A Randomized Phase 1/2 Trial of Low Dose Anti-Thymocyte Globulin (Atg) with Subsequent Adalimumab or Verapamil in New Onset Type 1 Diabetes (Wave T1D)
Investigating the Effects of Low Dose Anti-Thymocyte Globulin (ATG) with Adalimumab or Verapamil in Type 1 Diabetes
Hannah Lease
Primary Investigator
Linda DiMeglio, MD
Primary Investigator
Brief description of study
The purpose of this study is to learn if a low dose of a medication called ATG, combined with either Adalimumab or Verapamil, can help the pancreas continue to make insulin for a longer time which may also help to control blood glucose. This multi-center randomized controlled trial will assess the safety and efficacy of ATG followed by either adalimumab or verapamil in preserving insulin secretion 2 years from randomization in persons aged 9 to <21 with recent-onset stage 3 T1D.
Detailed description of study
• This study is being done in people with newly diagnosed Type 1 Diabetes (T1D). We want to see if using a treatment called Anti-thymocyte Globulin (ATG), followed by either Adalimumab or Verapamil, can help people keep making insulin for a longer time which may also help to control blood glucose. The primary objective of this study is to assess the safety and efficacy of ATG followed by either adalimumab or verapamil in preserving insulin secretion 2 years from randomization in persons with T1D. The secondary objectives are to assess metabolic and safety endpoints at 2 years and at timepoints between baseline and two years.
• The three drugs used in this study, ATG, Adalimumab and Verapamil, are not approved by the Food and Drug Administration (FDA) to treat T1D. ATG is approved by the FDA to help prevent organ rejection in people who have had kidney transplants and other types of organ transplants. Adalimumab is approved to treat diseases where the body’s immune system attacks itself, like Arthritis or Crohn’s Disease. Verapamil is a drug that is approved to treat heart problems and high blood pressure. Because these drugs are not yet approved for T1D, they are called “investigational” in this study. Involvement will last about 3 years for each participant.
Eligibility of study
You may be eligible for this study if you meet the following criteria:
- Conditions: Type 1 Diabetes, T1D, Riley
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Age: 9 years - 20 years
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Gender: All
Key Inclusion Criteria:
Recent-onset stage 3 T1D diagnosed by standard ADA criteria, with the ability to be randomized within 6 months from the date of T1D diagnosis and within 37 days of Screening Visit.
- At least one positive T1D auto-antibody.
- If clearly positive (≥20% above local lab's ULN) at screening, repeat antibody testing for central lab is not required.
- Insulin auto-antibodies are only considered if exogenous insulin use is <10 days when blood is drawn.
- Must have stimulated C-peptide levels ≥0.2 pmol/mL measured during MMTT conducted prior to randomization.
- Age 9 to <21 years at the time of randomization.
- Body weight >30kg.
- BMI <95th percentile for age and gender.
- Willing to comply with intensive diabetes management.
- Female participants with childbearing potential are not currently pregnant, are willing to avoid pregnancy and breastfeeding, and to undergo pregnancy testing prior to MMTTs for the duration of the study.
- Women of childbearing potential (WOCBP) must use an acceptable form of birth control. Acceptable forms include oral/injection contraceptives, transdermal contraceptives, diaphragm, intrauterine devices, condoms with spermicide, documented surgical sterilization of either the participant or their partner or abstinence.
- Male participants with potential to father children must be willing to use abstinence or adequate contraceptive methods for the duration of the study.
- Males must agree to be sexually abstinent or use a condom and agree not to donate sperm for the treatment period and for a minimum of 1 spermatogenesis cycle (90 days after last dose of study drug) after last treatment.
- Willing to provide informed consent and child assent as applicable.
- Sufficient cognitive ability, per investigator judgment, to provide informed consent for study participation on an IRB approved consent form.
- Able to read and understand English or Spanish (both participant and legally authorized representative, if applicable).
- Must be fully vaccinated for age.
- Must have been vaccinated for flu (if currently in flu season).
- Must be willing to not receive live vaccines throughout the treatment period.
- Must be willing to not use any non-insulin glucose-lowering agents such as GLP-1 agonists (including for weight loss indication), symlin, DPP-4 inhibitors, SGLT-2 inhibitors, biguanides, sulfonylureas) for the duration of study treatment. Participants are required to go off these drugs at least 30 days prior to screening.
Key Exclusion Criteria:
- 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.
The purpose of this study is to investigate if a low dose of an investigational medication called ATG, combined with either Adalimumab or Verapamil, can help the pancreas continue to make insulin for a longer time in people with Type 1 diabetes. Type 1 diabetes is a chronic disease where the body's defense system mistakenly attacks specific cells within the pancreas, which make insulin. Insulin helps control sugar in the blood. When these cells are damaged, they cannot make enough insulin. This means people with Type 1 diabetes need to take insulin every day to keep their blood sugar at safe levels.
Participants will first receive an infusion of ATG over two days. Six weeks later, they will be randomly assigned to receive either Adalimumab, Verapamil, or a placebo for up to two years. If they respond well, treatment may continue for another year. The study includes up to 12 office visits and 6 phone contacts, where participants will undergo various tests, including blood tests, and wear a Continuous Glucose Monitor (CGM). A placebo is an inactive substance that looks like the investigational medicine but does not contain any medicine.
- Who can participate: Participants must be 9 to 30 years old, recently diagnosed with Type 1 diabetes, and have a positive T1D auto-antibody. They must meet specific health criteria, including a body weight over 30 kg, and agree to use birth control if applicable.
- Study details: Participants will receive an ATG infusion, followed by either Adalimumab, Verapamil, or a placebo. They will have regular tests and check-ups, including wearing a Continuous Glucose Monitor (CGM).
- Study timelines and visits: The study will last 3 years. The study requires 12 visits.
Interested in the study?
This study is accepting only persons who receive care at a certain clinic or doctor or who are part of an invited group. Questions about this study can be directed to the study team listed in the description or contact your doctor to see if you are eligible.
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