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 |
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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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067585 |
E.1.2 | Term | Type 2 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 compare lixisenatide versus insulin glulisine in terms of HbA1c reduction and body weight change at week 26 in type 2 diabetic patients not adequately controlled on insulin glargine ± metformin. |
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E.2.2 | Secondary objectives of the trial |
To compare the treatments/regimens on:
• The percentage of patients reaching the target of HbA1c <7% or ≤6.5%
• Body weight;
• Self-Monitored Glucose profiles
• Fasting Plasma Glucose (FPG)
• Post-prandial plasma glucose /glucose excursions during a standardized
meal test (subset of patients)
• Daily doses of insulins
• Safety and tolerability
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Patients with type 2 diabetes mellitus diagnosed at least 1 year before screening visit (V1) .
• Patients treated with basal insulin for at least 6 months.
• Patients treated for at least 3 months prior to visit 1 with a stable basal insulin regimen (ie type of insulin and time/frequency of the injection). The insulin dose should be stable (± 20 %) and ≥20 U/day for at least 2 months prior to visit 1.
• Patients treated with basal insulin alone or in combination with 1 to 3 oral anti-diabetic drugs (OADs) that can be: metformin (≥1.5g/day or maximal tolerated dose), a sulfonylurea (SU), a dipeptidyl-peptidase-4 (DPP-4) inhibitor, a glinide. The dose of OADs should be stable for at least 3 months prior to visit 1.
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E.4 | Principal exclusion criteria |
• At screening: age < legal age of majority
• At screening, HbA1c: < 7.5% and > 10.0% for patients treated with basal insulin alone or in combination with metformin only; < 7.0% and > 10.0% for patients treated with basal insulin and a combination of oral anti-diabetic drugs which includes a SU and/or a DPP4 inhibitor and/or a glinide
•Women of childbearing potential with no effective contraceptive method, pregnancy or lactation
• Type 1 diabetes mellitus
•Treatment with glucose-lowering agent(s) other than stated in the inclusion criteria within 3 months prior to screening.
•Previous treatment with short or rapid acting insulin other than in relation to hospitalization or an acute illness.
• Any previous treatment with lixisenatide, or any discontinuation from another GLP-1 receptor agonist due to safety/tolerability issue or lack of efficacy.
•At screening, Body Mass Index (BMI) ≤20 or >40 kg/m².
•Weight change of more than 5 kg during the 3 months prior to the screening visit; use of weight loss drugs within 3 months prior to screening.
• Within the last 6 months prior to screening: history of myocardial infarction, stroke, or heart failure requiring hospitalization. Planned coronary, carotid or peripheral artery revascularisation procedures.
• History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy, stomach/gastric surgery.
• At screening resting systolic blood pressure > 180 mmHg or diastolic blood pressure > 95 mmHg
• Personal or immediate family history of medullary thyroid cancer (MTC) or genetic condition that predisposes to MTC (e.g. multiple endocrine neoplasia syndromes)
• Contraindication related to metformin (for patient receiving this treatment), insulin glargine, insulin glulisine or lixisenatide.
• Patients with severe renal impairment (creatinine clearance less than 30 ml/min) or end-stage renal disease, if no treatment with metformin
• At screening, amylase and/or lipase > 3 times the upper limit of the normal laboratory range (ULN)
• At screening ALT or AST>3ULN
• At screening calcitonin ≥20 pg/ml (5.9 pmol/L)
Exclusion Criteria for randomization at the end of the screening period before randomization:
• HbA1c <7.0% or >9.0%.
• 7-day mean fasting SMPG >140 mg/dl (7.8 mmol/L).
• Amylase and/or lipase > 3 times ULN.
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E.5 End points |
E.5.1 | Primary end point(s) |
- Change from baseline in HbA1c
- Change from baseline in body weight |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
- Percentage of patients reaching HbA1c <7%
- Percentage of patients reaching HbA1c ≤6.5%
- Change in body weight from baseline
- Percentage of patients with no weight gain.
- Change in 7-point SMPG profiles from baseline
- Change from baseline in FPG
- Change from baseline in post-prandial glucose /glucose excursions during a standardized meal test (subset of patients)
- Change from baseline in insulin glargine dose
- Daily dose of insulin glulisine
- Total daily dose of insulins
- Documented (PG <60 mg/dl) symptomatic hypoglycemia (percentage of subjects with at least one episode, number of events per patient-year)
- Severe hypoglycemia
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- week 26
- 26 weeks for:
Documented (PG <60 mg/dl) symptomatic hypoglycemia (percentage of subjects with at least one episode, number of events per patient-year)
and
Severe hypoglycemia
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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 | Yes |
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 | 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 | 3 |
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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 121 |
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 |
Canada |
Chile |
Czech Republic |
Estonia |
France |
Germany |
Hungary |
Italy |
Latvia |
Lithuania |
Spain |
Mexico |
Poland |
Romania |
Russian Federation |
Ukraine |
United Kingdom |
United States |
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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 | 8 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 8 |