Key

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

Eligibility last updated 5/18/23. Questions regarding updates should be directed to the study team contact.

• Between 18 and 85 years of age (inclusive) at the initial screening visit.
• Meets 2011 consensus criteria for svPPA (Gorno-Tempini et al. 2011).
• MRI at screening is consistent with the underlying svPPA with no large strokes or severe white matter disease (Fazekas Grade ≤ 2; Fazekas et al. 1987);
• CDR® plus NACC FTLD (Miyagawa et al. 2020) global score at screening ≤1.
• The following medications are allowed, but must be stable for 2 months prior to the initial screening visit:
  • Food and Drug Administration (FDA)-approved Alzheimer's disease (AD) medications;
  • FDA-approved psychotropic medications;
  • Other medications (except those listed under exclusion criteria) are allowed as long as the dose is stable for 30 days prior to the initial screening visit.
• Has a reliable study partner who agrees to accompany the participant to visits, and spends at least 5 hours per week with the participant.
• Agrees to 2 LPs.
• Signed and dated written informed consent obtained from the participant and the participant's study partner in accordance with local Institutional Review Board (IRB) regulations.
• WOCBP must agree to abstain from sex or use highly effective birth control that includes two methods of contraception (one of which must be a barrier method) for the duration of the screening period, the RDBPC treatment period, and for 30 days after the last dose of study drug (active or placebo).
• Males must agree to abstain from sex with WOCBP or use an adequate method of contraception for the duration of the RDBPC treatment period and for 90 days after the last dose of study drug (active or placebo).
• Able to swallow pills whole without crushing or chewing.

• A clinical diagnosis of probable AD (McKhann et al. 2011) or previous biomarker evidence of AD biology using amyloid positron emission tomography (PET) imaging, CSF amyloid beta (A?)/total tau (t-tau) ratio, CSF/plasma amyloid beta isoform with 40 amino acid residues (Aβ40)/amyloid beta isoform with 42 amino acid residues (Aβ42) ratio, or plasma phosphorylated tau [phosphorylated tau at residue 181 (p-tau181) and phosphorylated tau at residue 217 (p-tau217)] assessments.
• A clinical diagnosis of a comorbid FTLD-associated clinical syndrome other than svPPA, including:
  • logopenic primary progressive aphasia (lvPPA; Gorno-Tempini et al. 2011);
  • non-fluent/agrammatic variant primary progressive aphasia (nfvPPA; Gorno-Tempini et al. 2011);
  • behavioral variant for frontotemporal dementia (bvFTD; Rascovsky et al. 2011). Patients who meet diagnostic criteria for svPPA (Gorno-Tempini et al. 2011) may still be included if they have a secondary diagnosis of bvFTD, so long as the PI can reasonably attribute their disinhibition, dietary changes, compulsions, and/or loss of empathy to anterior temporal lobe atrophy (Seeley et al. 2005) and MRI is consistent with right anterior atrophy (or left temporal atrophy in participants with suspected right hemispheric language dominance);
  • progressive supranuclear palsy (PSP; Höglinger et al. 2017); e. corticobasal syndrome (CBS; Armstrong et al. 2013).
• Any other medical condition other than FTLD that is likely to account for cognitive or behavioral deficits (e.g., uncontrolled seizure disorder, stroke, vascular dementia, substance abuse or alcoholism, Lewy body disease).
• History of uncontrolled thyroid disease or evidence thereof [i.e., abnormal free thyroxine (T4) levels and thyroid stimulating hormone (TSH) > 10 milli-international units (mIU)/liter (L) at screening (confirmed by repeat)].
• Serious autoimmune disease, or ongoing immunocompromised state.
• History of significant cardiovascular, hematologic, renal, or hepatic disease (or laboratory evidence thereof at screening).
• History or presence of gastrointestinal (GI) or other disease known to interfere with absorption, distribution, metabolism, or excretion of drugs, or a history of surgery known to interfere with absorption or excretion of drugs (i.e., gastric bypass).
• Within 1 year prior to initial screening visit or between screening and baseline (pre-dose Day 1), any of the following: myocardial infarction; hospitalization for congestive heart failure; hospitalization for, or symptoms of, unstable angina; or syncope.
• History of major psychiatric illness or untreated depression that in the opinion of the PI would pose a safety risk or interfere with the appropriate interpretation of study data.
• Neutrophil count <1,500/cubic millimeter (mm3), platelets <100,000/mm3, serum creatinine >1.5 x upper limit of normal (ULN), total bilirubin (TBL) >1.5 x ULN, alanine aminotransferase (ALT) >1.5 x ULN, aspartate aminotransferase (AST) >1.5 x ULN, or international normalized ratio (INR) >1.2 at screening (confirmed by repeat).
• Evidence of any clinically significant findings on screening or baseline evaluations which, in the opinion of the PI would pose a safety risk or interfere with appropriate interpretation of study data.
• Corrected QT interval by Fridericia (QTcF) ≥ 470 milliseconds (msec) or uncontrolled arrhythmia or frequent premature ventricular contractions (PVCs; >5/minute) or Mobitz Type II second or third degree atrioventricular (AV) block or left bundle branch block or right bundle branch block with a QRS duration ≥ 150 msec or intraventricular conduction defect with a QRS duration ≥ 150 msec or evidence of acute or sub-acute myocardial infarction or ischemia or other ECG findings at screening or baseline that, in the PI's opinion, would preclude participation in the study.
• Pathologic renal findings at screening as defined by the presence of either of the following criteria:
  • Estimated glomerular filtration rate (eGFR) [determined by the Modification of Diet in Renal Disease (MDRD) Study equation] < 30 milliliter (mL)/minute/1.73 square meter (m^2). The MDRD Study equation is as follows: eGFR (mL/minute/1.73 m^2) = 175 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if African American), where Scr = serum creatinine in mg/deciliter (dL) as measured by a method calibrated to an isotope dilution mass spectrometry (IDMS) reference method;
  • Serum creatinine ≥ 2.5 mg/dL;
  • Hemoglobin A1C > 7.5% at screening (confirmed by repeat);
• Current or recent history (within four weeks prior to initial screening visit) of a clinically significant bacterial, fungal, or mycobacterial infection.
• Current clinically significant viral infection, including "known" positive status for human immunodeficiency virus (HIV) (i.e., based on prior testing; HIV testing will not be performed as part of the screening evaluations for this trial).
• Major surgery within four weeks prior to initial screening visit.
• Blood transfusion within 4 weeks of initial screening visit.
• History of stem cell treatment.
• Any contraindication for MRI or unable to tolerate MRI at screening.
• Any contraindication to or unable to tolerate LP at screening, including the use of anti-coagulant medications such as warfarin. Daily administration of 81 mg aspirin will be allowed as long as the dose is stable for 30 days prior to the initial screening visit.
• Participants who, in the opinion of the PI, are unable or unlikely to comply with the dosing schedule or study evaluations.
• Prior treatment with verdiperstat.
• Treatment with another investigational drug within 30 days or 5 half-lives of drug before initial screening visit, whichever is longer. Treatment with investigational drugs other than verdiperstat while on study will not be allowed.
• Treatment with systemic corticosteroids or steroid sparing systemic immunosuppressive agents within 30 days or 5 half-lives of drug before initial screening visit, whichever is longer. Treatment with systemic corticosteroids or other systemic immunosuppressive therapy while on study will not be allowed.
• Treatment with strong inhibitors of CYP1A2 (i.e., ciprofloxacin, enoxacin, fluvoxamine) within 30 days or 5 half-lives of drug before initial screening visit, whichever is longer. Treatment with strong inhibitors of CYP1A2 while on study will not be allowed.
• Known hypersensitivity to the inactive ingredients in the study drug products (active or placebo).
• Known to be pregnant or lactating, or positive pregnancy test at screening or baseline (pre-dose Day 1).
• Cancer within 5 years of initial screening visit, except for basal cell carcinoma.
• History or evidence at screening of known disease-associated mutations associated with FTLD without trans-activation response deoxyribonucleic acid-binding protein of 43 kilodaltons (TDP-43) inclusions [e.g., mutations in the genes encoding chromatin-modifying protein/charged multivesicular body protein B2 (CHMPB2), microtubule-associated protein tau (MAPT), or fused in sarcoma (FUS)].

