptor blockers, colchicine).
• Has used treatments for GI symptoms including antiemetics, antidiarrheals, antispasmodics, medical marijuana, and constipation agents other than fiber, within 2 weeks of Screening.
• Has a known or suspected severe enteric infection (viral, bacterial, or parasitic) within 6 months before randomization. Severe enteric infection is defined as requiring emergency room visit or hospitalization or treatment with antibiotics or anti-infectives due to infection. Non enteric viral infections, either resolved or well-controlled are not exclusionary.

• Has a contraindication to endoscopy with duodenal biopsy.

  --Contraindication to VCE (strictures, anastomoses, etc) is not an exclusion if the participant is able to complete the other aspects of the study.

• Has additional food allergies (tapioca syrup, oats, almonds, rice crisp, chocolate, almond, butter, wheat gluten, cocoa butter, oat flour, glycerin, sunflower lecithin, salt, and natural flavors) to nongluten ingredients in the SIGE bar study food or significant symptoms upon ingestion of the gluten-free SIGE bar during screening.
• Has a history of intolerance, hypersensitivity, or idiosyncratic reaction to an aminoglycoside.
• Has a known human immunodeficiency virus (HIV) infection or positive tests for hepatitis B or C. The participant has a known clinically significant chronically active hepatopathy of any origin, including cirrhosis, and participants with persistent positive hepatitis B virus surface antigen and quantitative hepatitis B virus polymerase chain reaction (PCR), or positive serology for hepatitis C virus (HCV) and quantitative HCV PCR within 6 months before the screening visit.
• Has known or suspected coronavirus disease 2019 (COVID-19) as determined by the investigator within the past month or COVID-19-related symptoms that have not resolved (direct viral or serologic testing may be performed according to site procedures at the discretion of the investigator).
• Has a known hypersensitivity reaction and/or allergy, including anaphylaxis, to wheat and/or gluten.

• Has known history of hypersensitivity, idiosyncratic reaction, or intolerance to any ingredients or excipients in TAK-062 and/or placebo.

  Region-specific

  ---

  Exclusion Criteria:

• Participant enrolling in a study in France is not affiliated to a social security scheme or a beneficiary of such a scheme.
• Participant enrolling in a study in France is deprived of their liberty by a judicial or administrative decision.

Eligibility last updated 6/21/23. Questions regarding updates should be directed to the study team contact.

• Male or female patients 18 years of age and older.
• Documented diagnosis of erythromelalgia, as characterized by redness, warmth, and burning pain of the extremities (most commonly feet), typically precipitated by heat or exercise and relieved by cooling.
• Mean pain attack intensity, measured on the 11-point NPRS, of ≥4 and ≤9 at baseline and ≥4 pain attacks per week as documented through eDiary use during the 3 weeks prior to randomization (Day -21 to Day -1).
• Use of concomitant medications, with the exception of topical agents applied to the hands or feet, are permitted if the dose has been stable for at least 4 weeks preceding the screening visit and is planned to be maintained at the same regimen during the course of the study (prior treatment includes pharmacological and nonpharmacological treatments).
• Patients having signed a written informed consent prior to any study related procedure.
• Male patients should agree to use a condom along with another medically acceptable contraceptive method, where applicable according to local guidelines, if he is engaged in sexual activity with a woman of childbearing potential (WOCBP) from the day of the signature of the informed consent and up to 90 days after the end-of-study visit. Male patients should agree not to donate sperm until 90 calendar days after the last dose of study drug.
• Females must comply with the following in order to be enrolled:
  • WOCBP with negative pregnancy test results can be enrolled only if willing to use an acceptable contraceptive method, i.e. oral contraceptives, patch contraceptives, injection contraceptives, implantable hormonal contraceptives,male condom with intravaginal spermicide, diaphragm or cervical cap with spermicide, vaginal contraceptive ring, intrauterine device or system, surgical sterilization (hysterectomy, bilateral oophorectomy, and/or bilateral salpingectomy), tubal ligation/ occlusion, vasectomized partner, or sexual abstinence, if this is the patient's current practice, from at least 14 days prior to the screening visit and throughout the study and for at least 30 days after the completion of the study;
  • Or surgically sterilized for at least 6 months; or
  • Menopausal for at least 1 year.

