• Ulnar nerve injuries:
  • High ulnar nerve traumatic injuries: proximal to the junction of the proximal and middle thirds of the forearm;
  • Severe compression injuries: intrinsic muscle weakness and atrophy.
• Treated with anterior interosseous to ulnar motor branch nerve transfer performed at Mayo Clinic.
• More than 1 year follow-up.

Exclusion Criteria: 

• Nerve transfer performed at a different hospital.
• Insufficient follow up and data.

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

Eligibility last updated 12/9/22. Questions regarding updates should be directed to the study team contact.

• Moderate or severe tricuspid valve regurgitation of primary or secondary etiology.
• Subject is adequately treated with medical therapy for heart failure 30 days prior to index procedure, including a diuretic.
• Heart Team determines patient is a recommended candidate for the VDyne System.
• Age 18 years or older.
• Clinical Screening Committee (CSC) and Imaging Core Labs confirm suitability for
• treatment with the VDyne System.

• Patient anatomy (cardiac and vascular) is not suitable for the VDyne System as assessed by Imaging Core Labs.
• Intolerance to procedural anticoagulation or post-procedural antiplatelet/anticoagulation regimen that cannot be medically managed.
• Hypersensitivity to nickel or titanium.

Clinical Exclusion Criteria (assessed by pre-procedural imaging):

• Left Ventricular Ejection Fraction (LVEF) < 30%.
• Severe RV dysfunction.
• Significant abnormalities of the tricuspid valve and sub-valvular apparatus.
• Sepsis including active infective endocarditis (IE) (within last 6 months).
• Right ventricular or atrial thrombus or vegetation.
• Severe tricuspid annular or leaflets calcification.
• Systolic pulmonary hypertension with systolic pulmonary artery pressure ≥70 mmHg.

CONCOMITANT PROCEDURES

• Significant coronary artery disease requiring treatment such as symptomatic, unresolved multi-vessel or unprotected left main coronary artery disease.
• Any planned surgery or interventional procedure within the period of 30 days prior to 30 days following the implant procedure. This includes any planned concomitant cardiovascular procedure such as CABG, PCI, pulmonary vein ablation, left atrial appendage occlusion, septal defect repair, etc.
• Unresolved severe symptomatic carotid stenosis (> 70% by ultrasound).
• Cardiac resynchronization therapy device or implantable pulse generator implanted within 60 days of planned implant procedure.
• Permanent pacing leads that will interfere with delivery or implantation of the VDyne Valve.
• Cardiogenic shock or hemodynamic instability requiring inotropes or mechanical support devices at the time of planned implant procedure.
• Prior tricuspid valve surgery or catheter-based therapy with permanent residual devices implanted that would preclude delivery or implantation of the VDyne Valve (e.g., valve replacement, edge to edge repair).
• Severe valvular heart disease requiring intervention other than the tricuspid valve.
• Known significant intracardiac shunt (e.g., septal defect) (PFO's without significant shunts are allowed).

COMORBIDITIES

• Cerebrovascular accident (stroke, TIA) within 6 months of treatment procedure.
• Severe lung disease (severe COPD or continuous use of home oxygen or oral steroids).
• Acute myocardial infarction (AMI) within 30 days.
• Significant renal dysfunction (eGFR<30 ml/min/1.73m^2) or on dialysis.
• End-stage liver disease (MELD > 11 / CHILD class C).
• Bleeding requiring transfusion within 30 days.
• Coagulopathy or other clotting disorder that cannot be medically managed.
• Chronic immunosuppression or other condition that could impair healing response.
• Any of the following: leukopenia, chronic anemia (Hgb < 9), thrombocytopenia, history of bleeding diathesis, or coagulopathy
• Unwilling to receive blood products.

General

• Known hypersensitivity or contraindication to procedural or post-procedural medications (e.g., contrast solution) which cannot be adequately managed medically.
• Life expectancy less than 12 months due to non-cardiac comorbidities.
• Treatment is not expected to provide benefit (futile).
• Current IV Drug user (must be free drug abuse for > 1 year).
• Pregnant, lactating or planning pregnancy within next 12 months. (female of child-bearing potential use two reliable contraceptive methods during the study -hormonal methods such as pill and condom).
• Vulnerable patient groups (minors, cognitively impaired persons, prisoners, persons whose willingness to volunteer could be unduly influenced by the expectation of benefits associated with participation or of retaliatory response from senior members of a hierarchy in case of refusal to participate, such as students, residents, and employees).
• Currently participating in an investigational drug or device trial that has not reached its primary endpoint or is likely to interfere with this study.
• Patient (or legal guardian) unable or unwilling to provide written informed consent before study-specific procedures are conducted.
• Patient unable or unwilling to comply with study required testing and follow-up visits.

