| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects with type 2 diabetes mellitus who are being treated with metformin. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Type 2 (non-insulin dependent) Diabetes. |
|
| 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 | 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 |
|
| 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 investigate the safety and efficacy of 12 weeks of daily dosing with GSK256073 in subjects with T2DM who are on metformin monotherapy.
In Part B of the study ,an open label active commercial comparator arm, sitagliptin 100mg tablets will be used and will be locally sourced by the clinical study centers.
The decision to initiate Part B will be made by the GSK clinical study team based on an evaluation of data from part A. Futility criteria will be applied to allow the study to be terminated, if the part A interim analyses show that there is little chance that the desired week 12 HbA1c effects could be demonstrated in the final study analysis (pooled part A
and part B data). The predefined futility criteria is detailed in section 6.3.2. in the protocol. If safety issues are identified across all doses such that none of the doses studies in Part A are deemed safe for progression, the study will stopped. |
|
| E.2.2 | Secondary objectives of the trial |
•To characterize the exposure-response PK/PD relationship for change from baseline in week 12 HbA1c.
• To assess the effects of 12 weeks daily dosing with GSK256073 on fasting plasma glucose
• To assess the effects of 12 weeks daily dosing with GSK 256073 on insulin sensitivity relative to placebo.
• To assess the effects of 6 weeks and 12 weeks daily dosing with GSK256073 on fructosamine
• To determine number of subjects achieving HbA1c treatment targets for diabetes management.
• To characterize the exposure response PK/PD relationship with selected secondary endpoints, if feasible.
Secondary (Part A)
• To evaluate the sustainability of effects, and to examine the correlation between week 6 NEFA inhibition and glucose lowering.
Exploratory
• To assess changes from baseline in body weight and additional metabolic biomarkers, including plasma lipids. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in this study only if all of the following criteria
apply:
1. A diagnosis of T2DM as determined by a responsible physician based on a medical evaluation including medical history, physical examination, and laboratory tests, with onset at least 6 months prior to Screening. Subjects may be entered if they have stable hypertension or dyslipidemia on therapy. Subjects with other conditions except as noted in the Exclusion criteria may be included only if the investigator and GSK medical monitor agree that the condition is unlikely to introduce additional risk factors and will not interfere with study procedures.
2. HbA1c levels ≥ 7.0 % and ≤ 9.5%; at Screening.
3. On monotherapy with metformin at the time of screening, and at a total daily dose greater than or equal to 1000 mg for at least 2 months prior to dosing.
4. Fasting plasma glucose level < 13.3 mmol/L (240 mg/dL) at Screening.
5. Male or female between 20 and 70 years of age, inclusive, at the time of signing the informed consent.
6. Fasting Triglycerides lower than 4.52 mmol/L (400 mg/dL).
7. A female subject is able to participate is she if of:
Non-childbearing potential, defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea. FSH and estradiol levels will be checked at Screening for postmenopausal women. Simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<147 pmol/L), or values consistent with applicable lab reference ranges, are confirmatory for women who are not on hormone replacement therapy (HRT). For post-menopausal women taking HRT, a suppressed FSH will be adequate confirmation.
8. Male subjects must agree to use one of the contraception methods listed in Section 8.1. This criterion must be followed from the time of the first dose of study medication until 3 days after last dose of the study medication.
9. Overweight with BMI ≥ 25 kg/m2 for non-Asian Indians and ≥ 24 kg/m2 for Asian-Indian, and < 40 kg/m2.
10. The subject is capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
11. Subjects in France will be eligible only if they are affiliated to or a beneficiary of a social security category.
12. Subjects in other countries must meet all local and/or country-specific requirements for registration and reimbursement, as applicable. |
|
| E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
1. Requiring insulin therapy or use of combination oral antidiabetic medications or use of monotherapy other than metformin within the 3 months prior to screening.
2. Past or present disease (other than type 2 diabetes mellitus) that in the opinion of the Investigator may affect the outcome of this study. These diseases include the following but are not limited to, cardiovascular disease, malignancy, hepatic disease, renal disease, haematological disease, neurological disease, gastrointestinal disease and endocrine disease.
3. A positive pre-study Hepatitis B surface antigen, or positive Hepatitis C result within 3 months of screening.
4. Renal impairment as defined by a calculated GFR < 60 mL/min [Cockcroft, 1976]
5. Any concurrent serious illness (e.g., severe COPD, history of malignancy other than skin cancer within 5 years of initial diagnosis or with evidence of recurrence) that may interfere with a subject from completing the study.
6. AST, ALT, alkaline phosphatase ≥ 3ULN and bilirubin ≥ 1.5xULN (isolated bilirubin > 2xULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%).
7. Significant ECG abnormalities at Screening or Baseline, defined as follows:
Heart Rate < 50 and >100 bpm
PR Interval <120 and > 220 ms
QRS duration < 70 and >120 ms
QTC Interval (Bazett’s, or Frederica’s if it is
automatically calculated)*
> 450 ms (>480 msec in subjects with partial
Right Bundle Branch Block)
Subjects with Left Bundle Branch Block are excluded from the study. Subjects with partial Right Bundle Branch Block may be considered for inclusion following consultation with the GSK Medical Monitor.
* Note that if ECG abnormalities are identified, the average of 3 values taken approximately 5 minutes apart should be used to determine eligibility.
8. Systolic blood pressure greater than 160 mmHg, or diastolic blood pressure greater than 100 mmHg at Screening.
9. History of uric acid kidney stone, and being treated with drugs for hyperuricemia including Allopurinol or Probenicid.
10. History of peptic ulcer disease (PUD) and/or other gastrointestinal bleeding within the 12 months prior to screening.
11. Use of the following blood pressure medications or other medications that are renally excreted via OAT is prohibited: Enalapril (at any dose), Losartan (at any dose), Captopril (at any dose) and ongoing use of niacin or niacin containing medication. Please refer to Section 9.2 of protocol or consult GSK medical monitor.
12. History of myopathy or CPK value > 3 x ULN at screening.
13. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
14. Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
15. Any change in diet, exercise habits or smoking status within six weeks prior to screening. Any subject that cannot refrain from smoking while in the unit must be excluded.
16. History of sensitivity to any of the study medications, including sitagliptin or metformin, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
17. The subject has a positive pre-study drug screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines.
18. History of regular alcohol consumption within 6 months of the study defined as: An average weekly intake of >21 drinks/week for men or >14 drinks/week for women (Europe), or > 14 drinks/week for men or > 7 drinks/week for women (US). One drink is equivalent to (12 g alcohol) = 5 ounces (150 ml) of wine or 12 ounces (360 ml) of beer or 1.5 ounces (45 ml) of 80 proof distilled spirits.
19. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
20. Pregnant females as determined by positive serum and/or urine hCG test at screening and prior to dosing.
21. Lactating females.
22. Subjects who are unwilling or unable to follow the procedures outlined in the protocol.
23. Subject is mentally or legally incapacitated. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Safety and tolerability parameters include: adverse events, clinical laboratory tests, electrocardiograms (ECGs), and vital signs.
• The primary efficacy endpoint is change from baseline in HbA1c at week 12. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary
• GSK256073 AUC and HbA1c at week 12 will be evaluated to establish the exposure-response (PK/PD) relationship.
• Change from baseline in fasting plasma glucose at week 12.
• Change from baseline in fasting insulin and fasting glucose at week 12. These values will be used to calculate the Homeostatic Model Assessment (HOMA) index.
• Change from baseline in fructosamine at week 6 and week 12.
• Percentage of subjects with HbA1c < 7.0% and < 6.5%.
• Dose/exposure response relationship using PK/PD modeling for selected secondary endpoints.
Secondary (Part A)
• Change from baseline in 12 hour NEFA and glucose weighted mean AUC on day 2 and at week 6.
Exploratory
• Change from baseline in Total cholesterol, HDL, LDL and triglycerides at week 12.
• Change from baseline in body weight at week 12.
• Change from baseline in uric acid at week 12.
• Change from baseline in microalbuminuria at week 12.
• Metabolic markers to be analyzed at study completion after review of primary endpoint (examples include but are not limited to: Leptin, Adiponectin, IGF-1, IL-6, CRP, Homocysteine) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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 | No |
| 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 |
| Two parts - Part B will dependent on the results of Part A, Part A single blind, Part B double blind |
|
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Commercial Sitagliptin tablets will be locally sourced by the clinical trial centers |
|
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| 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 | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
|
| 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
|
| The end of the study is defined as the last subject’s last visit. |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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