A Randomized Phase 1/2 Trial of Low Dose Anti-thymocyte Globulin (ATG) With Subsequent Adalimumab or Verapamil in New Onset Type 1 Diabetes

Exclusion Criteria44

• Prior treatment with ATG or known allergy to ATG or rabbit-derived products.
• Local lab draw at screening:
• Immunodeficient or have clinically significant chronic lymphopenia: Leukopenia (\<3,000 leukocytes /μL), neutropenia (\<1,500 neutrophils/μL), lymphopenia (\<800 lymphocytes/μL).
• Thrombocytopenia (\<100,000 platelets/μL) or anemia (hemoglobin \< 10g/dL).
• Leukocytosis (\>14,000/mL)
• Infections:
• Ongoing infection or had recently had a major infection requiring hospitalization or intravenous antibiotics.within 30 days prior to randomization.
• Have active signs or symptoms of acute infection at the time of randomization.
• Have evidence of prior or current tuberculosis infection as assessed interferon gamma release assay (QuantiFERON), or a positive test for latent tuberculosis.
• Have evidence of current or past HIV or Hepatitis B or current Hepatitis C infection.
• History of serious bacterial, viral, fungal, or other opportunistic infections.
• Have active signs or symptoms of CMV or EBV compatible illness lasting more than 7 days within 30 days of randomization.
• Have positive CMV and/or EBV PCR test within 30 days prior to randomization.
• Have positive COVID-19 self-antigen test within 3 days of randomization.
• History of underlying cardiac disease (ex. left ventricular dysfunction, hypertrophic cardiomyopathy), certain arrhythmias (e.g. AV block, accessory pathway such as Wolff- Parkinson-White or Lown-Ganong-Levine syndromes) or abnormal ECG (unless cleared by cardiology).
• Blood pressure (either systolic or diastolic) \<5th percentile for age, gender, and height on two out of three measurements.
• Pulse \<2nd percentile for age and gender on two out of three measurements.
• History of vasovagal syncopal episodes related to hypotension.
• History of malignancies other than of skin.
• Use of medications likely to interfere with study results:
• Any immunomodulators, including systemic steroids or participation in prior research study in which a potential participant received an immunomodulatory agent (may participate if received placebo only).
• Current or previous use of Teplizumab.
• Ongoing use of medications known to influence glycemia or glucose tolerance. Only topical steroids are allowed.
• Need to use of any of the following medications during the study: beta blocker, seizure medication (carbamazepine, phenobarbital, phenytoin), other antihypertensive medications, HMG-CoA reductase inhibitors, lithium, theophylline, clonidine.
• Receipt of live vaccine (e.g., varicella, measles, mumps, rubella, cold-attenuated intranasal influenza vaccine, bacillus Calmette-Guerin, and smallpox) within the 90 days before randomization.
• Any known hypersensitivity reaction to any of the study medications or their components.
• Unable to swallow pills (tested with an inert imitation tablet in clinic at screening).
• History of significant allergy (e.g., anaphylaxis) to milk or soy proteins in the Boost drink required for study MMTT testing.
• Current use of hydroxyurea or unable to avoid hydroxyurea use during the study (interferes with accuracy of Dexcom sensor).
• Established history of allergy or severe reaction to adhesive or tape that must be used in the study.
• Participation in another treatment research study that involves diabetes care or immune modulation, unless the participant is able to confirm that they were in the placebo arm.
• Presence of a medical condition or use of a medication that, in the judgment of the investigator, clinical protocol chair, or medical monitor, could compromise the results of the study or the safety of the participant. Conditions to be considered by the investigator may include the following:
• Alcohol or drug abuse
• Untreated or inadequately treated mental illness
• Liver disease or LFTs \>2x ULN.
• Renal disease or creatinine greater than 1.5x ULN.
• Other autoimmune diseases except for stable and treated hypothyroidism
• Graves' disease, or celiac disease (e.g., symptom-free on a gluten free diet).
• Nervous system disorder including but not limited to Guillain-Barre
• Syndrome, multiple sclerosis, progressive multifocal leukoencephalopathy.
• History of multiple abdominal surgeries and/or at increased risk for bowel obstruction.
• Any clinical or laboratory conditions that the investigator feels would interfere with the study or participant safety (e.g., increased risk to pre-existing disease).
• Any lab abnormality believed to be transient may be repeated at the discretion of the site PI. If repeat value does not preclude participation, and potential participant would otherwise qualify for the study, then may proceed with enrollment per investigator discretion.
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