• Obese men and women ≥ 20 and ≤ 45 years of age. 

• Diabetes or fasting plasma glucose > 126 mg/dL.
• Anemia (female subjects hemoglobin of < 11 g/dl and male subjects hemoglobin < 12 g/dl).
• Active coronary artery disease or history of unstable macrovascular disease (unstable angina, myocardial infarction, stroke, and revascularization of coronary, peripheral or carotid artery within 3 months of recruitment).
• Renal failure (serum creatinine > 1.5mg/dl).
• Chronic active liver disease (AST > 144IU/L or ALT > 165IU/L).
• Oral warfarin group medications or history of blood clotting disorders.
• Smoking.
• Pregnancy or breastfeeding.
• Alcohol consumption greater than 2 glasses/day or other substance abuse.
• Untreated or uncontrolled hypothyroidism.
• Debilitating chronic disease (at the discretion of the investigators).

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

Eligibility last updated 11/28/22. Questions regarding updates should be directed to the study team contact.

• Study subjects will be patients who meet the International Classification of Headache Disorders 3rd Edition (ICHD-3) criteria for a diagnosis of SIH or the Schievink criteria with imaging confirmed CSF-venous fistulas on DSM or CTM.
• Availability of a clinically prescribed contrast enhanced MRI positive for SIH. 
• Adult patients ≥ 18 years old.

• Patients who have a contraindication or inability to undergo the procedure (i.e., severe contrast allergy), inability to provide informed consent.
• Expected inability to complete the follow-up assessment.
• Current pregnancy.

Eligibility last updated 3/24/22. Questions regarding updates should be directed to the study team contact.

• Patient must have a diagnosis of lumbar stenosis.
• Patients must be 60 years old or older.
• Patients must have no other significant musculoskeletal, cardiovascular, psychiatric, respiratory, neurological, urinary conditions or malignant comorbidities.
• Patients who can walk 100 feet independently.
• Patients must be willing to wear Fitbit throughout the requested duration of the study.

• Patients outside the age bracket.
• Patients with a prior history of spine surgery.
• Patients with debilitating pain that is not caused by lumbar stenosis.
• Patients on narcotic medication.
• Patients with an extensive social history of alcohol abuse.
• Patients with an extensive social history of tobacco abuse.
• Patients who are not indicated for lumbar decompressive laminectomy.

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

Eligibility last updated 12/26/23. Questions regarding updates should be directed to the study team contact.

• Ability to provide informed consent for study participation.
• Clinical diagnosis of T1D (per the Investigator).
• Treatment with insulin for at least 6 months prior to the collection of the baseline continuous glucose monitoring (CGM) data.
• Same treatment regimen (MDI, an AID system, or an insulin pump without automation) for the 3 months prior to screening:
  • Current (at time of screening) rapid-acting insulin analog (RAA) in use for at least 4 weeks;
  • If AID system used, automated insulin delivery must be active > 85% of the time in the 4 weeks prior to screening;
  • If MDI used, participant must be using a long-acting basal insulin plus injecting a RAA bolus for meals, per Investigator.
• Total daily insulin dose 20 to 100 units.
• Age ≥ 18 years.
• HbA1c < 11.0%:
  • Eligibility assessment based on point-of-care or local lab value and not baseline central lab value;
  • The cohort will be limited to no more than ~ 20% having a central lab HbA1c value <7.0%.
• Participant uses real-time CGM (any type of real-time CGM) on a regular basis (at least 70% of the time in the 4 weeks prior to screening):
  • Personal CGM data will be reviewed at the site but not uploaded to the study database;
  • A potential participant who is not using CGM could start CGM as part of usual care and be assessed for eligibility after 4 weeks of CGM use.
• No use of inhaled insulin in the 3 months prior to screening.
• If female of childbearing potential, willing and able to have pregnancy testing.
• Investigator believes that the participant can safely use the study treatment and will follow the protocol 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.

• History of recent blood transfusions (within previous 3 months prior to randomization), hemoglobinopathies (sickle cell trait is not an exclusion), or any other medical conditions expected to significantly affect HbA1c measurement.
• Recent history of asthma (defined as using any medications to treat asthma within the last year), chronic obstructive pulmonary disease (COPD), or any other clinically important pulmonary disease (e.g., cystic fibrosis or bronchopulmonary dysplasia), or significant congenital or acquired cardiopulmonary disease.
• Exposure to any investigational product(s), including drugs or devices, in the 90 days prior to the start of screening:
  • Devices that are no longer investigational are acceptable.
• Any disease other than diabetes or current use (or anticipated use during the study) of any medication that, in the judgment of the Investigator, may impact glucose metabolism
• Current or anticipated acute uses of oral, inhaled or injectable glucocorticoids during the time period of the trial (topical glucocorticoid use is acceptable).
• Use of a non-insulin glucose-lowering medication within 3 months prior to signing informed consent.
• Smoking (includes cigarettes, cigars, pipes, marijuana, and vaping devices) within 3 months prior to screening.
• Pregnant or lactating, planning to become pregnant during the study, or is a woman of childbearing potential and not on acceptable form of birth control (acceptable includes abstinence, condoms, oral/injectable contraceptives, IUD, or implant); childbearing potential means that menstruation has started, and the participant is not surgically sterile or greater than 12 months post-menopausal).
• No known stage 4/5 renal failure or on dialysis.
• Taking Hydroxyurea medication.
• An event of severe hypoglycemia, as judged by the Investigator, within the last 90 days prior to screening.
• An episode of diabetic ketoacidosis (DKA) diagnosed at a health care facility or severe hypoglycemia event within the 90 days prior to screening.
• Employed by, or having immediate family members employed by MannKind, Corporation, or having a direct supervisor at place of employment who is also directly involved in conducting the clinical trial (as a study Investigator, coordinator, etc.); or having a first-degree relative who is directly involved in conducting the clinical trial.
• Have a history or current diagnosis of lung cancer.

Eligibility last updated 9/18/23. Questions regarding updates should be directed to the study team contact.

HF Inclusion Criteria (HeartShare Registry):

• Age ≥ 30 years.
• Prior diagnosis of HF in the EHR (any left ventricular ejection fraction).

