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

Eligibility last updated 1/13/23. Questions regarding updates should be directed to the study team contact.

• Female age 21 or older.
• BMI < 30.
• Candidate for an NSM procedure with immediate reconstruction.
• Diagnosis of early stage brest cancer.
• Breast ptosis ≤ Grade 2.
• Cup size ≤ C.

• Previous breast surgery.
• Diagnosis of metastatic breast cancer.
• Prior radiation treatment to the chest.
• Current smokers.
• Contraindication for general anesthesia or surgery.
• Known bleeding or clotting disorder.
• Pregnant or suspected to be pregnant, or actively breastfeeding.

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

Eligibility last updated 5/9/23. Questions regarding updates should be directed to the study team contact.

• Participant must be ≥ 18 years at the time of screening.
• Documented TN CLL/SLL requiring treatment according to iwCLL guidelines 2018 (Hallek et al 2018).
• Adequate BM function independent of growth factor or platelet transfusion support within 2 weeks of screening initiation as follows, unless cytopenia is due to CLL/SLL:
  • Absolute neutrophil count ≥ 1.0 × 10^9 /L;
  • Platelet counts ≥ 30 × 10^9 /L; in cases of thrombocytopenia clearly due to CLL/SLL (per the discretion of the investigator), platelet count should be ≥ 10 × 10^9 /L.
• Estimated CrCL > 30 mL/min calculated according to Cockcroft-Gault (using actual body weight) or directly measured with 24-hour urine collection,.
• Males:  CrCL = Weight (kg) × (140 Age) (mL/min) 72 × serum creatinine (mg/dL).
• Females:  CrCL = Weight (kg) × (140 Age) × 0.85 (mL/min) 72 × serum creatinine (mg/dL).
• Adequate liver function, as indicated by a total bilirubin ≤ 1.5 × ULN, AST and ALT ≤ 3 × ULN value, unless directly attributable to the participant's CLL/SLL or to Gilbert's Syndrome (The ULN is based on institutional values).
• Eastern Cooperative Oncology Group Performance Status performance status 0 to 2 with no deterioration over the previous 2 weeks prior to baseline or day of first dosing.
• Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local patient privacy regulations).
• Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules and tablets without difficulty.

• As judged by the investigator, any evidence of past or current diseases that, in the investigator's opinion, makes it undesirable for the participant to participate in the study or that would jeopardize their safety or compliance with the protocol or would put the study at risk.
• Clinically significant cardiovascular disease, such as symptomatic arrhythmias, congestive heart failure, or myocardial infarction, within 6 months of screening or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification.
  • Note: Participants with controlled, asymptomatic atrial fibrillation can enroll in the study.
• Active bleeding or history of bleeding diathesis (e.g., hemophilia or von Willebrand disease).
• Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura.
• History of significant cerebrovascular disease/event, including stroke or intracranial hemorrhage, within 6 months before the first dose of study intervention.
• Child-Pugh B/C liver cirrhosis.
• History of prior or current malignancy (including but not limited to known CNS lymphoma/leukemia or known prolymphocytic leukemia or history of, or currently suspected, Richter's syndrome) that could affect compliance with the protocol or interpretation of results. Exceptions can be made for the following based on physician discretion:
  • Curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or carcinoma in situ of the prostate at any time prior to study;
  • Other cancers not specified above that have been curatively treated by surgery and/or radiation therapy from which the participant is disease-free for ≥ 3 years without further treatment.
• An individual organ system dysfunction limiting the ability to receive the study intervention or any other life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the participants' safety or interfere with the absorption, distribution, metabolism, or excretion of the study interventions (e.g., refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow the formulated product, previous significant bowel resection, or impaired resorption in the gastrointestinal tract).
• Known history of infection with HIV or any active significant infection (e.g., bacterial, viral, or fungal; including participants with positive cytomegalovirus DNA PCR).
• History of or ongoing confirmed PML.
• Serologic status reflecting active hepatitis B or C infection:
  • Participants who are anti-HBc positive and who are hepatitis B surface antigen (HBsAg) negative will need to have a negative PCR result before randomization and must be willing to undergo DNA PCR testing during the study. Those who are HbsAg-positive or hepatitis B PCR positive will be excluded;
  • Participants who are hepatitis C antibody positive will need to have a negative PCR result before randomization. Those who are hepatitis C PCR positive will be excluded.
• Any prior CLL/SLL-specific therapies, except prior rituximab if used for autoimmune cytopenias and not as anti-CLL/SLL treatment.
• Corticosteroid use > 20 mg within 1 week before the first dose of study intervention, except as indicated for other medical conditions, such as autoimmune cytopenias, inhaled steroid for asthma, topical steroid use, or as premedication for administration of study intervention or contrast. Participants requiring steroids at daily doses > 20 mg prednisone equivalent systemic exposure daily, or those who are administered steroids for leukemia control or white blood cell count lowering, are excluded. Of note, patients may receive corticosteroids as doses > 20 mg as per institutional standards for obinutuzumab pre-medication prior to C1D1.
• Prior radio- or toxin-conjugated antibody therapy.
• Prior allogeneic stem cell or autologous transplant.
• Known history of hypersensitivity or anaphylaxis to study intervention(s), including active product or excipient components.
• Requires treatment with a strong cytochrome CYP3A4 inhibitor/inducer. The use of strong CYP3A inhibitors within 1 week or strong CYP3A inducers within 3 weeks of the first dose of study drug is prohibited.
• Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (other anticoagulants allowed).
• Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).
  • Note: Participants receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study.
• Vaccination with live vaccines 28 days prior to registration for study screening.
• Major surgical procedure within 28 days of first dose of study intervention.
  • Note: If a participant had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study intervention.
• Concurrent participation in another therapeutic clinical trial. Use of investigational agents that interfere with the study intervention(s) within 28 days or 5 half-lives (whichever is shorter) prior to registration for study screening.
• Prothrombin time (PT)/INR or activated partial thromboplastin time, in the absence of lupus anticoagulant, > 2 × ULN.
• Currently pregnant (confirmed with positive pregnancy test) or breast feeding.
• Women of Childbearing Potential (WOCBP) a negative pregnancy test is required for all WOCBP within 21 days before start of study intervention, followed by immediate highly effective contraception; further pregnancy testing will be performed monthly).
• Fertile men or WOCBP unless the following criteria are met: Willing to use 2 methods of reliable contraception, including one highly effective contraceptive method (Pearl Index < 1) and one additional effective (barrier) method during study intervention and for 2 days after last acalabrutinib dose (for WOCBP), 30 days after last venetoclax dose (fertile men and WOCBP), and 6 months after last obinutuzumab dose for fertile men and 18 months after last obinutuzumab dose for WOCBP.

