E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10045242 |
E.1.2 | Term | Type II diabetes mellitus |
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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 absolute change in HbA1c concentration from baseline to the end of the treatment period compared to placebo |
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E.2.2 | Secondary objectives of the trial |
To determine additional efficacy parameters, safety and tolerability following RO4998452 administration compared to placebo, including • the absolute change in fasting plasma glucose from baseline to the end of the treatment period • the glycemic response with additional parameters of glycemic control (such as mean daily blood glucose obtained from 7-point plasma glucose profile, fructosamine, Meal Tolerance Test) • the tolerability and safety profile • the effects on body weight • the pharmacokinetics and the exposure-response relationship of RO4998452 including the influence of covariates (by a population analysis approach)
Exploratory objectives: • to determine the effects on feeling of hunger and thirst • to determine the dose-response curve of RO4998452 on 24-h urinary glucose excretion
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Title: Roche Sample Repository Research Project in association with protocol BC21587
Protocol number/Version: BC21587RG/A (dated 13 October 2008)
Objective for substudy BC21587RG: • To obtain a single blood sample from consenting patient enrolled in associated study BC21587 for pharmacogenetic and genetic research analysis |
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E.3 | Principal inclusion criteria |
• Patients with type 2 diabetes, diagnosed for at least 3 months at screening examination, based on WHO criteria • Patients who are either (1) treated with diet and exercise and a stable dose of metformin (daily dose 1.5 g to 3.0 g but not higher than recommended in the locally approved label) for at least 3 months or (2) treated with diet and exercise • HbA1c equal to or greater than 7.0 % and equal to or less than 10.0 % at screening and at the visit preceding randomization • Age 18 to 75 years (inclusive) at the time of screening • BMI > 22 kg/m2 and equal to or less than 45 kg/m2 at screening • Able and willing to give written informed consent and able to comply independently to all study requirements
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E.4 | Principal exclusion criteria |
• Type 1 diabetes mellitus patients • History of ketoacidosis or lactic acidosis • Fasting serum C-peptide equal to or less than 1 ng/ml at screening for patients with a BMI equal to or less than 25 kg/m2 • Fasting plasma glucose > 240 mg/dl (13.3 mmol/l) • Any contraindication to metformin as indicated in the label such as congestive heart failure (NYHA class III or IV or requiring pharmacological treatment) or respiratory failure • History of body weight changes within 3 months prior to screening > 10% of body weight measured at screening • Patients currently or within 12 months prior screening treated with insulin (with the exception of emergency situations in which insulin was given for < 7 consecutive days) • Patients currently or within 2 months prior to screening treated with any oral or injectable anti-diabetic agent except stable dose of metformin • Patients currently or within 6 months prior to screening treated with any PPARγ agonist • History of antidiabetic triple therapy • Patients currently or within 3 months prior to screening treated with any prescription weight-lowering medication or orlistat • Patients treated with lipoprotein modifying therapy (e.g. niacin, statin) if dosage or dosing regimen was changed within 4 weeks prior to screening. Dosage and dosing regimen for fibrates need to be stable for 3 months prior to screening. • Patients receiving antihypertensive medication, and/or thyroid hormones if the dose(s) has (have) not been stable for at least 4 weeks prior to randomization • Systemic, inhaled or topical corticosteroid therapy for > 14 treatment days within 3 months prior to screening • Impaired liver function (as suggested by ALT, AST, total bilirubin or alkaline phosphatase > 2.5x ULN) at screening • Hyponatremia (< 120 mM) or hypernatremia (> 150 mM) at screening or within 3 months prior to screening • Renal disease or renal dysfunction (as suggested by serum creatinine levels equal to or greater than 1.5 mg/dl (133 µmol/l) [males], equal to or greater than 1.4 mg/dl (124 µmol/l) [females]) at screening • Personal or family history of renal glucosuria (= glucosuria in the absence of diabetes mellitus) • History of bariatric surgery or small bowel resection • History of uncontrolled hypertension (SBP > 150 mmHg and/or DBP > 95 mmHg, despite treatment) < 3 months prior to screening • Myocardial infarction or stroke within 6 months prior to screening • Evidence of significant pre-diagnosed diabetic complication requiring medical treatment (e.g., medically treated gastroparesis, diagnosed proliferative diabetic retinopathy) • Any known serious illness (such as cancer, major active infection, severe psychiatric disorders, clinical significant gastrointestinal disorder, active autoimmune disease, chronic inflammatory condition, chronic anemia, all hemoglobino¬pathies) at screening which could interfere with the conduct of the study • Any new conditions diagnosed at screening requiring treatment longer than 10 days or chronic therapies that can not be stabilized during the screening period • Any abnormalities in clinical laboratory tests or ECG (e.g., clinically relevant QTc prolongation, family history of long QT syndrome, concomitant use of class I antiarrythmic drugs such as disopyramide, quinidine, procainamide, mexiletine, flecainide, propafenone) which precludes safe involvement in the study as judged by the investigator • Participation in an investigational drug study within 2 months (or five half-lives, whichever is longer) prior to screening • Pregnant or lactating women, positive pregnancy test, and women of childbearing potential not using two adequate methods of contraception, including a barrier method • History of alcohol or drug abuse • Known hypersensitivity to RO4998452 or any of the components of its formulation • Persons with albinism
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E.5 End points |
E.5.1 | Primary end point(s) |
• Absolute change in HbA1c from baseline to the end of the treatment period |
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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 | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
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.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 22 |
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 | Information not present in EudraCT |
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 |
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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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The end of the trial is defined as the last visit of the last patient in the trial (LPLV). |
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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 | |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 11 |