Multi-center, randomized, double-blind, 5-arm parallel group, placebo controlled 4 week study to investigate the safety, tolerability and efficacy of two doses each (near to maximum tolerated dose and lower dose) of RO5093151 administered twice daily (BID regimen) and RO5027838 administered once daily (QD regimen) in patients with type 2 diabetes mellitus on a stable dose of metformin - N/A

• Register: EUCTR
• Last refreshed on: 19 March 2012
• Main ID: EUCTR2008-001122-13-AT
• Date of registration: 09/12/2008
• Prospective Registration: Yes
• Primary sponsor: F. Hoffmann-La Roche Ltd
• Public title: Multi-center, randomized, double-blind, 5-arm parallel group, placebo controlled 4 week study to investigate the safety, tolerability and efficacy of two doses each (near to maximum tolerated dose and lower dose) of RO5093151 administered twice daily (BID regimen) and RO5027838 administered once daily (QD regimen) in patients with type 2 diabetes mellitus on a stable dose of metformin - N/A
• Scientific title: Multi-center, randomized, double-blind, 5-arm parallel group, placebo controlled 4 week study to investigate the safety, tolerability and efficacy of two doses each (near to maximum tolerated dose and lower dose) of RO5093151 administered twice daily (BID regimen) and RO5027838 administered once daily (QD regimen) in patients with type 2 diabetes mellitus on a stable dose of metformin - N/A
• Date of first enrolment: 13/03/2009
• Target sample size: 110
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2008-001122-13
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: yes Other trial design description: double dummy (placebo) will be used If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

Austria, Germany

Key inclusion & exclusion criteria

Inclusion criteria:
1. Male and female patients with type 2 diabetes, diagnosed for at least 3 months at screening examination based on WHO criteria
2. Patients who have been treated for at least 3 months with a stable dose of metformin = 1.5 g/day or maximum tolerated dose (MTD), but not higher than recommended in the locally approved label prior to screening
3. If patients are taking any additional oral anti-diabetic and/or weight-lowering medication besides metformin except thiazolidinediones (pioglitazone, rosiglitazone) or dual PPAR a/? agonists and are willing to drop this additional T2D medication during the trial, they will be considered providing their medical status including plasma glucose level matches all selection criteria at the end of the pre-randomization period
4. HbA1c = 7.0 % and = 10.0 % at screening
5. Fasting serum C-peptide =1 ng/ml (0.33nmol/l) at screening
6. Age 35-65 years (inclusive) at the time of screening
7. BMI > 27 kg/m2 and = 42 kg/m2 at screening
8. Females of non-childbearing potential, i.e. postmenopausal (defined as more than one year after the cessation of menses without an alternative medical cause and documented by FSH levels >40 UI/L) or surgically sterilized (by means of hysterectomy, bilateral oopherectomies or tubal ligations) for at least 3 months
9. Negative drug screen for cannabinoids, amphetamines, opiates, methadone, cocaine, benzodiazepines, and barbiturates (retest at the discretion of the investigator).
10. Able and willing to give written informed consent and to comply with the requirements of the study
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. History of diabetic ketoacidosis
2. Fasting plasma glucose (FPG) >240 mg/dL (13.3 mmol/L) at pre-randomization visit (stopping rule)
3. Patients currently or previously treated with insulin (with the exception of emergency situations in which insulin was given for less than 7 consecutive days, but not within the last 6 months before screening)
4. Patients currently or within the previous 6 months before screening treated with a thiazolidinedione (pioglitazone, rosiglitazone) or a dual PPAR a/? agonist
5. Patients treated with lipoprotein modifying therapy (fibrates, niacin) within a month before screening (stable statin therapy unchanged for at least 1 month prior to screening is allowed)
6. If receiving antihypertensive medication and/or thyroid hormones, and the dose(s) have not been stable for at least 6 weeks prior to baseline
7. Systemic, topical, intranasal or inhaled corticosteroid therapy for more than 2 weeks, within 3 months prior to screening examination
8. Impaired liver function (as suggested by SGOT, SGPT, GGT > 2.5 x ULN, bilirubin or alkaline phosphatase > 1.5 x ULN) at screening
9. Myocardial infarction or stroke within 6 months prior to screening
10. Uncontrolled hypertension (SBP = 160 mmHg and/or DBP = 100 mmHg) at the time of screening
11. Known proliferative diabetic retinopathy
12. Known autoimmune disease or chronic inflammatory condition.
13. Known Glucose-6-phosphate dehydrogenase deficiency
14. Any other clinically significant major organ system disease at screening (other than diabetes mellitus Type 2) such as relevant cardiovascular, gastrointestinal, hepatic, neurologic, psychiatric, endocrine (i.e. pancreatic), hematologic, malignant, infection or other major systemic diseases making implementation of the protocol or interpretation of the study results difficult
15. Any contraindication to metformin or lidocaine as indicated in the local label such as congestive heart failure (NYHA class III or IV or requiring pharmacological treatment), respiratory failure
16. Renal disease or dysfunction (as suggested by serum creatinine levels =1.5 mg/dL (133 µmol/L) [males], =1.4 mg/dL (124 µmol/L) [females]) at screening and Creatinine Clearance based upon the Cockcroft-Gault formula of <60ml/min at screening.
17. Positive result on hepatitis B (HBs-AG), hepatitis C (HCV-AB), or HIV 1 and 2
18. Donation of blood (>400 ml) during the previous 3 months prior to the screening visit or during the duration of the study
19. Clinically relevant QTc prolongation (e.g. QTc > 480 ms), history of additional risk factor for torsade de point (e.g. family history of long QT syndrome, hearth failure, hypokalemia) or concomitant use of medications, that prolong the QT/QTc interval.
20. Any other abnormalities in clinical laboratory tests which precludes safe involvement in the study as judged by the Investigator
21. Participation in another trial having received study medication within two months or 5 half-lives of that drug (whichever is longer) before the screening visit
22. History of alcohol or drug abuse
23. Patient treated with concomitant medication that are known to be strong CYP3A4 inhibitors and inducers
24. Smoking more than 10 cigarettes or equivalent / day
25. Known hypersensitivity to RO5093151 or RO5027838 or
any of the components of their formulation
26. Night shift workers
27. Any subject who is the investigator or any sub-investigator, research assistant, pharmacist, study coordinator, other staff thereof, dir

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Type 2 Diabetes (T2D)
MedDRA version: 9.1 Level: LLT Classification code 10012613 Term: Diabetes mellitus non-insulin-dependent

Intervention(s)

Product Name: 11Beta-HSD1 Inhibitor
Product Code: RO5093151/F02
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: not yet available
CAS Number: n/a
Current Sponsor code: RO5093151
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Product Name: 11Beta-HSD1 Inhibitor
Product Code: RO5093151/F04
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: not yet available
CAS Number: n/a
Current Sponsor code: RO5093151
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Product Name: 11Beta-HSD1 Inhibitor
Product Code: RO5027838/F04
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: not yet available
CAS Number: 918873-34-4
Current Sponsor code: RO5027838
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: To measure the effect of the two 11ß-HSD1 inhibitors RO5093151 and RO5027838 on mean daily plasma glucose (change from baseline at Week 4) in type 2 diabetic patients treated with a stable dose of metformin compared to placebo

Secondary Objective: 1. To measure the effect of RO5093151 and RO5027838 on fasting plasma glucose, insulin, C-peptide, glucagon, HbA1c as well as ß-cell function
2. To evaluate the tolerability/safety of RO5093151 and RO5027838, including measurements of the function of the hypothalamic-pituitary-adrenal axis
3. To measure the effect of RO5093151 and RO5027838 on lipid parameters
4. To measure the effect of RO5093151 and RO5027838 on arterial blood pressure and body weight
5. To investigate, using population analysis approach, the pharmacokinetics and the exposure-response relationship of RO5093151 and RO5027838 in the target population, including the influence of covariates such as age, gender and body weight
6. To assess the systemic concentration of metformin in combination with RO5093151 or RO5027838 in patients

Primary end point(s): The primary endpoint for this study is the absolute change in mean daily plasma glucose from baseline (Day -1) to Day 27 of the treatment period.Mean daily plasma glucose (assessed by a 9-point plasma glucose profile before and after 3 standardized test meals at bedtime, 3:00 am and 8:00 am) absolute change from
baseline to Day 27 of the treatment period

Secondary ID(s)

2008-001122-13-DE

BP21850

N/A