Eligibility last updated 4/14/23. Questions regarding updates should be directed to the study team contact.

• Assenting adolescents (13-17 years).
• Consenting adolescents (18-21 years).
• Parent / legal guardian of assenting or  consenting adolescent.
• Ability to participate in remote study visits, if applicable.

• Individuals who do not meet inclusion criteria.
• Those who do not communicate in English.
• Individuals with developmental disabilities that interfere with their ability to make independent decisions.
• Participants whose permanent address is more than 100 miles from Cincinnati Children's Hospital Medical Center.

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

Eligibility last updated 5/11/23. Questions regarding updates should be directed to the study team contact.

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

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

• Able to read English fluently.
• Can consent for themselves.
• Age 18 years or older.
• Diagnosis of vestibular schwannoma (also called acoustic neuroma).
• Prior enrollment in IRB protocol 21-003059.

• Lack of capacity to consent since enrollment in IRB protocol 21-003059.
• Unable to participate in an interview by Zoom.

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

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

• Age ≥ 18 years.
• Diagnosis of AML, HR-MDS, or high marrow blast MDS/MPN (including CMML).
• Prior treatment history must include 1-4 prior lines of therapy.
• Adequate organ function evidenced by the following laboratory values:
  • Creatinine clearance (CL) ≥ 60 mL/min;
  • Total serum bilirubin < 1.5 × upper limit of normal (ULN);
  • Alanine aminotransferase (ALT) ;
  • Aspartate aminotransferase(AST) < 2.5 × ULN;
  • White blood cell count at the time of the first dose < 10 k/µL.
• Eastern Cooperative Oncology Group performance status ≤ 2.
• Female patients of childbearing potential must have a negative pregnancy test within 7 days before study treatment initiation and if sexually active, agree to use a highly effective form of contraception throughout their participation during study treatment and up to 4 months after the last dose of study drug
• Male patients with female partners of childbearing potential must, even if surgically sterilized, agree to practice effective barrier contraception during the entire study treatment period and through four months after the last dose of study drug, or practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant.

• Diagnosis of acute promyelocytic leukemia.
• Isolated extramedullary relapse (phase 2 only).
• Active central nervous system (CNS) leukemia.
• History of other malignancy.
• Any of the following cardiopulmonary abnormalities:
  • Myocardial infarction within six months prior to registration;
  • New York Heart Association Class III or IV heart failure or known left ventricular ejection fraction < 50%;
  • A history of familial long QT syndrome;
  • Symptomatic atrial or ventricular arrhythmias not controlled by medications;
  • QTcF ≥ 470 msec calculated according to institutional guidelines, unless due to underlying bundle branch block and/or pacemaker and with approval of the medical monitor;
  • Known moderate to severe and clinically significant chronic obstructive pulmonary disease, interstitial lung disease and/or pulmonary fibrosis (e.g., requiring home oxygen therapy).
• Pregnancy and/or lactation.
• Major surgery (excluding placement of vascular access) within 4 weeks prior to first dose of CTX-712.
• History of allogeneic organ transplantation (excluding cornea).
• History of allogenic hematopoietic stem cell transplantation within 6 months of planned study treatment initiation and/or graft-versus host disease grade ≥ 1 following allogenic hematopoietic stem cell transplantation.
• History of or chimeric antigen receptor T-cell therapy or other modified T cell therapy.
• Active, uncontrolled bacterial, fungal, or viral infection, including hepatitis B virus, hepatitis C virus, known human immunodeficiency virus, or acquired immunodeficiency syndrome related illness. Infections controlled with oral anti-infective agents, including prophylactic treatments, are allowed. Patient must be viral load negative.
• Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol.

Eligibility last updated 4/12/23. Questions regarding updates should be directed to the study team contact.

• Healthy male and female volunteers ≥ 18 years of age.
• Patients diagnosed with irritable bowel syndrome (IBS) ≥ 18 years of age.
• Patients with risk of developing POI or with clinical diagnosis ≥ 18 years of age.
• Patients with evidence of partial bowel obstruction ≥ 18 years of age.

