Type 1 Diabetes Mellitus
Conditions
Keywords
TrialNet, T1D, Teplizumab, ATG
Brief summary
This is a 2-arm, multi-center, open label study to learn if ATG works the same or better than teplizumab in delaying or preventing Stage 3 Type 1 diabetes. Participants will be administered either 2 infusions of ATG or 14 infusions of teplizumab and will be followed for 12 months after administration.
Detailed description
This protocol will enroll 60 participants with Stage 2 diabetes. Oral glucose tolerance testing will be done at the screening, baseline visit (V0) and at 3, 6 and 12 months after study drug administration. Participants will continue follow-up visits until 12 months from the baseline visit.
Interventions
Thymoglobulin
DRUGTeplizumab
Intravenous infusions of teplizumab given for 14 consecutive days. Each infusion takes about 30 minutes and is followed by an observation period of at least 30 minutes.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Intervention model description
This trial will enroll 60 participants who will be randomly assigned in a 2:1 allocation to the following treatment arms: 40 participants will be randomized to ATG and 20 participants will be randomized to teplizumab.
Eligibility
Sex/Gender
ALL
Age
4 Years to 34 Years
Healthy volunteers
No
Inclusion criteria
* Willing to provide informed consent or have a parent or legal guardians provide informed consent when the participant is \<18 years of age. * Aged ≥4 to \<35 years * A history of 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. * Participants must meet ADA stage 2 T1D glycemic criteria\* by TrialNet testing within 100 days of the baseline visit. \*The ADA definition of stage 2 T1D is characterized by glucose intolerance or dysglycemia in the presence of two or more islet autoantibodies, impaired fasting glucose (≥ 100mg/dL), impaired glucose tolerance (2-hour post 75g glucose load ≥ 140mg/dL), high glucose levels at intermediate time points on OGTT (30, 60, 90 min timepoints of ≥ 200 mg/dL), and/or HbA1c between 5.7% and 6.4% or ≥ 10% increase in HbA1c within a two year window, with the most recent HbA1c value obtained within 100 days of the baseline visit. * CMV and/or EBV seronegative participants must be CMV and EBV PCR negative within 30 days prior to 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 the baseline visit. * CMV seropositive participants must be CMV PCR negative and all EBV seropositive participants must have EBV PCR \< 2,000 IU/mL within 30 days prior to randomization and may not have had signs or symptoms of a CMV or EBV-compatible illness lasting longer than 7 days within 30 days prior to the baseline visit. * Be at least 8 weeks from last live immunization at the time of the baseline visit. * Be willing to forgo vaccines (other than non-live influenza and COVID-19) during the 3 months after study drug treatment period and forgo live vaccines for 12 months after study drug treatment period. * Must meet TrialNet eligibility minimum immunization recommendations found in Appendix A of the manual of operations (MOO). * With the exception of stage 2 T1D, participants must be healthy, as defined by absence of any other untreated diagnoses that the investigator deems to be a potential confounder. * 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. * Must be residing or have accommodations within 1 hour of the infusion site during study drug infusions and must be within 1 hour of a medical care facility for 1 day after completion of infusions. * Participants must live in a location with rapid access to emergency medical services.