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

Eligibility last updated 1/18/23. Questions regarding updates should be directed to the study team contact.

• Two groups of adults will be tracked:
  • Adults who do not have chronic pain (control group); and
  • Adults who have had fibromyalgia greater than 6 months. The groups will be matched for age, body mass index, and sex.
• Men and women, 18-80 years of age.
• Non-obese class III (body mass index BMI ≤ 39.9 kg/m^2).

• Body mass index greater or equal to 40 kg/m^2.
• Current nicotine use (e.g., smoking, chewing tobacco, vaping, etc.).
• Significant metabolic (e.g., diabetes), cardiovascular (including stage II hypertension) or neurologic disease.
• Known skin allergies or disease, disorders of pigmentation, or rash; history of angioedema.
• Renal disease, renal artery stenosis, and/or renal impairment.
• Any current medications which could conceivably alter cardiovascular responses (e.g. antihypertension medication, diuretic, digoxin, CYP3A4 inhibitors, Lithium, etc.).
• Taking hormone replacement therapy.
• Women who are pregnant or breastfeeding.

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

Eligibility last updated 7/19/23. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria
•Patients:

• Adults ≥ 18 years.
• Have an appointment scheduled in primary care.

Inclusion Criteria
•Clinicians:

• Clinicians who meet with patients in primary care.

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

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

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

• Age ≥ 18 years.
• Diagnosis of primary liver diseases.
• Diagnosis of suspected portal hypertension.
• Patients undergoing endoscopy (EGD) exam; OR
• Patients undergoing follow-up EGD exams in compliance with the practice guideline and clinical indication; OR
• Patients undergoing transjugular hepatic venogram with hepatic venous pressure gradient (HVPG) measurement. 

• Age < 18 years.
• History of liver transplantation or hepatic resection
• History of splenectomy.
• Absolute contraindications to MRI, including pacemaker, AICD device, cochlear implant, VP shunt, aneurysm clip, a deep brain stimulator, and severe claustrophobia.
• Women who are pregnant or breastfeeding.
• Any severe medical condition that, in the opinion of the Principal Investigator, would serve as exclusion criteria for study enrollment.

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

Eligibility last updated 1/19/23. Questions regarding updates should be directed to the study team contact.

• Fluent in English (does not need an interpreter).
• Able to give consent for self.

• History of upper respiratory infection in the past month.
• Vocal surgery or surgery targeted at altering vocal symptoms such as recurrent laryngeal nerve denervation renervation, Type I-IV thyroplasty, or deep brain stimulator. 
• Botulinum toxin injection within 3 months (90days) of study enrollment.
• Congenital or acquired hearing loss to the degree testing process is impaired. 
• Subjects wearing hearing aids will be excluded from the speech in noise stressor task.
• Severe comorbidities such as major depressive disorder or neurodegenerative disease will be excluded.

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

Eligibility last updated 1/27/23. Questions regarding updates should be directed to the study team contact.

• ≥ 18 years of age.

• Coronary artery disease.
• Heart failure.
• Pregnancy.
• Diabetes.
• Sleep disorders.
• Shift workers.
• Individuals who typically go to sleep after midnight.
• Individuals who traveled across ≥2 time zones within one week of study visits.
• BMI ≥ 35.0kg/m^2.
• Use of nicotine-containing products within the two years preceding study visits.
• Use of allopurinol, proton pump inhibitors, or other medications/supplements which interfere with the nitrate-nitrite-nitric oxide pathway or outcome measures.

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

Eligibility last updated 1/24/23. Questions regarding updates should be directed to the study team contact.

• Males or females aged 18 to 65 years (inclusive).
• Clinical diagnosis of sAH based on all the following:
  • History of excess alcohol (> 60 g/day [male] or > 40 g/day [female]) use for ≥6 months, with < 60 days of abstinence prior to the onset of jaundice;
  • Serum total bilirubin > 3.0 mg/dL;
  • AST ≥ 50 U/L;
  • AST/ALT ratio ≥ 1.5;
  • Maddrey's Discriminant Factor (MDF) ≥ 32 and ≤ 60;
  • MELD-Na score 18 to 25 (inclusive).
• Onset of jaundice within 8 weeks from the time of admission to the hospital.
• Up to and not more than 7 days since admission to the hospital.
• Female subjects must be postmenopausal, surgically sterile, or, if premenopausal (and not surgically sterile), be prepared to use ≥1 highly effective method of contraception during the study and for 90 days after the last dose of investigational product as follows:
  • Surgical sterilization (bilateral tubal occlusion, etc.);
  • Placement of an intrauterine device (IUD) or intrauterine system (e.g.,  intrauterine hormone-releasing system [IUS]);
  • Combined (estrogen and progesterone containing) hormonal contraceptive associated with inhibition of ovulation:
    • Oral;
    • Intravaginal;
    • Transdermal.
  • Progesterone-only hormonal contraception associated with inhibition of ovulation:
    • Oral;
    • Injectable;
    • Implantable;
    • Sexual abstinence, if in line with the preferred and usual lifestyle of the subject (where true abstinence is defined as refraining from heterosexual contact intercourse during the entire period of risk associated with study treatments).
• Male subjects who are sexually active with female partners of childbearing potential must agree to use a condom with spermicide and to use one other approved method of highly effective contraception from the time of investigational product administration for at least 90 days after the dose of investigational product as listed in Inclusion Criteria #5.
• Male subjects must refrain from sperm donation from Screening through at least 90 days following the last dose of investigational product.
• Must provide written informed consent and agree to comply with the study protocol. In subjects with hepatic encephalopathy which may impair decision-making, consent will be obtained per hospital procedures (e.g., by Legally Authorized Representative).
• Subjects must agree to participate in an alcohol use disorder program during the study period, as recommended by the local institution's addiction medicine specialists, including post-hospitalization.