• Inability or unwillingness to participate in study.
• Age ≤ 17 years old.

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

Eligibility last updated 12/19/22. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria
•Patient Enrollment:

- 6 months to < 22 years at enrollment.

- Diagnosed with ALL, AML, or MDS for which an allogeneic hematopoietic stem cell
transplant is indicated. Complete Remission (CR) status will not be confirmed at the
time of enrollment. CR as defined in these sections is required to proceed with the
actual HCT treatment plan.

- Has not received a prior allogeneic hematopoietic stem cell transplant.

- Does not have a suitable human leukocyte antigen (HLA)-matched sibling donor available
for stem cell donation.

- Has an eligible haploidentical related family donor based on at least intermediate
resolution HLA typing.

- Patients who also have an eligible 8/8 MUD adult donor based on confirmatory high
resolution HLA typing are eligible for randomization to Arm A or Arm B.

- Patients who do not have an eligible MUD donor are eligible for enrollment to Arm
C.

- All patients and/or their parents or legal guardians must sign a written informed
consent.

- All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met.

- Co-Enrollment on other trials.

- Patients will not be excluded from enrollment on this study if already enrolled
on other protocols for treatment of high risk and/or relapsed ALL, AML and MDS.
This is including, but not limited to, COG AAML1831, COG AALL1821, the EndRAD
Trial, as well as local institutional trials. We will collect information on all
co-enrollments.

- Patients will not be excluded from enrollment on this study if receiving
immunotherapy prior to transplant as a way to achieve remission and bridge to
transplant. This includes chimeric antigen receptor (CAR) T cell therapy and
other immunotherapies.

Inclusion Criteria
•Patient to Proceed to HCT:

- Karnofsky Index or Lansky Play-Performance Scale ≥60 on pre-transplant evaluation.
Karnofsky scores must be used for patients ≥ 16 years of age and Lansky scores for
patients =< 16 years of age (within 4 weeks of starting therapy).

- A serum creatinine based on age/gender as follows:

6 months to < 1 year: 0.5 mg/dL (Male); 0.5 mg/dL (Female);

1. to < 2 years 0.6 mg/dL (Male); 0.6 mg/dL (Female);

2. to < 6 years 0.8 mg/dL (Male); 0.8 mg/dL (Female);

6 to < 10 years: 1 mg/dL (Male); 1 mg/dL (Female) 10 to < 13 years: 1.2 mg/dL (Male);
1.2 mg/dL (Female) 13 to < 16 years: 1.5 mg/dL (Male); 1.4 mg/dL (Female) >= 16 years:
1.7 mg/dL (Male); 1.4 mg/dL (Female); OR

- A 24 hour urine Creatinine clearance ≥ 60 mL/min/1.73 m^2; OR

- A glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m^2. GFR must be performed using
direct measurement with a nuclear blood sampling method OR direct small molecule
clearance method (iothalamate or other molecule per institutional standard).

- Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates
are not acceptable for determining eligibility.

- Serum glutamic-oxaloacetic transaminase (SGOT) aspartate aminotransferase [AST] or
serum glutamate pyruvate transaminase (SGPT) aminotransferase [ALT] < 5 x upper limit
of normal (ULN) for age.

- Total bilirubin < 2.5 mg/dL, unless attributable to Gilbert's Syndrome.

- Shortening fraction of ≥ 27% by echocardiogram or radionuclide scan (MUGA); OR

- Ejection fraction of ≥ 50% by echocardiogram or radionuclide scan (MUGA), choice of
test according to local standard of care.

- Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and
corrected carbon monoxide diffusing capability (DLCO) must all be ≥ 50% of predicted
by pulmonary function tests (PFTs).

- For children who are unable to perform for PFTs (e.g., due to age or
developmental delay), the criteria are: no evidence of dyspnea at rest, oxygen
(O2) saturation (Sat) > 92% on room air by pulse oximetry, not on supplemental O2
at rest, and not on supplemental O2 at rest.

- ALL high-risk in first complete remission (CR1) for whom transplant is indicated.
Examples include: induction failure, treatment failure as per minimal residual disease
by flow cytometry > 0.01% after consolidation and not eligible for AALL1721 or
AALL1721 not available/unwilling to enroll, hypodiploidy (< 44 chromosomes) with MRD+
> 0.01% after induction, persistent or recurrent cytogenetic or molecular evidence of
disease during therapy requiring additional therapy after induction to achieve
remission (e.g. persistent molecular BCR-ABL positivity), T cell ALL with persistent
MRD > 0.01% after consolidation.