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

• Adult men and post-menopausal women between age 45 and 80.
• Symptoms of numbness or tingling for at least 4 weeks in at least two digits on one hand that include thumb, index, long, or radial border of ring finger.
• Classic or probable carpal tunnel syndrome on Katz-Stirrat hand diagram.
• A clinical diagnosis of carpal tunnel syndrome.
• Able to complete English-language questionnaires and clinical evaluations.

• Unable or unwilling to give informed consent.
• Previous carpal tunnel release on the study hand.
• History of steroid injection into carpal tunnel or surgery on the affected wrist within the past 6 months.
• Currently take a steroid medication either regularly or on as needed basis.
• Currently taking warfarin (medication can be safely held during the following times:
  • Immediately before the 1st IP administration (Day 0) until at least 10 hours after the 2nd IP administration (Day 1);
  • Immediately before the 3rd IP administration (Day 29) until at least 10 hours after the 4th IP administration (Day 30).
• Patient currently taking Sirolimus, Tacrolimus, or other mTOR inhibitors for other indications (mainly chronic indications represented by organ transplantation or autoimmune diseases).
• Drugs listed as part of the exclusion criteria are not permitted during each of the two 2-day courses of treatment with Fisetin. If patients are required to initiate these medications within the 2-day period then they will be removed from the study primarily due to risk of drug-drug interaction.
• Any of the following clinical diagnoses or conditions:
  • Cervical radiculopathy; 
  • Renal failure (see below);
  • Liver disease (see below);
  • Taking warfarin;
  • Peripheral nerve disease;
  • Uncontrolled diabetes (see below); or
  • Other metabolic disorder (as per clinical judgement).
• The following laboratory tests as indicated or as per clinical judgement:
  • fasting plasma glucose > 200 as a marker of poor diabetic control;
  • CBC w/diff with Hgb < 12 as a marker of poor nutrition, creatinine > 2.5 as a marker of advanced kidney disease;
  • AST > 100 as a marker of liver disease;
  • Bilirubin > 2.0 as a marker of liver disease;
  • Cystatin c > 3 as a marker of advanced kidney disease;
  • A1c > 8 as a marker of poor diabetic control;
  • CRP > 10 as a marker of systemic inflammation;
  • ESR > 25 as a marker of systemic inflammation.
• Prisoners, institutionalized individuals, or others who may be considered vulnerable populations, such as individuals with dementia.
• Women of child-bearing potential.

Eligibility last updated 2/25/22. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 8/16/22. Questions regarding updates should be directed to the study team contact

• Willing and able to provide written informed consent.
• Males or females, ≥ 18 years of age.
• Receiving a human leukocyte antigen (HLA) matched allogeneic peripheral BMT from a family or unrelated donor, HLA-mismatched related or unrelated donor, or haploidentical donor.
• Diagnosed with 1 of the following underlying diseases:
  • Refractory anemia;
  • Refractory anemia with ringed sideroblasts;
  • Refractory cytopenia with multilineage dysplasia;
  • Refractory cytopenia with multilineage dysplasia and ringed sideroblasts;
  • Refractory anemia with excess blasts
    •1 (5-10% blasts);
  • Refractory anemia with excess blasts
    •2 (10-20% blasts);
  • Myelodysplastic syndrome, unclassified;
  • Myelodysplastic syndrome associated with isolated del (5q);
  • Chronic myelomonocytic leukemia;
  • Lymphoma (including Hodgkin's) with chemosensitive disease (i.e., response to chemotherapy) and receiving a related donor transplant;
  • Aplastic anemia;
  • Primary or secondary myelofibrosis.
• Acute myeloid leukemia (AML), with or without a history of myelodysplastic syndrome, in first or second complete remission.
• Acute lymphoblastic leukemia, in first or second complete remission.
• Acute undifferentiated leukemia in first or second remission.
• Acute biphenotypic leukemia in first or second complete remission.
• Chronic myelogenous leukemia in either chronic or accelerated phase.
• One of the following myelodysplastic syndrome(s) defined by the following:
  • Receiving myeloablative or reduced-intensity conditioning regimens.
• Adequate renal and hepatic function, within 6 weeks of initiation of conditioning, as measured by:
  • Hepatic (within 72 hours of Day 0): alanine aminotransferase;
  • Renal (within 72 hours of Day 0): Serum creatinine within normal range for age or if serum creatinine above ULN range for age, a creatinine clearance [CrCl]) ≥60 mL/min.;
  • Baseline blood samples drawn for serum Platelia galactomannan enzyme immunoassay (GM EIA) and β-D glucan levels within 14 days before randomization, with results available prior to randomization;
  • Baseline Toxoplasma serologies available within 6 weeks prior to randomization;
  • Baseline glucose-6-phosphate dehydrogenase (G6PD) deficiency testing with no evidence of G6PD deficiency performed within 6 weeks prior to randomization.
• Female subjects of child-bearing potential < 2 years post-menopausal must agree to and comply with using 1 barrier method (e.g., female condom with spermicide) plus one other highly effective method of birth control (e.g., oral contraceptive, implant, injectable, indwelling intrauterine device, vasectomized partner), or sexual abstinence while participating in this study. Male subjects must be vasectomized, abstain from sexual intercourse, agree to use barrier contraception (condom with spermicide), and also agree not to donate sperm while participating in the study and for 120 days from the last IV dose of study drug.

