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Concerns arising at screening visit (any of the following):
i. Weight loss of ≥ 3.0% of baseline within the previous 6 months
ii. Abnormal blood pressure (including on treatment, if prescribed)
Systolic blood pressure < 95 mm Hg or > 160 mm Hg, and/or
Diastolic blood pressure < 65 mm Hg or > 100 mm Hg
iii. Abnormal resting heart rate ≤ 60 bpm or ≥ 100 bpm
• Sinus brady- or tachycardia that has been appropriately evaluated and considered benign by the recruit’s personal physician may be permitted at PI’s discretion
iv. Abnormal screening electrocardiogram (or if on file, performed within previous 90 d) • Non-sinus rhythm • Significant corrected QT segment (QTc) prolongation (≥ 480 ms)
New or previously unknown ischaemic changes that persist on repeat EKG:
•• ST segment elevations
•• T-wave inversions
v. Laboratory evidence of diabetes mellitus:
Hemoglobin A1c ≥ 6.5%, and/or
Fasting plasma glucose ≥ 126 mg/dL
vi. Positive qualitative serum β-hCG (human chorionic gonadotropin, beta subunit; i.e., pregnancy test) in women of childbearing potential
vii. Liver function abnormalities
Transaminases (AST or ALT) > 2.0 x the upper limit of normal, and/or
Total bilirubin > 1.25 x the upper limit of normal
viii. Abnormal screening lipids
Triglycerides > 400 mg/dL, and/or
LDL-cholesterol > 190 mg/dL
ix. Abnormal screening serum electrolytes (any of the following)
• Sodium, potassium, chloride, or bicarbonate outside of the reference range
xi. Uric acid level > upper limit of normal
xii. Glucose-6-phosphate dehydrogenase < lower limit of normal
COVID-19 precautions
i. Not fully vaccinated against COVID-19 (4 doses if age ≥ 50, 3 doses if ages 18-49)
ii. Unwillingness to comply with masking requirements per hospital policy
iii. Active, documented COVID-19 at any time after screening
Reproductive concerns
i. Women of childbearing potential not using highly effective contraception, defined as:
Surgical sterilization (e.g., bilateral tubal occlusion, bilateral oophorectomy and/or salpingectomy, hysterectomy)
Combined oral contraceptive pills taken daily, including during the study
Intrauterine device (levonorgestrel-eluting or copper) active at the time of the study
Medroxyprogesterone acetate (Depo-Provera®) injection active at the time of the study
Etonogestrel implants (e.g., Implanon®, etc.) active at the time of the study
Norelgestromin/ethinyl estradiol transdermal system (e.g., Ortho-Evra®) active at the time of the study
ii. Women currently pregnant (tested by serum and/or urine β-hCG)
iii. Women currently breastfeeding
Concerns related to glucose metabolism
i. History of having met any of the American Diabetes Association’s definitions of diabetes mellitus (i.e., overt diabetes):
Hemoglobin A1c ≥ 6.5%, or rapid rise in documented HbA1c values causing clinical concern for evolving insulin deficiency
Plasma glucose ≥ 126 mg/dL after 8-h fast
Plasma glucose of ≥ 200 mg/dL at 2 h after ingestion of a 75-g glucose load
Random plasma glucose ≥ 200 mg/dL associated with typical hyperglycemic symptoms, diabetic ketoacidosis, or hyperglycemic-hyperosmolar state
ii. History of gestational diabetes mellitus
iii. Use of antidiabetic medications within the 90 days prior to screening, including those prescribed for other indications (e.g., weight control, restoration of ovulation in of polycystic ovarian syndrome), including: • Metformin, thiazolidinediones, sulfonylureas, meglitinides, dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, sodium-glucose cotransporter 2 (SGLT2) inhibitors, amylin mimetics, acarbose, insulin
iv. Clinical concern for absolute insulin deficiency (e.g., type 1 diabetes, pancreatic disease)
Concerns related to lipid metabolism
i. Known diagnoses of familial hypercholesterolemia, familial combined hyperlipidemia, or familial hyperchylomicronemia
ii. Use of lipid-lowering drugs other than statins for primary prevention within the 90 days prior to screening, including:
Statins for secondary prevention or treatment of familial hypercholesterolemia
PCSK9 inhibitors (alirocumab, evolocumab, inclisiran) (for inclisiran, use within the previous year is exclusionary)
Fibrates (e.g., fenofibrate, clofibrate, gemfibrozil)
High-dose niacin (>100 mg daily)
Fish oils or purified supplements of omega-3 fatty acids
Vitamin E supplements
Known, documented history (i.e., not to be newly screened/tested for study purposes), at the time of screening, of any of the following medical conditions:
i. Pancreatic pathology, including but not limited to:
Pancreatic neoplasia
Chronic pancreatitis
Acute pancreatitis within the previous 5 years
Autoimmune pancreatitis
Surgical removal of any portion of the pancreas
ii. Cardiovascular disease (N.B. uncomplicated hypertension is not exclusionary)
Atherosclerotic cardiovascular disease
Stable or unstable angina
Myocardial infarction
Ischaemic or hemorrhagic stroke, or transient ischaemic attack
Carotid artery stenosis on imaging
Peripheral arterial disease (claudication)
Use of dual antiplatelet therapy (aspirin + P2Y12 inhibitor)
History of percutaneous coronary intervention
Heart rhythm abnormalities
Congestive heart failure of any New York Heart Association class
Valvular heart disease (e.g., aortic stenosis)
Pulmonary hypertension
iii. Chronic kidney disease, Stage 2 or higher (estimated glomerular filtration rate < 60 mL/min/1.73 m2), of any cause