• Subjects taking systemic corticosteroids or products containing obeticholic acid in the 30 days prior to Screening, up to and including randomization.
• Pregnancy, planned pregnancy, potential for pregnancy (e.g., unwillingness to use effective birth control during the study), or current or planned breast feeding.
• Cessation of alcohol consumption for ≥2 months before Day 1.
• AST or ALT > 400 U/L.
• MDF < 32 or > 60 at Screening.
• MELD-Na score < 18 or > 25 at Screening (confirmed by repeat labs within 48 hours).
• Other causes of liver disease including chronic hepatitis B (hepatitis B surface antigen [HBsAg] positive), chronic hepatitis C virus (HCV) RNA positive, acetaminophen hepatotoxicity, biliary obstruction, and autoimmune liver disease.
• Current or previous history of hepatocellular carcinoma (HCC).
• History of liver transplantation or currently listed for liver transplant.
• Untreated sepsis (e.g., has not initiated appropriate medical treatment for infection and/or septic shock).
• Known positivity for human immunodeficiency virus infection.
• Uncontrolled gastrointestinal (GI) bleeding or controlled GI bleeding within 7 days of Screening that was associated with shock or required transfusion of more than 3 units of blood.
• Kidney injury defined as a serum creatinine >133 µmol/L (> 1.5 mg/dL) confirmed by repeat testing within 48 hours or the requirement for renal replacement therapy.
• Portal vein thrombosis.
• Acute pancreatitis or acute gallbladder disease (e.g., cholecystitis).
• Severe associated disease (e.g., cardiac failure, acute myocardial infarction, severe cardiac arrhythmias, severe pulmonary disease, neurologic disease).
• Malignancy within the 2 years prior to Screening, with the exception of specific cancers that have been cured by surgical resection (e.g., basal cell skin cancer).
• Subjects under evaluation for possible malignancy are not eligible.
• Positive urine drug screen (amphetamines, barbiturates, benzodiazepines, cocaine, and opiates) except tetrahydrocannabinol or in the setting of documented prescription medications (e.g., opiates, benzodiazepines, amphetamines, barbiturates), including medications prescribed as part of in-patient management. Subjects being treated for alcohol withdrawal may be exempt, if verified by the Medical Monitor..
• Participated in a clinical research study and received any active investigational product being evaluated for the treatment of sAH within 3 months before Day 1.
• Participation in a study of another investigational medicine or device within 30 days before Screening.
• Any other condition or clinical laboratory result that, in the opinion of the Investigator, might confound the results, or would impede compliance or hinder completion of the study.
• Received a positive Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) test result within 4 weeks of Screening or a SARS-CoV-2 vaccination within 2 weeks of Screening.

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

Eligibility last updated 1/24/23. Questions regarding updates should be directed to the study team contact.

• ≥ 18 years of age. 
• Brain tumor referrals for presurgical brain mapping with fMRI

• < 18 years of age.

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

Eligibility last updated 1/26/23. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria

• 18 years of age or older.
• Histologically or cytologically confirmed unresectable advanced, metastatic, or recurrent biliary tract cancers (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer, and ampullary carcinoma).
• Patients must have radiologically documented progression after a prior gemcitabine and platinum containing chemotherapy regimen as initial therapy for locally advanced or metastatic disease. Patients who relapse within 6 months of receiving gemcitabine and platinum containing chemotherapy regimen in the adjuvant setting are also eligible.
• At least one lesion measurable as defined by RECIST v1.1.
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
• Predicted life expectancy of at least 12 weeks.
• No evidence of ongoing infection and adequate biliary excretion or patients whose adequate biliary excretion can be confirmed with the following procedures:
  • Patients who underwent endoscopic retrograde biliary drainage (ERBD) at least 1 week before the investigational drug treatment;
  • Patients who underwent percutaneous transhepatic biliary drainage (PTBD) at least 4 weeks before the investigational drug treatment;
  • Patients free of any signs of active or suspected uncontrolled infection after a drainage procedure;
  • Patients free of any risk of hemorrhage and with incision completely healed.
• Adequate bone marrow, hepatic, and renal function within 14 days of randomization as described below. (Patient must be free of granulocyte colony-stimulating factor (G-CSF) treatment and blood transfusion within 14 days prior to the lab test):
  • Absolute neutrophil count (ANC) ≥ 1,500/mm^3;
  • Hemoglobin ≥ 9.0 g/dL;
  • Platelet count ≥ 100,000/mm^3;
  • White Blood Cell ≥ 3,000/mm^3;
  • Total bilirubin ≤ 1.5 X Upper Limit of Normal (ULN);
  • Aspartate aminotransferase (AST)/ alanine transaminase (ALT) ≤ 3.0 X ULN (≤ 5 X ULN in case of hepatic metastasis);
  • Estimated creatinine clearance ≥ 30 mL/min based on Cockcroft-Gault;
  • Urine protein ≤ 1+ by Dipstick (Only when urinalysis shows a protein dipstick result of > 1 positive (+), the total protein volume (< 1.0 g/24hr) can be confirmed with a 24-hour urine test.);
  • Serum amylase and lipase level ≤ 1.5 X ULN;
  • Serum Albumin ≥ 3.0 g/dL.
• Female patients who are women of childbearing potential (WCBP) must have a negative pregnancy test (serum-human chorionic gonadotropin (hCG) or urine-hCG performed at the Investigator's discretion) within 14 days of randomization.
• Female patients must be surgically sterile (or have a monogamous partner who is surgically sterile) or be at least 2 years postmenopausal or commit to use 2 acceptable forms of birth control (defined as the use of an intrauterine device (IUD), a barrier method with spermicide, condoms, any form of hormonal contraceptives, or abstinence) for the duration of the study and for 4 months following the las t dose ofstudy treatment. Male patients must be sterile (biologically or surgically) or commit to the use of a reliable method of birth control (condoms with spermicide) for the duration of the study and for 4 months following the last dose of study treatment.
• Signed and dated Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved Informed Consent Form (ICF) before any protocol-directed screening procedures are performed.