• Clinical evidence of a pre-existing pain disorder in the extremities resulting from another cause than erythromelalgia; e.g. complex regional pain syndrome (CRPS), diabetic neuropathy, chemotherapy-induced peripheral neuropathy (CIPN).
• Evidence of skin breakdown, ulcers, papules and > +2 pitting edema of the affected limbs.
• Presence of glaucoma.
• Presence of urinary retention (or significant prostatic hypertrophy at risk of urinary retention).
• History of coronary artery disease.
• History and /or presence of major depressive episode.
• The patient has suicidal risk in the opinion of the investigator based upon clinical interview and the Columbia Suicide-Severity Rating Scale.
• Pregnant or lactating women.
• Abnormality in the 12-lead electrocardiogram (ECG) at screening that in the opinion of the investigator increases the risk of participating in the study, such as a corrected QT Fridericia (QTcF) interval >430 ms for males or >450 ms for females.
• A history of additional risk factors for Torsade de Pointe (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
• The use of concomitant medications within 24 weeks prior to Day 1 and/or during the study or the equivalent of 5 half-lives that prolong the QT/QTc interval, eg, Class 1 antiarrhythmics (e.g., quinidine, disopyramide, procainamide) and Class 3 antiarrhythmics (e.g., amiodarone, sotalol), antihistamines, antipsychotics known to prolong QT interval, and antimalarials (e.g., mefloquine, quinine),  tricyclic antidepressants (e.g., AMT), tetracyclic antidepressants (e.g., maprotiline), cisapride.
• The use of monoamine oxidase inhibitors within 24 weeks (or the equivalent of 5 half-lives) prior to Day 1 and/or during the study.
• The use of opioids within 4 weeks (or the equivalent of 5 half-lives) prior to Day 1 and/or during the study.
• History of illicit drug use or confirmed drugs of abuse at screening. Positive urine drug screen for prescribed medication is allowed at the discretion of the investigator.
• Use of more than 2 analgesics (regardless of the route of administration) from different drug classes (including antidepressants and antiepileptics) on top of study drug.
• Treatment with oral or topical amitriptyline or nortriptyline in the past 4 weeks or current treatment with any other tricyclic antidepressant.
• Any known hypersensitivity to amitriptyline (regardless of the route of administration) in any salt form or to any constituent of the topical formulation.
• Any topical treatment on treated extremities for any indication, other than cosmetic use of creams and lotions, within the 12 weeks prior to screening.
• Any topical treatment for pain including use of:
  • over-the-counter capsaicin on extremities within 12 weeks of screening; and/or
  • Qutenza within 24 weeks of screening; and/or
  • nonsteroidal anti-inflammatory drugs, menthol, methyl salicylate, local anesthetics within 1 week of screening.
• Implanted active medical device (e.g., spinal cord stimulator, intrathecal pump, or peripheral nerve stimulator) for the treatment of pain or any etiology.
• Regional anesthetic block for pain of any etiology within 3 months prior to screening.
• Intake in the 4 weeks preceding screening visit of any medication susceptible to inhibit or induce cytochrome P450 CYP2D6.
• Poor metabolizers of CYP2D6 substrates.
• Treatment with an investigational drug in the previous 4 weeks or greater, according to local requirements
• Any condition that the investigator feels would place the patient at increased risk if the investigational therapy is initiated, such as, but not limited to, hyperthyroidism, convulsive disorder, advanced hepatic disease, pylorus, stenosis, or paralytic ileus.
• The investigator considers the patient unfit for the study as a result of the medical interview, physical examination, or screening  investigations, in particular any status or disease making the patient unable to follow instructions.
• The patient is unable to apply the study drug on feet and/or hands.
• The patient is an employee of the investigator, study site, sponsor, or contract research organization with direct involvement in the proposed study or other studies under the direction of the investigator, study site, or sponsor, or a family member of the site employee or the Investigator.

Eligibility last updated 9/14/23. Questions regarding updates should be directed to the study team contact.

