ATG + Verapamil for Type 1 Diabetes

Overseen By Jennifer L Hosford, MPH

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Florida

Must not be taking: Immunosuppressants, Systemic steroids

Disqualifiers: Immunodeficiency, Pregnancy, HIV, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

60 Participants Needed

Trial Summary

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications, but you cannot use non-insulin drugs that affect blood sugar control within 7 days before screening.

What data supports the effectiveness of the drug ATG + Verapamil for Type 1 Diabetes?

Research shows that anti-thymocyte globulin (ATG) can help preserve insulin-producing cells and reduce blood sugar levels in people with new-onset type 1 diabetes. Additionally, verapamil has been found to delay the progression of type 1 diabetes and improve the function of insulin-producing cells. ^{1 2 3 4 5}

Is the combination of ATG and Verapamil safe for humans?

ATG has been studied in humans for type 1 diabetes and has shown some safety over 1 to 2 years, with trials indicating it can preserve certain cell functions and reduce blood sugar levels. Verapamil, also known as Calan, Isoptin, or Verelan, is a medication commonly used for heart conditions and has a well-established safety profile in humans. ^{1 2 3 4 6}

How does the drug ATG + Verapamil differ from other treatments for type 1 diabetes?

The combination of ATG (Anti-thymocyte globulin) and Verapamil is unique because ATG helps reduce the autoimmune response that destroys insulin-producing cells, while Verapamil, a blood pressure medication, promotes the survival of these cells and reduces inflammation. This dual approach aims to preserve the body's ability to produce insulin, which is not addressed by standard insulin therapy alone. ^{1 4 5 6 7}

What is the purpose of this trial?

T cell directed therapy, anti-thymocyte globulin (ATG), in low doses, has been shown to lower HbA1c and preserve endogenous insulin production (measured by C-peptide) in individuals with recently diagnosed type 1 diabetes (T1D). However, not all individuals who received ATG responded to the therapy (i.e., non-responders). Additionally, use of ATG alone does not address inherent beta cell stress. A calcium channel blocker, verapamil, has demonstrated C-peptide preservation in newly diagnosed T1D. Investigators will identify those mostly likely to respond to ATG using an ex vivo predictive biomarker of response to ATG. In addition, Investigators will use sequential therapies to increase efficacy (ATG followed by verapamil) and explore synergistic mechanisms. This will be assessing with in depth immunophenotyping and quantify biomarkers of beta cell stress, cell death, and abnormal prohormone processing. Finally, novel clinical trial endpoints will be assessed for their ability to predict treatment efficacy earlier than the standard endpoint at 1 year.

Research Team

Laura M Jacobsen, MD

Principal Investigator

University of Florida

Eligibility Criteria

This trial is for individuals recently diagnosed with type 1 diabetes. It aims to find out if low doses of ATG can help control blood sugar and preserve insulin production. Participants should likely respond to ATG, as determined by a specific biomarker test.

Inclusion Criteria

I am between 6 and 35 years old.

Be willing to comply with intensive diabetes management

It has been over 6 weeks since my last live vaccine.

Exclusion Criteria

Have evidence of current or past HIV, Hepatitis B or Hepatitis C infection

Be currently pregnant or lactating, or anticipate getting pregnant within the two-year study period

Any condition that in the investigator's opinion may adversely affect study participation or may compromise the study results

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive low-dose ATG or placebo for 1 year to assess C-peptide levels

12 months

Open-label extension

Participants are re-randomized to receive verapamil or not for an additional year to explore mechanistic endpoints

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• Anti-thymocyte globulin (ATG)
• Verapamil

Trial Overview The study tests the effectiveness of anti-thymocyte globulin (ATG) alone or followed by verapamil in preserving insulin production in type 1 diabetes patients. It also explores whether combining these treatments has synergistic effects.

Participant Groups

Group I: verapamil extended release capsule Experimental Treatment 1 Intervention

Open label administration at 120, 240 or 360 mg daily based on weight and ECG findings

Group II: Anti-thymocyte globulin (ATG) intravenous infusion Experimental Treatment 1 Intervention

ATG (brand name Thymoglobulin) a polyclonal T cell antibody preparation. It will be given at low doses (0.5 mg/kg Day 1 then 2 mg/kg Day 2).

Group III: Placebo-ATG Placebo Group 1 Intervention

Saline placebo

Who Is Running the Clinical Trial?

University of Florida

Lead Sponsor

Trials

1,428

Recruited

987,000+

University of Colorado, Denver

Collaborator

Trials

1,842

Recruited

3,028,000+

University of Miami

Collaborator

Trials

976

Recruited

423,000+

Findings from Research

In a phase 2 clinical trial involving 58 participants with recent-onset type 1 diabetes, treatment with antithymocyte globulin (ATG) did not preserve β-cell function compared to placebo after 12 months, indicating it may not be an effective treatment for this condition.

While ATG treatment led to significant T-cell depletion and associated adverse events, it did not result in a difference in the incidence of infections between the ATG and placebo groups, suggesting that the safety profile may be concerning due to the high rate of severe adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antithymocyte globulin treatment for patients with recent-onset type 1 diabetes: 12-month results of a randomised, placebo-controlled, phase 2 trial. Gitelman, SE., Gottlieb, PA., Rigby, MR., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Study protocol: Minimum effective low dose: anti-human thymocyte globulin (MELD-ATG): phase II, dose ranging, efficacy study of antithymocyte globulin (ATG) within 6 weeks of diagnosis of type 1 diabetes. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Low-Dose Anti-Thymocyte Globulin Preserves C-Peptide, Reduces HbA1c, and Increases Regulatory to Conventional T-Cell Ratios in New-Onset Type 1 Diabetes: Two-Year Clinical Trial Data. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Anti-thymoglobulin (ATG) treatment does not reverse type 1 diabetes in the acute virally induced rat insulin promoter-lymphocytic choriomeningitis virus (RIP-LCMV) model. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Antithymocyte globulin treatment for patients with recent-onset type 1 diabetes: 12-month results of a randomised, placebo-controlled, phase 2 trial. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Exploratory study reveals far reaching systemic and cellular effects of verapamil treatment in subjects with type 1 diabetes. [2023]

6. Germany pubmed.ncbi.nlm.nih.gov

Antithymocyte globulin therapy for patients with recent-onset type 1 diabetes: 2 year results of a randomised trial. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Verapamil and beta cell function in adults with recent-onset type 1 diabetes. [2021]