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Low Dose Antithymocyte Globulin (ATG) to Delay or Prevent Progression to Stage 3 T1D (TN28)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04291703
Recruitment Status : Not yet recruiting
First Posted : March 2, 2020
Last Update Posted : March 3, 2021
Information provided by (Responsible Party):
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 1 Drug: Antithymocyte Globulin Drug: Placebo (for ATG) Phase 2

Detailed Description:
This study has an enrollment period of three years and once the enrollment phase has concluded, an additional two years of follow-up visits will be conducted for all participants. Participants enrolled in the first year of the study can expect to complete follow-up visits for approximately four additional years if progression to stage 3 (Type 1 Diabetes Onset) does not occur. Participant follow-up visits after the treatment phase of the study includes general assessments (medical history, physical exam, medications and adverse events) and laboratory assessments to determine current health status and glucose tolerance.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 99 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Eligible study participants will be randomized in a 2:1 allocation to either ATG vs. placebo treatment arms by the TrialNet Coordinating Center at the baseline visit once eligibility has been confirmed. Randomization will be conducted using block randomization with variable block sizes with stratification on TrialNet study site and age group (< 12 years old vs. 12 years old or older). Subjects will be assigned a study randomization number corresponding to the treatment group assignment.
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: The randomization method will be stratified by TrialNet study site. The participants will not be informed regarding the intervention assignment until the end of the study. The investigator and clinic personnel will also be masked as to study assignment. Laboratories performing assays for this protocol will be masked as to the identity of biological material to be studied.
Primary Purpose: Prevention
Official Title: Low Dose Antithymocyte Globulin (ATG) to Delay or Prevent Progression to Stage 3 T1D
Estimated Study Start Date : October 2021
Estimated Primary Completion Date : October 2026
Estimated Study Completion Date : October 2026

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Antithymocyte globulin (ATG)
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 24 hours after completion of the previous dose. 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.
Drug: Antithymocyte Globulin
Other Name: Thymoglobulin

Placebo Comparator: Placebo
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 24 hours after completion of the previous dose. Infusions may be administered either in a hospital or outpatient setting at the investigator's or institutions discretion.
Drug: Placebo (for ATG)
Normal Saline administered by IV infusion to mimic ATG

Primary Outcome Measures :
  1. Progression to Stage 3 T1D [ Time Frame: 5 years ]
    The primary outcome is the elapsed time from random treatment assignment to the development of diabetes or time of last contact among those randomized

Information from the National Library of Medicine

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Ages Eligible for Study:   6 Years to 45 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Age > 6 and < 46 years
  2. Willing to provide Informed Consent or have a parent or legal guardian provide informed consent if the subject is <18 years of age
  3. At least two or more diabetes-related biochemical autoantibodies (mIAA, GADA, ICA, IA-2A, ZnT8A present on the same sample. Of note, ICA and GADA positivity alone cannot be used to define eligibility in this trial).
  4. Must have at least two of the high-risk markers defined below (defining a 50% two year progression risk):

    a. Abnormal glucose tolerance: i. 2-hr glucose ≥ 140 and <200 mg/dL, fasting glucose ≥ 110 and <126, or 30-, 60-, or 90-minute glucose ≥ 200 mg/dL b. HbA1c ≥ 5.7 c. Index60 ≥ 1.4 d. DPTRS ≥ 7.4

  5. 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
  6. Be at least 4 weeks from last live immunization
  7. 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
  8. Be willing to forgo vaccines during the 3 months after study drug treatment period (Days 0 and 1)
  9. Be up to date on all recommended vaccinations based on age of subject*
  10. Subjects who have met all above criteria must have a non-diabetic OGTT performed within 100 days of randomization.

    • Adult subjects must be fully immunized. Pediatric subjects who have not completed their primary vaccination schedule must receive all vaccinations allowable per the AAP immunization guidelines for their current age prior to study drug delivery. Any remaining vaccinations should be given and continue per the schedule at least 3 months after study drug is administered.

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 interferon gamma release assay (QuantiFERON) .
  4. Be currently pregnant or lactating, or anticipate getting pregnant within the study period
  5. Require use of other immunosuppressive agents including chronic use of systemic steroids
  6. Have evidence of current or past HIV or Hepatitis B or current 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 disease, or blood count abnormalities
  8. Have a history of malignancies other than of 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 4 weeks
  12. Current or ongoing use of non-insulin pharmaceuticals that affect glycemic control within 7 days of screening
  13. Active participation in another intervention study in the previous 30 days*
  14. Prior treatment with active study agent from a previous clinical trial*
  15. Known allergy to ATG
  16. Prior treatment with ATG 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
  18. Previously diagnosed with TID according to ADA criteria

    • Potential participants who participated in a previous clinical trial will require review and approval by the protocol committee and/or TrialNet medical monitor before screening for this protocol.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04291703

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Contact: Melissa A Parker, MHA 8133969378 MELISSA.PARKER@EPI.USF.EDU
Contact: Ryan O'Donnell 8133969551 Ryan.O'

Sponsors and Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Additional Information:
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Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Identifier: NCT04291703    
Other Study ID Numbers: TrialNet TN28
UC4DK117009 ( U.S. NIH Grant/Contract )
First Posted: March 2, 2020    Key Record Dates
Last Update Posted: March 3, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Data will be available at the NIDDK Central Repository

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):
Additional relevant MeSH terms:
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Diabetes Mellitus, Type 1
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Antilymphocyte Serum
Immunologic Factors
Physiological Effects of Drugs
Immunosuppressive Agents