• Diagnosis of AML not in morphological remission.
• Diagnosis of chemotherapy-resistant lymphoma.
• Suspected or diagnosed invasive fungal disease (IFD) within 4 weeks of screening.
• Diagnosed symptomatic heart failure with left ventricular ejection fraction (LVEF) at rest ≤ 40%, LVEF > 40% but fails to improve with exercise, or shortening fraction ≤ 26%.
• Personal or family history of Long QT interval on ECG (QT) syndrome or a prolonged QT interval corrected (QTc) interval (> 470 msec in males and > 480 msec in females); or concurrent administration of terfenadine, cisapride, astemizole, erythromycin, pimozide, or quinidine.
• Diagnosed reduced lung function with either diffusion capacity (corrected for hemoglobin), forced expiratory volume 1, forced vital capacity ≤ 45% of predicted value, or O2 saturation ≤ 85% on room air.
• Suspected or documented PCP within 2 years of screening.
• Positive baseline serum Platelia GM EIA (≥ 0.5) and/or β-D glucan assay (≥ 80 pg/mL).
• Receipt of previous allogeneic BMT.
• Planned receipt of cord blood for transplantation.
• Planned peripheral blood or marrow autograft.
• Underlying diagnosis of multiple myeloma.
• Grade 2 or higher ataxia, tremor, motor neuropathy, or sensory neuropathy, per NCI CTCAE version 5.0.
• History of severe ataxia, neuropathy or tremors; or a diagnosis of multiple sclerosis or a movement disorder (including Parkinson's disease or Huntington's disease).
• Planned or ongoing therapy at screening with a known neurotoxic medication for a complete list of prohibited neurotoxic medications).
• Known hypersensitivity to Rezafungin for Injection, any echinocandin, fluconazole, posaconazole, other azole antifungal, or to any of their excipients.
• Known hypersensitivity or inability to receive TMP/SMX or any of its excipients.
• Recent use of an investigational medicinal product within 28 days of the first dose of prophylactic study drug or presence of an investigational device at the time of screening.
• Known infection with HIV.
• Pregnant or lactating females.
• The Principal Investigator (PI) determines that the subject should not participate in the study.
• Considered unlikely to follow up for 90 days after receipt of the BMT due to logistic concerns (i.e., location relative to transplant center).

Eligibility last updated 10/5/21. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 12/13/22. Questions regarding updates should be directed to the study team contact.

• Men at least 18 years of age referred with clinical suspicion of prostate cancer.
• Serum PSA ≤ 20ng/ml.
• Fit to undergo all procedures listed in protocol.
• Able to provide written informed consent.

• Prior prostate biopsy.
• Prior treatment for prostate cancer.
• Prior prostate MRI on a previous encounter.
• Contraindication to MRI.
• Contraindication to prostate biopsy.
• Unfit to undergo any procedures listed in protocol.

Eligibility last updated 10/5/21. Questions regarding updates should be directed to the study team contact.

• Age ≥ 65 years.
• Diagnosis of MM based on IMWG diagnostic criteria 64.
• Newly diagnosed or have received 1 prior line of treatment.
• Planned to start a new treatment for MM within 30 days.
• Transplant eligible or ineligible.
• Fluent in English (all assessment tools are in English).
• Able to provide written informed consent.

• Received > 1 prior line of treatment.
• Patients included in an interventional therapeutic trial.
• Not able to give informed consent.
• Severe mental or cognitive disorder precluding geriatric assessment.

Eligibility last updated 1/20/22. Questions regarding updates should be directed to the study team contact.

• BMI 18-25 kg/m^2.
• Age > 21 and < 50 years.
• Weight stable for 3 months prior to study entry.
• For females: study days will be scheduled during the follicular phase of their menstrual cycle (i.e., the first 13 days (about 2 weeks) of the cycle).
• Able to provide written informed consent prior to any study procedures and be willing and able to follow study procedures.
• Ability to perform light to moderate physical activity.

• Any contraindication for MRI scanning.
• Any history of childhood (> 95th percentile) or adult obesity (BMI >30 kg/m^2).
• Claustrophobia.
• High intensity training or physical activity.
• Any contraindication for intragastric balloon insertion.
• Any allergies to the study meals.
• Any history of eating disorder.
• Any substance abuse disorder (including alcohol and tobacco).
• Any history of psychiatric disorders.
• Any cardiovascular, endocrine, pulmonary, neurological, or gastrointestinal comorbidities.
• Pregnancy or nursing.
• Any history of bariatric surgery or endoscopic bariatric procedure.
• Use of any medication or supplement that alters appetite.
• Patient has a known history of any condition or factor judged by the investigator to prevent participation in the study or which might hinder study adherence.

Eligibility last updated 10/6/21. Questions regarding updates should be directed to the study team contact.

Eligibility last updated 7/20/22. Questions regarding updates should be directed to the study team contact.

• Children aged 14 days
  •17 years.
• At least moderate PARDS, bilateral lung disease, intubated within four days of severe PARDS and no exclusion criteria.

• Children will be excluded if they have any of the following at the start of mechanical ventilation: perinatal related lung disease, congenital diaphragmatic hernia or congenital/acquired diaphragm paralysis, respiratory failure explained by cardiac failure or fluid overload, cyanotic heart disease, cardiomyopathy, unilateral lung disease, primary pulmonary hypertension, status asthmaticus (patient with a severe asthma exacerbation. A previous history of asthma or the use of bronchodilators is NOT an exclusion if the primary disease process is not considered to be obstructive airway disease), obstructive airway disease (e.g., severe airways disease without parenchymal involvement or disease characterized by hypercapnia with FiO2 < 0.30 and/or evidence of increased resistance visible on the flow – time scalar and/or presence of intrinsic PEEP),  bronchiolitis obliterans, post Hematopoietic Stem Cell Transplant, post lung transplant, home ventilator (including noninvasive) dependent, neuromuscular respiratory failure, critical airway (e.g., post laryngotracheal surgery or new tracheostomy) or anatomical obstruction of the lower airway (e.g., mediastinal mass), facial surgery or trauma in previous 15 days, head trauma, intracranial bleeding, unstable spine, femur or pelvic fractures, acute abdominal process/open abdomen, supported on ECMO, previously enrolled in current study, family/medical team deciding not to provide full support, enrolled in any other critical care interventional clinical trial concurrently and known pregnancy.

Eligibility last updated 10/7/21. Questions regarding updates should be directed to the study team contact.

• Unaffected first degree relative from Familial Interstitial Pneumonia families (two or more family members with IIP).
• Age at least 40 years old and younger than 75 years old.

• Diagnosed with known (physician-diagnosed) pulmonary fibrosis prior to informed consent.
• Other genetic diseases associated with interstitial lung disease.
• Pregnant women.

Eligibility last updated 10/7/21. Questions regarding updates should be directed to the study team contact.

• 100 subjects > 18 (200 eyes) with visual acuity at any level.

Exclusion Criteria:

• Patients with no ability to sign the consent forms with no LAR.
• Subjects with limited comprehension of English.

