E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Type 1 diabetes mellitus(T1DM) |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067584 |
E.1.2 | Term | Type 1 diabetes mellitus |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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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 |
To determine the changes in stimulated C-peptide response during the first two hours of a mixed meal tolerance test (MMTT) at baseline and after 12 months for 360mg Verapamil SR administered orally once daily versus placebo. |
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E.2.2 | Secondary objectives of the trial |
To determine the effects of 360mg Verapamil SR administered orally once daily on fasting C-peptide and Dried Blood Spot (DBS) C-peptide measurements over time. To determine the effects of 360mg Verapamil SR administered orally once daily on HbA1c daily total insulin dose and continous glucose monitoring (CGM) time in range. To determine the effects of treatment on other biomarkers related to immunological changes and beta-cell death and survival in this population. To determine the effects of 360mg Verapamil SR administered orally once daily on safety (vital signs, ECG). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Have given written informed consent • Age ≥18 and <45 years at consent • Must have a diagnosis of T1D of within 6 weeks duration at screening (from date of the first insulin injection) • Must have at least one or more diabetes-related autoantibodies present at screening • Must have random C-peptide levels ≥200 pmol/L measured at screening • Be willing to comply with intensive diabetes management |
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E.4 | Principal exclusion criteria |
• Be immunodeficient or have clinically significant chronic lymphopenia: Leukopenia (< 3,000 leukocytes /μL), neutropenia (<1,500 neutrophils/μL), lymphopenia (<800 lymphocytes/μL), or thrombocytopenia (<100,000 platelets/μL) • Have active signs or symptoms of acute infection at the time of screening • Be currently pregnant or lactating, or anticipate getting pregnant during the 12 months study period • Require use of immunosuppressive agents including chronic use of systemic steroids • Have evidence of current or past human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C infection • Have any complicating medical issues or abnormal clinical laboratory results that may interfere with study conduct, or cause increased risk to include pre-existing cardiac disease, chronic obstructive pulmonary disease (COPD), sickle cell disease, neurological, or blood count abnormalities as judged by the investigator • Have a history of malignancies other than skin • Evidence of liver dysfunction with aspartate aminotransferase (AST) or alanine transaminase (ALT) greater than 3 times the upper limits of normal • Evidence of renal dysfunction with creatinine greater than 1.5 times the upper limit of normal • Current or ongoing use of non-insulin pharmaceuticals that affect glycaemic control within prior 7 days of screening • Use of any other investigational drug in the previous 30 days and/or intent on using any investigational drug for the duration of the trial • Current use of verapamil or other calcium channel blockers • Known hypersensitivity to verapamil or to any of the excipients, use of beta-blockers in patients with poor ventricular function, concomitant ingestion of grapefruit juice, combination with ivabradine • Hypotension (of less than 90mmHg systolic), sick sinus syndrome (except in patients with a functioning artificial pacemaker); uncompensated heart failure; marked bradycardia (less than 50 beats/minute), Wolff-Parkinson- White syndrome, acute myocardial infarction complicated by bradycardia, marked hypotension or left ventricular failure • ECG second or third degree atrioventricular block • Any condition that in the investigator's opinion may adversely affect study participation or may compromise the study results |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Outcome Measure: 1. Area under the stimulated C-peptide response curve The primary objective is to determine the changes in stimulated C-peptide response during the first two hours of a mixed meal tolerance test (MMTT) at baseline and after 12 months for 360mg Verapamil SR administered orally once daily versus placebo.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
[Time Frame: At baseline and after 12 Months of therapy] |
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E.5.2 | Secondary end point(s) |
Secondary Outcome Measure: 2. Area under the stimulated C-peptide response curve The area under the stimulated C-peptide response curve over the first two hours of a mixed meal tolerance test (MMTT) [Time Frame: At baseline, and 3, 6, 9 and 24 months] 3. Proinsulin and preproinsulin secretion Proinsulin and preproinsulin secretion during the first two hours of a mixed meal tolerance test (MMTT) [Time Frame: At baseline and 3, 6, 9 and 12 months] 4. Fasting C-peptide To determine the effects of 360mg Verapamil SR administered orally once daily on fasting C-peptide and Dried Blood Spot (DBS) C-peptide measurements over time. [Time Frame: At baseline and after 12 months therapy] 5. DBS C-peptide The DBS (Dried blood spot) C-peptide measurements at all observation times [Time Frame: At all observation times] 6. Change in HbA1c To determine the effects of 360mg Verapamil SR administered orally once daily on HbA1c daily total insulin dose and continous glucose monitoring (CGM) time in range. [Time Frame: Baseline to 12 months and baseline to 24 months] 7. Severe hypoglycaemic episodes Number of treatment emergent severe hypoglycaemic episodes. Severe hypoglycaemia denotes severe cognitive impairment requiring external assistance for recovery according to the American Diabetes Association (ADA) [Time Frame: Baseline to 12 months] 8. DKA Number of treatment emergent episodes of diabetic ketoacidosis [Time Frame: Baseline to 12 months] 9. Change in insulin requirements Change in insulin requirements, baseline to 12 months as the daily total dose (three days average) in units per kg body weight (BW) [Time Frame: Baseline to 12 months and baseline to 24 months] 10. Change in T1D associated autoantibodies Change in T1D associated autoantibodies (GADA, IAA, IA-2A and ZnT8A) from baseline to 12 months [Time Frame: Baseline to 12 months] 11. Continous glucose monitoring (CGM) Continous glucose monitoring (CGM) time in range (70-140 mg/dL, 3.9-7.8 mmol/L) and (70-180 mg/dL, 3.9-10.0 mmol/L), time above range (>180 mg/dL, >10.0 mmol/L), time below range (<70 mg/dL, < 3.9 mmol/L) [Time Frame: Baseline to 12 months] Other Pre-specified Outcome Measures: 12. DTSQs, DTSQc, ADDQoL, and HypoFear questionnaires Patients’ quality of life will be assessed by participant-reported outcome measures (PROMS): the Diabetes Treatment Satisfaction Questionnaire – DTSQs, DTSQc • the Audit of Diabetes Dependent Quality of Life - ADDQoL • the Hypoglycaemia Fear Survey - HFS [Time Frame: DTSQs and HFS questionnaires at week 4 , month 6 and month 12. ADDQoL questionnaire at month 6 and month 12. DTSQc questionnaire will be administered to participants at month 12 only.] |
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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) | 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 | 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 | 2 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
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 | 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 | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |