Targeted low-dose ATG with optional verapamil for recent-onset type 1 diabetes

Precision Administration of Anti-thymocyte Globulin With or Without Verapamil in Adolescents and Young Adults With Type 1 Diabetes

This trial will test whether giving targeted low-dose anti-thymocyte globulin (ATG), followed by or without verapamil, helps people aged 6–35 with recent-onset type 1 diabetes preserve their own insulin production.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 60 (estimated)
• Ages: 6 Years to 35 Years
• Sex: All
• Sponsor: University of Florida (other)
• Locations: 2 sites (Aurora, Colorado and 1 other locations)
• Trial ID: NCT06455319 on ClinicalTrials.gov

What this trial studies

This is a Phase 2, randomized, double-blind 1:1 trial comparing low-dose ATG to placebo in people recently diagnosed with type 1 diabetes, with participants stratified by an ex vivo biomarker that predicts response to ATG. Co-primary endpoints are the 2-hour mixed meal tolerance test (MMTT) stimulated C-peptide area under the curve (AUC) at 12 months and the change in that measure over the first 6 months. After completing the year-long randomized portion, participants enter a one-year open-label extension where they are re-randomized to receive extended-release verapamil or not, and mechanistic measures are collected. The protocol includes deep immunophenotyping, gene expression and DNA methylation analyses, and multiple biomarkers of beta cell stress, death, and prohormone processing.

Who should consider this trial

Good fit: Ideal candidates are people aged 6–35 with a type 1 diabetes diagnosis within the past 100 days, positive islet autoantibody(s), and a stimulated C-peptide of at least 0.2 pmol/mL on an MMTT done at least 21 days after diagnosis.

Not a fit: People with longer-standing diabetes, very low or absent C-peptide, or other exclusions such as recent live vaccination or unresolved EBV concerns are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, this approach could help preserve endogenous insulin production, lower HbA1c, and reduce insulin requirements in people with newly diagnosed type 1 diabetes.

How similar studies have performed: Prior studies have shown low-dose ATG can preserve C-peptide in some newly diagnosed patients and verapamil has shown C-peptide benefits, but biomarker-guided sequencing of ATG followed by verapamil is a novel, incompletely tested approach.

Eligibility criteria

Inclusion Criteria:

1. Must be \>= 6 years \<= 35
2. Must have a diagnosis of T1D for less than 100 days at randomization
3. Willing to provide Informed Consent or have a parent or legal guardian provide informed consent if the subject is \<18 years of age
4. Positive for at least one islet cell autoantibody; GAD65A, mIAA, if obtained within 10 days of the onset of insulin therapy, IA-2A, ICA, or ZnT8A
5. Must have stimulated C-peptide levels of 0.2 pmol/ml measured during a mixed meal tolerance test (MMTT) conducted at least 21 days from diagnosis of diabetes. Randomization should occur within one month (37 days) of the MMTT.
6. Subjects who are EBV seronegative at screening must be EBV PCR negative within 30 days of randomization and may not have had signs or symptoms of an EBV compatible illness lasting longer than 7 days within 30 days of randomization
7. Be at least 6 weeks from last live immunization
8. Participants are required to receive killed influenza vaccination at least 2 weeks prior to randomization when vaccine for the current or upcoming flu season is available
9. Be willing to forgo live vaccines during the treatment period and for 3 months following last dose of study drug
10. Be willing to comply with intensive diabetes management

Exclusion Criteria:

1. Be immunodeficient or have clinically significant chronic lymphopenia: (Leukopenia (\< 3,000 leukocytes /μL), neutropenia (\<1,500 neutrophils/μL), lymphopenia (\<800 lymphocytes/μL), or thrombocytopenia (\<100,000 platelets/μL).
2. Have active signs or symptoms of acute infection at the time of randomization
3. Have evidence of prior or current tuberculosis infection as assessed by PPD, interferon gamma release assay or by history
4. Be currently pregnant or lactating, or anticipate getting pregnant within the two year study period
5. Require use of other immunosuppressive agents including chronic use of systemic steroids
6. Have evidence of current or past HIV, Hepatitis B or Hepatitis C infection
7. Have any complicating medical issues or abnormal clinical laboratory results that may interfere with study conduct, or cause increased risk to include pre-existing cardiac disease, COPD, sickle cell disease, neurological, or blood count abnormalities
8. Have a history of malignancies other than skin
9. Evidence of liver dysfunction with AST or ALT greater than 3 times the upper limits of normal
10. Evidence of renal dysfunction with creatinine greater than 1.5 times the upper limit of normal
11. Vaccination with a live virus within the last 6 weeks
12. Current or ongoing use of non-insulin pharmaceuticals that affect glycemic control within prior 7 days of screening
13. Active participation in another T1D treatment study in the previous 30 days
14. Prior treatment with any investigational agent to delay beta cell loss in T1D
15. Known allergy to ATG or Verapamil
16. Prior treatment with ATG, Verapamil or known allergy to rabbit derived products
17. Any condition that in the investigator's opinion may adversely affect study participation or may compromise the study results

Where this trial is running

Aurora, Colorado and 1 other locations

• Barbara Davis Center for Diabetes — Aurora, Colorado, United States (RECRUITING)
• University of Florida — Gainesville, Florida, United States (RECRUITING)

Study contacts

• Principal investigator: Laura M Jacobsen, MD — University of Florida
• Study coordinator: Jennifer L Hosford, MPH

Conditions: Type 1 Diabetes