Eligibility last updated 10/18/21. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 9/15/22. Questions regarding updates should be directed to the study team contact.

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.

• Adult (18-90), male/female/other.
• Self-reported racial/ ethnic minority.
• Internet access via mobile device and/or computer/tablet.
• Able to read and write in English or Spanish.

• Legal inability or restricted legal ability. Medical or psychological conditions not allowing proper study completion or informed consent signature.
• Under the age of 18 years old.
• Identified as non-underrepresented racial/ethnic minority or medically underserved minority.
• Unable to read and write in English or Spanish.

Eligibility last updated 11/8/21. Questions regarding updates should be directed to the study team contact.

• English speaking.
• Ability to complete a questionnaire.
• ≥ 18 years of age.
• Patients treated for endometrial cancer from 2013-2018 (about 590 patients treated between 2013-2018 per Rad Onc Outcomes):
• Status post-surgery +:
  • Pelvic +/- para-aortic external beam radiotherapy;
  • External beam radiotherapy +/- vaginal cuff brachytherapy;
  • Brachytherapy alone.
• Patients treated for cervical cancer from 2013-2018 (62 definitive or adjuvant treated between 2015-2018 per Rad Onc outcomes):
  • Status post-surgery and external beam radiotherapy +/- chemotherapy;
  • Definitive radiotherapy +/- chemotherapy.
• Patients treated for vulvar cancer from 2013-2018 receiving radiotherapy +/- surgery +/- chemotherapy (40 treated between 2013-2018 per Rad Onc outcomes).
• Patients treated for vaginal cancer from 2013-2018 receiving radiotherapy +/- surgery +/- chemotherapy (34 treated between 2013-2018 per Rad Onc outcomes).
• Patients treated for anal cancer from 2013-2018 receiving radiotherapy +/- chemotherapy +/- surgery (243 treated between 2013-2018 per Rad Onc outcomes).

• Females < 18 years of age.
• Any exception to above Inclusion Criteria.

Eligibility last updated 11/18/21. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years old; AND
• Were treated with curative intent; AND
• Are planning to undergo regular follow-up and monitoring for cancer recurrence per standard of care at the enrolling site; AND
• Provided written informed consent to participate in the study; AND
• Are willing to have de-identified clinical data shared with investigators at regular intervals as outlined in the study protocol and informed consent; AND
• Are willing to provide blood samples at enrollment and at subsequent clinical visits coinciding with standard of care follow-up, for up to 5 years as outlined in the study protocol and informed consent; AND
• Have at least one blood sample collected 4-12 weeks after completion of primary treatment of the Index Cancer.
• Have a histologically confirmed Index Cancer that qualifies for inclusion, defined as:

Primary Study Cohorts:

• Cohort 1: Muscle invasive carcinoma of the bladder, ureter, or renal pelvis (stage II-III).
• Cohort 2: Non-small cell lung cancer (stage II-III).
• Cohort 3: Invasive breast carcinoma with all of the following:
  • Clinical stage T1-4/N0-3/M0 at presentation; AND
  • Completed preoperative systemic chemotherapy-containing regimen; AND
  • Underwent definitive surgical resection of the primary tumor; AND
  • Has pathological evidence of residual invasive carcinoma in the breast and/or axillary lymph nodes; AND
  • Hormone receptor and HER2 status are known.

Exploratory Cohorts:

• Cohort 4: Stage IIb-III cutaneous melanoma or limited (resectable) stage IV melanoma treated with curative intent.
• Cohort 5: Esophageal or gastroesophageal junction carcinoma (stage II-III).
• Cohort 6: Gastric adenocarcinoma (stage II-III).
• Cohort 7: Surgically resected pancreatic adenocarcinoma.
• Cohort 8: Invasive squamous cell carcinoma of the head and neck (includes stage I-III oral cavity, oropharynx, hypopharynx, larynx, nasopharynx, nasal cavity, paranasal sinus, and salivary gland cancers).
• Cohort 9: High-risk epithelial ovarian or Fallopian tube carcinoma (defined as stage IC-III or stage I that has high grade (grade 3-4) or clear cell histology).
• Cohort 10: High-risk endometrial carcinoma (defined as having any of the following: serous or clear cell adenocarcinoma histology (any stage), grade 3 or 4 deeply invasive (T1b or greater) endometrioid carcinoma, stage III disease (any histology)).
• Cohort 11: High-risk renal cell carcinoma (defined as high grade (grade 3-4) stage II, stage III or limited (resectable) stage IV treated with curative intent).
• For the purposes of this study, participants receiving extended (> 6 months planned duration) non-chemotherapy systemic treatment will be considered in their end of primary treatment phase after the initial planned surgery, chemotherapy and/or radiation.
• Determination of stage for eligibility assessment and enrollment should be based on pathologic stage unless the participant received pre-surgical/neoadjuvant therapy, in which case standard pre-treatment clinical staging will be used to determine eligibility.

• History of allogeneic organ or tissue transplant.
• Index cancer has neuroendocrine histology.
• History of another primary cancer, with the exception of the following (if adequately treated and the patient is without evidence of disease at the time of enrollment): in situ cancers, non-melanoma skin carcinoma, localized low-risk prostate cancer (Gleason score < 6) with PSA in the normal range, and stage I papillary thyroid carcinoma.
• Known distant metastasis at time of enrollment (with the exception of participants with limited/resectable stage IV cutaneous melanoma or RCC).
• Is participating in a clinical trial or another observational study that is evaluating the performance of another genomic test in the post-treatment surveillance setting at predicting/detecting recurrence.

Eligibility last updated 11/3/21. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria
•Clinician:

• All clinicians responsible for caring for eligible patients will be considered for inclusion in the qualitative research. 

Exclusion Criteria
•Clinician:

• If the clinician declines to participate, the patient is still eligible for the study, but qualitative evaluations will be omitted.

Inclusion Criteria
•Patient:

• Participants will be recruited from those identified by a developed electronic health record list of patients with AKI. 
• Included individuals that populate the list are those with stage III AKI (severe) during a hospitalization based on serum creatinine rise or urine output decline from Olmsted County.

Exclusion Criteria
•Patient: 

• Dementia.
• Non-English speaking.
• Expected to be dismissed to a skilled nursing facility or hospice at discharge.
• Expected to need dialysis at discharge.
• Primary Care Transitions Program enrollment.
• Transplant recipients within 100 days of transplant.
• Can only have one time enrollment.  

Eligibility last updated 1/18/22. Questions regarding updates should be directed to the study team contact.

 Inclustion Criteria:

• Patients must have a pre-identified genetic variant in an established MC4R pathway gene that contributes to obesity.

For a gene variant to be eligible for inclusion in the study, the variant must be categorized by a CLIA/CAP/ISO15189 -certified laboratory using ACMG criteria as (1) Pathogenic, (2) Likely Pathogenic or (3) a VUS. In the case where an investigator has genetic results on a patient who may be eligible for the study, but the genetics have not yet been categorized by a CLIA/CAP/ISO15189 -certified laboratory, then the Sponsor may provide testing and/or categorization through a third-party laboratory.

