| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Recent-onset type I diabetes mellitus (T1DM)
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045228 |
| E.1.2 | Term | Type I diabetes mellitus |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to assess, relative to placebo, the efficacy, tolerability, and safety of teplizumab when administered according to 3 different teplizumab dosing regimens in subjects with recent-onset (onset within the past 12 weeks) type 1 diabetes. All regimens will be administered in addition to standard of care. |
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| E.2.2 | Secondary objectives of the trial |
| The secondary objectives are to assess the durability of clinical benefit and the pharmacokinetics, pharmacodynamics, and immunogenicity of teplizumab. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following criteria:
1. Written informed consent obtained from the subject (assent will be obtained for subjects under age 18, according to all applicable regulations) including consent for the use of research-related health information.
2. Enrollment (Segment #1) or randomization (Segment #2) on Study Day 0 within 12 weeks of first visit to physician for symptoms or signs of diabetes.
3. Diagnosis of diabetes mellitus, according to the American Diabetes Association (ADA) criteria (See Appendix A of the protocol) and must have a diagnosis of type 1 diabetes mellitus.
4. Requirement for injected insulin therapy currently or in recent past.
5. Have a detectable fasting or stimulated C-peptide level (above the lower limit of detection of the assay).
6. One positive result on testing for any of the following antibodies:
a. islet-cell autoantibodies (ICA512/IA-2),
b. glutamic acid decarboxylase autoantibodies, or
c. insulin autoantibodies (if present during first 2 weeks, but not beyond 2 weeks, of insulin treatment)
7. Male or female.
8. Subjects must be in one of the following age groups:
- Age 18–35 years (initiation of enrollment in segment #2 requires approval by DMC and, if required, other authorities according to all applicable regulations) or
- Age 12–17 years pending approval by DMC and, if required, other authorities according to all applicable regulations; or
- Age 8–11 years pending approval by DMC and, if required, other authorities according to all applicable regulations.
- Estonia only: Subjects must be aged 13-35 years. (Subjects aged 8-12 years are excluded. At Tartu University Hospital and East Talinn Central Hospital, subjects aged 13-15 years are also excluded).
- Germany only: Subjects must be aged 18-35 years. (Subjects aged 8-17 years are excluded).
- Latvia only: Subjects must be aged 18-35 years. (Subjects aged 8-17 years are excluded).
9. Body weight ≥ 36 kg.
10. Body surface area (BSA) ≤2.4 m2 (Interactive Voice Response System [IVRS] will be used to calculate BSA using Mosteller formula) (see Appendix B of the protocol).
11. Sexually active females, unless surgically sterile, must use 2 forms of contraception (including oral, transdermal, injectable, or implanted contraceptives, IUD, female condom, diaphragm with spermicide, cervical cap, abstinence*, use of a condom by the sexual partner or sterile sexual partner) for 30 days before the first dose of study drug and must agree to continue using such precautions through the end of the study (Study Day 728). Cessation of birth control after this point should be discussed with a responsible physician. Male subjects with partners of child-bearing potential should use barrier contraception in addition to having their partners use another method of contraception.
* Abstinence is only an acceptable form of contraception if it is the subject’s preexisting normal status.
12. Willing to forego other forms of experimental treatment during the study, particularly immunomodulatory agents and agents that stimulate pancreatic beta cell regeneration or insulin secretion.
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| E.4 | Principal exclusion criteria |
Subjects must have none of the following:
1. Prior administration of a monoclonal antibody—within the 1 year before enrollment or randomization at Study Day 0— that could potentially prevent or confound a therapeutic response to teplizumab.
2. Participation in any type of therapeutic drug or vaccine clinical trial within the last 12 weeks before enrollment or randomization at Study Day 0.
3. Any medical condition that, in the opinion of the investigator, would interfere with safe completion of the trial.
4. Pregnant females or lactating females who intend to provide their own breast milk to the baby during the study.
5. Prior murine OKT®3 treatment at any time before enrollment or randomization.
6. Current or planned therapy with Exenatide or any other agents that stimulate pancreatic beta cell regeneration or insulin secretion, or any oral antidiabetic agents.
7. Current or planned therapy with inhaled insulin, if it becomes available.
8. Uncompensated heart failure, fluid overload, or myocardial infarction or evidence of ischemic heart disease or other serious cardiac disease within the 12 weeks before enrollment or randomization.
9. History of epilepsy, cancer, cystic fibrosis, sickle cell anemia, neuropathy, peripheral vascular disease or cerebrovascular disease.
10. Newly diagnosed hypothyroidism (not currently being treated but which, in the opinion of the investigator, should be treated) or active Graves’ disease. Subjects with preexisting hypothyroidism may join the study if their medication is stable with no expected change in dosage or status of disease.
11. Eczema, asthma or severe atopic disease requiring treatment, including topical or inhaled corticosteroids within the 12 weeks before enrollment or randomization.
12. Evidence of active infection, such as fever ≥ 38.0 degrees Celcius (100.5 degrees Fahrenheit).
13. Known or suspected infection with human immunodeficiency virus (HIV).
14. Evidence of active hepatitis B (HBV) or hepatitis C virus (HCV), such as positive hepatitis B surface antigen (HBsAg) or anti-hepatitis C antibody.
15. Total bilirubin >1.5 x upper limit of normal (ULN).
16. AST or ALT >1.5 x ULN.
17. Evidence of active or latent tuberculosis, which may include a positive purified protein derivative (PPD) skin test result (≥10 mm induration); a chest X-ray consistent with tuberculosis; or household contact with a person with active tuberculosis, unless appropriate isoniazid (INH) prophylaxis for tuberculosis was previously given.
18. Vaccination with a live virus within the 8 weeks before enrollment randomization or planned live virus vaccination continuing through week 52 of the study. Vaccination with an antigen or killed organism must not be given within 8 weeks before or planned within 8 weeks after each dosing cycle. (For additional information on vaccines see section 3.3.5.2 of the clinical trial protocol).
19. Any infectious mononucleosis-like illness within the 6 months before enrollment or randomization.
20. Serologic and clinical evidence of acute infection with Epstein-Barr virus (EBV), including a positive EBV IgM. (Viral load does not have to be positive.)
21. Serologic evidence of acute infection with cytomegalovirus (CMV), defined as a positive CMV IgG and a positive viral load.
22. Lymphopenia (<1000 lymphocytes/µL).
23. Neutropenia (<1000 Polymorphonuclear leukocytes (PMN) /µL on 2 consecutive evaluations performed on different days).
24. Thrombocytopenia (<150,000 platelets/µL).
25. Anemia (Hgb <10 g/dL).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
There are two primary endpoints for this study.
1. The first endpoint is a composite endpoint. This is defined as the proportion of subjects, who at 52 weeks after randomization, have both a total daily insulin dose of less than 0.5 U/kg/day and HbA1c level of less than 6.5%.
2. The second primary endpoint is the mean HbA1c change from baseline at 52 weeks after randomization.
The two primary endpoints will be assessed in a hierarchical manner with the composite being assessed first. The mean HbA1c l change from baseline will only be assessed if a statistically significant difference is obtained with the composite endpoint.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Immunologic parameters, biomarkers |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| 4-arm controlled, dose-ranging |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 55 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The study will be completed when the database is locked after the last subject’s last visit. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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