- ALL in second complete remission (CR2) for whom transplant is indicated. Examples
include: B-cell: early (≥ 36 months from initiation of therapy) bone marrow (BM)
relapse, late BM relapse (≥ 36 months) with MRD ≥ 0.1% by flow cytometry after first re-induction therapy; T or B-cell: early (< 18 months) isolated extramedullary (IEM),
late (≥ 18 months) IEM, end-Block 1 MRD ≥ 0.1%; T-cell or Philadelphia chromosome positive (Ph+): BM relapse at any time.

- ALL in ≥ third complete remission (CR3).

- Patients treated with chimeric antigen receptor T-cells (CART) cells for whom
transplant is indicated. Examples include: transplant for consolidation of CART, loss
of CART persistence and/or B cell aplasia < 6 months from infusion or have other
evidence (e.g., MRD+) that transplant is indicated to prevent relapse.

- AML in CR1 for whom transplant is indicated. Examples include those deemed high risk
for relapse as described in AAML1831:

- FLT3/ITD+ with allelic ratio > 0.1 without bZIP CEBPA, NPM1;

- FLT3/ITD+ with allelic ratio > 0.1 with concurrent bZIP CEBPA or NPM1 and with
evidence of residual AML (MRD >= 0.05%) at end of Induction;

- Presence of RAM phenotype or unfavorable prognostic markers (other than FLT3/ITD)
per cytogenetics, fluorescence in situ hybridization (FISH), next generation
sequencing (NGS) results, regardless of favorable genetic markers, MRD status or
FLT3/ITD mutation status;

- AML without favorable or unfavorable cytogenetic or molecular features but with
evidence of residual AML (MRD ≥ 0.05%) at end of Induction;

- Presence of a non-ITD FLT3 activating mutation and positive MRD (≥ 0.05%) at end
of Induction 1 regardless of presence of favorable genetic markers;

- AML in ≥ CR2;

- MDS with < 5% blasts by morphology and flow cytometry (if available) on the
pre-transplant bone marrow evaluation;

- Complete remission (CR) is defined as < 5% blasts by morphology and flow cytometry (if
available) on the pre-transplant bone marrow evaluation with minimum sustained
absolute neutrophil count (ANC) of 300 cells/microliter for 1 week or ANC > 500
cells/microliter. We will be collecting data from all approaches to MRD evaluation
performed including NGS and polymerase chain reaction (PCR).

Donor Eligibility Criteria:

- Matched Unrelated Donors:

Unrelated donor candidates must be matched at high resolution at a minimum of 8/8 alleles
(HLA-A, -B, -C, -DRB1). One-antigen HLA mismatches are not permitted. HLA matching of
additional alleles is recommended according to National Marrow Donor Program (NMDP)
guidelines,110 but will be at the discretion of local centers.

- Haploidentical Matched Family Members:

- Minimum match level full haploidentical (at least 5/10; HLA-A, -B, -C, -DRB1,
-DQB1 alleles). The following issues (in no particular order) should be
considered in choosing a haploidentical donor:

- Absent or low patient donor-specific antibodies (DSA);

- Mean fluorescence intensity (MFI) of any anti-donor HLA antibody by
solid phase immunoassay should be < 2000. Donors with higher levels are
not eligible;

- If a screening assay against pooled HLA antigens is used, positive
results must be followed with specificity testing using a single
antigen assay. The MFI must be < 2000 unless the laboratory has
validated higher threshold values for reactivity for HLA antigens
(such as HLA-C, -DQ, and -DP), that may be enhanced in
concentration on the single antigen assays. Donor anti- recipient
antibodies are of unknown clinical significance and do not need to
be sent or reported.

- Consult with Study Chair for the clinical significance of any
recipient anti-donor HLA antibody.

- If centers are unable to perform this type of testing, please
contact the Study Chair to make arrangements for testing.

- If killer immunoglobulin testing (KIR) is performed: KIR status by mismatch,
KIR-B, or KIR content criteria can be used according to institutional
guidelines.

- ABO compatibility (in order of priority):

- Compatible or minor ABO incompatibility

- Major ABO incompatibility

- CMV serostatus:

- For a CMV seronegative recipient: the priority is to use a CMV
seronegative donor when feasible.

- For a CMV seropositive recipient: the priority is to use a CMV
seropositive donor when feasible.

