A Phase 2/3, Randomized, Double-Blind, Multicenter, Multinational, 4-Arm, Controlled, Dose-Ranging Study to Evaluate Efficacy and Safety of Teplizumab (MGA031), a Humanized, FcR Non-Binding, Anti-CD3 Monoclonal Antibody, in Children and Adults with Recent-Onset Type 1 Diabetes Mellitus - Protege

• Register: EUCTR
• Last refreshed on: 18 September 2012
• Main ID: EUCTR2006-002457-69-SE
• Date of registration: 13/11/2006
• Prospective Registration: Yes
• Primary sponsor: MacroGenics, Inc.
• Public title: A Phase 2/3, Randomized, Double-Blind, Multicenter, Multinational, 4-Arm, Controlled, Dose-Ranging Study to Evaluate Efficacy and Safety of Teplizumab (MGA031), a Humanized, FcR Non-Binding, Anti-CD3 Monoclonal Antibody, in Children and Adults with Recent-Onset Type 1 Diabetes Mellitus - Protege
• Scientific title: A Phase 2/3, Randomized, Double-Blind, Multicenter, Multinational, 4-Arm, Controlled, Dose-Ranging Study to Evaluate Efficacy and Safety of Teplizumab (MGA031), a Humanized, FcR Non-Binding, Anti-CD3 Monoclonal Antibody, in Children and Adults with Recent-Onset Type 1 Diabetes Mellitus - Protege
• Date of first enrolment: 30/01/2007
• Target sample size: 530
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2006-002457-69
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: yes Other trial design description: 4-arm controlled, dose-ranging If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

Estonia, Germany, Latvia, Netherlands, Spain, Sweden, United Kingdom

Key inclusion & exclusion criteria

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 any physician for symptoms or signs of diabetes

3. Diagnosis of type 1 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 Tallinn 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.






Are the trial subjects under 18? yes
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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 MGA031 (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 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 cortocosteroids 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 (<1

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Recent-onset type I diabetes mellitus (T1DM)
MedDRA version: 9.1 Level: LLT Classification code 10045228 Term: Type I diabetes mellitus

Intervention(s)

Product Name: Teplizumab / MGA031 (hOKT3?1 (Ala-Ala) )
Product Code: MGA031
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Teplizumab
CAS Number: 876387-05-2
Current Sponsor code: MGA031
Other descriptive name: Immunoglobin G1,anti(human CD3(antigen)epsilon-chain)(human-mouse monoclonal MGA031 heavy chain"..."
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 1-
Pharmaceutical form of the placebo: Solution for infusion
Route of administration of the placebo: Intravenous use

Primary Outcome(s)

Primary end point(s): There are two primary endpoits 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 randomisation.

The two primary endpoints will be assessed in a hierarchical manner with the composite being assessed first. The mean HbA1c 1 change from baseline will only be assessed if a statistically significant difference is obtained with the composite endpoint.

Main Objective: 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.

Secondary Objective: The secondary objectives are to assess the durability of clinical benefit and the pharmacokinetics, pharmacodynamics, and immunogenicity of teplizumab.

Secondary ID(s)

CP-MGA031-01

2006-002457-69-DE