Low-Dose ATG for Type 1 Diabetes

(TN28 Trial)

No longer 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a low dose of Antithymocyte Globulin (ATG), an immune system treatment, can slow the progression to type 1 diabetes in high-risk individuals. Researchers compare ATG to a placebo to determine if it can delay or prevent the disease's full onset. It targets individuals identified as having a high risk of developing type 1 diabetes, with specific antibodies indicating this risk. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that Antithymocyte Globulin (ATG) has been tested in people with newly diagnosed type 1 diabetes, yielding encouraging safety results. One study found that a low dose of ATG, specifically 0.5 mg per kilogram of body weight, was generally safe and well-tolerated by patients. Another study reported no major safety issues with ATG. These findings suggest that ATG can be used safely in individuals who might develop more severe type 1 diabetes. However, individual experiences can differ, so discussing any concerns with a healthcare provider is important. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Type 1 Diabetes?

Unlike the standard treatments for Type 1 Diabetes, which often involve insulin therapy and immunosuppressive drugs, Antithymocyte Globulin (ATG) works by targeting and reducing T-cells, which play a role in the autoimmune attack on pancreatic cells. This unique mechanism of action sets ATG apart, as it aims to protect the body's insulin-producing cells and potentially slow down the progression of the disease. Researchers are excited about ATG because it offers a novel approach that could complement existing therapies and improve outcomes for patients with Type 1 Diabetes.

What evidence suggests that low-dose ATG might be an effective treatment for Type 1 Diabetes?

Research has shown that antithymocyte globulin (ATG), which participants in this trial may receive, might help slow the progression of type 1 diabetes. Studies have found that ATG can protect beta cells, which produce insulin to control blood sugar levels. In one study, a low dose of ATG helped some individuals remain free of diabetes for several years. Although not everyone experienced the same results, these findings suggest that ATG could be useful in treating type 1 diabetes by preserving beta cells. ^{1 2 3 4 6}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

Citations

1. thelancet.com thelancet.com/journals/lancet/article/PIIS0140-6736(25)01773-8/fulltext?rss=yes

ATG as disease-modifying therapy for new-onset type 1 ... A standardized metric to enhance clinical trial design and outcome interpretation in type 1 diabetes. Nat Commun. 2023; 14, 7214. Crossref.

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0140673625016745

Minimum effective low dose of antithymocyte globulin in ... In young people with recent-onset, clinical type 1 diabetes, 2·5 mg/kg and 0·5 mg/kg ATG reduced loss of β-cell function, showing the potential of an affordable ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6489466/

Antithymocyte globulin treatment for patients with recent-onset ... Findings from preclinical studies and pilot clinical trials suggest that antithymocyte globulin (ATG) might be effective for reducing this autoimmune response.

4. diabetesjournals.org diabetesjournals.org/care/article/47/2/285/154034/Low-Dose-Antithymocyte-Globulin-A-Pragmatic

Low-Dose Antithymocyte Globulin: A Pragmatic Approach to ... Three subjects (50%) remained diabetes free after 1.5, 3, and 4 years of follow-up, while three developed stage 3 within 1–2 months after ...

5. journals.plos.org journals.plos.org/plosone/article?id=10.1371/journal.pone.0323642

Therapeutic potential of anti-thymocyte globulin in type 1 ... Results indicated that ATG showed potential in preserving beta-cell function and improving clinical outcomes in recent-onset T1D. However, the incidence of ...

6. trialnet.org trialnet.org/our-research/prevention-studies/atg-stop-t1d

ATG Prevention Study (STOP-T1D) There were no safety concerns. Researchers remain excited about anti-thymocyte globulin (ATG) in Stage 2 of type 1 diabetes (T1D). TrialNet investigators ...