iv. Chronic liver disease other than uncomplicated NAFLD, including but not limited to:
Advanced liver fibrosis, as determined by non-invasive testing
Cirrhosis of any etiology
Autoimmune hepatitis or other rheumatologic disorder affecting the liver
Biliopathy (e.g., progressive sclerosing cholangitis, primary biliary cholangitis)
Chronic liver infection (e.g., viral hepatitis, parasitic infestation)
Hepatocellular carcinoma
Infiltrative disorders (e.g., sarcoidosis, hemochromatosis, Wilson disease)
v. Gout
vi. Chronic viral illness (N.B. diagnosis based only on medical history; the investigators will not test for any of these viruses at any point in this study)
• Hepatitis B virus (HBV), unless previously successfully eradicated with antiviral drugs that have been discontinued for at least 90 days prior to screening
Hepatitis C virus (HCV) infection, unless previously successfully eradicated with antiviral drugs that have been discontinued for at least 90 d prior to screening
Human immunodeficiency virus (HIV) infection
vii. Malabsorptive conditions
Active inflammatory bowel disease (quiescent and off medication is acceptable)
Celiac disease (in remission on gluten-free diet is acceptable)
Surgical removal of a significant length of intestine
viii. Active seizure disorder (including controlled with antiepileptic drugs)
ix. Psychiatric diseases that…
Are or have been decompensated within 1 year of screening, and/or
Require use of anti-dopaminergic antipsychotic drugs, monoamine oxidase inhibitors, tricyclic antidepressants, or lithium
x. Glucose-6-phosphate dehydrogenase (G6PD) deficiency
Due to presence of quinine in tonic water placebo
xi. Other endocrinopathies:
Cushing syndrome (okay if considered in remission after treatment, provided that no exogenous corticosteroids are required)
Adrenal insufficiency
Primary aldosteronism
Thyroid disease
Hypothyroidism if thyroid-stimulating hormone (TSH) ≥ 10 mIU/L, with or without treatment
Hyperthyroidism (TSH < lower limit of normal), with or without treatment
xii. Venous thromboembolic disease (deep vein thrombosis or pulmonary embolism) or any required use of therapeutic anticoagulation
xiii. Active malignancy, or hormonally active benign neoplasm, except allowances for:
Non-melanoma skin cancer
Differentiated thyroid cancer (AJCC Stage I only)
Clinical concern for increased risk of volume overload or hypotension (systolic blood pressure <90 and/or diastolic blood pressure <60 mm Hg), including due to medications and/or heart/liver/kidney problems, as listed above
Use of certain medications currently or within 90 d prior to screening:
i. Prescribed medications used for any of the indications in the preceding list of excluded conditions, or their use within 90 d prior to screening, except allowances for:
Levothyroxine treatment of hypothyroidism, if TSH < 10 mIU/L at screening
Statins for primary prevention of cardiovascular disease
Use of drugs prescribed for indications other than the exclusionary diagnoses/purposes listed above (e.g., non-hydantoin antiepileptic drugs used for non-seizure indications, angiotensin converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) used for uncomplicated hypertension rather than for congestive heart failure, etc.) •• Note, as above, that antidiabetic drugs for any indication within 90 d of screening are excluded
ii. Thiazide diuretics, loop diuretics, or beta blockers for any indication
• Note, as above, that other antihypertensive drugs (e.g., ACEi/ARB, calcium channel blockers, pure alpha blockers) are permitted
iii. Vasodilating drugs for any indication: hydralazine, nitrates, phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil), minoxidil (oral)
iv. Phenytoin or fosphenytoin for any indication
v. Oral or parenteral corticosteroids (at greater than prednisone 5 mg daily, or equivalent) for more than 3 days within the previous 90 days; topical and inhaled formulations are permitted
vi. Fludrocortisone
vii. Opioids
History of weight-loss (bariatric) surgery, including:
i. Adjustable lap banding
ii. Vertical sleeve gastrectomy
iii. Roux-en-Y gastric bypass
iv. Biliopancreatic diversion
Clinical concern for alcohol overuse, including phosphatidylethanol ≥ 0.05 µmol/L at screening and/or by participant’s report of consuming more than 14 standard drinks per week for males or more than 7 standard drinks per week for females
Positive urine drug screen
Tobacco smoking currently or within the previous 6 months
History of severe infection or ongoing febrile illness within 30 days of screening
Any other disease or condition or laboratory value that, in the opinion of the investigator, would place the participant at an unacceptable risk and/or interfere with the analysis of study data.
Known allergy/hypersensitivity to any component of the medicinal product formulations (including sulfa drugs), other biologics, IV infusion equipment, plastics, adhesive or silicone, history of infusion site reactions with IV administration of other medicines, or ongoing clinically important allergy/hypersensitivity as judged by the investigator.
Concurrent enrollment in another clinical study of any investigational drug therapy or use of any biologicals within 6 months prior to screening or within 5 half-lives of an investigational agent or biologic, whichever is longer.
Source: View full study details on ClinicalTrials.gov
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