• Patients who are eligible to be treated with a molecularly targeted therapy on a labelled regimen after receiving first-line chemotherapy. Patients who received a molecularly targeted therapy as part of their first line treatment may be eligible, as determined by the Sponsor Medical Monitor.
• From the time point of screening.
• Less than 4 weeks have elapsed since patients had a surgery or major procedure.
• Less than 2 weeks have elapsed from the last treatment date since patients had any radiation therapy.
• Patients with percutaneous transhepatic biliary drains (PTBD).
• Prior to the initial treatment of study drug.
• Less than 2 weeks have elapsed since patients had chemotherapy or hormone therapy.
• Less than 2 weeks have elapsed since patients had anticancer immunotherapy or investigational drug treatment.
• Less than 4 weeks since cryotherapy, radiofrequency ablation, anhydrous alcohol therapy, or photodynamic therapy, including TACE and TARE.
• A history of the following cardiovascular diseases (please, consult the Sponsor Medical Monitor for a case by case evaluation):
  • Congestive heart failure (CHF) that corresponds to Class II or a higher class under New York Heart Association (NYHA) classification, or less than 50% of left ventricular ejection fraction (LVEF);
  • Uncontrolled hypertension (SBP/DBP > 140/90 mmHg) (e.g., patient with SBP/DBP > 140/90 mmHg despite the best care including optimizing the anti-hypertensive medication regimen);
  • Patients with any history of hypertensive crisis or pre-existing hypertensive encephalopathy;
  • Pulmonary hypertension;
  • Myocardial infarction;
  • Uncontrolled arrhythmia;
  • Unstable angina;
  • Patients with any significant vascular diseases (e.g., aortic aneurysm requiring surgery or recent peripheral artery thrombosis) within 6 months prior to the initial treatment of the investigational product.
• History of hypersensitivity reactions to any components of the investigational product or other drugs of the same class (humanized/human monoclonal antibody drugs) or paclitaxel.
• Patients with contraindications to paclitaxel therapy.
• Patients with persistent, clinically significant toxicities (excluding hair loss) from previous anticancer treatment that corresponds to Grade 2 or a higher grade under NCI-CTCAE v5.0.
• Symptomatic or uncontrolled central nervous system (CNS) metastasis (However, patients with asymptomatic CNS metastasis that have been treated with either surgery or radiation can participate provided that systemic corticosteroid treatment was discontinued at least 4 weeks prior to screening and that the patient is radiologically and neurologically stable or improving).
• A history of the following hemorrhage-related or gastroenterological disease:
  • Active hemorrhage, hemorrhagic diathesis, coagulopathy or tumor in great arteries.
  • History of clinically significant gastroenterological disease, such as peptic ulcer, GI bleeding, GI or non-GI fistula, perforation, abdominal abscess, clinical symptoms, and signs of GI obstruction, need for parenteral hydration or nutrition, or inflammatory bowel disease (IBD).
  • Current or recent (within 10 days prior to study treatment) use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic) purpose will be excluded.
• Prophylactic (i.e., for the patency of venous access devices) use of low molecular weight heparin (i.e., enoxaparin 40 mg/day) is allowed if patient has INR < 2 or aPTT </=2x ULN within 14 days of study treatment.
• Patients with current or recent (within 10 days of study treatment) use of aspirin (>81 mg/day), or other nonsteroidal anti-inflammatory drugs (NSAIDs), or other antiplatelets (i.e., dipyramidole, ticlopidine, clopidogrel, and cilostazol) will be excluded.
• Severe infection requiring ongoing systemic antibiotics, antivirus drugs, etc., or other uncontrolled acute active infectious diseases.
• Patients with evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Patients with positive HBsAg and/or detectable HBV DNA are eligible only if adequately controlled on antiviral therapy according to institutional standards and liver function eligibility criteria are also met. HCV patients showing sustained viral response or patients with immunity to HBV infection may enroll.
• Patients with other severe diseases or uncontrolled illnesses that warrant the exclusion from the study (permitted only if medically controlled) including but not limited to:
  • Pre-existing hemoptysis (≥ 1/2 teaspoon of bright red blood per episode) within 28 days prior to screening;
  • Major, unhealed injury, active ulcer, or untreated fracture;
  • Pre-existing conditions of cerebrovascular incident (ischemic or hemorrhagic stroke), transient ischemic attack or subarachnoid hemorrhage within 6 months prior to screening;
  • Moderate to severe ascites and/or pleural effusion. However, enrollment is permitted for patients with ascitic fluid as long as paracentesis is not required to improve the condition;
  • Interstitial lung disease or pulmonary fibrosis;
  • Patients expected to require anticancer treatment other than the investigational product during the clinical study.
• Pregnant or lactating patients, or patients planning to become pregnant during the clinical study.
• A history of primary malignancy other than BTC will be excluded, except for malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate >90%). Prior malignancy history will be evaluated on a case-by-case basis by the Sponsor Medical Monitor.
• Clinically significant abnormal ECG findings or history determined as clinically significant by the Investigator.
• QT interval (Fridericia's formula) (QTcF) interval > 450 msec at the time of screening.

