E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Type1 diabetes: disorder of human immune system so that body can't produce insulin. Without insulin, the body can't convert sugar from food into nutrients for cells, later resulting in organ damage. |
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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 | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10045228 |
E.1.2 | Term | Type I diabetes mellitus |
E.1.2 | System Organ Class | 100000004861 |
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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 |
Long term effect of DiaPep277® : long term safety and tolerability of quarterly treatment, and long term effect on clinical outcome and on preservation of beta-cell function in subjects with up to 4 years of total treatment.
Major Criteria:
• Assess the safety and tolerability of DiaPep277®
• Assess the effect of DiaPep277® on glycemic control
• Assess the effect of DiaPep277® on daily insulin dose/body weight at study end
• Assess the effect of DiaPep277® on hypoglycemic events
• Assess the effect of DiaPep277® on maintenance of partial remission
• Assess the effect of DiaPep277® treatment on pancreatic beta-cell function as measured by stimulated C-peptide secretion after I.V. glucagon- stimulated test (GST) or a mixed-meal tolerance test (MMTT), and by fasting C-peptide level. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. A patient who completed the 1001 study. Subjects who have completed 1001 study with a minimum of 80% compliance to the drug injections (8 study drug injections) may be selected. Female patients who interrupted the study drug injections because of a pregnancy, but were otherwise compliant to all the study requirements, or male subjects who may have missed a visit and/or an administration of study drug, may be considered for inclusion on a case by case basis, at the discretion of the investigator.
2. Evidence of clinically significant residual beta-cell function demonstrated by GST stimulated C-peptide concentrations ≥ 0.20nmol/l.
3. If a female is of childbearing potential, the subject must not be pregnant or lactating, and must agree to use oral hormonal contraception or other equally effective contraceptive methods throughout the study.
4. Stable medical condition for diseases, other than diabetes, during 30 days before the Screening-Ext Visit.
5. Signed informed consent to participate in the study
6. Ability to comply with all study requirements.
7. The subject is compliant to the implementation of intensive insulin therapy (basal / bolus insulin) in the opinion of the investigator or is willing to initiate intensive insulin therapy, or is using an insulin pump. Patients on conventional insulin regime who maintained HbA1c ≤7% over the last 6 months can be recruited without switching to intensive insulin regime. |
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E.4 | Principal exclusion criteria |
1. The subject has any significant ongoing diseases or conditions, including psychiatric disorders and substance abuse that, in the opinion of the Investigator, are likely to affect the subject's response to treatment or their ability to complete the study.
2. The subject has a history of any kind of malignant tumor (not including basal cell skin cancer or adequately treated in situ carcinoma of the cervix).
3. The subject has clinical evidence of any diabetes-related complication that in the opinion of the Investigator would interfere with the subject's participation in and/or completion of the study.
4. Subject has history of endogenous allergic reactivity:
a. Severe allergic reaction or severe exacerbation of allergic asthma within 12 months prior to the Screening-Ext Visit.
b. Ongoing systemic parenteral or oral steroids for asthma treatment.
c. Subjects with history of life threatening or severe allergy, re-occurrence of which cannot be ruled out based on the Investigator’s judgment. The subject has known allergy to lipid emulsions.
5. The subject has a known immune deficiency from any disease, or a condition associated with an immune deficiency.
6. The subject is receiving immunosuppressive or immunomodulating agents or cytotoxic therapy or any medication that in the opinion of the Investigator might interfere with the study.
7. The subject has any of the following clinically significant laboratory abnormalities:
a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than three times the upper limit of the normal (ULN) at the Screening-Ext Visit.
b. Total bilirubin greater than 1.3 times the ULN at the Screening-Ext Visit.
c. Subjects with severe renal failure at the Screening-Ext visit (as defined by glomerular filtration rate < 30 mL/min/1.73 m2 by Cockroft and Gault calculation (13) or by Kidney Disease Epidemiology Collaboration (CKD-EPI) calculation (14))
d. Clinically significant laboratory abnormalities, confirmed by repeat measurement, which may interfere with the assessment of safety and / or efficacy of the study drug, other than hyperglycemia and glycosuria at the Screening-Ext Visit.
e. Fasting triglycerides >1000 mg/dl (11.3 mmol/l) at the Screening-Ext Visit. Suitable medical therapy for treatment of hyperlipidemia is allowed.
