E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Oral insulin is to be used for the prevention of type 1 diabetes mellitus in relatives at risk of developing the disease. |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10066284 |
E.1.2 | Term | Diabetes prophylaxis |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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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 is to determine whether intervention with repeated oral administration of recombinant human insulin, the potential autoantigen, will prevent or delay the development of clinical Type 1 Diabetes Mellitus (T1DM) in non-diabetic relatives of patients with T1DM who are positive for insulin autoantibodies but who do not have a metabolic defect. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives include the description of the effects of treatment with oral insulin versus placebo in other catagories of subjects defined using different combinations of autoantibodies and metabolic status and an assessment of the consistency of treatment effect among strata. Secondary objectives also include the assessment of the effects of treatment on immunologic and metabolic markers, and the association of these markers with the risk of diabetes onset, among other possible risk factors. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Have a proband* with T1DM.
2. If the proband is a sibling, parent or a child, the study participant must be 3 - 45 years of age. If the proband is a second or third degree relative (i.e. Niece, Nephew, Aunt, Uncle, Grandparent, Cousin), the study participant must be 3-20 years of age.
3. Willing to sign Informed Consent Form.
4. Has normal glucose tolerance on an OGTT performed within 7 weeks prior to randomization. If previous abnormal glucose tolerance, has had two consecutive OGTT with normal glucose tolerance.
5. mIAA confirmed positive within the previous six months.
6. At least one other antibody present on two separate samples, one of which was drawn within the past six months.
* A proband is an individual diagnosed with diabetes before age 40 and started on insulin therapy within 1- year of diagnosis. Probands considered to have type 1 diabetes by their physician who do not meet this definition will be referred to the TrialNet Eligibility Committee. |
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E.4 | Principal exclusion criteria |
1. Does not satisfy the above inclusion criteria.
2. Has severe active disease, e.g. chronic active hepatitis, severe cardiac, pulmonary, renal, hepatic, immune deficiency and/or disease that is likely to limit life expectancy or lead to therapies such as immunosuppression during the time of the study.
3. Prior participation in a clinical trial for secondary prevention of T1DM.
4. History of treatment with insulin or oral hypoglycemic agent.
5. History of therapy with immunosuppressive drugs or non-physiologic glucocorticoids within the past two years for a period of more than three months.
6. Ongoing use of medications known to influence glucose tolerance, i.e. sulfonylureas, growth hormone, metformin, anticonvulsants, thiazide or potassium depleting diuretics, beta adrenergic blockers, niacin. Subjects on such medications should be changed to a suitable alternative, if available, and will become eligible one month after medication is discontinued.
7. Pregnant or intends to become pregnant while on study or lactating.
8. Deemed unlikely or unable to comply with the protocol.
9. OGTT that reveals abnormal glucose tolerance unless two subsequent
consecutive OGTT have normal glucose tolerance. Abnormal glucose
tolerance is defined as:
• fasting plasma glucose ≥ 110 mg/dL (6.1 mmol/l), AND/OR
• 2 hour plasma glucose ≥ 140 mg/dL (7.8 mmol/l) AND/OR
• 30, 60, or 90 minute plasma glucose ≥ 200 mg/dL (11.1 mmol/l)
10. Subject has HLA DQA1*0102, DQB1*0602 haplotype. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The elapsed time from treatment randomisation to the development of diabetes among those enrolled in the primary analysis cohort consisting of subjects with insulin autoimmunity and absence of metabolic abnormalities. Criteria for Diabetes onset are defined by the American Diabetes Association (ADA) based on glucose testing, or the presence of symptoms and unequivocal hyperglyglycemia. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
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 | No |
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.8.2.4 | Number of treatment arms in the trial | 1 |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
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 | No |
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 |
Australia |
Canada |
Finland |
Germany |
Italy |
New Zealand |
Sweden |
United Kingdom |
United States |
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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 end when the accrued numbers of subjects developing diabetes provide I = 27.551. I = (DO DC)/DT. where DO and DC refer to the number of subjects who have developed diabetes in the oral insulin and control groups, respectively, and DT refers to the total number of such subjects.
The information required to provide 85% power to detect a 40% risk reduction with a one-sided logrank test at the 0.05 significance level is I = 27.551. |
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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 | 10 |
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 | 10 |
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 |