Clinical trial NCT04291703: STOP-T1D Low-Dose (ATG)
Official title: Low Dose Antithymocyte Globulin (ATG) to Delay or Prevent Progression to Stage 3 T1D
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Diabetes Mellitus, Type 1
Keywords: TrialNet
T1D
Lead sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Sponsor class: NIH
First posted: 2020-03-02
Enrollment: 101
Sex: ALL
Minimum age (years): 6
Maximum age (years): 34
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: PREVENTION

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.

Detailed description: This study has an enrollment period of 4 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.

Eligibility criteria: Inclusion Criteria:

1. Willing to provide informed consent or have a parent or legal guardian provide informed consent when the subject is \<18 years of age.
2. Age greater than or equal to 6 and \< 35 years
3. At least two or more diabetes-related biochemical autoantibodies (mIAA, GADA, ICA, IA-2A, ZnT8A) present on the same sample. In the absence of other antibodies, ICA and GADA positivity alone will not suffice for eligibility in this trial.
4. Weight greater than the 5th percentile for age and sex.
5. BMI \< 95th and \> 5th percentile for age for those under age 18 years and \< 30 and \> 15 for adults (≥ 18)
6. ADA Stage 2 criteria\* AND at least one of the following high-risk markers (occurring at the same visit) within 7 weeks (52 days) of randomization, defined below (for defining a 2-year 50% risk for progression to Stage 3 T1D):

   a. HbA1c ≥ 5.7 and \<6.5% b. Index60 ≥ 1.4 i. Index60 = 0.3695 × (log fasting C-peptide \[ng/mL\]) + 0.0165 × 60-min glucose (mg/dL) - 0.3644 × 60-min C-peptide (ng/mL) c. DPTRS ≥ 7.4 DPTRS = (1.57 x log BMI) - (0.06 x age) + (0.81 x glucose sum from 30 to 120 min/100) - (0.85 x C-peptide sum from 30 to 120 min/10) + (0.48 x log fasting C-peptide)

   \*Dysglycemia is defined as 2-hr glucose ≥ 140 and \<200 mg/dL or fasting glucose ≥ 110 and \<126 or 30, 60, or 90 minute glucose ≥ 200 mg/dL from OGTT
7. All subjects must be CMV and EBV PCR negative within 30 days of randomization and may not have had signs or symptoms of a CMV or EBV-compatible illness lasting longer than 7 days within 30 days of randomization
8. Seated blood pressure less than 130/80 mmHg for participants ≥ 18 years. For participants \< 18 years seated blood pressure less than 95th percentile for age, sex and height.
9. Be at least 4 weeks from last live immunization
10. Participants are required to receive non-live influenza vaccination at least 2 weeks prior to randomization when vaccine for the current or upcoming flu season is available.
11. Participants must also have a negative COVID-19 test within 7 days of the first day of treatment if otherwise eligible
12. Willingness to comply with study directed social distancing and protection from SARS-Cov-2 infection.
13. Be willing to forgo vaccines (other than killed influenza) during the 3 months after study drug treatment period (Days 0 and 1)
14. Be up to date on all recommended vaccinations based on age of subject\*
15. With the exception of stage 2 T1D, subjects must be healthy, as defined by absence of any other untreated diagnoses that the protocol committee deems to be a potential confounder.
16. If a female participant with reproductive potential, willing to avoid pregnancy (abstinence or adequate contraceptive method) through the completion of the study infusions and up to 3 months after study drug administration and undergo pregnancy testing prior to each study visit.
17. Must be residing or have accommodations within 1 hour of the infusion site during the two days of study drug infusions and must be within 1 hour of a medical care facility for 1 day after completion of infusion 2.
18. Participants must live in a location with rapid access to emergency medical services.

    * Adult participants must be fully immunized. Pediatric participants who have not completed their primary vaccination schedule must receive all vaccinations allowable per the national/country-specific 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. For COVID-19 vaccination, all participants will be strongly encouraged to be up-to-date with COVID-19 vaccine(s) as indicated by country-specific guidelines at least 2 weeks prior to randomization.

Exclusion Criteria:

1. Immunodeficiency or clinically significant chronic lymphopenia: (Leukopenia (\< 3,000 leukocytes /μL), neutropenia (\<1,500 neutrophils/μL), lymphopenia (\<800 lymphocytes/μL), thrombocytopenia (\<100,000 platelets/μL).
2. Hemoglobin less than 13.5 g/dL for adult men and less than 12 g/dL for adult females and less than 11 g/dL for participants under age 18
3. Active signs or symptoms of acute infection at the time of randomization including SARS-Cov-2.
4. Uncontrolled autoimmune thyroid disease and/or celiac disease (participants must be well controlled for the previous 6 months).
5. Evidence of prior or current tuberculosis infection as assessed interferon gamma release assay (QuantiFERON).
6. Currently pregnant or lactating or anticipate getting pregnant within the study period.
7. Require use of other immunosuppressive agents including chronic use of systemic steroids.
8. Evidence of current or past HIV or Hepatitis B or current Hepatitis C infection.
9. 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.
10. A history of malignancies other than of skin.
11. Evidence of liver dysfunction with AST or ALT outside of the reference range.
12. Evidence of renal dysfunction with creatinine outside of the reference range.
13. Increased bilirubin (total and direct) outside of the normal limit (Participants with documentation of Gilbert's Disease permitted).
14. Vaccination with a live virus within the last 4 weeks.
15. Current or ongoing use of non-insulin pharmaceuticals that affect glycemic control within 7 days of screening
16. Prior treatment with Teplizumab (either in a previous clinical trial or clinically).
17. Has participated in a clinical trial for diabetes prevention previously and received active study agent within 3 months of randomization.
18. Known allergy to ATG or any product excipient
19. Prior treatment with ATG or known allergy to rabbit-derived products or to any product excipient
20. Prior adverse reactions to heparin.
21. Any condition that in the investigator's opinion may adversely affect study participation will be reviewed by the Study Chair to ensure consistency and adjudicate whether or not the subject may compromise the study results
22. Any screening/baseline laboratory result not otherwise stated out of normal reference range and/or medical history that may increase the risk of the subject's participation in this trial.
23. Previously diagnosed with Stage 3 TID according to ADA criteria (see Appendix 3 for Criteria for diagnosis of diabetes)

Primary outcomes:
measure: Progression to Stage 3 T1D
timeFrame: 5 years
Secondary outcomes:
Other outcomes:
Locations:
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: San Francisco
country: United States
facility: University of California - San Francisco
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Aurora
country: United States
facility: Barbara Davis Center at University of Colorado Anschutz Medical Campus
state: Colorado
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Tampa
country: United States
facility: University of South Florida Diabetes Center
state: Florida
city: Atlanta
country: United States
facility: Emory Children's Center
state: Georgia
city: Indianapolis
country: United States
facility: Indiana University - Riley Hospital for Children
state: Indiana
city: Iowa City
country: United States
facility: Children's Hospital of Iowa
state: Iowa
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Kansas City
country: United States
facility: The Children's Mercy Hospital
state: Missouri
city: New York
country: United States
facility: Columbia University-Naomi Berrie Diabetes Center
state: New York
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Greenville
country: United States
facility: Prisma Health
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt Eskind Diabetes Center
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Seattle
country: United States
facility: Benaroya Research Institute
state: Washington
city: South Brisbane
country: Australia
facility: Queensland Children's Hospital
state: Queensland
city: Melbourne
country: Australia
facility: Walter and Eliza Hall Institute of Medical Research
state: Victoria
Study officials:
References: