Low-Dose ATG for Type 1 Diabetes

(TN28 Trial)

Recruiting at 21 trial locations

Overseen By Melissa A Parker, MHA

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

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: 2

Duration: 2 days

101 Participants Needed

Trial Summary

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

The trial does not specify if you need to stop taking your current medications, but it does exclude those using non-insulin drugs that affect blood sugar control within 7 days of screening. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug Antithymocyte Globulin (ATG) for treating type 1 diabetes?

Research shows that Antithymocyte Globulin (ATG) may help preserve the function of insulin-producing cells in people with new-onset type 1 diabetes, as seen in studies that reported positive results over 12 months and 2 years. ^{1 2 3 4 5}

Is low-dose ATG safe for humans?

Antithymocyte globulin (ATG) has been used in various conditions like type 1 diabetes and aplastic anemia. While it can cause mild reactions like fever and chills, serious side effects are rare but can include severe allergic reactions and lung issues. It's important that ATG is given by experienced doctors in specialized centers to manage any potential risks. ^{1 2 3 6 7}

How does the drug Antithymocyte Globulin (ATG) differ from other treatments for type 1 diabetes?

Antithymocyte Globulin (ATG) is unique because it targets the immune system by depleting T cells, which are responsible for attacking insulin-producing cells in type 1 diabetes. This approach aims to preserve the function of the remaining insulin-producing cells, potentially reducing the need for insulin therapy. ^{1 2 4 8 9}

What is the purpose of this trial?

A multi-center, placebo-controlled, double blind, 2:1 randomized control clinical trial testing low-dose ATG vs. placebo in subjects with a 2 year 50% risk of progression to stage 3 T1D.

Eligibility Criteria

This trial is for people aged 12-35 with a high risk of developing stage 3 Type 1 Diabetes, as indicated by specific blood markers. They must be healthy, not pregnant, willing to avoid live vaccines and comply with COVID-19 safety measures. Participants cannot have certain infections or immune conditions.

Inclusion Criteria

Willingness to comply with study directed social distancing and protection from SARS-Cov-2 infection

I have received or will receive the flu shot at least 2 weeks before joining the study.

I am up to date on vaccinations and have no untreated health issues.

Exclusion Criteria

My hemoglobin levels are below the normal range for my age and gender.

You have had tuberculosis in the past or currently have tuberculosis.

My autoimmune thyroid or celiac disease has been under control for the last 6 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive low-dose ATG or placebo intravenously over two days

2 days

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including general and laboratory assessments

4 years

Regular follow-up visits

Long-term follow-up

Additional follow-up visits for participants enrolled in the first year if progression to stage 3 T1D does not occur

2 years

Treatment Details

Interventions

• Antithymocyte Globulin
• Placebo (for ATG)

Trial Overview The study tests if low-dose Antithymocyte Globulin (ATG) can prevent progression to stage 3 Type 1 Diabetes compared to a placebo. It's double-blind and participants are randomly assigned in a ratio of two ATG recipients for every one placebo recipient.

Participant Groups

Group I: Antithymocyte globulin (ATG) Experimental Treatment 1 Intervention

Antithymocyte globulin (ATG) will be intravenously administered over two days, with a total of 2 infusion periods. The first infusion is given at baseline visit (day 1), the second is given the next day at baseline visit (day 2). Body weight at baseline (Day 0- admission for the ATG/placebo infusion) will be used in calculating the doses for all infusions. The first dose (0.5mg/kg) will be infused over a minimum of 4 hours, and the second dose (2mg/kg) over a minimum of 4 hours with a maximum infusion time for each infusion of 10 hours. The second dose should be given no less than 12 and no more than 30 hours from the start of the first infusion. The final prepared product is to be labeled to protect the blind. Infusions may be administered either in a hospital or outpatient setting at the investigator's or institutions discretion.

Group II: Placebo Placebo Group 1 Intervention

0.9% Sodium Chloride Injection USP ("Normal" saline) is to be dispensed as the placebo for this study. The placebo is to be prepared dispensing an infusion bag of 0.9% Sodium Chloride Injection USP ("Normal" saline) with no additives (no ATG, no premedications) and label the product to protect the blind. The placebo will also be administered over a minimum of 4 hours for the first and second doses with a maximum infusion time of 10 hours. The second dose of the placebo arm should be given no less than 12 and no more than 30 hours from the start of the first infusion. Infusions may be administered either in a hospital or outpatient setting at the investigator's or institutions discretion.

Who Is Running the Clinical Trial?

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Lead Sponsor

Trials

2,513

Recruited

4,366,000+

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]

Antithymocyte globulins (ATG) not only deplete T cells but also induce significant changes in immune cell activity, including increased levels of chemokines and cytokines like interferon-γ (IFN-γ) after ex vivo stimulation, suggesting additional immunosuppressive mechanisms.

ATG treatment enhances the expression of programmed death ligand 1 (PDL-1) on monocytes, which inhibits the proliferation and activity of activated CD8+ T cells through the JAK/STAT signaling pathway, representing a novel mode of action for ATG in preventing graft rejection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antithymocyte Globulin Inhibits CD8+ T Cell Effector Functions via the Paracrine Induction of PDL-1 on Monocytes. Copic, D., Direder, M., Klas, K., et al.[2023]

References

1. 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]

2. 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]

3. Germany pubmed.ncbi.nlm.nih.gov

Rapid progression of fibrosing alveolitis and thyrotoxicosis after antithymocyte globulin therapy for aplastic anemia. [2019]

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

One center's experience with antithymocyte globulin treatment for acute rejection in renal transplantation. [2013]

5. 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]

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

Monitoring of CD3(+) T-cell count in patients receiving antithymocyte globulin induction after cadaveric renal transplantation. [2017]

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

Management of patients receiving antithymocyte globulin for aplastic anemia and myelodysplastic syndrome. [2007]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Antithymocyte Globulin Inhibits CD8+ T Cell Effector Functions via the Paracrine Induction of PDL-1 on Monocytes. [2023]

9. Singapore pubmed.ncbi.nlm.nih.gov

Polyclonal anti-T-cell therapy for type 1 diabetes mellitus of recent onset. [2020]