- Age: younger donors including siblings/half-siblings, and second degree
relatives (aunts, uncles, cousins) are recommended, even if < 18 years.

- Size and vascular access appropriate by center standard for peripheral blood stem cell
(PBSC) collection if needed.

- Haploidentical matched family members: screened by center health screens and found to
be eligible.

- Unrelated donors: meet eligibility criteria as defined by the NMDP or other unrelated
donor registries. If the donor does not meet the registry eligibility criteria but an
acceptable eligibility waiver is completed and signed per registry guidelines, the
donor will be considered eligible for this study.

- Human immunodeficiency virus (HIV) negative.

- MUD donors and post-transplant cyclophosphamide haplo donors should be asked to
provide BM. If donors refuse and other donors are not available, PBSC is allowed.
TCR-alpha beta/CD19 depleted haplo donors must agree to donate PBSC.

- Must give informed consent.

- Haploidentical matched family members: Institution standard of care donor consent
and Protocol-specific Donor Consent for Optional Studies.

- Unrelated donors: standard NMDP Unrelated Donor Consent.

- Not pregnant.

Exclusion Criteriam
•Patient Enrollment:

- Patients with genetic disorders (generally marrow failure syndromes) prone to
secondary AML/ALL with known poor outcomes because of sensitivity to alkylator therapy
and/or TBI are not eligible (Fanconi Anemia, Kostmann Syndrome, Dyskeratosis
Congenita, etc). Patients with Downs syndrome because of increased toxicity with
intensive conditioning regimens.

- Patients with any obvious contraindication to myeloablative HCT at the time of
enrollment.

- Female patients who are pregnant are ineligible as many of the medications used in
this protocol could be harmful to unborn children and infants.

- Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation.

Exclusion Criteria
•Patient to Proceed to HCT:

- Patients with uncontrolled fungal, bacterial, viral, or parasitic infections are
excluded. Patients with history of fungal disease during chemotherapy may proceed if
they have a significant response to antifungal therapy with no or minimal evidence of
disease remaining by computed tomography (CT) evaluation.

- Patients with active central nervous system (CNS) leukemia or any other active site of
extramedullary disease at the time of initiation of the conditioning regimen are not
permitted.

- Note: Those with prior history of CNS or extramedullary disease, but with no
active disease at the time of pre-transplant workup, are eligible.

- Pregnant or breastfeeding females are ineligible as many of the medications used in
this protocol could be harmful to unborn children and infants.

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

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

• Scheduled for two-stage exchange arthroplasty due to hip or knee periprosthetic joint infection (PJI).
• Signed informed consent.
• 22 to 84 years of age (inclusive).
• Medical clearance for surgery.
• Preoperative diagnosis of PJI of the hip or knee per the International Consensus.
• Meeting of Musculoskeletal Infection (ICMMI) 2018 definition of Periprosthetic Hip andmKnee Infection.