Non-HF Group Inclusion Criteria (HeartShare Registry):

• Age ≥ 30 years.
• No known prior diagnosis of HF or use of loop diuretics.
• No known prior history of BNP >100 pg/ml or NTproBNP > 300 pg/ml, if prior laboratory tests are available in the EHR.

Exclusion Criteria (HeartShare Registry):

• For non-HF group: any prior known left ventricular ejection fraction <50%.
• Prior history of solid organ transplantation.
• Prior history of mechanical circulatory support.
• Prior history of non-cardiac cirrhosis.
• Inability to provide written consent to the study.

HFpEF Inclusion for the HeartShare Deep Phenotyping Cohort:

• Age ≥ 30 years.
• Left ventricular ejection fraction ≥ 50% measured by echocardiography.
• Definition of HFpEF: signs and symptoms of HF, NYHA functional class II-IV, and at least one of the following:
  • Elevated BNP (> 100 pg/ml in sinus rhythm or > 300 pg/ml in atrial fibrillation/flutter) or NTproBNP (> 300 pg/ml in sinus rhythm or > 900 in atrial fibrillation/flutter) at baseline. Choice of BNP or NTproBNP is based on availability at each clinical center;
  • Prior HF hospitalization (primary reason for the hospitalization is HF with elevated natriuretic peptide levels [using the thresholds listed above], requiring IV diuresis for HF, or pulmonary edema or pulmonary vascular congestion on chest radiography);
  • Elevated pulmonary capillary wedge pressure (PCWP) at rest (≥ 15 mmHg) or during exercise (≥ 25 mmHg for supine exercise or PCWP/cardiac output ratio ≥ 2 mmHg/L/min for upright exercise);
  • Elevated H2FPEF score26 (≥ 5) or HFA-PEFF27 score (≥ 5).

Non-HFpEF Group Inclusion Criteria (HeartShare Deep Phenotyping Cohort):

• Age ≥ 30 years.
• Left ventricular ejection fraction ≥ 50% measured by echocardiography.
• No known prior diagnosis of HF or use of diuretics for fluid management.
• No known prior history of BNP > 100 pg/ml or NTproBNP > 300 pg/ml, if prior laboratory tests are available in the EHR.
• BNP < 100 pg/ml or NTproBNP < 300 pg/ml at the time of screening. Choice of BNP or NTproBNP is based on availability at each clinical center.

Exclusion Criteria (HeartShare Deep Phenotyping Cohort):

• Life expectancy estimated to be < 1 year.
• Primary cardiomyopathy (including amyloid, hypertrophic cardiomyopathy, cardiac sarcoidosis, hemochromatosis, or other infiltrative cardiomyopathies) or pulmonary arterial hypertension (WHO Group I, III, or IV pulmonary hypertension).
• Any prior known left ventricular ejection fraction <40%, except if this occurred only in the setting of an acute tachycardia episode (e.g., acute atrial fibrillation).
• Clinically significant valvular heart disease defined as:
  • Moderate to greater aortic stenosis, pulmonic stenosis, or tricuspid stenosis;
  • Any mitral stenosis;
  • Moderate or greater aortic regurgitation;
  • Greater than moderate mitral regurgitation.
• Any planned cardiac surgery or cardiac intervention in the next 3 months.
• Alternative primary reason for symptoms of shortness of breath and exercise intolerance in HFpEF participants in the opinion of the enrolling investigator.
• Cardiac surgery, acute coronary syndrome, percutaneous coronary intervention, stroke, transient ischemic attack, or carotid intervention in the preceding 6 months prior to enrollment.
• Known symptomatic epicardial coronary artery disease that is not revascularized.
• Any non-elective hospitalization in the preceding 2 weeks.
• Prior history of solid organ transplantation.
• Prior history of chronic infection (HIV, hepatitis C, hepatitis B, tuberculosis) unless treated and not clinically active in the opinion of the enrolling investigator.
• Prior history of mechanical circulatory support.
• Prior history of non-cardiac cirrhosis.
• Estimated GFR < 20 ml/min/1.73m^2 or currently on dialysis.
• Any condition that may preclude participation or adherence to the study protocol, in the opinion of the enrolling investigator.
• Inability to provide written consent to the study.
• Current acute decompensated heart failure.
• Currently pregnant.
• Uncontrolled heart rate (> 110 bpm) at time of screening.

Eligibility last updated 5/3/23. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria (Patient/Caregiver):

• ≥ 18 years of age.
• EHR-flagged as primarily English-speaking.
• Must be able to participate in interviews or focus groups lasting up to 2 hours.
• Patient or caregiver of patient recently discharged from acute care to home or SNF.
• Patient or caregiver of patient with cognitive impairment (50% with an AD/ADRD diagnosis).

Inclusion Criteria (Clinician/Staff):

• Over 18 years of age.
• Primary language is English speaking.
• Must be able to participate in interviews or focus groups lasting up to 2 hours.
• Involved the discharge planning process for patients in acute care.

• Acute intoxication.
• Aggressive/combative behavior.
• Interpreter requirement.
• Patients hospitalized with a diagnosis of Traumatic Brain Injury (TBI).
• Subject requests not to be audio recorded during interviews.

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

Eligibility last updated 12/5/22. Questions regarding updates should be directed to the study team contact.

• ≥ 18 years of age.
• Fall into one of the following categories: clinical geneticist, genetic counselor, scientist, investigator, physician working at, or are members of, professional organizations in the spaces of genetics and/or human reproduction.
• Willing and able to participate in study activities in either Spanish or English.

• Under 18 years of age.
• Unable or lack the capacity to provide consent; Individuals who are not clinicians or scientists working at, or are members of, professional organizations in the spaces of genetics and/or human reproduction.
• Does not speak English or Spanish.

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

Eligibility last updated 12/1/22. Questions regarding updates should be directed to the study team contact.

• Human subjects will be recruited for the project from the Mayo Alzheimer’s Disease Research Center.
• Cognitively normal elderly patients.
• Patients with mild cognitive impairment.
• Patients with Alzheimer’s disease.
• Agse 18 to 100 years of age. 
• Their dementia will not be due to other medical or psychiatric problems.

• Exclude individuals with contraindications to MRI scanning such as a cardiac pacemaker, the presence of intraocular or intracranial metallic objects and MRI incompatible devices.