• Adult female subjects aged 18 to 75 years, inclusive, or adult male subjects aged 50 to 75 years, inclusive, at the time of signing the ICF prior to initiation of any study-specific activities/procedures.
• A current diagnosis of symptomatic PAH classified by one of the following:
  • Idiopathic PAH (IPAH) or heritable pulmonary arterial hypertension (HPAH);
  • PAH associated with connective tissue diseases (CTD-APAHs):
    • Systemic sclerosis;
    • Mixed CTD or overlap syndrome;
    • Systemic lupus erythematosus.
  • Other CTD established by ACR/EULAR guidelines;
  • PAH associated with anorexigen or methamphetamine use;
  • Congenital heart disease with simple systemic to pulmonary shunt at least 1 year after surgical repair.
• 6MWD ≥ 150 meters and ≤ 550 meters at screening.
• WHO FC II or III symptomatology.
• Treatment with standard of care PAH background therapies.
• Documentation of cardiac catheterization within the screening period that is consistent with the diagnosis of PAH and meeting all the following criteria, to be confirmed by a central hemodynamic core laboratory:
  • Mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg (at rest);
  • Pulmonary capillary wedge pressure ≤ 15 mmHg, or mean left atrial pressure (mLAP) or left ventricular-end diastolic pressure (LVEDP) ≤ 15 mmHg in the absence of left atrial obstruction;
  • PVR ≥ 400 dyne•s/cm^5.
• Pulmonary function tests (PFTs) at screening with the following criteria met:
  • Forced expiratory volume in 1 second (FEV1) divided by the forced vital capacity (FVC) ≥ 760% (predicted);
  • Total lung capacity (TLC) or FVC ≥ 70% predicted.

• Evidence of chronic thromboembolic disease or acute pulmonary embolism as assessed by ventilation-perfusion (V/Q) scan, computed tomography (CT)-angiogram, or pulmonary angiogram prior to screening.
• Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure > 160 mm Hg or sitting diastolic blood pressure > 100 mm Hg during screening visit after a period of rest.
• Systolic blood pressure < 90 mm Hg during screening and baseline visits.
• WHO Pulmonary Hypertension Group 2-5.
• Human immunodeficiency virus (HIV)-associated PAH.
• History of left-sided heart disease and/or clinically significant cardiac disease, including but not limited to any of the following:
  • Aortic or mitral valve disease (stenosis or regurgitation) defined as greater than mild aortic insufficiency, mild aortic stenosis (AS), mild mitral stenosis (MS), moderate mitral regurgitation (MR);
  • Mechanical cardiac valve requiring anticoagulation;
  • Pericardial constriction or pericardial effusion with tamponade physiology;
  • Restrictive cardiomyopathy;
  • Left ventricular ejection fraction (LVEF) ≤ 50% by echocardiography (ECHO) within 6 weeks prior to screening; if  ECHO from the prior 6 weeks is not available, the screening ECHO results may be used to establish this criterion.
  • Note: If ECHO images are not adequate to provide an accurate estimate of LVEF then a multigated acquisition (MUGA) or cardiac magnetic resonance imaging (cMRI) scan or single photon emission computed tomography (SPECT) imaging can be used to obtain an accurate LVEF.
  • Left Atrial Area greater than 29cm2 by ECHO within 6 weeks prior to screening; if historical ECHO from the prior 6 weeks is not available, screening ECHO results may be used to establish this criterion. g. Documented uncontrolled symptomatic coronary disease (ie, unstable angina or percutaneous coronary intervention or coronary artery bypass graft within 12 months prior to screening, or planned coronary intervention or coronary artery bypass surgery).
• Untreated obstructive sleep apnea.
• History of atrial septostomy within 180 days prior to screening.
• Pulmonary venous occlusive disease (PVOD).
• Subjects with a history of portopulmonary hypertension or portal hypertension due to cirrhosis classified as Child-Pugh Class A or higher; or baseline ALT or AST > 2 x ULN or Total Bilirubin ≥ 2 X ULN.
• History of malignancy within 5 years prior to screening, with the exception of localized nonmetastatic basal cell carcinoma of the skin and in-situ carcinoma of the cervix.
• History of a potentially life-threatening cardiac arrhythmia with an ongoing risk.
• Uncontrolled bacterial, viral, or fungal infections which require systemic therapy.
• Severe acute or chronic medical or laboratory abnormality that may increase the risk associated with study participation or IP administration (eg, history of intracranial hemorrhage), or absolute neutrophil count (ANC) < 1 x 10^9 /L or platelet count < 50 x10^ 9 /L.
• Any musculoskeletal disease or any other disease that limits evaluation of 6MWT.
• Pregnant or nursing or intends to become pregnant during the duration of the study.
• Body weight < 40 kg at screening.
• Chronic renal insufficiency as defined by an estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73m^2 via CKD-epi (Levey, 2009) at screening or requires dialytic therapy or hemofiltration.
• Hemoglobin (Hgb) concentration < 8.5 g/dL at screening.
• Evidence of active human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C, or tuberculosis (TB) infections.
• Inhaled prostanoids; these drugs may be withdrawn ≥ 4 weeks prior to screening, if clinically indicated.
• Use of oral anticoagulants (i.e., coumadin warfarin or novel oral anticoagulants [NOAC]) at randomization; if on coumadin warfarin or a NOAC, these drugs can be withdrawn, if clinically appropriate, during the screening period, and subjects should have normal coagulation parameters prior to the randomization for examples of prohibited anticoagulants).
• Requirement of intravenous (IV) inotropes (i.e., levosimendan, dopamine, dobutamine, milrinone, norepinephrine) other than an IV prostanoid within 4 weeks of screening. Prior/Concurrent Clinical Study Experience.
• Prior participation in GB002 studies and/or prior treatment with GB002.
• Currently participating in or has participated in a study of an investigational agent or has used an investigational device for the treatment of PAH within 4 weeks prior to screening.
  • Note: Subjects who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks or at least 5 half-lives (whichever is greater) after the last dose of the previous investigational agent.
• Current use of inhaled tobacco and/or inhaled marijuana.
• Current alcohol use disorder as defined by DSM-5 and/or a positive test for drugs of abuse (amphetamines, methamphetamines, cocaine, phencyclidine [PCP]). Retest may be performed for potential false positive results. Subjects with a history of methamphetamine abuse must be abstinent for a minimum of 1 year prior to screening, in the opinion of the investigator.as documented by at least two negative urine or serology tests during the 12 months prior to screening. Certain drugs may be allowed IF prescribed by medical personnel and is under medical supervision for documented medical conditions (ie, opioids for pain, benzodiazepines for anxiety). Ingestible or topical marijuana is allowed, per local restrictions and regulations.
• Subjects with a history of severe milk protein allergy. In addition, subjects with known intolerance or hypersensitivity to lactose who, in the opinion of the investigator, may experience severe symptoms following the ingestion of lactose. 
• QTcF of > 480 msec recorded on a screening or baseline ECG or receiving concurrent treatment with medications that prolong QT interval. 
• Have any other condition or reason that, in the opinion of the Investigator or Medical Monitor, would prohibit the subject from participating in the study.