8. The subject is a known or suspected drug abuser.
9. The subject is known to test positive for HIV antibodies.
10. The subject has chronic hematologic disease.
11. The subject has liver disease such as cirrhosis or chronic active hepatitis.
12. The subject has received any investigational drug within 3 months prior to Visit 12, other than DiaPep277 and/or placebo which were administered during study 1001.
13. The subject has had a severe blood loss (≥ 400 ml, e.g., blood donation) within 2 months before the first dose of the study medication. For forbidden prior and concomitant medications/treatments please refer to section 7.2. of the protocol |
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E.5 End points |
E.5.1 | Primary end point(s) |
The efficacy endpoints will be:
• Assess the effect of DiaPep277® on glycemic control - HbA1c level: the percentage of patients with HbA1c ≤7%
• Assess the effect of DiaPep277® on daily insulin dose/body weight at study end and the percentage of patients with a daily insulin dose/body weight ≤0.5 IU/day.
• Assess the percentage of subjects with HbA1c ≤7% AND a daily insulin dose/body weight ≤0.5 IU/day (partial remission).
• Assess the percentage of subjects in partial remission defined as IDAA1c≤9 (insulin dose-adjusted haemoglobin A1c). IDAA1c = %HbA1c + 4x daily insulin dose.
• Assess the effect of DiaPep277® on the number of hypoglycemic events and the event rate.
• Assess the effect of DiaPep277® on mean amplitude of glucose excursions.
• Investigate the long term treatment effect on beta-cell function, as determined by change from Baseline-Ext in stimulated C-peptide AUC0-20 min and Cmax secretion during the Glucagon stimulation test (GST), and the AUC0-120 min and Cmax secretion during the mixed-meal test (MMTT).
• Investigate the long term treatment effect on beta-cell function, as determined by change from Baseline-Ext in basal, fasting C-peptide secretion.
• Assess the percentage of subjects with a maximal stimulated C-peptide level ≥ 0.2 nmol/l at each time point • Assess the percent of subjects who maintain a basal, fasting C-peptide level ≥ 0.22 nmol/l at each time point
• Lowering the mean amplitude of post-prandial glucose excursions in subjects in the DiaPep277® group compared to the placebo group, as recorded by CGMS
• Lowering the event rate and duration of hypoglycemic events and on the glucose AUC0-24 hours in subjects in the DiaPep277® group compared to the placebo group, as recorded by CGMS.
Safety Endpoints
• To determine clinical safety and tolerability of DiaPep277® during the study.
• To determine the effect of DiaPep277® on DiaPep277®-specific antibodies during the study.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
• Glycemic control - HbA1c level: each visit (0,3,6,9,12,15,18,21 and 24 months)
• Daily insulin dose: every 6 months (0,6,12,18 and 24 months)
• Glucose profile: each visit (0,3,6,9,12,15,18,21 and 24 months)
• C-peptide secretion during GST: every 12 months (0,12 and 24 months)
• C-peptide secretion during the MMTT: twice (at extra visits at 12 and 24 months)
• Basal, fasting C-peptide secretion: every 6 months (0,6,12,18 and 24 months)
Safety relevant measurements at each visit, like hematology and chemistry, dermal hypersensitivity test, or every 6 months like fasting chemistry and plasma glucose. ECG (12 and 24 months) and others as indicated in the protocol. DiaPep277 specific antibodies at 0, 12 and 24 months |
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | 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 | No |
E.6.3 | Therapy | Yes |
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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 21 |
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 |
Austria |
Belarus |
Czech Republic |
Germany |
Hungary |
Israel |
Italy |
Lithuania |
Poland |
Russian Federation |
Serbia |
Spain |
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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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 | 1 |
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 | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |