Preventing Diabetes with an Antibody in Relatives at Risk for the Disease

Phase 1

Conditions: Anti-CD3 monoclonal antibody is to be used for the prevention of type 1 diabetes mellitus in relatives at risk for developing the disease.
MedDRA version: 19.1Level: PTClassification code 10066284Term: Diabetes prophylaxisSystem Organ Class: 10042613 - Surgical and medical procedures
Therapeutic area: Diseases [C] - Nutritional and Metabolic Diseases [C18]

Registration Number: EUCTR2013-002248-98-GB

Lead Sponsor: TrialNet Coordinating Center University of South Florida

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 170

Inclusion Criteria

Study subjects must be or have:
1. Participant in TrialNet Natural History Study (TN01) and thus a relative of a proband** with T1DM.
2. Between the ages of 1-45 years at the time of enrollment in TN01 and age = 8
at time of randomization in this trial
3. Subject (or parent or legal guardian if the subject is a minor) is willing to provide Informed Consent.
4. Individuals <18 years of age at time of randomization must have had a TrialNet conducted OGTT demonstrating abnormal glucose tolerance* within 7 weeks (52 days) of the baseline visit (visit 0).
5. Individuals =18 years of age at time of randomization must have had two consecutive TrialNet conducted OGTTs demonstrating abnormal glucose tolerance, the most recent of which must have been within 7 weeks (52 days) of the baseline visit (visit 0).
6. The participant must be positive for two or more diabetes-related autoantibodies on two occasions. The second occasion must occur within the six months prior to study drug administration, but does not need to involve the same two autoantibodies as were found on the first occasion. The autoantibodies that are to be confirmed are anti-GAD65, anti-ICA512, anti-insulin (MIAA), ZnT8 and/or ICA.
7. Weigh at least 26 kg at randomization.
8. If participant is female with reproductive potential, she must have a negative pregnancy test on Day 0 and be willing to avoid pregnancy for at least one year from randomization.
9. If participant is male, he must be willing to avoid pregnancy in any partners for at least one year from randomization.
10. Willing and medically acceptable to postpone live vaccine immunizations for one year after treatment.
11. Willing to forego other forms of experimental treatment during the study.
* a. Fasting plasma glucose = 110mg/dL, and <126mgdL
or
b. 2 hour plasma glucose =140mg/dL, and <200mg/dL
or
c. 30, 60, or 90 minute value on OGTT =200mg/dL

Fasting glucose levels of 110-125 mg/dL qualify subjects as having abnormal glucose tolerance in this protocol as it reflects the criteria used for entry into the DPT-1 (33) study and the DPT-1 data was used for the calculation of diabetes risk for this trial. Using data for individuals with Type 2 diabetes, the ADA uses a different glucose range to define impaired fasting glucose(34).

** A proband is an individual diagnosed with diabetes before age 40 and started on insulin therapy within one year of diagnosis, or if subjects with probands considered to have type 1 diabetes by their physician who do not meet this definition, the TrialNet Eligibility Committee for the TrialNet Natural History/Pathway to Prevention Study (TN01) must have approved enrollment in TN01.
Are the trial subjects under 18? yes
Number of subjects for this age range: 95
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 75
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range 0

Exclusion Criteria

Study subjects cannot be randomized if they have:
1. If =18yo: Diabetes, or have a screening OGTT with:
a. Fasting plasma glucose =126 mg/dL, or
b. 2 hour plasma glucose = 200mg/dL
2. If <18yo: Diabetes, or have a screening random glucose =200mg/dL
3. Lymphopenia (< 1000 lymphocytes/µL).
4. Neutropenia (< 1500 PMN/µL ).
5. Thrombocytopenia (< 150,000 platelets/µL).
6. Anemia (Hgb = 11.2 grams/deciliter [g/dL]).
7. AST or ALT >1.5 x ULN.
8. Total bilirubin >1.5 x upper limit of normal (ULN) with the exception of subjects with the diagnosis of Gilbert’s syndrome who may be eligible provided they have no other causes leading to hyperbilirubinemia.
9. INR > 0.1 above the upper limit of normal at the participating center’s laboratory.
10. Chronic active infection other than localized skin infections.
11. A positive PPD test.
12. Vaccination with a live virus within 8 weeks of randomization
13. Vaccination with a killed virus within 4 weeks of randomization.
14. A history of infectious mononucleosis within the 3 months prior to enrollment.
15. Laboratory or clinical evidence of acute infection with EBV or CMV.
16. Serological evidence of current or past HIV, Hepatitis B or Hepatitis C infection.
17. Be currently pregnant or lactating, or anticipate getting pregnant.
18. Chronic use of steroids or other immunosuppressive agents.
19. A history of asthma or atopic disease requiring chronic treatment.
20. Untreated hypothyroidism or active Graves’ disease at randomization.
21. Current use of non-insulin pharmaceuticals that affect glycemic control.
22. Prior OKT®3 or other anti-CD3 treatment.
23. Administration of a monoclonal antibody within the year before randomization.
24. Participation in any type of therapeutic drug or vaccine clinical trial within the 12 weeks before randomization.
25. Any condition that, in the opinion of the investigator, would interfere with the study conduct or the safety of the subject.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The primary objective of the study is to determine whether treatment of at-risk subjects with teplizumab results in a delay or prevention of type 1 diabetes mellitus (T1DM).;Secondary Objective: Secondary objectives are to determine whether treatment with teplizumab is superior to placebo with respect to C-peptide responses to oral glucose, as obtained from timed collections during longitudinal tests, to compare the safety and tolerability of teplizumab to placebo, and to assess the effects of treatment on mechanistic outcomes;Primary end point(s): The elapsed time from treatment randomisation to the development of diabetes.;Timepoint(s) of evaluation of this end point: 6 Years

Secondary Outcome Measures