Eligibility last updated 1/25/22. Questions regarding updates should be directed to the study team contact.

• Histologically proven intracranial glioblastoma or gliosarcoma at initial surgery
  • Patients will be eligible if the original histology was low-grade glioma and a subsequent diagnosis of glioblastoma or gliosarcoma is made (high-grade transformation)
• Karnofsky performance status >= 70
• Women must not be pregnant or breast-feeding
• Progression of disease assessed by local site using Revised Assessment in Neuro-Oncology (RANO) criteria, with plan to give whole-dose bevacizumab therapeutically, either as single therapy or in conjunction with other chemotherapeutic regimens; patients getting bevacizumab to support additional radiation therapy or immunotherapy, or primarily for reduction of edema rather than for tumor treatment, are excluded; this must be the patient?s initial recurrence
• Patient must not have been treated previously with immunotherapies (vaccines, checkpoint inhibitors, T-cells)
• Intratumoral hemorrhage (acute, subacute, or chronic) as seen on hemosiderin-sensitive (gradient-echo) MRI may preclude patient inclusion because of anticipated limited evaluation due to magnetic susceptibility artifact on the heavily T2-weighted DSC-MRI images; if the region of enhancing tumor not affected by blooming artifact on the hemosiderin-sensitive images does not meet the 10 x 10 x 10 mm ?measurable enhancement? threshold specified elsewhere, the patient is ineligible
• Progressive enhancement (> 25% increase in contrast enhancing volume compared to nadir) on MRI within 14 days of registration, >= 42 days since completion of radiation/temozolomide therapy, and >= 28 days since surgical resection or cytotoxic chemotherapy; measurable enhancement is defined as two perpendicular in-plane diameters of at least 10 mm and at least 10 mm in the 3rd orthogonal direction
• Patients must be able to tolerate brain MRI scans with dynamic intravenous gadolinium-based contrast agent injections
  • Ability to withstand 22 gauge intravenous (IV) placement
  • No history of untreatable claustrophobia
  • No magnetic resonance (MR) incompatible implants/devices or metallic foreign bodies
  • No contraindication to intravenous contrast administration
    • Adequate organ function, including adequate renal function defined as estimated glomerular filtration rate (eGFR) >= 40 mL/min/1.73 m^2 as calculated per institution standard of care, and meeting local site requirements for intravenous administration of gadolinium-based MRI contrast agents
  • No known allergy-like reaction to gadolinium or moderate or severe allergic reactions to one or more allergens as defined by the American College of Radiology (ACR); patient may be eligible if willing to undergo pre-treatment as defined by the institution's policy and/or ACR guidance
  • Weight compatible with limits imposed by the MRI scanner table
• Patient must be scheduled to receive treatment with a standard dose regimen of bevacizumab (bevacizumab infusion on days 1 and 15 of a 28-day treatment cycle); patient can be treated with bevacizumab alone or in combination with other chemotherapies

• Diagnosis of Alzheimer’s Dementia according to NIA-AA Criteria for dementia.
• MMSE ≤ 15.
• Cohen-Mansfield Agitation Inventory Nursing Home Version (CMAI) score of >5 on at least one item of aggression or a physical nonaggressive item that holds potentially dangerous consequences including hitting (including self), kicking, grabbing onto people, pushing, throwing things, biting, scratching, spitting, hurting self or other, tearing things or destroying property, making physical sexual advances, trying to get to a different place, intentional falling, screaming, making verbal sexual advances, and cursing or verbal aggression (items 1-11, 14, 15, 22-24).
• At least three failed pharmacological interventions from different drug classes (including antidepressants, antipsychotics, anticonvulsants, prazosin, and cannabinoids) at therapeutic doses (to be determined by clinical judgment) and duration of at least two weeks each to manage behavioral symptoms. These interventions may also include medications discontinued after 1 week due to tolerability concerns. Furthermore, medication trials that occur prior to admission to the hospital may count towards the three failed trials. The trials can be inpatient and/or outpatient. These trials can also be concurrent, such as using two medications from different classes for at least one week  at the same time (i.e., polypharmacy).
• Medically stable for safe administration of ECT verified by standard physical examination, urinalysis and serum chemistries.
• Comprehension of English language.
• Authorized legal representative able and willing to give informed consent.
• Age 55
  •89 years old (inclusive).

• Current diagnosis of co-morbid delirium, measured by the Confusion Assessment Method (CAM) and by clinical diagnosis.
• Diagnosis of Non-AD Dementia.
• Lifetime or current diagnosis of Schizophrenia, Bipolar Disorder or Schizoaffective Disorder.
• Active substance use disorder within past 6 months.
• Treatment with ECT or other neurostimulation therapies (e.g., TMS or vagal nerve stimulation) within the past 3 months.

• Presence of metastasized or locally advanced, inoperable (curative intent) histologically proven, well differentiated Grade 2 or Grade 3 gastroenteropancreatic neuroendocrine (GEP-NET) tumor diagnosed within 6 months prior to screening.
• Ki67 index ≥ 10 and ≤ 55%
• Patients ≥ 15 years of age and a body weight of > 40 kg at screening
• Expression of somatostatin receptors on all target lesions documented by CT/MRI scans, assessed by any of the following somatostatin receptor imaging (SRI) modalities within 3 months prior to randomization:  [68Ga]-DOTA-TOC (e.g., Somakit-TOC®) PET/CT (or MRI when applicable based on target lesions) imaging,  [68Ga]-DOTA-TATE PET/CT (or MRI when applicable based on target lesions) imaging (e.g., NETSPOT®), Somatostatin Receptor scintigraphy (SRS) with [111In]-pentetreotide (Octreoscan® SPECT/CT),  SRS with [99mTc]-Tektrotyd, [64Cu]-DOTA-TATE PET/CT (or MRI when applicable based on target lesions) imaging.
• The tumor uptake observed in the target lesions must be > normal liver uptake observed on planar imaging.
• Karnofsky Performance Score (KPS) ≥ 60.
• Presence of at least 1 measurable site of disease.
• Patients who have provided a signed informed consent form to participate in the study, obtained prior to the start of any protocol related activities.

• Creatinine clearance < 40 mL/min calculated by the Cockroft Gault method.
• Hb concentration < 5.0 mmol/L (< 8.0 g/dL); WBC < 2 x 10E^9/L (2000/mm^3); platelets < 75 x 10E^9/L (75x10E3/mm^3).
• Total bilirubin > 3 x ULN.
• Serum albumin < 3.0 g/dL unless prothrombin time is within the normal range.
• Pregnancy or lactation.
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, are not allowed to participate in this study UNLESS they are using highly effective methods of contraception throughout the study and for 6 months after study drug discontinuation.
• Peptide receptor radionuclide therapy (PRRT) at any time prior to randomization in the study.
• Documented RECIST progression to previous treatments for the current GEP-NET at any time prior to randomization.
• Patients for whom, in the opinion of the investigator, other therapeutic options (e.g., chemo-, targeted therapy) are considered more appropriate than therapy offered in the study, based on patient and disease characteristics.
• Any previous therapy with Interferons, Everolimus (mTOR-inhibitors), chemotherapy or other systemic therapies of GEP-NET administered for more than 1 month or within 12 weeks prior to randomization in the study.
• Any previous radioembolization, chemoembolization and radiofrequency ablation.
• Any surgery within 12 weeks prior to randomization in the study.
• Known brain metastases, unless these metastases have been treated and stabilized for at least 24 weeks, prior to screening in the study. Patients with a history of brain metastases must have a head CT or MRI with contrast to document stable disease prior to randomization in the study.
• Uncontrolled congestive heart failure (NYHA II, III, IV). Patients with history of congestive heart failure who do not violate this exclusion criterion will undergo an evaluation of their cardiac ejection fraction prior to randomization via echocardiography. The results from an earlier assessment (not exceeding 30 days prior to randomization) may substitute the evaluation at the discretion of the Investigator, if no clinical worsening is noted. The patient’s measured cardiac ejection fraction in these patients must be >40% before randomization.
• QTcF > 470 msec for females and QTcF > 450 msec for males or congenital long QT syndrome.
• Uncontrolled diabetes mellitus as defined by hemoglobin A1c value > 7.5%.
• Hyperkaleamia > 6.0 mmol/L (CTCAE Grade 3) which is not corrected prior to study enrolment.
• Any patient receiving treatment with short-acting octreotide, which cannot be interrupted for 24 h before and 24 h after the administration of Lutathera, or any patient receiving treatment with SSAs (e.g., octreotide long-acting), which cannot be interrupted for at least 6 weeks before the administration of Lutathera, unless the tumor uptake on target lesions observed by study-permitted somatostatin receptor imaging (SRI) modalities during continued long-acting SSA treatment is greater than the liver uptake observed by planar imaging.
• Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with the completion of the study.
• Prior external beam radiation therapy to more than 25% of the bone marrow.
• Current spontaneous urinary incontinence.
• Other known co-existing malignancies except non-melanoma skin cancer and carcinoma in situ of the uterine cervix, unless definitively treated and proven no evidence of recurrence for 5 years.
• Patient with known incompatibility to CT Scans with I.V. contrast due to allergic reaction or renal insufficiency. If such a patient can be imaged with MRI, then the patient would not be excluded.
• Hypersensitivity to any somatostatin analogues, the IMPs active substance or to any of the excipients.
• Patients who have participated in any therapeutic clinical study/received any investigational agent within the last 30 days.

Eligibility last updated 2/28/22. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria

• Age 1 to 30 years
• Clinically planned, elective surgical Ebstein repair
• Individuals able to undergo bone marrow aspirate according to clinical consultation with Hematology (cell treatment group only)
• Individuals able to undergo preoperative MRI or CT examination
• Individual and/or parent willing and able to give informed consent and willing to commit to completion of follow-up

Exclusion Criteria

• Individuals requiring cavopulmonary shunt at the time of surgical Ebstein repair; planned preoperatively or required intraoperatively
• Individuals with, or reasonably expected to have, complications during surgical Ebstein repair or during post-operative recovery
• Individual has not completed or will not be completing all pre-procedure work-up within 30 days of surgical Ebstein repair as listed in section 6 of this protocol AND lack of pre-procedure work-up documented as a safety concern by a site investigator
• Other clinical concerns as documented by a site investigator that could reasonably increase the risk of complications during or after surgical Ebstein repair
• Individual whose cells have been determined, by the sponsor, to not be acceptable for release to the investigational site or individual whose cells have been compromised after cells released to investigational site (cell treatment group only)
• Individuals who require surgery on pulmonary, mitral, or aortic valve
• Individuals with pulmonary atresia or atrioventricular discordance with ventriculoarterial discordance

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

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

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