• Patients between the ages of 6 and 65 at the time of signing Informed Consent or Assent are eligible for the study.
• Patients must be obese, defined as BMI ≥40 kg/m2 for patients ≥18 years of age or BMI ≥97th percentile for age and gender for patients 6 up to 17 years of age based on based on the US Centers for Disease Control and Prevention criteria.
• Study participant and/or parent or guardian is able to communicate well with the Investigator, to understand and comply with the requirements of the study (including QD injection regimen and all other study procedures) and is able to understand and sign the written informed consent/assent. Patients who are unable to comply with all study procedures due to cognitive limitations or any other reason should not be enrolled into the study.
• If male or a childbearing female, including pre-pubertal females if relevant, the patient must agree to use a highly reliable form of contraception throughout the study and for 90 days following the study.
• Highly reliable acceptable forms of contraception include hormonal (i.e., oral, implantable, or injectable) AND single-barrier method (i.e., condom), or an intrauterine device (IUD) AND single-barrier method (i.e., condom) or vasectomy/vasectomized partner. True abstinence is acceptable only if it is the preferred and usual lifestyle of the patient. Female participants of non-childbearing potential, defined as surgically sterile (status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation), post-menopausal for at least 12 months (and confirmed with a screening follicle-stimulating hormone [FSH] level in the post-menopausal lab range), and failure to have achieved menarche, do not require contraception during the study. Female patients must not become pregnant and male patients must not donate sperm during and for 90 days following their participation in the study.

• Recent intensive (within 2 months) diet and/or exercise regimen with or without the use of weight loss agents including herbal medications that has resulted in > 3% weight loss.
• Use of any medication that is approved to treat obesity within 3 months of first dose of study drug (e.g., orlistat, lorcaserin, phentermine-topiramate, naltrexone-bupropion).
• Note: Glucagon-like peptide-1 (GLP-1) receptor agonists may be used up to the dose approved for the treatment of diabetes mellitus (e.g., liraglutide up to a daily dose of 1.8 mg) as long as (1) it is not being prescribed for the treatment of obesity, (2) the dose has been stable for at least 3 months prior to enrollment, (3) the patient has not experienced weight loss during the previous 3 months, AND (4) the patient intends to keep the dose stable throughout the course of the study.
• Bariatric surgery within the previous 6 months. Note: Patients with a history of gastric bypass surgery should have documented evidence of stable weight, defined as weight loss in the last 3 months of < 3% of body weight.
• Diagnosis of schizophrenia, bipolar disorder, personality disorder, major depressive disorder, or other psychiatric disorder(s) that the Investigator believes will interfere significantly with study compliance.
• Any suicidal ideation of type 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) during Screening, any suicide attempt in the past 20 years or any suicidal behavior in the last month.
• Current, clinically significant pulmonary, cardiac, or oncologic disease considered severe enough to interfere with the study and/or confound the results. Any patient with a potentially clinically significant disease should be reviewed with the Sponsor to determine eligibility.
• Has significant features of (or meets the diagnostic criteria for) a genetic syndrome that is associated with obesity, such as Tatton-Brown-Rahman syndrome (DNMT3A), Rett Syndrome (MECP2), Chung-Jansen syndrome (PHIP), Schaaf-Yang syndrome (MAGEL2), ulnar mammary syndrome (TBX3), or Rubinstein-Taybi syndrome (CREBBP).
  • Note: Although some of the genetic variants that are eligible to be enrolled into this study are associated with specific syndromes, the intent of this study is not to enroll children with significant cognitive impairment or other significant co-morbidities. Patients with the correct genetic variants, but who otherwise do not exhibit the syndrome, are eligible for enrollment.
• HbA1C > 10.0% at Screening.
• History of significant liver disease other than non-alcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH).
• Glomerular filtration rate (GFR) < 60 mL/min at Screening.
• History or close family history (parents or siblings) of melanoma, or patient history of oculocutaneous albinism.
  • Note: If the type of skin cancer is not known, then the patient should not be enrolled into the study.
• Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions (excluding non-invasive basal or squamous cell lesion), determined as part of a comprehensive skin evaluation performed by the Investigator during Screening. Any concerning lesions identified during Screening will be biopsied and results known to be benign prior to enrollment. If the pretreatment biopsy results are of concern, the patient may need to be excluded from the study.
• Patient is, in the opinion of the Study Investigator, not suitable to participate in the study.
• Participation in any clinical study with an investigational drug/device within 3 months prior to the first day of dosing.
• Patients previously enrolled in a clinical study involving setmelanotide or any previous exposure to setmelanotide.
• Significant hypersensitivity to any excipient in the study drug.
• Females who are breastfeeding or nursing.

Eligibility last updated 4/8/22. Questions regarding updates should be directed to the study team contact.

• Adults with unresectable, locally advanced or metastatic gastric or gastroesophageal junction cancer not amenable to curative therapy.
• Confirmed fibroblast growth factor receptor 2b (FGFR2b) overexpression by immunohistochemistry (IHC) (central testing result).
• Eastern Cooperative Oncology Group (ECOG) less than or equal to 1.
• Measurable, evaluable, or non-evaluable disease as long as evaluable by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
• Participant has no contraindications to mFOLFOX6 chemotherapy.
• Adequate organ and bone marrow function:
  • absolute neutrophil count greater than or equal to 1.5 times 10^9/L;
  • platelet count greater than or equal to 100 times 10^9/L;
  • hemoglobin greater than or equal to 9 g/dl;
  • aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than 3 times the upper limit of normal (ULN) (or less than 5 times ULN if liver involvement).
  • total bilirubin less than 1.5 times ULN (or less than 2 times ULN if liver involvement); with the exception of participants with Gilbert's disease);
  • calculated or measured creatinine clearance (CrCl) of greater than or equal to 30 mL/minute calculated using the formula of Cockcroft and Gault -international normalized ratio (INR) or prothrombin time (PT) less than 1.5 times ULN except for participants receiving anticoagulation, who must be on a stable dose of anticoagulant therapy for 6 weeks prior to enrollment.

• Prior treatment for metastatic or unresectable disease.
  • Note: prior adjuvant or neo-adjuvant therapy for local disease is allowed if ended more than 6 months of 1st dose.
• Prior treatment with any selective inhibitor of fibroblast growth factor.
• ibroblast growth factor receptor (FGF-FGFR) pathway.
• Known human epidermal growth factor receptor 2 (HER2) positive.
• Untreated or symptomatic central nervous system (CNS) disease or brain metastases.
• Peripheral sensory neuropathy greater than or equal to Grade 2.
• Clinically significant cardiac disease.
• Other malignancy within the last 2 years (exceptions for definitively treated disease).
• Chronic or systemic ophthalmological disorders.
• Major surgery or other investigational study within 28 days prior to first dose of study treatment.
• Palliative radiotherapy within 14 days prior to the first dose of study treatment.
• Abnormalities of the cornea that may pose an increased risk of developing a corneal ulcer.

Eligibility last updated 10/22/21. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria Part 1 and Part 2:

- Adult with unresectable, locally advanced or metastatic (not amenable to curative
therapy) histologically documented gastric or gastroesophageal junction adenocarcinoma

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1

- Measurable disease or non-measurable, but evaluable disease, according to Response
Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1)

- Participant has no contraindications to mFOLFOX6 chemotherapy or nivolumab

- Adequate organ function as follows:

- Absolute neutrophil count ≥ 1.5 x 10^9/L

- Platelet count ≥ 100 x 10^9/L

- Hemoglobin ≥ 9 g/dL without red blood cell (RBC) transfusion within 7 days prior
to the first dose of study treatment

- Aspartate aminotransaminase (AST) and Alanine aminotransaminase (ALT) <3 x upper
limit of normal (ULN) (or < 5 x ULN if liver involvement)

- Total bilirubin <1.5 x ULN (or < 2 x ULN if liver involvement or Gilbert's
disease)

- Calculated or measured creatinine clearance (CrCl) of ≥ 50 mL/minute calculated
using the formula of Cockcroft and Gault

- International Normalized Ratio (INR) or prothrombin time (PT) < 1.5 × ULN except
for participants receiving anticoagulation, who must be on a stable dose of
anticoagulant therapy for 6 weeks prior to enrollment

Additional Inclusion Criteria Part 2:

- No prior treatment for metastatic or unresectable disease except for a maximum of 1
dose of mFOLFOX6 with or without nivolumab. Prior adjuvant, neo-adjuvant, and
peri-operative therapy is allowed, provided it has been completed more than 6 months
prior to the first dose of study treatment

- Fibroblast growth factor receptor 2b (FGFR2b) ≥ 10% 2+/3+ tumor cells (TC) as
determined by centrally performed immunohistochemistry (IHC) testing, based on tumor
sample either archival (obtained within 6 months/180 days prior to signing
pre-screening informed consent) or a fresh biopsy.

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

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

• Male and female patient’s age ≥ 18 at the time of informed consent.
• Patient clinically meets indication for peripheral lung nodule biopsy and has been scheduled for robotic bronchoscopy.

Lesion Criteria:

• Pulmonary nodules of 8-50mm in largest dimension.

• Patients with known bleeding diathesis; Platelet count < 50,000.
• Current use of systemic anticoagulation or antiplatelet therapy without the ability to hold therapy for the recommended amount of time prior to an invasive procedure (aspirin monotherapy is acceptable).
• Inability or unwillingness to give informed consent.
• Pregnant or nursing females, or females of child-bearing potential who decline a pregnancy test prior to enrollment.
• Pulmonary hypertension, defined as a right ventricular systolic pressure > 50 mmHg.
• Individuals with current or recent systematic conditions, such as, acute kidney injury, or conditions that would mandate anticoagulation, such as a recent coronary stent.
• International Normalized Ratio (INR) < 1.5.
• Do Not Resuscitate (DNR) status; Do Not Intubate (DNI) status.

Eligibility last updated 10/20/21. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years and ≤ 80 years.
• High risk myeloma, which is untreated, defined as any of:
  • ISS stage 3 and gain of chr1q or del17p);
  • bi-allelic deletion of TP53;
  • t(4;14) or t(14;16) and gain of chr1q;
  • t(4;14) or t(14;16) and presence of del17p; or
  • presence of a high-risk gene expression signature on Sky92 assays (Skyline Diagnostics).
• The following laboratory values obtained ≤ 14 days prior to registration.
  • Calculated creatinine clearance (using Cockcroft-Gault equation below)* ≥ 30 mL/min;
  • Absolute neutrophil count (ANC) ≥ 1000/mm^3 (without the use of growth factors);
  • Platelet count ≥ 75000/mm^3;
  • Hemoglobin ≥ 8.0 g/dL;
  • Total bilirubin ≤ 1.5 x ULN;
  • ALT and AST ≤ 3 x ULN;
  • *Cockcroft-Gault Equation:
  • Creatinine clearance for males =
  • (140
    •age)(actual body weight in kg)/ (72)(serum creatinine in mg/dL)
  • Creatinine clearance for females =
  • (140
    •age)(actual body weight in kg)(0.85)/(72)(serum creatinine in mg/dL).
• LVEF ≥ 40%.
• ECOG performance status (PS) 0 or 1.
• Provide informed written consent. 
• Negative pregnancy test done ≤ 14 days prior to registration, for women of childbearing potential only.
  • Note: All study participants must be registered into the mandatory Revlimid REMS® program and be willing and able to comply with the requirements of the REMS® program.
  • Note: Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS® program.
• Willing to follow strict birth control measures as outlined in the protocol.
• Female subjects: If they are of childbearing potential, agree to one of the following:
  • Practice two effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of trial drug, AND must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable; OR
  • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject.  (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception).
• Male subjects: even if surgically sterilized (i.e., status post-vasectomy), must agree to one of the following:
  • Agree to practice effective barrier contraception during the entire trial treatment period and through 90 days after the last dose of trial drug, OR
  • Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable; OR
  • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject.  (Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception). 
• Willing to return to enrolling institution for follow-up during the Active Treatment Phase of the trial.
• Able to take aspirin (325 mg) daily as prophylactic anticoagulation. 
  • Note: Subjects intolerant to aspirin may use warfarin, novel oral anticoagulants, or low dose molecular weight heparin.
• Male subjects must agree not to donate sperm for at least 90 days after the last dose of study treatment.
• Willing to provide blood and bone marrow samples for planned research.
• Life expectancy > 6 months.
• Able to take aspirin (325 mg) daily as prophylactic anticoagulation.  Note: Subjects intolerant to aspirin may use warfarin, novel oral anticoagulants, or low dose molecular weight heparin.

• MGUS, smoldering myeloma, light chain amyloidosis with organ involvement
• Diagnosed or treated for another malignancy ≤ 1 year prior to registration or previously diagnosed with another malignancy and have any evidence of residual disease.  Note: Subjects with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
• If any of the following exist at screening, subject will not be eligible for trial because this trial involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
  • Pregnant women;
  • Nursing women;
  • Men or women of childbearing potential who are unwilling to employ adequate contraception (per protocol).
• Other co-morbidity which would interfere with subject's ability to participate in trial; e.g., uncontrolled infection, uncompensated heart or lung disease.
• Other concurrent chemotherapy, or any ancillary therapy considered investigational. 
  • NOTE: Bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment.
• Peripheral neuropathy ≥ Grade 3 on clinical examination or grade 2 with pain ≤ 30 days prior to registration.
• Major surgery ≤ 14 days prior to registration.
• Evidence of current uncontrolled cardiovascular conditions, including hypertension, cardiac arrhythmias, congestive heart failure, unstable angina, or myocardial infarction within the past 6 months.  Note: Prior to trial entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant.
• Known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts or Investigator's Brochure) or known sensitivity to mammalian-derived products.  Known allergies, hypersensitivity, or intolerance to trial drugs.
• NYHA II, III, IV heart failure
• Known human immunodeficiency virus (HIV) positive.
• Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]).  Subjects with resolved infection (i.e., subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels.  Those who are PCR positive will be excluded. 
  • EXCEPTION: subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.
• Known or suspected active hepatitis C infection.
• Any medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol.
• Prior radiation therapy for bony lesions or plasmacytomasKnown allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts or Investigator's Brochure) or known sensitivity to mammalian-derived products.  Known allergies, hypersensitivity, or intolerance to trial drugs.
• Inability to comply with protocol/procedures.