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

Eligibility last updated 9/26/23. Questions regarding updates should be directed to the study team contact.

• ≥ 18 years of age.
• No additional confounding cardiorespiratory, metabolic, or musculoskeletal conditions.   
• All inclusion criteria will be at the discretion of the principal investigator.

• < 18 years of age.

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

Eligibility last updated 1/31/23. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria:

• Patients age ≥ 18 years.
• Patients who previously underwent a total laryngectomy or tracheostomy by an Otorhinolaryngology-Head and Neck Surgery department provider at Mayo Clinic Rochester [VAKM(M3] between January 1st, 1950 – present.
• Patients who plan to undergo a total laryngectomy or tracheostomy by an Otorhinolaryngology-Head and Neck Surgery department provider at Mayo Clinic Rochester.
• Patients with capacity to consent to the study.

Exclusion criteria:

• Patients who declined Minnesota research authorization for the retrospective patient identification.

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

Eligibility last updated 1/31/23. Questions regarding updates should be directed to the study team contact.

• Candidate on the kidney transplant waiting list for more than 3 months..
• 18 years of age or older.
• English-speaking.

• Non-English speaking.
• < 18 years of age.
• Patients who choose to opt out of research.
• Unable to provide informed consent.

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

Eligibility last updated 2/6/23. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years old at time of screening.
• Currently resides in the U.S. or Canada with the ability to complete in-person study visits at one of the participating clinical sites.
• Clinical diagnosis, based on investigator assessment, of type 2 diabetes of at least 6 months duration at time of screening.
• Using basal-bolus insulin therapy with at least one injection containing rapid-acting insulin per day or an insulin pump for at least 3 months prior to enrollment, with no major modification to insulin regime in the last 3 months (mixed insulin with a rapid component is acceptable).
• If using noninsulin glucose-lowering medications (such as GLP-1 receptor agonist, SGLT2 inhibitor, or other) or weight-reduction medications, dose has been stable for the 3 months prior to screening; and participant is willing to not change the dose unless required for safety purposes.
• Participant willing to not initiate use of any new glucose-lowering medications during the trial.
• Willing to use an approved insulin while using the study pump if assigned to the AID group.
• Willing to not use concentrated insulin above U-100 or inhaled insulin while using the study pump.
• Willing to participate in the study meal and exercise challenges if assigned to the AID group, and have a care partner, trained in hypoglycemia treatment guidelines, to include glucagon use, present during and immediately after the exercise challenges.
• Has the ability to read and understand written English.
• Investigator believes that the participant has the cognitive capacity to provide informed consent.
• Investigator believes that the participant can successfully and safely operate all study devices and is capable of adhering to the protocol and completing the study.
• No medical, psychiatric, or other conditions, or medications being taken that in the investigator's judgement would be a safety concern for participation in the study.  This includes considering the potential impact of medical conditions known to be present including cardiovascular, liver, kidney disease, thyroid disease, adrenal disease, malignancies, vision difficulties, active proliferative retinopathy, and other medical conditions; psychiatric conditions including eating disorders; drug or alcohol abuse.
• Participants capable of becoming pregnant must meet one of the following criteria:
  • has a negative urine pregnancy test and agrees to use one of the accepted contraceptive regimens throughout the entire duration of the trial from screening until last follow-up visit. The following contraceptive measures are considered adequate:
  • Combined estrogen and progestogen containing hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal);
  • Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable);
  • Placement of an intrauterine device or intrauterine hormone-releasing system;
  • Bilateral tubal occlusion;
  • Barrier methods of contraception (condom or occlusive cap with spermicidal foam/gel/film/cream/suppository);
  • Has a vasectomized or sterile partner (where partner is sole partner of subject) and where vasectomy has been confirmed by medical assessment; 
  • Exercises true sexual abstinence. Sexual abstinence is defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject; or
  • Participant is of non-childbearing potential due to menopause with at least one year since last menses or a medical condition confirmed by the investigator.

• Current use of hybrid closed-loop system.
• Current use of systemic glucocorticoids or anticipated use of glucocorticoids during the RCT (topical or inhaled -ie, non-systemic is acceptable).
• Current use of sulfonylurea or meglitinide medications.
• Current use of hydroxyurea.
• Tape allergy or skin condition that will preclude use of the study pump or CGM.
• Presence of a hemoglobinopathy or other condition that is expected to affect the measurement of HbA1c.
• Pregnant (positive urine hCG), breast feeding, plan to become pregnant in the next 2 months, or sexually active without use of contraception.
• Current participation in another diabetes-related interventional clinical trial.
• Anticipated change of residency or travel for more than 7 days at a time during the study that may, per investigator judgment, interfere with the completion of study visits, contacts, or procedures.
• Immediate family member (spouse, biological or legal guardian, child, sibling, parent) who is an investigative site personnel directly affiliated with this study or who is an employee of Tandem Diabetes Care, Inc.

Eligibility last updated 5/2/23. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 2/7/23. Questions regarding updates should be directed to the study team contact.

• Routine coronary angiography.
• Age ≥ 18 years.

• < 18 years of age.

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

Eligibility last updated 9/22/23. Questions regarding updates should be directed to the study team contact.

• Renal function at screening:
• Creatinine clearance: < 50 mL/min as determined using the Cockcroft-Gault formula; 
• Albumin: < LLN;
• Hepatic function at screening: AST and/or ALT: > 2.5 x ULN;
• Total Bilirubin (serum): >1.5 x ULN.

