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 |
Patient with Diabetes Type 1, that are on the waiting list for Islet Transplantation. |
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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 | 21.1 |
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 | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to study safety and tolerability of IBsolvMIR® in comparison to Heparin, in combination with standard immunosuppressive therapy in islet transplantation. |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the effect of IBsolvMIR on transplant-induced coagulation biomarkers (TAT complexes, D-dimer, platelet consumption,) in comparison to heparin • To evaluate the effect of IBsolvMIR on transplant induced humoral immunity biomarkers (C3a, soluble C5b-9) in comparison to heparin • To evaluate the effect of IBsolvMIR on transplant induced cellular immunity biomarkers (cytokines) in comparison to heparin • To evaluate the effect of IBsolvMIR on engraftment stimulation biomarkers (HGF, VEGF-A, FGF) in comparison to heparin • To evaluate the effect of IBsolvMIR on transplant induced islet destruction biomarkers (C-peptide, soluble TF and PECAM-1) in comparison to heparin • To evaluate the effect of IBsolvMIR on c-peptide/glucose/creatinine ratio at 14 days, compared to baseline and to heparin • To evaluate the pharmacokinetics of IBsolvMIR |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patient on a waiting list for islet transplantation 2. Male and female patients age 18 to 60 years of age. 3. Ability to understand and provide written informed consent. 4. Mentally stable and able to comply with the procedures of the study protocol. 5. Clinical history compatible with type 1 diabetes with onset of disease at < 40 years of age and insulin-dependence for > 5 years at the time of enrolment. 6. Documented C-peptide <0.1 nmol/L before first islet transplantation (stimulated in response to a MMTT or other confirmatory method). 7. All subjects must have received medical treatment of their diabetes under the guidance from an experienced endocrinologist.
If not previously transplanted the patient must also have; 8. At least one episode of severe hypoglycemia in the past 1 year defined as an event with at least one of the following symptoms; memory loss, confusion, uncontrollable behavior, unusual difficulty in awakening, suspected seizure, loss of consciousness, or visual symptoms, in which the subject was unable to treat him/herself and which was associated with either a blood/plasma glucose level < 54 mg/dl [3.0 mmol/L] or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration
OR 9. Reduced awareness of hypoglycemia as defined by a Clarke score of 4 or more. |
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E.4 | Principal exclusion criteria |
1. Patients with prior organ transplants other than a kidney graft and/or islets. A previous pancreas transplant can be accepted if it failed within the first week due to thrombosis and the graft was removed. 2. Patients with body mass index (BMI) > 30. 3. Insulin requirement > 0.7 Unit/kg/day at screening. 4. Consistently abnormal liver function tests (> 1.5 x ULN on two consecutive measurements > 2 weeks apart) at screening. 5. Proliferative untreated diabetic retinopathy 6. Increased risk for thrombosis (ex. homozygous APC-resistance) or bleeding (INR>1.5) 7. Any history of malignancy except for completely resected squamous or basal cell carcinoma of the skin 8. Patients with increased cardiac risk defined as; o unstable coronary artery disease requiring hospitalization or revascularization within 6 months prior to baseline visit o chronic heart failure which required hospitalization 30 days prior to baseline visit 9. Patients with active infections, unless treatment is not judged necessary by the investigators 10. Patients with serological evidence of infection with HIV, hepatitis B (patients with serology consistent with previous vaccination and a history of vaccination are acceptable) or hepatitis C. 11. Patients with active peptic ulcer disease, symptomatic gallstones or portal hypertension. 12. Patients who are pregnant or breastfeeding, or who intend to become pregnant. 13. Patients of childbearing potential not willing to use adequate double contraception with < 1% failure rate after the screening visit until the last visit. 14. Active alcohol or substance abuse 15. Patients with evidence of high-level sensitization (PRA> 50% with flow cytometry). 16. Patients with psychological conditions that make it unsafe to undergo islet transplantation or which preclude compliance with prescribed therapy 17. HbA1c > IFCC 100 mmol/mol, at screening. 18. Patients with any condition or any circumstance that in the opinion of the investigator would make it unsafe to undergo treatment with IBsolvMIR. 19. Patients participating in or having participated in any other clinical drug studies in the past four weeks. 20. History of bleeding disorders 21. History of severe hypersensitivity 22. Previous known heparin-induced thrombocytopenia (HIT) 23. Patients with severe hepatic or renal impairment |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Bleeding events after islet transplantation with total dose of 27 mg/kg BW IBsolvMIR in comparison to active comparator Heparin 2. Other AEs/SAEs after islet transplantation with total dose of 27 mg/kg BW IBsolvMIR in comparison to Active comparator Heparin |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At 8 visits over 1.5 months |
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E.5.2 | Secondary end point(s) |
1. Difference between groups in levels of biomarkers after transplant 2. Change in levels of C-peptide/(glucose x creatinine) ratio |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
For endpoint 1 (all biomarkers except engraftment stimulation biomarkers): at 8 time-points within the first 24 hours from start of transplant, and Before and after dosing day 1, 3, and 6, and at day 7
For endpoint 1 (engraftment stimulation biomarkers): at 10 time-points within the first 24 hours from start of transplant, and Before and after dosing day 1, 3, and 6, and at day 7
For endpoint 2: at 14 days post transplant compared to baseline |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 4 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |