| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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 | 10012601 |
| E.1.2 | Term | Diabetes mellitus |
|
| 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 evaluate the effect of five oral doses of LCQ908 (2 mg, 5 mg, 10 mg, 15 mg or 20 mg) and placebo over 12 weeks on HbA1c in obese patients with T2DM. The patients will have been on prior metformin monotherapy for at least 3 months prior to screening and will remain on a stable dose of metformin (≥ 1500 mg daily) throughout the study. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of LCQ908 (2 mg, 5 mg, 10 mg, 15 mg, 20 mg) vs. placebo and to evaluate the effect of LCQ908:
•As a potential therapy for obesity, assessed by changes in body weight and waist circumference
•On other measures reflecting short term control of hyperglycemia, assessed by changes in fasting plasma glucose and plasma fructosamine
•As a potential therapy for dyslipidemia, assessed by changes in fasting plasma lipids
•On apparent insulin sensitivity assessed by HOMA-IR
•On gastrointestinal tolerability
•On pharmacokinetics |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Written informed consent to participate in the study, before any study related activities are performed, and is likely to comply with all study requirements, including dietary guidelines.
2.Age 18-75 years, inclusive.
3.Males, non-fertile females, and females of non-childbearing potential. Women must be (a) postmenopausal, defined as age >48 with 12 months of natural (i.e. spontaneous) amenorrhea or age >42 with >6 months of spontaneous amenorrhea with serum FSH levels > 30 mIU/mL and estradiol <30 pg/ml ; (b) 6 weeks post-surgical bilateral oophorectomy with or without hysterectomy; or (c) have a documented history of tubal ligation at least 1 year prior to screening.
4.Patients with T2DM with HbA1c 7.0 to 10.0%, inclusive.
5.Fasting plasma glucose ≤250mg/dL (13.9 mmol/L) at Visit 1 assessed by the central laboratory
6.Patients treated with metformin for at least three months prior to Visit 1 (screening) and on a stable dose ≥1500 mg for 4 weeks prior to Visit 3 (randomization). Patients must agree to maintain the same dose of metformin from 4 weeks before Visit 3 to the end of the study.
7.Body mass index (BMI) of 28 to 42 kg/m2 inclusive
8.Body weight at Visit 1 within 5% of their self-reported weight over the past three months and agreement to maintain the study-recommended diet (counseled during screening) and usual exercise habits during the full course of the study.
9.Patients on stable doses of statins or fibrates for 6 weeks prior to Visit 1 must agree to maintain those doses during the study period. |
|
| E.4 | Principal exclusion criteria |
1.A history of type 1 diabetes, diabetes that is a result of pancreatic injury, or secondary forms of diabetes, e.g. Cushing’s syndrome and acromegaly
2.A history of acute metabolic diabetic complications such as ketoacidosis or hyperosmolar state (coma) within the past 6 months.
3.Evidence of significant diabetic complications, e.g., symptomatic autonomic neuropathy, severe diabetic retinopathy (e.g. associated with retinal hemorrhages or repeated photocoagulation therapy), diabetic gastroparesis or enteropathy.
4.Treatment with any oral antidiabetic agent other than metformin within 12 weeks prior to Visit 1.
5.Chronic insulin treatment (> 1 week of treatment in the absence of concurrent illness) within the 6 months prior to Visit 1.
6.Acute infections which may affect blood glucose control 4 weeks prior to Visit 1 and other concurrent medical conditions that may interfere with the interpretation of efficacy and safety during the study.
7.Donation of one unit (500 ml) or more of blood, significant blood loss equaling at least one unit of blood within 2 weeks, or a blood transfusion within 8 weeks prior to Visit 1
8.Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL).
9.Severe illness, trauma, or major surgery within 3 months prior to Visit 1.
10.Mean (of the last 2 of 3 consecutive determinations) sitting diastolic blood pressure >100 mmHg and/or mean sitting systolic blood pressure >150 mmHg. (patients may their blood pressure re-evaluated on one occasion only no sooner than 4 weeks after adjustment of antihypertensive medications)
11.History of Congestive Heart Failure (New York Heart Association (NYHA) Class III-IV) or pacemaker use within the past 5 years.
12.Any of the following within the past 12 months:
a.Myocardial infarction (MI). If the screening ECG reveals patterns consistent with a MI in the absence of clinical signs and symptoms of acute MI and in the absence of elevated troponin and CK-MB enzymes and the date of the event can not be determined, then the patient can enter the trial at the discretion of the investigator and/or local medical monitor
b.Unstable angina
c.Arterial revascularization, coronary artery bypass graft surgery, or percutaneous coronary intervention
d.Cerebrovascular accident or recurrent transient ischemic attacks
13.Any of the following ECG abnormalities:
a.Torsades de pointes, sustained and clinically relevant atrial or ventricular tachycardia, or atrial or ventricular fibrillation
b.Second degree AV block (Mobitz 1 and 2)
c.Third degree AV block
d.Prolonged QTc (>450 ms for males and >470 ms for females) at screening confirmed by visual inspection of the electrocardiogram
14.Liver disease such as cirrhosis or chronic active hepatitis B and C
15.Impaired renal function including a history of dialysis or of nephrotic syndrome and/or estimated creatinine clearance less than 60 ml/min (using the Modification of Diet in Renal Disease (MDRD) formula). Proteinuria <300 mg/gram creatinine will be allowed.
16.Any of the following significant laboratory abnormalities at Visit 1:
a.Alanine aminotransferase (ALT) and/or Aspartate aminotransferase (AST) > 2 times the upper limit of normal (ULN), confirmed by a repeat measurement within 3 working days
b.Total bilirubin >2 times ULN and/or direct bilirubin greater than the ULN, confirmed by a repeat measurement within 3 working days
c.Thyroid stimulating hormone (TSH) <0.3 and >5.5 µU/ml. Patients on a stable dose of L-thyroxine for 2 months prior to Visit 1 can be included if their TSH is within the acceptable range. If the TSH is outside the acceptable range, patients may be re-evaluated on one occasion only no sooner than 2 months after adjustment of their thyroid replacement dose.
d.Platelet count <100,000/ml, or white blood cell count <4000/ml
e.Hemoglobin <12 g/L in men, <11 g/L in women
f.Fasting Triglycerides >500 mg/dL (>5.65 mmol/L)
g.Fasting LDL cholesterol >130 mg/L (>3.4 mmol/L) unless on a statin
h.Self-reported positive HIV test, currently treated for HIV, presence of Hepatitis C antibodies or positive Hepatitis B serology indicative of ongoing or latent disease |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy variable is the change from baseline of HbA1c at 12 weeks (or the last available post-randomization value). |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| 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
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 55 |
| 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 |
|
| 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
| |
| 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 | 12 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 12 |
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