4. Subject has received neo-adjuvant therapy, radiation therapy, focal ablation therapy, hormonal therapy, or androgen deprivation therapy within the last 4 months.

5. Subject is currently receiving an investigational therapeutic agent; or has participated in a study of an investigational therapeutic agent within the past 6 months prior to the day of IS-002 infusion; or is involved in a significant risk
investigational device study within the past 6 months prior to the day of IS-002 infusion.

6. Subject has any other condition or personal circumstance that, in the judgment of the site Investigator, might interfere with the collection of complete quality data or represents an unacceptable safety profile.

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

Eligibility last updated 9/28/23. Questions regarding updates should be directed to the study team contact.

• Male and female patients ≥ 12 and ≤ 20 years of age at informed consent signature.
• Total SARA score ≥ 1 at Baseline.

GM2:

• Genetically and biochemically confirmed diagnosis of Tay-Sachs or Sandhoff disease NA.

NP-C:

• Genetically confirmed diagnosis of NP-C;
• Miglustat-naïve patients unwilling or unable to take miglustat, OR, Patients who have discontinued miglustat because of confirmed gastrointestinal safety/tolerability issues. Miglustat must have been discontinued at least 1 month prior to Baseline visit.

• A male participant with a female partner of childbearing potential is eligible if he agrees to follow the contraceptive guidance.
• If a female participant is a WOCBP and is having a male partner, she must agree to follow the contraceptive guidance.
• Willing and able to complete protocol assessments.
• Parent and/or legal guardian is able to read, understand, and sign the informed consent. Where appropriate, assent will also be sought for patients who have not reached the age of majority or who are not able to sign the consent form. A consent maybe be sought for patients who have reached the age of majority (PI decision). No genetic test will be done as part of the study.

• Any abnormal conditions at baseline visit which in the opinion of the PI could interfere with study assessments (e.g., severe infection).
• History of medical conditions other than GM2 gangliosidosis/NP-C that in the opinion of the PI would confound scientific rigor or interpretation of results.
• Presence of another inherited neurologic disease.
• The dose of anti-epileptic treatment(s) was not stable and/or a new anti-epileptic treatment (drug or procedure) was prescribed during the last month before baseline.
• Patient with Gilbert syndrome and/or total bilirubin > 2 x ULN (isolated bilirubin > 2 x ULN is acceptable if bilirubin is fractionated and direct bilirubin is < 35%).
• Platelet count < 100 x 10^9 /L.
• Presence of moderate or severe renal impairment (estimated GFR < 60 mL/min/1.73 m^2 )
• Prior participation in a clinical study with an investigational drug within 3 months prior to Baseline.
• Patient with a positive serum pregnancy test (tested only for women of childbearing potential) at baseline.
• Breast feeding ongoing at baseline or planned during the study.
• ECG with an average of triplicate QTcF interval > 440 msec.
• Received treatment with enantiomers of N-Acetyl-Leucine, gene therapy, stem cell transplantation, or with any other azasugars (iminosugars) compound with similar mechanism of action within 3 months before baseline (except for miglustat for which it is 1 month).
• Any known allergy to azasugars or any excipients.
• Evidence of suicidal ideation with intent (Type 4-5) on the Columbia Suicide Severity Rating Scale (C-SSRS) at Screening. Only in patients judged by the PI cognitively capable to understand the concept of suicide.

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

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

Inclusion Criteria
•Progressive Multiple Sclerosis: 

• PPMS or SPMS according to the 2017 revised McDonald criteria.
• Age ≥ 18 years.
• Have 1 year or more of disease progression plus two of the following criteria:
  • Time from first reported symptoms of 2–10 years before study entry;
  • Evidence of disability progression documented by an increase in EDSS score of 0.5 points or more in the past 2 years;
  • Objective evidence of disability measured by EDSS score of 3.5 – 6;
  • Pyramidal functional system score of 2 or more.
• A timed 25-foot walk of less than 30 minutes.
• Agree to undergo lumbar puncture and skin biopsy.

Inclusion Criteria
•Paraneoplastic CNS Disorders:

• Diagnosed with definite or probable paraneoplastic syndrome according to PNS-Care criteria or immune mediated progressive gait disorder occurring in the absence of cancer.
• Age > 18 years.
• Gait disorder is mainly contributed by paraneoplastic CNS disorder.
• Onset within 6 months.
• A timed 25-foot walk of less than 30 minutes.
• Agree to undergo lumbar puncture and skin biopsy.

Exclusion Criteria
•Progressive Multiple Sclerosis:

• Gait impairment from other conditions (e.g., orthopedic disorders, diabetic neuropathy).
• BMI > 40 kg/m^2 – (difficult LP and gait limitation from obesity).
• Claustrophobic – unable to have annual MRI.

Exclusion Criteria
•Paraneoplastic CNS Disorders:

• Gait impairment is mainly contributed by peripheral nervous system involvement or severe encephalopathy.
• Gait impairment from other conditions (e.g., cancer, orthopedic disorders, diabetic neuropathy).
• BMI > 40 kg/m^2 – (difficult LP and gait limitation from obesity).
• Claustrophobic – unable to have annual MRI.

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

Eligibility last updated 7/3/23. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years.
• Histological confirmation of esophageal or gastroesophageal junction adenocarcinoma, AJCC 8th ed stage T1-4N0-3M0.
• Candidate for trimodality therapy: neoadjuvant chemotherapy and esophagectomy.
• Surgical consultation to confirm that patient is an appropriate candidate for esophagectomy.
• Medical oncology consultation to confirm that patient is an appropriate candidate for chemotherapy.
• ECOG Performance Status (PS) ≤ 1.
• Negative pregnancy test done ≤ 7 days prior to chemotherapy, for women of childbearing potential only.
• Ability to provide written informed consent and complete questionnaire(s) by themselves or with assistance.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study) and provide blood samples for correlative research purposes.