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

Eligibility last updated 4/19/23. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria for Newly Enrolled Participants
•CN Cohort:

• Participant may or may not have a significant subjective memory concern as reported by participant, study partner, or clinician.
• Normal memory function documented by scoring above demographically-adjusted cutoffs on the Logical Memory II subscale (Delayed Paragraph Recall, Paragraph A only) from the Wechsler Memory Scale
  •Revised (the maximum score is 25):
  • ≥ 9 for 16 or more years of education;
  • ≥ 5 for 8-15 years of education;
  • ≥ 3 for 0-7 years of education;
  • Note: cut-offs may be modified over time as the field evolves in this area.
• Mini-Mental State Exam score between 24 and 30 (inclusive) (Exceptions may be made for participants with less than 8 years of education at the discretion of the Project Director and/or Clinical Core).
• Clinical Dementia Rating = 0. Memory Box score must be 0.
• Cognitively normal, based on an absence of significant impairment in cognitive functions or activities of daily living.
• Stability of Permitted Medications for 4 weeks. In particular, participants may:
  • Take stable doses of antidepressants lacking significant anticholinergic side effects (if they are not currently depressed and do not have a history of major depression within the past 1 years);
  • Estrogen replacement therapy is permissible;
  • Gingko biloba is permissible, but discouraged;
  • Washout from psychoactive medication (e.g., excluded antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics, etc.) for at least 4 weeks prior to screening.

Inclusion Criteria for Newly Enrolled Participants
•MCI Cohort:

• Participant must have a subjective memory concern as reported by participant, study partner, or clinician.
• Abnormal memory function documented by scoring within the demographically- adjusted ranges on the Logical Memory II subscale (Delayed Paragraph Recall, Paragraph A only) from the Wechsler Memory Scale
  •Revised (the maximum score is 25):
  • ≤ 11 for 16 or more years of education;
  • ≤ 9 for 8-15 years of education;
  • ≤ 6 for 0-7 years of education;
  • Note: cut-offs may be modified over time as the field evolves in this area.
• Mini-Mental State Exam score between 24 and 30 (inclusive) (Exceptions may be made for participants with less than 8 years of education at the discretion of the Project Director and/or Clinical Core).
• Clinical Dementia Rating = 0.5. Memory Box score must be at least 0.5.
• General cognition and functional performance sufficiently preserved such that a diagnosis of dementia cannot be made by the site physician at the time of the screening visit.
• Stability of Permitted Medications for 4 weeks. In particular, participants may:
  • Take stable doses of antidepressants lacking significant anticholinergic side effects (if they are not currently depressed and do not have a history of major depression within the past 1 year);
  • Estrogen replacement therapy is permissible;
  • Gingko biloba is permissible, but discouraged;
  • Washout from psychoactive medication (e.g., excluded antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics, etc.) for at least 4 weeks prior to screening;
  • Cholinesterase inhibitors and memantine are allowable if stable for 12 weeks prior to screen;
  • Aducanumab and any other approved treatments for the neurobiology of AD if stable for 24 weeks prior to screen.

Inclusion Criteria for Newly Enrolled Participants
•DEM Cohort:

• Participant must have a subjective memory concern as reported by participant, study partner, or clinician.
• Abnormal memory function documented by scoring within the demographically- adjusted ranges on the Logical Memory II subscale (Delayed Paragraph Recall, Paragraph A only) from the Wechsler Memory Scale
  •Revised (the maximum score is 25):
  • ≤ 11 for 16 or more years of education;
  • ≤ 9 for 8-15 years of education;
  • ≤ 6 for 0-7 years of education;
  • Note: cut-offs may be modified over time as the field evolves in this area.
• Mini-Mental State Exam score between 20 and 28 (inclusive) (Exceptions may be made for participants with less than 8 years of education at the discretion of the Project Director and/or Clinical Core).
• Clinical Dementia Rating = 0.5 or 1.0.
• Meets the National Institute on Aging/Alzheimer's Association Diagnostic Guidelines for Dementia (2011).
• Stability of Permitted Medications for 4 weeks. In particular, participants may:
  • Take stable doses of antidepressants lacking significant anticholinergic side effects (if they are not currently depressed and do not have a history of major depression within the past 1 year);
  • Estrogen replacement therapy is permissible;
  • Gingko biloba is permissible, but discouraged;
  • Washout from psychoactive medication (e.g., excluded antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics, etc.) for at least 4 weeks prior to screening;
  • Cholinesterase inhibitors and memantine are allowable if stable for 12 weeks prior to screen;
  • Aducanumab and any other approved treatments for the neurobiology of AD if stable for 24 weeks prior to screen.

Inclusion Criteria for Newly Enrolled Participants
•All Cohorts:

• Geriatric Depression Scale score less than 10.
• Age between 55-90 years (inclusive).
• Study partner who has frequent contact with the participant (i.e., minimum average of 2 hours per week) and may be able to accompany the participant to clinic visits or provide information remotely (e.g. over the phone).
• Visual and auditory acuity adequate for neuropsychological testing.
• Good general health with no diseases expected to interfere with the study.
• Participant is not pregnant, lactating, or of childbearing potential (i.e., women must be two years post-menopausal or surgically sterile).
• Willing and able to participate in a longitudinal imaging study.
• Must be literate and speak English or Spanish fluently.
• Agrees to collection of blood for GWAS, APOE testing, DNA and RNA testing
• Agrees to collection of blood for biomarker testing.  The Administrative Core will collaborate with leadership from all Cores to review the blood biomarker data from the remote blood cohort and select participants to join the in-clinic cohort. See ADNI4: Remote protocol.
• Agrees to participate in the ADNI study which includes cognitive evaluation, MRI and PET scans.
• Flexibility can be made to all criteria for those with at least 8 years in a low socio-economic status (SES) neighborhood.

Inclusion Criteria for Rollover Participants - All Cohorts:

The following additional inclusion criteria apply to all diagnostic categories for rollover participants only:

• Must have been enrolled and followed in one of the following previous ADNI studies:
  • ADNIGO, ADNI2, ADNI3 for at least one year;
  • Willing and able to continue to participant in an ongoing longitudinal study. A reduced battery of tests is allowable;
  • Study partner may be available who has frequent contact with the participant (i.e., minimum average of 2 hours per week), and may be able to accompany the participant to clinic visits or provide information remotely (e.g., over the phone).

Exclusion Criteria for Newly Enrolled Participants - CN Cohort:

• Any significant neurologic disease, such as Parkinson's disease, vascular cognitive impairment/dementia, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma followed by persistent neurologic defaults or known structural brain abnormalities

Exclusion Criteria for Newly Enrolled Participants
•MCI and DEM Cohorts:

• Any significant neurologic disease other than suspected Alzheimer's disease, such as Parkinson's disease (Parkinsonian symptoms complicating MCI/AD are acceptable), vascular cognitive impairment dementia (multiple lacunes less than or equal to 1.5 cm and/or extensive white matter changes are acceptable), Huntington's disease, normal pressure hydrocephalus, brain tumor (clinically insignificant meningioma acceptable), progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma followed by persistent neurologic defaults or known structural brain abnormalities.

Exclusion Criteria for Newly Enrolled Participants
•All Cohorts:

• Additional exclusion criteria apply to all diagnostic categories for newly enrolled participants:
  • Screening/Baseline MRI brain scan with evidence of infection, or other clinically significant focal lesions. Participants with cortical strokes, not large enough to distort anatomy, multiple lacunar infarctions or extensive white matter disease are allowed;
  • Screening/Baseline MRI brain scan with evidence of large structural abnormalities that would corrupt image analytical pipelines; e.g., large hemispheric infarcts, large areas of encephalomalacia, large arachnoid cysts;
  • Unable to complete MRIs for any reason (e.g., pacemaker or other implanted metal devices, severe claustrophobia, anxiety which prevents MRI scans, too large to fit, etc.);
  • Current major depression, bipolar disorder as described in DMS-IV within the past 1 year. Psychotic features, agitation or behavioral problems within the last 3 months which could lead to difficulty complying with the protocol;
  • Currently treated with medication for obsessive-compulsive disorder or attention deficit disorder;
  • History of schizophrenia (DSM-5 criteria);
  • History of alcohol or substance disorder within the past 2 years (DSM-5 criteria);
  • Any significant systemic illness or unstable medical condition which could lead to difficulty complying with the protocol;
  • Clinically significant abnormalities in B12, or thyroid function tests that might interfere with the study. A low B12 is exclusionary, unless follow-up labs (homocysteine (HC) and methylmalonic acid (MMA)) indicate that it is  not physiologically significant;
  • Residence in skilled nursing facility;
  • Current use of specific psychoactive medications (e.g., certain antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics, etc.), at the discretion of the clinician;
  • Current use of any other exclusionary medications;
  • Investigational agents are prohibited for five half-lives or one month, whichever time period is longer, prior to entry and for the duration of the trial;
  • Participation in clinical studies involving neuropsychological measures being collected more than once time per year;
  • Female that is pregnant, lactating, or of childbearing potential;
  • Flexibility can be made to all criteria for those with at least 8 years in a low socio-economic status (SES) neighborhood.

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

Eligibility last updated 3/6/23. Questions regarding updates should be directed to the study team contact.

Subjects must meet all the following criteria for enrollment in the study:

1. Age of at least 18 years at the time of signing the informed consent.
2. Histologically proven, Grade 1-2 well differentiated, inoperable, advanced GEP-NETs. (Note:  For Part 1, eligibility will be determined based on local assessment; however, for Part 2, apart from local assessment, adequate tumor tissue must be available for retrospective central
confirmation of tumor grade.)
3. Ki67 (mitotic) index ≤20%. (Note: For Part 1, eligibility will be determined based on locally assessed Ki67 index; however, for Part 2, apart from local assessment, adequate tumor tissue must be available for retrospective central confirmation.)
4. Eastern Cooperative Oncology Group (ECOG) status 0-2.
5. Life expectancy of at least 12 weeks.
6. Subjects with functional tumors who are receiving octreotide LAR or lanreotide for symptom control must be on a stable dose for at least 12 weeks prior to enrollment (Part 1) or randomization (Part 2).
a. Subjects with nonfunctional tumors or functional tumors that do not require octreotide LAR or lanreotide for symptom control must discontinue octreotide LAR or lanreotide at
least 4 weeks prior to enrollment (Part 1) or randomization (Part 2).
7. Progressive GEP-NET (GI or pancreas) based on RECIST v1.1 following a minimum of 2 cycles and a maximum of 4 cycles of treatment with 177Lu-DOTATATE (7.4 GBq ±10% each cycle or a total cumulative dose of up to 29.6 GBq ±10%), 177Lu-DOTATOC (7.5 GBq ±10% each cycle or a total cumulative dose of up to 30 GBq ±10%), or 177Lu-HA-DOTATATE (7.4 GBq ±10% each cycle or a total cumulative dose of up to 29.6 GBq ±10%). Radiographic progression must be demonstrated within 18 months from enrollment (Part 1) or randomization (Part 2). Premature discontinuation of 177Lu-DOTATATE, 177Lu-DOTATOC, or 177Lu-HADOTATATE (i.e., 177Lu-SSA) treatment should not have been due to PD. Dose reductions for toxicity based on local labeling are allowed. No maximum time limit is defined between 177Lu-SSA treatment and enrollment (Part 1)/randomization (Part 2). Other anticancer treatments that do not meet exclusion criteria are allowed in this interval. Subjects must have progressed on or after the last non-177Lu-SSA anticancer treatment. a. CT/MRI scan should be completed within 90 days (inclusive) prior to enrollment (Part 1) or randomization (Part 2) and show disease progression compared to a previous scan obtained at least 6 months following the last 177Lu-DOTATATE/TOC or 177Lu-HADOTATATE treatment (see Exclusion Criterion #1) and within 18 months from screening (Figure 1-3). No non-SSA anticancer treatment is permitted between the most recent scan used for eligibility confirmation and the first dose of study treatment. A baseline CT/MRI scan must always be obtained within 6 weeks (42 days) prior to the first dose of study treatment for on-study response assessment (the most recent scan for confirmation of progression may be used as the baseline scan if obtained prior to enrollment/randomization and within 42 days prior to the first dose of study treatment).
b. For subjects on octreotide LAR or lanreotide, progression should be documented while
the subject was on a fixed dose of octreotide LAR or lanreotide.
c. There must be at least 1 SSTR-PET imaging-positive (using a regulatory agency-approved imaging method, e.g., 68Gallium [68Ga] or 64Copper [64Cu]-based), measurable site of disease (according to RECIST v1.1) and no RECIST v1.1 measurable metastatic lesions that are SSTR imaging-negative. Assessment of SSTR expression must be within 90 days (inclusive) prior to enrollment (Part 1) or randomization (Part 2) without any intervening non-SSA anticancer treatments for GEP-NET.
d. Tumor uptake observed in each RECIST v1.1 measurable lesion using a regulatory agency-approved SSTR-PET imaging method must be greater than the liver uptake observed on regulatory agency-approved SSTR-PET imaging (i.e., Krenning score 3 or 4) (Hope et al.
2019), to be centrally confirmed in Part 2.
8. Part 2: Subject is a candidate for therapy with 1 of the following SoC options:
a. Everolimus 10 mg daily by mouth
b. Sunitinib 37.5 mg daily by mouth
c. High-dose octreotide LAR 60 mg Q4W by intramuscular (i.m.) injection
d. High dose frequency lanreotide 120 mg every 2 weeks (Q2W) by deep subcutaneous (s.c.) injection.
9. Adequate renal function, as evidenced by creatinine clearance (CrCl) ≥50 mL/min (calculated using the Cockcroft-Gault formula) (Cockcroft and Gault, 1976) (Appendix 7)
10. Adequate hematologic function, defined by the following laboratory results:
a. Part 1: Hemoglobin concentration ≥5.6 mmol/L (≥9.0 g/dL); absolute neutrophil count (ANC) ≥1500 cells/µL (≥1500 cells/mm3 ); platelets ≥100 x 109/L (100 x 103/mm3)
b. Part 2: Hemoglobin concentration ≥5.0 mmol/L (≥8.0 g/dL); ANC ≥1000 cells/µL (≥1000 cells/mm3); platelets >100 x 109
/L (100 x 103/mm3).
Note: Colony-stimulating factors, platelet-production stimulators and/or transfusions within 4 weeks prior to screening are not permitted to meet these criteria.
11. Total bilirubin ≤3 x upper limit normal (ULN)
12. Serum albumin ≥3.0 g/dL unless prothrombin time is within the normal range
13. For women of childbearing potential (WOCBP):
a. Negative serum pregnancy test within 48 hours prior to the first dose of study treatment
b. Agreement to use barrier contraception and a second form of highly effective contraception (Clinical Trials Facilitation Group [CTFG] 2014) while receiving study treatment and for 6 months following their last dose of study treatment. Alternatively, total abstinence is also considered a highly effective contraception method when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable
methods of contraception.
c. A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥12 continuous months of amenorrhea [no menstrual
bleeding of any kind, including menstrual period, irregular bleeding, spotting, etc.] with no identified cause other than menopause), and has not undergone surgical sterilization
(total hysterectomy, or bilateral tubal ligation or bilateral oophorectomy at least 6 weeks before taking study treatment).
14. Sexually active male subjects must use a condom during intercourse while receiving study treatment and for 3 months after the last dose of the study treatment and should not father a child during this period. 
a. Male study participants whose sexual partners are WOCBP must also agree to use a second form of highly effective contraception (CTFG 2014) while receiving study treatment and for 3 months following their last dose of RYZ101. Alternatively, total abstinence is also considered a highly effective contraception method when this is in line with the preferred and usual lifestyle of the subject.
b. A condom is required to be used also by vasectomized men as well as during intercourse with a male partner to prevent delivery of the drug via seminal fluid.
15. Able to read and/or understand the details of the study and provide written informed consent prior to any study-specific assessments and procedures commence.

Subjects who meet any of the following criteria will be excluded from the study:

1. Subjects with a GEP-NET deemed nonresponsive to PRRT, defined as no disease control (PR,
CR, or SD) achieved for at least 6 months following the last dose of prior 177Lu-DOTATATE/TOC or 177Lu-HA-DOTATATE treatment.
2. Known hypersensitivity to 225Actinium, 68Gallium, 64Copper, octreotate, or any of the excipients of DOTATATE imaging agents
3. Part 1: Prior treatment with alkylating agents
4. Prior radioembolization
5. Any surgery, chemoembolization, and radiofrequency ablation within 12 weeks prior to first dose of study treatment
6. Use of anticancer agents within the following intervals prior to the first dose of study treatment:
a. PRRT: within <6 months ( 177Lu-DOTATATE/TOC or 177Lu-HA-DOTATATE only, as described in Inclusion Criterion #7)
b. Chemotherapy: within <6 weeks
c. Small molecule inhibitors: within <4 weeks
d. Biological agents: within 4 weeks.
7. Prior radiation therapy as defined below:
a. Part 1: Any prior external beam radiation therapy, including stereotactic body radiation therapy (SBRT)
b. Part 2: Any of the following:
i. Radiation therapy within 6 weeks prior to study enrollment
ii. Prior external beam radiation therapy to more than 25% of the bone marrow
8. Prior participation in any interventional clinical study within 30 days prior to first dose of study
treatment
9. Current somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study
10. Significant cardiovascular disease, such as New York Heart Association (NYHA) Class ≥II heart failure
a. Subjects with a known left ventricular ejection fraction (LVEF) <40% will be excluded.
b. Subjects with known coronary artery disease, congestive heart failure not meeting the above criteria, or LVEF <50% must be on a stable medical regimen that is optimized in
the opinion of the treating physician.
c. QT interval corrected for heart rate using Fridericia’s formula (QTcF) >470 ms for females and >450 ms for males, demonstrated by the average value of 3 consecutive ECGs
11. Resistant hypertension, defined as persistent uncontrolled blood pressure (BP) >140/90 mmHg
while on optimal doses of at least 3 antihypertensive medications with 1 being a diuretic (Whelton et al. 2018). Patients with baseline hypertension may be eligible after initiation of anti-hypertensive therapy.
12. Uncontrolled diabetes mellitus as defined by hemoglobin A1C (HgB A1C) ≥8%
13. Have a history of primary malignancy within the past 3 years other than (1) GEP-NET, (2) adequately treated carcinoma in situ or non-melanoma carcinoma of the skin, (3) any other curatively treated malignancy that is not expected to require treatment for recurrence during participation in the study, or (4) an untreated cancer on active surveillance that may not affect the subject’s survival status for ≥3 years based on clinician assessment/statement and with Medical Monitor approval.
14. Known brain, meningeal or spinal cord metastases. In Part 2, subjects with previously treated brain metastases will be allowed if the following conditions are met: (a) there is no evidence of central nervous system (CNS) progression for at least 6 months as assessed by local MRI for brain metastasis during screening; (b) the subject has recovered from acute side effects of radiotherapy; and (c) the subject is receiving a stable or decreasing dose of steroids.
15. For subjects with functional tumors that require treatment with SSAs for symptom control:
a. Any subject receiving treatment with short-acting octreotide, which cannot be interrupted for 24 hours before the administration of RYZ101.
b. Any subject receiving treatment with octreotide LAR or lanreotide, which cannot be interrupted for at least 4 weeks before the administration of RYZ101.
SSAs can be transitioned to short-acting SSAs for these 4 weeks. Long-acting SSAs can be re-started as soon as 4 hours after a RYZ101 infusion.)
16. Subject requires other treatment that in the opinion of the investigator would be more appropriate than the therapy offered in the study 
17. Pregnancy or lactation
18. Unable or unwilling to comply with the requirements of the study protocol
19. PRRT other than 177Lu-DOTATATE/TOC or 177Lu-HA-DOTATATE as described in Inclusion Criterion #7
20. Any condition requiring systemic treatment with high-dose glucocorticoids (≥20 mg prednisone per day or equivalent) within 14 days prior to first dose of study treatment and/or which cannot be stopped while on study (unless solely for the purpose of adrenal replacement). Inhaled or topical steroids and single dose of steroids as pre-medication for CT scans with contrast are permitted.