• Patients with 2 or more prior exchange arthroplasties (septic or aseptic) of the infected joint. Exchange of modular components only is not considered an exchange arthroplasty.
• Patients with 2 or more prior failed spacers for PJI.
• Patients for whom a Stage 2 procedure within one year is contraindicated.
• Patients with bacteremia or positive bacterial blood culture in the last 30 days.
• Patients with concurrent PJI of more than one joint.
• Patients with ongoing active infection of an intravenous (IV) site.
• Patients who require long-term anticoagulation or antiplatelet therapy, and for whom bridging or withholding therapy is not recommended based on the individual's clinical condition.
• Patients with advanced renal insufficiency (i.e., chronic kidney disease Stage 4 or 5 or patients with an estimated glomerular filtration rate < 30 mL/min).
• Patients on chemotherapy for malignant disease.
• Patients on systemic glucocorticoid therapy (prednisone >10 mg/day or equivalent).
• Patients who are immunodeficient (e.g., splenectomy, sickle cell anemia, Stage 3 human immunodeficiency virus infection, primary immunodeficiency disease), except patients who are immunodeficient due to immunosuppressive therapy.
• Patients who have an allergy to vancomycin hydrochloride or tobramycin sulfate.
  • Note: prior history of red man syndrome is not considered an allergy.
• Patients who have an allergy to titanium, titanium alloys, polymethylmethacrylate or polyurethane.
• Patients who are pregnant or planning to become pregnant in the next 12 months.
• Patients with a fungal PJI as determined by one or more positive fluid and/or tissue cultures.
• Patients who have a skeletal defect greater than 150 mm in length in the tibia or femur of the infected joint.
• Patients who have a planned surgical procedure within 6 months of enrollment that can impact the conduct of the study.
• Patients who are breastfeeding.
• Patients who are incarcerated or are facing impending incarceration.
• Patients who have been in treatment or referred to treatment for substance abuse within the past year.
• Patients with any medical condition, including schizophrenia or another psychiatric disorder with hallucinations and/or delusions, that would interfere with the interpretation of the study results, the conduct of the study, or patient participation would not be in the best interest of the patient in the opinion of the Study Site Principal Investigator.
• Patients who will participate in another clinical study of an investigational drug or investigational device or have participated in another clinical study of an investigational drug or investigational device within the past 30 days that would interfere with the interpretation of the study results or the conduct of the study.
• Patients who are judged by the Study Site PI to be unsuitable for the study.
• Patients receiving immunosuppressive drug therapy for bone marrow or another transplant.
• Patients currently or previously enrolled in this study or the APEX study (JPS-0301).
• Patients who receive therapy including any of the following biologic agents, which will not be withheld for a period beginning at least one dosing cycle (minimum 7 days) prior to planned surgery and ending at least 14 days following planned surgery:
  • Adalimumab (Humira); Tocilizumab (Actemra); Etanercept (Enbrel); Anakinra (Kineret);
  • Golimumab (Simponi); Secukinumab (Cosentyx); Infliximab (Remicade); Ustekinumab (Stelara);
  • Abatacept (Orencia); Rituximab (Rituxan); Certolizumab (Cimzia); Tofacitinib (Xeljanz);
  • Belimumab (Benlysta).

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

Eligibility last updated 12/28/22. Questions regarding updates should be directed to the study team contact.

Eligibility last updated 8/3/23. Questions regarding updates should be directed to the study team contact.

• Male and female subjects, 15
  •70 years of age.
• Previous diagnosis of ADPKD (based on Ravine et al. criteria).
• Class 1 A-E according to imaging classification.
• Estimated GFR > 45 mL/min/1.73 m^2 (CKD-EPI).
• Ability to provide written, informed consent.

• Class 2, according to imaging classification.
• A concomitant systemic disease affecting the kidney.
• Diabetes mellitus.
• Predicted urine protein excretion in > 1 g/24 hrs and/or Abnormal urinalysis.
• Use of antioxidants; i.e., vitamins, Nrf2 activators.
• Patients that are part of an interventional study.

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

Eligibility last updated 1/5/23. Questions regarding updates should be directed to the study team contact.

• Patient is able to communicate well with the Investigator, understands and is willing to comply with all requirements of the study, and understands and signs the written informed consent form (ICF).
• At least 18 years of age.
• Cirrhosis and ascites.
• AKI stage 2 or 3. AKI defined by any of the following:
  • increase in SCr (SCr) ≥ 0.3 mg/dl (or ≥ 26.5 micromolar/L) within 48 h; or
  • increase ≥ 50% in baseline SCr, which is known or presumed to have occurred within the prior seven days.
• QLY SCr ≥ to 1.5 mg/dl.
• No sustained improvement in renal function (less than 20% decrease in SCr and SCr ≥ 1.5 mg/dL) after 48 h of diuretic withdrawal and the beginning of plasma volume expansion with albumin.
• Female patients as well as female partners of male patients must be willing to avoid pregnancy for the duration of the study (> 90 days).