• Clinical or biopsy-proven distant metastatic disease (AJCC 8th ed stage TanyNanyM1).
• Cervical or upper esophageal tumor.
• Prior chemotherapy or radiotherapy for esophageal cancer OR history of radiotherapy to the thorax.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgement of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with proper assessment of adverse events.
• Receiving any investigational agent which would be considered as a treatment for the primary neoplasm OR other active malignancy ≤ 1 year prior to registration that is considered by the investigator to interfere with the current treatment or measurement of outcomes.
• Any of the following:
  • Pregnant women;
  • Nursing women;
  • Men or women of childbearing potential who are unwilling to employ adequate contraception.

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

Eligibility last updated 11/20/23. Questions regarding updates should be directed to the study team contact.

• Patients presenting to the catheterization laboratory to undergo non-emergent cardiac catheterization procedures including coronary angiography, percutaneous coronary intervention, right heart cath, ablation, myocardial biopsy.
• Adult patients (18 years old or older).
• Patient willing and able to give informed consent.

• Emergent procedure.
• ST elevation > 1 mm on any two contiguous ECG leads.
• Hemodynamic instability (SBP > 220 or < 80, HR > 160).
• Patients < 18 years old (children).
• Patients known or suspected to be pregnant.
• Incarcerated patients (FMC patients).
• Patients with a pacemaker or defibrillator.
• Metal implants in the body (that are not MRI safe).
• Patients that are unable to lie down in the MCG machine or stay still.
• Patients who are unable to understand the informed consent process (ex: non-English speakers without an available interpreter, cognitive delay).
• Patients without the capacity to provide written informed consent.

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

Eligibility last updated 2/17/23. Questions regarding updates should be directed to the study team contact.

• Self-identify as Hispanic, Latino/a/x/e, or Chicano/a/x.
• For breast cancer screening: age 50-74 years; for cervical cancer screening: age 21-65 years; for colorectal cancer screening: age 45-75 year.
• Receive primary care at either HH or MPHC.
• At least one office visit within the previous 12 months to the primary care site.
• Eligibility for breast, cervical, or colorectal cancer screening documented in the electronic medical record (EMR).
• Intention to continue to receive medical care at HH or MPCHC for the next three months.
• If a potential participant is eligible for more than one screening, they will be given the option of participating in multiple versions of the intervention.

Exclusion Criteria: 

• Individuals with previous breast, cervical, or colorectal cancer diagnoses.
• For the participants in the colorectal cancer screening intervention, those under surveillance (i.e., did not have a cancer diagnosis but did have polyps) will also be excluded.

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

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

• ≥ 50 years of age; with life expectancy of ≥ 10 years.
• 20-80 cc prostate size measured by MRI.
• ≤ 15 ng/ml PSA.
• Cancer stage less than or equal to T2c.
• Within 6 months of signing consent, have undergone a multiparametric MRI software guided fusion biopsy of the prostate (transrectal or transperineal). This must include a standard sector biopsy obtaining 12-16 cores.
• ≤ 15mm diameter of lesion as measure by greatest diameter.
• Subject is willing and able to adhere to specific protocol visits and required testing throughout study.
• Is geographically stable and near the site or able and willing to travel back to site for follow-up visits involving diagnostic tests or treatment.
• Able and willing to provide written consent to participate in the study.

• MRI evidence of extracapsular extension of cancer (MRI read as "definite", "frank" or "gross" ECE).
• Contraindications to MRI.
• Subjects with an installed pacemaker or other potentially electrically conductive implants implanted within 200mm (8 inches) of the procedure area. Implants that are within 200mm (8 inches) and can be turned off for the duration of the study procedure are acceptable.
• Any prior surgery, intervention, or minimally invasive therapy, (MIST) for the prostate cancer or bladder neck.
• Previous treatment for genital cancer.
• Presence of any urethral or prostatic condition that precludes water vapor ablation per Instructions for Use.
• Currently taking medications that have hormonal effects on the prostate or PSA, such as: 5 alpha reductase inhibitors (if on for <6 months), Androgen blockers, Luteinizing hormone-releasing hormone (LHRH) agonists or antagonists (12 month wash-out), or Testosterone supplementation.
• Active urinary tract infection.
• Active or clinically chronic prostatitis or granulomatous prostatitis.
• Active lower and upper urinary tract malignancy (excluding prostate cancer meeting the inclusion criteria).
• Any rectal pathology, anomaly or previous treatment that could change properties of rectal wall or insertion and use of TRUS.
• Unable to stop taking antiplatelet medications or other blood thinning agents.
• Known allergy to nickel.
• Alergic to medication required by the study such as MRI contrast or anesthesia.
• Any significant medical history that would pose an unreasonable risk or make the subject unsuitable for the study.
• Any cognitive or psychiatric condition that interferes with or precludes direct and accurate communication with the study Investigator regarding the study or affects the ability to complete the study quality of life questionnaires.
• Subject currently participating in other premarket investigational studies unless approved by Sponsor in writing.
• Subject is considered vulnerable such as incarcerated or cognitively impaired.

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

Eligibility last updated 2//2203. Questions regarding updates should be directed to the study team contact.

Sequelae Group

• Age ≥18 years at screening, PCR confirmed COVID19 illness (+PCR defines day 0 of illness), hospitalization for COVID-19, absence of pre-existing history of interstitial lung disease, or significant other lung disease.
• Severity of illness will be categorized as moderate disease (supplemental oxygen need 1-8L at any time during hospitalization), severe disease (need for high flow oxygen delivery ≥ 8L at any time during hospitalization) and critical illness (need for ICU admission or mechanical ventilation).