Exclusion criteria
* 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). * Hemoglobin less that 12 g/dL for adult men and less than 11.5g/dL for adult females and less than 11 g/dL for participants under age 18. * Active signs or symptoms of acute or chronic infection at the time of randomization including SARS-Cov-2. * Uncontrolled autoimmune thyroid disease and/or celiac disease (participants must be well controlled for the previous 6 months). * Evidence of prior or current tuberculosis infection through any one or more of the following: 1. A history of latent or active TB 2. Signs and/or symptoms of TB 3. Recent close contact with a person with known or suspected active TB unless appropriate prophylaxis for TB was given 4. A history of a chest X-ray consistent with active TB or old, inactive TB, or interferon gamma release assay IGRA (QuantiFERON) test 5. A history of a positive purified protein derivative (PPD) skin test result (\>10 mm induration), or positive/repeatedly indeterminate on an interferon-gamma release assay (IGRA; e.g., QuantiFERON-TB test). * Currently pregnant or lactating or anticipate getting pregnant within the study period. * Require use of other immunosuppressive agents including chronic use of oral or intravenous injectable steroids. * Evidence of current or past HIV or Hepatitis B or current Hepatitis C infection. * 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. * A history of malignancies other than of skin. * Evidence of liver dysfunction with AST or ALT ≥ 2 times the upper limit of the reference range. * Evidence of renal dysfunction with creatinine ≥ 1.5 times the upper limit of the reference range. * Increased bilirubin ≥ 2 times (total) or ≥ 1.5 times (direct) the normal limit (Participants with documentation of Gilbert's Disease permitted). * Vaccination with a live vaccine within the last 8 weeks or killed/inactivated vaccine within the last 2 weeks of the baseline visit. * Current or ongoing use of non-insulin pharmaceuticals that affect glycemic control within 14 days of screening. * Prior treatment with Teplizumab or ATG (either in a previous clinical trial or clinically). * Has previously participated in a clinical trial for diabetes prevention and received active study agent within 6 months of treatment. * Known allergy to rabbits or rabbit derived products. * Prior adverse reactions to heparin. * Any condition that in the investigator's opinion may adversely affect study participation. * Any screening/baseline laboratory result not otherwise stated out of normal reference range and/or medical history that may increase the risk of the participant's participation in this trial. * Previously diagnosed with Stage 3 TID according to ADA criteria.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in DPTRS at six months | 6 months after completion of study drug administration | DPTRS is calculated as DPTRS = (1.569 x log-BMI) - (0.056 x age) + (0.813 x glucose sum from 30 to 120 min /100) - (0.848 x C-peptide sum from 30 to 120 min/10) + (0.476 x log-fasting C-peptide), where the units are years for age, kg/m2 for BMI, mg/dl for glucose, ng/ml for C-peptide |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression to Stage 3 T1D | 6 months after study drug administration | Elapsed time from study drug administration to the development of diabetes or time of last contact among those randomized |
| OGTT glucose AUC | 6 months after study drug administration | Mean area under the stimulated glucose curve (AUC) over the 2-hour oral glucose tolerance test. |
| M120 score | 6 months after study drug administration | This is an aggregated score from multiple measurements calculated as follows: M120 = 0.448×(sex) + 0.631×(IA-2A) - 0.0302×(age) + 0.0605×(BMI) \+ 1.380×(HbA1c) + 0.0265×(120 min glucose) - 0.191×(120 min C-peptide), where the units for BMI, age, glucose, C-peptide and HbA1c are, respectively, kg/m2, years, mg/dl, ng/ml and percentage units. Sex was assigned a score of 1 for male and 2 for female, and IA-2A status assigned 0 for absent and 1 for present. Glucose is converted from mmol/l to mg/dl by multiplying by 18; C-peptide is converted from nmol/l to ng/ml by dividing by 3.00; and HbA1c is converted from mmol/mol to percentage units by adding 23.5 and then dividing by 10.93. |
| Index 60 | 6 months after study drug administration | This is an aggregated score from multiple measurements calculated as follows: Index60 = 0.3695×loge(fasting C-peptide) + 0.0165×(60 min glucose) - 0.3644×(60 min C-peptide), where the units for glucose and C-peptide are, respectively, mg/dl and ng/ml. Glucose is converted from mmol/l to mg/dl by multiplying by 18; C-peptide is converted from nmol/l to ng/ml by dividing by 3.00. |
| OGTT C-peptide AUC | 6 months after study drug administration | Mean area under the stimulated C-peptide curve (AUC) over the 2-hour oral glucose tolerance test |
| HbA1c | 6 months after study drug administration | Measured as a percentage of total hemoglobin |
Countries
United States
Contacts
CONTACTMelissa Parker
Outcome results
None listed