Eligibility last updated 3/9/22. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria;

• Pre-menopausal (21
  •50 years of age).
• Study group will consist of women seeking hysterectomy for possible adenomyosis adenomyomectomy.
• Controls will consist of women seeking hysterectomy for uterine prolapse or pelvic pain or transgender men prior to androgen treatment and whose pathology shows a uterus < 100 grams with no evidence of adenomyosis, endometriosis, or leiomyomas.

• No ua\se of GnRH analogues, aromatase inhimitors, selective E2 or P4 receptor modulators, oral contraceptives, or immunotherapy within 3 months prior to surgery in any patient.
• No history /confirmation or suspicion of autoimmune disease, fibromyalgia, endometriosis, or leiomyomas in any patient.
• No current or previous history of STDs, pelvic inflammatory disease, endometrial/cervical cancer in any patient.
• Women who do not exhibit menstrual cycles.

Eligibility last updated 10/21/21. Questions regarding updates should be directed to the study team contact.

• Demographic characteristics: ≥ 18 and ≤ 65 years of age.
• Required laboratory results: negative pregnancy test for those with female sex assigned at birth (contraception will not be required to participate in the study).
• Health status: Schizophrenia spectrum disorder (as defined by the DSM-5; Delusional Disorder, Brief Psychotic Disorder, Schizophreniform Disorder, Schizophrenia, Schizoaffective Disorder, Catatonia, Other Specified Schizophrenia Spectrum Disorder, Unspecified Schizophrenia and Other Psychotic Disorder; but NOT Substance/Medication-Induced Psychotic Disorder or Psychotic Disorder Due to Another Medical Condition) for case group; control group can have any non-schizophrenia spectrum psychiatric illness with exceptions listed below  
• Ability to understand study procedures and to comply with them for the entire length of the study.
• Has an established mental health provider (e.g. ,integrated behavioral health, Mayo W11 psychiatric longitudinal clinic) or a follow up appointment with a new mental health provider within 2 weeks of study appointment.

• Demographic characteristics: < 18 or  ≥ 65 years of age.
• Any legal history of violence, or self-reported personal history of violence in the past 10 years (history of violence is routinely checked in everyday clinical work at the time of admission, and should be apparent in medical records).
• Any active movement disorder that would interfere with quality TMS-EEG.
• Any confirmed or suspected history of a seizure.
• Any major neurocognitive disorder.
• Current diagnosis of Bipolar Disorder with psychotic features or Major Depressive Disorder with psychotic features.
• Current diagnosis of Autism Spectrum Disorder.
• No follow up appointments with a primary care physician or mental health provider.
• Positive pregnancy test
• Positive or presumptive positive urine drug screen test for alcohol or any illicit substance (with the exception of cannabis) at time of recruitment.
• Those with female sex assigned at birth with negative pregnancy test actively trying to become pregnant. Women who are lactating will be included, as long as the infant/toddler can be away from mother for the duration of the study (per mother’s judgement).
• Use of benzodiazepines; any antiepileptic drugs (including gabapentin, valproate, topiramate, carbamazepine, lamotrigine, etc.), opioids, and opioid antagonists.
• TMS or electroconvulsive treatment within the past 12 months, and any past significant adverse events with TMS exposure.
• Any past neuroanatomic findings of gross structural abnormalities; or such findings detected on the MRI. Gross structural abnormalities of the brain include aneurysms, tumors, encephalomalacia and other anatomic sequalae of trauma, infarcts, etc. Of note, in routine clinical practice significant anatomic abnormalities are rarely discovered in patients undergoing workup for psychosis.
• Any active substance use disorder, apart from cannabis and nicotine use disorder.
• Claustrophobia and inability to tolerate MRI (including MRI non-compatible implants, and movement disorders that would interfere with obtaining a quality MRI image).
• Inability or unwillingness of individual to give written informed consent.
• Individual has a legal guardian (any legal guardian) or is in the process of awaiting court hearing for potential guardianship.
• Current involuntary hospitalization as evidenced by active 72h hold; any type of ongoing commitment process (including provisional discharge, stay of commitment, awaiting commitment hearing, etc.).
• Insufficient knowledge of English.
• Any metal, electronic, or other implant that is incompatible with TMS or MRI technology.

Eligibility last updated 5/31/22. Questions regarding updates should be directed to the study team contact. 

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

Eligibility last updated 2/28/23. Questions regarding updates should be directed to the study team contact.

• Male or female, age 21-80 (inclusive) with at least 3 years of life expectancy.
• Subject plans to undergo a one-level Open or Mini-Open TLIF procedure (stabilized with pedicle screws) independent of this research protocol.
• Subject is to be treated with on-label use of an FDA-cleared TLIF cage and pedicle screw system independent of this research protocol.
• The subject has a primary diagnosis of symptomatic lumbar degeneration with or without foraminal or recess stenosis of the lumbar spine at a single level from L1/L2 to L5/S1 confirmed by subject history and radiographic imaging (CT, MRI, X-rays) with no more than a Grade 1 (< 25% translation) spondylolisthesis. Symptomatic lumbar degeneration that may be associated with a co-morbid condition such as:
  • Herniated nucleus pulposus;
  • Scarring/thickening of the ligamentum flavum, annulus fibrosus, or facet joint capsule;
  • Facet joint degeneration/osteophyte formation;
  • Spondylosis (defined by the presence of osteophytes);
  • Disc degeneration and/or annular degeneration; and/or
  • Lumbar stenosis defined by spinal cord or nerve root compression.
• Exhausted conservative treatment (e.g., bed rest, physical therapy, medications, TENS, manipulation, and/or spinal injections) for at least 3 months or has a neurologic emergency.
• Preoperative Oswestry Disability Index score > 40/100 at baseline.
• Psychosocially, mentally and physically able and willing to fully comply with this protocol including adhering to follow-up schedule and requirements and filling out forms.
• Signed informed consent.