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

Eligibility last updated 11/17/23. Questions regarding updates should be directed to the study team contact.

• 18 years of age or older at the time of 1st interview.
• English-speaking.
• Self-reported non-cisgender.

• < 18 years of age.

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

Eligibility last updated 6/29/23. Questions regarding updates should be directed to the study team contact.

• All patients with rheumatoid arthritis (RA) diagnosed after 1995:
  • Diagnosis defined as a clinical diagnosis by a rheumatologist.

• Sustained remission (> 6 months) SDAI < 3.3 + normal CRP and no swollen joints.
• Stable DMARD regimen for > 6 months (bDMARD, csDMARD or combination).
• Decision to taper DMARDs by physician and patient.

• No Glucocorticoid use at inclusion.

Eligibility last updated 7/19/22. Questions regarding updates should be directed to the study team contact.

- For female participants: both pre-/peri- and postmenopausal status is allowed.

a. postmenopausal due to surgical or natural menopause requires at least 1 of the following:

i. prior bilateral oophorectomy or ovarian ablation;
ii. age ≥ 60 years;
iii. age < 60 years, amenorrheic for at least 12 months in the absence of ovarian function suppression (OFS), and FSH and estradiol levels in the postmenopausal range

b. pre-/peri-menopausal patients must agree to the following:

i. have a negative serum pregnancy test at baseline, within 14 days prior to Visit 1;
ii. if patient is premenopausal or peri-menopausal at enrollment, agree to use OFS with any locally approved GnRH agonist (received monthly and initiated at least 28 days prior to Visit 1) if receiving study treatment with imlunestrant or an AI.

Note: Participants established on a less frequent (that is, 3-month) GnRH agonist administration schedule will be permitted, if considered by the investigator to have adequate OFS based on serial estradiol and FSH assessments. iii. if patient is pre-menopausal or peri-menopausal at enrollment, agree to use highly effective, medically approved precautions to prevent pregnancy during the study and for 6 months following the last dose of study treatment.

- Have a Performance Status of 0 or 1 on the Eastern Cooperative Oncology Group scale.

- Have adequate organ function.

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

Eligibility last updated 10/24/23. Questions regarding updates should be directed to the study team contact.

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

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

• Age ≥ 18 years.
• A clinician-diagnosed Type 1, Type 2, or gestational diabetes.
• Receiving diabetes care by any clinician at the Division of Endocrinology.
• Use any treatment to achieve glycemic control.
• Users of any form of digital device or software for diabetes management.
• Ability to read, speak, and understand English.
• Access to telephone/videoconferencing technology for interviews or ability to meet study staff in person for an interview.
• Ability and willingness to participate in all study related surveys and questionnaires.

• Patients for whom caregivers are the main users of digital tools in support of the patient’s care.
• Participants who, in the opinion of the research staff, exhibit clinically significant cognitive or memory (e.g., the participant has trouble holding a conversation, or the participant exhibits signs of disorientation) or sensorial impairment that limits the participant’s ability to give informed consent.

Eligibility last updated 7/26/23. Questions regarding updates should be directed to the study team contact.

• Adult female patients (18-70 years old) with symptomatic macromastia scheduled for breast reduction using a Wise pattern incision design.

• Exclusion criteria include inability to provide informed consent, medical or surgical history precluding breast reduction, history of significant chronic pain requiring daily use of opioid or nonopioid analgesics, pregnancy, concomitant non-breast surgical procedure, previous chest wall irradiation, previous breast implant, breast reduction or breast lift surgery, known allergy to bupivacaine or liposomal bupivacaine, liver or kidney dysfunction, use of antiplatelet or anticoagulation therapy.

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

Eligibility last updated 1/11/23. Questions regarding updates should be directed to the study team contact.

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

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

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

Exclusion Criteria: 

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

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

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

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

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

• Positive SARS-CoV-2 PCR in a Mayo Clinic Employee.
• Able to complete swab within five days of initial positive test.

• Hospitalization at the time of diagnosis.
• Inability to complete nasopharyngeal and mid-turbinate swabs.

Eligibility last updated 12/29/23. Questions regarding updates should be directed to the study team contact.

• Individuals ≥ 18 years of age.
• Clinicians and interpreters with experience in engaging with patients with Limited English Proficienct (LEP) and complex care medical needs.

• Individuals < 18 years of age.
• Those without experience engaging with patients with LEP and complex care medical needs.

Eligibility last updated 3/18/22. Questions regarding updates should be directed to the study team contact.

Note:  Clinically node-positive disease is classified as cN1-3. cN1: without matted nodes, even if several/multiple appear matted on ultrasound or MRI; cN2: clinically fixed or
matted nodes on examination or clinically or imaging-detected internal mammary node involvement.

- Clips or fiducial placement within the biopsy-proven axillary lymph node and breast primary tumor are required.

- Multifocal and multicentric disease is permitted; however only one breast tumor may be preoperatively boosted.

--Note: For patients with multifocal disease and are randomized to receive a preoperative RT boost, all sites of multifocal disease should be contained within the
pre-operative boost volume. Subsequently, these patients will not need a post-op boost.

- Synchronous bilateral invasive breast cancer is permitted; however only one breast tumor may be preoperatively boosted.

- No indication of distant metastases. Staging scans are not required and are per the discretion of the treating physician.

- Neoadjuvant chemotherapy (NAC) with paclitaxel, dose-dense doxorubicin and cyclophosphamide (dd AC) is planned.

Note: For TNBC patients, administration of carboplatin with paclitaxel, either weekly AUC 1.5 or q3 wk AUC 5, is required.

- The boost volume is determined to be able to meet study dose constraints by the treating radiation oncologist.

- Breast-conserving surgery or mastectomy +/- reconstruction is planned following NAC.

- ECOG performance status score of 0 or 1.

- Have adequate organ function as defined in the following table. Bloodwork must be collected within 10 days prior to the start of study treatment.

- Hematological --- Absolute neutrophil count (ANC) ≥1500/µL

- Platelets ≥100 000/µL

- Hemoglobin ≥9.0 g/dL or ≥ 5.6 mmol/La

- Renal

--- Creatinine ≤1.5 × ULN OR Measured or calculated b creatinine clearance (GFR can also be used in place of creatinine or CrCl) OR ≥30 mL/min for participant
with creatinine levels >1.5 × institutional ULN

- Hepatic

- Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN

- AST (SGOT) and ALT (SGPT) ≤2.5 × ULN

- Coagulation

- International normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time (aPTT)

- ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants

- ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase);

AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal.

- Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks.

- Creatinine clearance (CrCl) should be calculated per institutional standard.

- Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for the administration of specific chemotherapies.

- A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

-- a) Not a woman of childbearing potential (WOCBP) OR b) A WOCBP who agrees to follow the contraceptive guidance throughout the study and for at least 4 months after the
last dose of pembrolizumab in such a manner that the risk of pregnancy is minimized.

- A male participant must agree to use a contraception as detailed in Appendix A of this protocol during the treatment period and for at least 4 months after the last dose of
after the last dose of study treatment and refrain from donating sperm during this period.

- Willingness to adhere to the study visit schedule and the prohibitions and restrictions specified in this protocol.

- Willingness to undergo mandatory research biopsy of the breast tumor between weeks 2-3 of Cycle 1.

- Written informed consent obtained from participant and ability for participant to comply with the requirements of the study.

- Patients unable to read/write English are eligible to participate in the overall study, but will not be required to participate in the Patient-Reported Outcome
questionnaires.

Note: No HIV testing is required unless mandated by local health authorities.

- Known active Hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] is detected).

Note:  Testing for hepatitis B or hepatitis C is not required, unless mandated by local health authorities or institutional guidelines.

- Has received a live vaccine within 30 days prior to the first dose of study drug.  Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza
vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.

- Has had an allogenic tissue/solid organ transplant

- A WOCBP who has a positive urine pregnancy test within 14 days before study registration. If the urine test cannot be confirmed as negative, a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.

Note: If the screening pregnancy test was conducted >72 hours prior to the first dose of study treatment, pregnancy status must be confirmed negative within 72 hours prior to treatment initiation

- Prohibited Treatments and/or Therapies:Use of immunosuppressants and/or systemic corticosteroids is exclusionary, except the following in the absence of active
autoimmune disease:

- As premedication for chemotherapy

- For the prevention of nausea in the three days following chemotherapy

- Participants are permitted the use of corticosteroids with minimal systemic absorption (e.g., topical, ocular, intra-articular, intranasal and inhaled)

- Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent permitted

- Adrenal replacement steroid doses including doses >10 mg daily prednisone is permitted

- A brief (less than 3 weeks) course of corticosteroids for prophylaxis (e.g., CT scan premedication against contrast dye allergy) or for treatment of
non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by a contact allergen is permitted (used in the management of cancer or
non-cancer-related illnesses). However, use of corticosteroids is allowed for the treatment of immune-related Adverse Events (irAEs), or adrenal insufficiency.

Eligibility last updated 8/25/23. Questions regarding updates should be directed to the study team contact.

• Aged 18 or over.
• Chronic Kidney Disease stage 4 or 5 at time of enrollment.

• Patients who are unable to read and write in English or with barriers to informed consent (e.g., cognitive impairment) will be excluded.

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

Eligibility last updated 3/21/23. Questions regarding updates should be directed to the study team contact.

• ≥ 20 years of age.
• Last chemotherapy more than 3 years ago.
• Scheduled to receive moderate to highly emetogenic chemotherapy with or without targeted therapies including immunotherapies.

• Concurrent radiation therapy.
• Concurrent antibiotic treatment.

Eligibility last updated 10/5/22. Questions regarding updates should be directed to the study team contact.

• the patient has a DaTscan image, obtained within 1 year (preferably within 6 months) before screening, that shows normal striatal uptake; and
• the patient has a clinical diagnosis (made by a board-certified neurologist who is qualified by training and experience in the diagnosis of movement disorders) that is consistent with the DaTscan image.

For Part 2 (if applicable):

• the patient has a DaTscan image, obtained within 1 year (preferably within 6 months) before screening, that shows abnormal (unilateral or bilateral reduced) striatal uptake; and
• the patient also has a confirmed clinical diagnosis of a dPS (such as Parkinson's disease, multiple system atrophy, corticobasal degeneration, progressive supranuclear palsy, etc.) made by a board-certified neurologist who is qualified by training and experience in the diagnosis of movement disorders; and
• the diagnosis is consistent with the DaTscan image.

- The patient is male or female, ≥18 years of age, of any race and ethnicity.

- The patient is able and willing to comply with study procedures and signed and dated informed consent is obtained.

- If the patient is a woman of childbearing potential*, she must use a highly effective method of contraception** from Screening until 30 days after the last administration
of Altropane, and the results of a serum or urine human chorionic gonadotropin (hCG) pregnancy test, performed at Screening and on the day of Altropane administration
(with the result known before Altropane administration), must be negative.

* A woman of childbearing potential is neither post-menopausal nor surgically sterile.  Post-menopausal means having had no menses for at least 12 months without an
alternative medical cause. Surgically sterile means having had a documented hysterectomy, bilateral salpingectomy, or bilateral oophorectomy, or any combination of these.

** A highly effective method of contraception is one that has a failure rate of less than 1% per year when used consistently and correctly; such methods include combined
(estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal); progestogen-only
hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable); intrauterine device; intrauterine hormone-releasing system; bilateral
tubal ligation/occlusion; vasectomized partner (with medical confirmation of success); and abstinence from heterosexual intercourse involving a woman of childbearing potential.

- If the patient is a male*** with a sexual partner who is a woman of childbearing potential*, he and his partner must use adequate contraception** from Screening until
30 days after the last administration of Altropane.

(***A male is considered fertile after puberty unless permanently sterile by bilateral orchidectomy, or vasectomized with confirmation of success.)

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

Eligibility last updated 11/15/23.  Questions regarding updates should be directed to the study team contact.

• Myelopathy secondary to Progressive MS.
• No clinical or radiologic MS relapses for > 5 years.
• EDSS score of 6.5 (constant bilateral assistance required to walk about 20 meters without resting) as assessed by a Neurologist with a specialty in MS.
• Able to ambulate 10 feet independently with or without gait aid use.
• At least 21 years of age.
• No changes to spasticity medications or dalfampridine over the last 3 months.

• Currently a prison inmate, or awaiting trial, related to criminal activity.
• Pregnancy at the time of enrollment.
• History of chronic and/or treatment resistant urinary tract infection.
• Spasticity (grade of 4) measured bilaterally in two muscle groups using Modified Ashworth Scale (MAS). Muscle groups tested will include bilateral knee flexors, extensors; ankle plantarflexors, dorsiflexors.
• Unhealed decubitus ulcer.
• Unhealed skeletal fracture.
• Receiving diathermy treatment.
• Active participation in an interventional clinical trial.
• Any illness or condition which, based on the research team’s assessment, will compromise the patient’s ability to comply with the protocol, patient safety, or the validity of the data collected during this study.
• History of coagulopathy or other significant cardiac or medical risk factors for surgery.
• Ventilator-dependent respiration.
• Diagnosed with cardiopulmonary dysfunction (e.g., chronic obstructive pulmonary disease, cardiac failure, or heart arrhythmia).
• Untreated clinical diagnosis of depression.
• History of frequent hypotension characterized by light headedness, or loss of consciousness.
• History of frequent hypertension characterized by headache, or bradycardia.
• Any active, implanted medical device.
• Treatment of chemodenervation and/or neurolysis during the trial, or within 6 months of initiating the trial.

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

Eligibility last updated 4/13/23. Questions regarding updates should be directed to the study team contact.

Cohort A will consist of epilepsy of unknown cause (high pretest probability):

• ≥ 18 years of age.
• Focal epilepsy diagnosis.
• Onset of epilepsy after age 5.
• No known cause of epilepsy OR presence of hippocampal sclerosis on MRI and;
• Brain MRI completed prior to enrollment.

Cohort B will consist of epilepsy of known cause (medium pretest probability):

• Age above 18.
• Focal epilepsy diagnosis.
• Known cause of epilepsy including any of the following:
  • confirmed viral;
  • bacterial or parasitic CNS infection;
  • traumatic brain injury, stroke;
  • intraventricular hemorrhage;
  • hypoxic-ischemic encephalopathy;
  • neurocutaneous syndrome;
  • confirmed inborn error of metabolism;
  • confirmed genetic and chromosomal developmental encephalopathy;
  • confirmed genetic epilepsy;
  • malformation of cortical development;
  • neoplasia;
  • neurodegenerative disease.
• Brain MRI completed prior to enrollment.

Cohort C will consist of idiopathic genetic generalized epilepsy (low pretest probability):

• Age above 18.
• Idiopathic generalized epilepsy (juvenile myoclonic epilepsy, juvenile absence epilepsy or generalized tonic-clonic seizures alone).
• Brain MRI completed prior to enrollment.

Exclusion Criteria

Cohort A :

• Contraindication for a lumbar puncture (i.e., intracranial mass, bleeding diathesis, spinal developmental anomalies, or local skin infection involving the lower back).
• Evidence of progressive neurological illness.
• Prior epilepsy surgery.
• Known diagnosis of autoimmune encephalitis.
• Prior treatment with immunosuppressive treatment for neurological symptoms.

Within Cohort A, a sub-cohort with probable autoimmune epilepsy (very high pretest probability
•Cohort A-1) will be selected with the following criteria:

• Seizure onset in the last 1 year.
• At least 3 out of the following 6 criteria:
• High frequency of seizures (at least 4/month for the last 3 months);
• Antiepileptic drug (AED) resistant (to at least 2 past and/or current AEDs);
• Comorbid depression and/or psychosis requiring psychotropic medication;
• History of status epilepticus;
• Seizures with autonomic semiology defined as any of the following (on history):
  •     cardiovascular (tachycardia, bradycardia, cardiac arrhythmia);
  •     respiratory (cough, hyperventilation, apnea);
  •     gastrointestinal (epigastric sensation, nausea, vomiting);
  •     thermoregulatory, vasomotor and secretory (fever, piloerection, flushing, hypersalivation, spitting);
  •     genitourinary (urinary urge or incontinence).
•  Fulminant onset of epilepsy characterized by any of the following:
•      status epilepticus;
•      ii. viral prodrome (fever, sore throat, runny nose);
•      iii. cognitive decline noted in the first 3 months following onset of seizures;
•      iv. new onset psychiatric symptoms (depression and/or anxiety and/or psychosis) in the first 3 months following onset of seizures.

Cohort B and C: 

• Contraindication for a lumbar puncture (i.e. intracranial mass, bleeding diathesis, spinal developmental anomalies, or local skin infection involving the lower back).
• Prior epilepsy surgery.
• Known diagnosis of autoimmune encephalitis.
• Prior treatment with immunosuppressive treatment for neurological symptoms.

Eligibility last updated 6/17/22. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 6/13/23. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 11/3/23. Questions regarding updates should be directed to the study team contact.