E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Recent-onset type 1 diabetes mellitus |
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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 of teplizumab when administered according to 3 different teplizumab dosing regimens in subjects with recent-onset Type 1 Diabetes Mellitus (within 12 weeks of presentation of first signs and symptoms of disease to a physician). All regimens were administered in addition to standard of care. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to assess the durability of clinical benefit and the safety and tolerability of teplizumab. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects must have met all of the following criteria: 1. Diagnosis of diabetes mellitus according to the American Diabetes Association (ADA) criteria. 2. Written informed consent obtained from the subject (assent will be obtained for subjects under age 18 years, according to all applicable regulations) including consent for the use of research-related health information at screening 3. Randomization on Study Day 0 within 12 weeks of first visit to any physician for symptoms or signs of diabetes 4. Requires insulin for T1DM or has required insulin at some time between diagnosis and administration of study drug 5. Detectable fasting or stimulated C-peptide level (above the lower limit of the reportable range of the assay) at screening 6. Diagnosis of T1DM as evidenced by one positive result on testing for any of the following antibodies at screening: a. Islet-cell autoantibodies 512 (ICA512)/islet antigen-2 (IA-2), b. Glutamic acid decarboxylase (GAD) autoantibodies, or c. Insulin autoantibodies (in subjects on insulin for more than 2 weeks, ICA512/IA-2 or GAD must be positive) 7. Subjects 8–35 years old 8. Body weight ≥ 36 Kg 9. BSA ≤2.4 m2 (Interactive Voice Response System [IVRS] will be used to calculate BSA using the Mosteller formula ) 10. Sexually active females, unless surgically sterile, must be willing to use 2 forms of contraception through the end of the study (Study Day 546 for subjects who received 1 course of study medication and study day 728 for subjects who received 2 courses of study medication). Acceptable forms of contraception for female subjects include: oral, transdermal, injectable or implanted contraceptives, intrauterine device (IUD), female condom, diaphragm with spermicide, cervical cap, use of a condom by the sexual partner, or sterile sexual partner. Abstinence is an acceptable form of contraception only if it is the subject’s pre-existing method of contraception. Male subjects with partners of child-bearing potential should use barrier contraception in addition to having their partners use another method of contraception 11. Willing to forego other forms of experimental treatment during the study
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E.4 | Principal exclusion criteria |
Subjects must not have had any of the following criteria: 1. Prior administration of a monoclonal antibody—within the 1 year before randomization at Study Day 0 2. Participation in any type of therapeutic drug or vaccine clinical trial within the last 12 weeks before 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 or other anti-CD3 treatment 6. Current therapy with GLP-1 receptor agonists (e.g., exenatide or pramlintide), or any other agents that might stimulate pancreatic beta cell regeneration or insulin secretion 7. Current treatment with oral antidiabetic agents 8. Current or planned therapy with inhaled insulin, if it becomes available 9. Uncompensated heart failure, fluid overload, myocardial infarction or evidence of ischemic heart disease or other serious cardiac disease as described in New York Heart Association (NYHA) Class III or IV criteria within the 12 weeks before randomization 10. History of epilepsy, cancer, cystic fibrosis, sickle cell anemia, neuropathy, peripheral vascular disease or cerebrovascular disease 11. Untreated hypothyroidism or active Graves’ disease at Study Day 0 12. Eczema, asthma or severe atopic disease requiring treatment, including topical or inhaled corticosteroids, within the 12 weeks before randomization 13. Treatment with systemic glucocorticoid therapy by oral, intravenous (IV), intramuscular (IM), or inhaled route within 12 weeks before randomization; patients who are likely to require treatment with systemic corticosteroids during the trial are also excluded 14. Evidence of active infection 15. History or positive test for human immunodeficiency virus (HIV) 16. Positive immunoglobulin M (IgM) test for hepatitis A 17. History of or positive test for hepatitis B, C or D 18. Total bilirubin > 1.5 x upper limit of normal (ULN) 19. AST or ALT > 1.5 x ULN 20. Evidence of active or latent tuberculosis (TB), which may include a positive purified protein derivative (PPD) skin test result (≥ 10 mm induration); a chest X-ray consistent with TB or household contact with a person with active TB, unless appropriate isoniazid (INH) prophylaxis for tuberculosis (TB) was previously given 21. Vaccination with a live virus or organism within the 8 weeks before randomization continuing through Week 52 (Study Day 364) of the study -Influenza vaccinations with killed virus, including booster vaccinations, within 4 weeks before or after each dosing course -Vaccination with other antigens or killed organisms within 8 weeks before or after each dosing course 22. Any infectious mononucleosis-like illness within the 6 months before randomization 23. Serologic or clinical evidence of acute infection with Epstein-Barr virus (EBV), including a positive Epstein-Barr virus (EBV) immunoglobulin M (IgM). (Viral load does not have to be positive) 24. Serologic evidence of acute infection with cytomegalovirus (CMV), defined as a positive cytomegalovirus (CMV) immunoglobulin G (IgG) and a positive viral load 25. Decreased lymphocytes (< 1000 lymphocytes/µL) 26. Decreased neutrophils (< 1000 polymorphonuclear neutrophil PMN/µL on 2 consecutive evaluations performed on different days) 27. Decreased platelet count (< 150,000 platelets/µL) 28. Decreased hemoglobin (Hgb < 10 grams/deciliter [g/dL]) 29. Investigative site personnel directly affiliated with this study and/or their immediate families. Immediate family is defined as a spouse, parent, child or sibling, whether biological or legally adopted. 30. Employees of MacroGenics, Inc. or Eli Lilly and Co., including permanent employees, temporary contract workers, or designees responsible for conducting this study. Immediate family of employees may participate in this study. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
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E.5 End points |
E.5.1 | Primary end point(s) |
1. The proportion of subjects who have both a total daily insulin dose < 0.5 Units (U)/kilogram (Kg)/day and hemoglobin A1c (HbA1c) level < 6.5% at Study Day 364
2. The mean HbA1c change from baseline to Study Day 364
For each endpoint, groups receiving different teplizumab treatment regimens will be compared independently to the placebo group with an adjustment made for multiplicity of statistical comparisons. The primary endpoints will be tested in the sequence in which they are listed, and the first endpoint must meet the required level of statistical significance in order for the second endpoint to be tested. Inclusion of the second primary endpoint ensures that a benefit of glycemic control results from teplizumab treatment and that meeting the first endpoint is not preferentially explained by lower insulin requirements in the teplizumab group. There will be no adjustment for multiplicity based on the two co-primary endpoints.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
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 | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Immunologic parameters; Patient Reported Outcomes |
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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) | No |
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 |
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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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 45 |
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 End of Trial is defined as database lock, following last patient 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 |