Control Recovery Group

• Age ≥ 18 years at screening.
• PCR confirmed COVID-19 cases who had nonsymptomatic or mild acute infection that do not require hospitalization.
• Absence of pre-existing history of interstitial lung disease, or significant other lung disease, absence of any ongoing respiratory and systemic symptoms.

• Inability to provide informed consent, evidence of pre-existing interstitial lung disease or chronic lung disease.
• Active cigarette smoking, vaping or other inhalation use.
• Immunocompromised host status due to ongoing therapy with methotrexate CellCept, azathioprine, rituximab, cyclophosphamide or other biologic agents.
• > 20 pack year smoking history.
• history of chemotherapy or radiation therapy in the last two years; and pregnancy.

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

Eligibility last updated 2/20/23. Questions regarding updates should be directed to the study team contact.

• ≥  18 years of age.  
• Capacity to consent.
• BMI ≤ 30.
• Systolic BP ≤ 140mmHg.
• Diastolic BP ≤ 90.
• eGFR > 30 (within prior 3 months).
• Able to undergo an MRI.

• History of Cardiovascular disease that may affect the results of the testing performed.
•  Any Current orthopedic limitations.
• Currently taking any cardiac medication.
• Pregnancy.

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

Eligibility last updated 2/21/23. Questions regarding updates should be directed to the study team contact.

• Satisfactory completion of Treatment Period and the End of Treatment Visit of the Index Study (ION-682884-CS2) OR diagnosis of ATTR-CM and satisfactory participation on ISIS 420915- CS101 study as judged by the Investigator and Sponsor.
• Investigator is willing to treat the participant with open-label eplontersen.
• Willingness to adhere to vitamin A supplementation per protocol.

• Permanently discontinued study drug administration while participating in the Index Study (ION 682884-CS2) or IST (ISIS 420915-CS101 Study).
• Have any new condition or worsening of an existing condition that in the opinion of the Investigator or Sponsor would make the participant unsuitable for enrolment, or which could interfere with the participant participating in or completing the study, including the need for treatment with medications disallowed in the Index Study. 

Eligibility last updated 5/25/23.   Questions regarding updates should be directed to the study team contact.

• Fifteen obese (BMI 30-50 kg/m2) older (65-85 years) adults.
• 15 normal weight (BMI 18.5-28 kg/m^2) older adults.
• 15 obese young adults (18-35 years).
• 15 normal weight young adults will be recruited.
• Participants will be weight-stable (≥ 3 months).
• Sedentary men and women.

• Participation in ≥ 30 minutes of structured physical activity ≥ 2 days per week.
• Smoking/tobacco use.
• Alcohol/substance abuse.
• Pregnancy and breastfeeding.
• Anemia.
• Abnormal renal function.
• Blood clotting disorders.
• Coronary artery disease.
• Uncontrolled thyroid disease.
• Liver disease.
• Use of medications known to influence the main outcomes of the study.
• Orthopedic problems that may be aggravated by exercise.
• Chronic disease at the discretion of the investigators.

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

Eligibility last updated 8/16/23. Questions regarding updates should be directed to the study team contact.

• Subject ≥ 18 years of age.
• The patient has medical conditions requiring esophageal reconstruction, such as, but not limited to: 
  • Refractory benign esophageal strictures (RBES);
  • Esophageal perforation (full thickness);
  • Chronic/persistent esophageal fistula;
  • Combination of esophageal perforations/fistula with RBES;
  • The patient must have failed at least 3 previous treatment modalities to correct the medical esophageal condition (a-d).
• If RBES:
  • Steroid treatment;
  • Esophageal balloon dilation (EBD);
  • Stent use > 6 months;
  • Endoscopic incisional repair.
• If esophageal perforation:
  • Fibrin glue;
  • Endoscopic clips and/or suturing;
  • Stent > 6 months;
  • Primary surgical repair.
• If Chronic/Persistent fistula(e):
  • Fibrin glue;
  • Endoscopic clips and/or suturing;
  • Stent > 6 months;
  • Primary surgical repair.
• If Combination Perforation/fistula with RBES:
  • Fibrin glue;
  • Endoscopic clips and/or suturing;
  • Stent use > 6 months;
  • Primary surgical repair. 
• The patient must be a surgical candidate for a short segment esophageal reconstruction (< 6 cm full circumferential segmental excision).
• The location of the esophageal segment for surgical resection is within the thoracic cavity, defined as, at least 4 cm above gastroesophageal junction (GEJ) and at least 4 cm below the larynx.
• Patient must be a high-risk candidate for minimally invasive esophageal reconstruction, based upon the investigator's determination (for example, laparoscopic gastric pull-up (GPU) is not an option due to a medical contraindication).
• All patients must be made aware and must be amenable to a delayed rescue repair surgical procedure in the event the CEI fails to restore a patent durable biologic esophageal conduit.

• Pre-existing implants/structures adjacent to target surgical location for implant that could cause abrasion of the scaffold/regenerated tissue (e.g., pacemaker lead, vascular clips, vascular grafts).
• Known clinical contraindication that would obfuscate the use of the covered metallic stent to be used as an adjunct to the procedure
• Post ablation stricture for Barrett's esophagus treated less than 1 year prior to planned procedure
• Patient has a comorbidity or contraindication that would preclude any study required procedures including adipose tissue biopsy and esophageal resection surgery.
• Comorbidities are defined from a subset of the Charlson Comorbidities Index (CCI, Yamashita 2018) scoring system and include:
  • diabetes mellitus (CCI = 1);
  • connective tissue disorders (CCI = 1);
  • immune compromised;
  • chemotherapy (within 60 day clearance);
  • inability to tolerate major thoracotomy;
  • active infection at the biopsy or thoracotomy incision site;
  • peripheral vascular disease (CCI = 1);
  • all patients with a CCI > 2.
• Life expectancy of less than 1 year.

Eligibility last updated 6/20/23. 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.