• More than one vertebral level requiring treatment.
• revious instrumented surgery (i.e., anterior disc replacement, spinal fusion, interspinous device, etc.) at the index lumbar level or an adjacent level.
• Degenerative or lytic spondylolisthesis greater than Grade 1 (< 25% translation).
• Rotatory scoliosis at the level to be treated.
• Congenital bony and/or spinal cord abnormalities at the level to be treated.
• Subcaudal defect, disrupting the integrity of the pedicle.
• Clinically compromised vertebral bodies at the involved level due to current or past trauma; e.g., by the radiographic appearance of the fracture callus, malunion or nonunion.
• Disrupted anterior longitudinal ligament at the index level.
• Overlying thoracolumbar kyphosis (greater than or equal to 15 degrees) within one level (includes target and adjacent level) of the level to be treated.
• Back pain of unknown etiology without leg pain.
• Severe spondylosis at the level to be treated as characterized by any of the following:
  • Autofusion (solid arthrodesis) determined radiographically (CT);
  • Totally collapsed disc; or
  • Vertebral body that cannot be mobilized.
• Known allergy to cobalt, chromium, molybdenum, nickel, polyethylene, titanium, or vitamin E.
• Unable to undergo a CT scan or other radiograph assessments.
• Osteopenia: All patients will completeThe SCORE/MORES will be utilized to screen if a DEXA scan is indicated. If SCORE/MORES value ≥ 6, then a DEXA scan is required. If DEXA is required, exclusion will be defined as a DEXA bone density measured T score ≤ -1. An existing DEXA is allowed if completed within 6 months of subject screening.
• Has history of any endocrine or metabolic disorder known to affect osteogenesis (e.g., Paget's disease, renal osteodystrophy, Ehler-Danlos syndrome, or osteogenesis imperfecta).
• Insulin-dependent diabetes mellitus.
• Lactating, pregnant or interested in becoming pregnant in the next 3 years.
• Active infection – systemic or local.
• Any medical condition requiring treatment with any drug known to potentially interfere with bone/soft tissue healing or receiving radiation therapy that is expected to continue for the duration of the study.
• Body Mass Index > 40.
• Recurrent history of deep vein thrombosis, symptoms of arterial insufficiency, or thromboembolic disease.
• Systemic disease including Lupus disease, Reiter’s disease, Rheumatoid disease, AIDS, HIV, hepatitis or autoimmune disease that requires immunosuppressive therapy, including biologics, for systemic inflammation.
• Spinal tumor.
• Active malignancy: A patient with a history of any invasive malignancy (except non-melanoma skin cancer), unless he/she has been treated with curative intent and there have been no clinical signs or symptoms of the malignancy for at least 5 years.
• Any degenerative muscular or neurological condition that would interfere with evaluation of outcomes, including but not limited to Parkinson’s disease, amyotrophic lateral sclerosis (ALS), or multiple sclerosis.
• Has chronic or acute renal and/or hepatic impairment and/or failure or prior history of renal and/or hepatic parenchymal disease.
• Has a Waddell Signs of Inorganic Behavior score of 3 or greater.
• In the opinion of the investigator, the subject has a behavioral, cognitive, social or medical problem that may interfere with the assessment of the safety or effectiveness of the device.
• Current or recent history of chemical/alcohol abuse or dependency using standard medical definition of DSM-5 code.
• Currently smoking or using tobacco products, including e-cigarette products (e.g., vaping) (Use within 30 days of screening date is considered ‘current’).
• Currently pursuing or in active spinal litigation for medical negligence, or trauma, or workers compensation.
• Is a prisoner, incarcerated, or has been coerced to participate in the study that could impact the validity of results.
• Is currently participating in an investigational therapy (device and/or pharmaceutical) within 30 days prior to entering the study or such treatment is planned during the 24 months following enrollment into the study.

Eligibility last updated 7/21/22. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years old and residing in the US.
• Clinical diagnosis, based on investigator assessment, of type 2 diabetes for at least one year.
• Using a stable insulin dose for at least 3 months, to include A) basal insulin only, or B) MDI, to include CSII (including use of AID systems other than Tandem Control-IQ).
• Total daily insulin dose ≤ 200 units/day.
• Willing to use only aspart (novolog) or lispro (humalog) insulin with the study pump, with no use of concentrated insulin above U-100, long-acting basal insulin injections, or inhaled insulin.
• For females, not currently known to be pregnant If female of childbearing potential, must agree to use a form of contraception to prevent pregnancy while a participant in the study as documented in the study records. A negative serum or urine pregnancy test will be required for all females of child-bearing potential. Participants who become pregnant will be discontinued from the study. Also, participants who during the study develop and express the intention to become pregnant within the timespan of the study will be discontinued.
• HbA1c ≥ 7.5% and ≤ 12% at screening.
• Has current glucagon product to treat severe hypoglycemia (injectable or nasal) at home (will provide prescription if they do not have one).
• Be willing to exercise for 30 minutes or more at least once per week during the main phase of the study.
• Has the ability to read and understand written English.
• Investigator believes that the participant has capacity such that they can provide informed consent and can successfully and safely operate all study devices and is capable of adhering to the protocol and completing the study.

• Prior use of Tandem t:slim X2 insulin pump with Control-IQ technology.
• Two or more episodes of severe hypoglycemia (needing assistance) in the past 6 months.
• History of inpatient psychiatric treatment in the past 6 months.
• History of drug abuse (defined as any illicit drug use) or history of alcohol abuse prior to screening or unwillingness to agree to abstain from illicit drugs throughout the study.
• History of significant heart disease, lung disease, liver disease, chronic kidney disease, or other systemic disease determined by investigator to interfere with the study, or make required exercise unsafe.
• History of significant vision, hearing, or dexterity problems that will impair use of the closed loop system.
• Use of glucocorticoids, beta blockers, sulfonylureas, meglitinides or other medications specifically listed in section 8.3 of the protocol or determined by investigator to interfere with the study.
• Unstable dose of SGLT-2 inhibitor, GLP-1 receptor agonist, or other adjuvant medication or starting a new glucose lowering agent during the trial.
• Unstable dose of any medication used for weight loss or starting a new medication for weight loss during the trial.　
• Abnormal screening electrocardiogram consistent with increased risk during exercise, such as arrhythmia, ischemia, or prolonged QTc interval (> 450 ms).
• History of hemodialysis.
• History of adrenal insufficiency.
• Uncontrolled hypo- or hyperthyroidism.
• Significant diabetes related complications, based on investigator assessment.
• 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 10/26/21. Questions regarding updates should be directed to the study team contact.

• ≥ 18 years of age.
• Capacity to consent.
• Patients undergoing a clinically indicated.

• Unable or not willing to consent.
• Pregnant women.
• < 17 years of age.
• External/Internal Electrical Devices – Left ventricular Assist Device, pacemaker dependence, implantable cardioverter defibrillator, transcutaneous electrical nerve stimulation (TENS) unit, or spinal cord stimulator.  (Rational – interference with interpretation).

Eligibility last updated 10/29/21. Questions regarding updates should be directed to the study team contact.