• Significant co-morbidities that in the opinion of the Investigator would preclude study participation.
• QLY SCr level > 5 mg/dL.
• AKI stage 1.
• ACLF stage 3.
• Model for End-Stage Liver Disease (MELD) score > 35.
• At least one event of large volume paracentesis (LVP) > 4 Liters in the last 4 days before enrollment.
• Current or recent (within 4 weeks) treatment with nephrotoxic drugs (e.g., aminoglycosides, amphotericin, cyclosporine, NSAIDS (e.g., ibuprofen, naproxen, celecoxib), significant exposure to radiographic contrast agents (large doses or multiple injections of iodinated contrast media).
• Shock (hypovolemic-, cardiogenic-, or vasodilatory/distributive shock) with mean arterial blood pressure (MAP) ≤ 70 mmHg or systolic blood pressure ≤ 90 mmHg along with hypoperfusion. 
• Sepsis or uncontrolled bacterial infection (e.g., persisting bacteremia, persisting ascitic fluid leucocytosis, fever, increasing leucocytosis with vasomotor instability) as measured with the quick sepsis-related organ dysfunction assessment (qSOFA) score.
• Fewer than two days of anti-infective therapy for documented or suspected infection.
• Superimposed acute liver injury induced by drugs, herbal preparation or dietary supplements, with the exception of alcoholic hepatitis.
• Estimated life expectancy less than 5 days.
• Hypoxia (< 90%) or worsening respiratory symptoms.
• Proteinuria > 500 mg/day.
• Tubular epithelial casts, heme granular casts.
• Haematuria or microhaematuria (more than 50 red blood cells per high power field).
• Abnormal renal ultra-sonography unless there is a known chronic structural disease (e.g., diabetic or hypertensive nephropathy).
• Current or recent (within 4 weeks) renal replacement therapy (RRT).
• Severe cardiovascular and pulmonary diseases including, but not limited to, unstable angina, pulmonary edema, congestive heart failure requiring increasing doses of drug therapy, persisting symptomatic peripheral vascular disease, or any other cardiovascular disease judged by the Investigator to be severe. 
• Transjugular intra-hepatic systemic shunt (TIPS) unless it is known to be non-functioning or occluded.
• Ongoing use of vasopressors, unless used for only 48 h before screening; in this case a wash-out period of 8 h before enrollment will be necessary. Patients receiving midodrine and octreotide may be enrolled but treatment must be discontinued prior to enrollment.
• Known allergy or hypersensitivity to terlipressin or other component of the study treatment.
• Subject is not suitable to participate in the study for any reason (including, but not limited to co-morbidities, history of non-compliance with study visits, procedures, or drug administration) in the opinion of the Investigator.
• Females of childbearing potential (those who are not surgically sterilized or post-menopausal for at least 1 year) are excluded from participation in the study unless they agree to use highly effective contraception.
• Males who have no sterilization history and whose female partners have child-bearing potential must agree to use a highly effective method of contraception during the  period from the time of signing the informed consent form (ICF) through 90 days after the last dose of study drug. A male patient must agree to immediately inform the Investigator if his partner becomes pregnant during the study.

Eligibility last updated 5/30/23. Questions regarding updates should be directed to the study team contact.

• Male and female adults aged ≥ 18 years (at the screening visit) with capacity to consent.
• Diagnosis of moderate-to-severe Atopic Dermatitis (AD) as defined by the Hanifin and Rajka (1980) criteria.
• AD duration of at least 3 months.
• IGA score of 2 to 3 at the screening visit.
• Treatment naïve and/or willing to pursue 30-day wash-out period if they are using topical medications, oral medications, or injectable medications.
• For participants who sign photography consent, at least 1 target lesion that measures at least 5 cm2 at the screening visit. The target lesion must be representative of the participant's disease state but not located on the hands, feet, genitalia, face, scalp, or intertriginous areas.

• Unstable history of atopic dermatitis (spontaneously improving or rapidly deteriorating) as determined by the investigator over the previous 4 weeks before baseline/visit 0.
• Disease history concerns, i.e., lymphoma, immunodeficiency, chronic infections such as HIV, hepatitis, or tuberculosis, dialysis, and/or history of skin cancer within 5 years.
• Chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals within 2 weeks before the baseline/visit 0.
• Active acute bacterial, fungal, or viral skin infection (e.g., herpes simplex, herpes zoster, chicken pox, clinically infected AD, impetigo) within 1 week before the baseline/visit 0.
• Insufficient area of uninvolved (control) skin.
• Relative contraindications to skin biopsy (e.g., serum platelets < 10; allergy to lidocaine).
• Atopic dermatitis exclusive to areas of the hands, feet, face, scalp, intertriginous areas, or genitalia.

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

Eligibility last updated 1/10/23. Questions regarding updates should be directed to the study team contact.

• All race/ethnicity categories, English speaking, men and women.
• Age ≥ 21 years.
• Current severe/massive/torrential tricuspid regurgitation (TR), considered symptomatic from TR.
• Goal Age/Sex/Race Distribution: ≥ 20% non-white, 40% women/men, 40% < 65/ ≥ 65 years of age.

• Unwillingness to participate.
• Cognitive barriers which would make it difficult to participate in discussion.
• Non-English speaking.

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

Eligibility last updated 1/10/23. Questions regarding updates should be directed to the study team contact.

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.

• 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.

• 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.

• 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.