| 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 | 7.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003601 |
|
| 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 safety and tolerability of repeated oral administration at 3 dose levels of GSK189075 in subjects with type 2 diabetes mellitus. |
|
| E.2.2 | Secondary objectives of the trial |
• To compare the safety, tolerability, pharmacokinetic and pharmacodynamic parameters of GW869682 with GSK189075 in a single, placebo-controlled 2 week repeated oral dose trial.
• To assess the pharmacokinetic profile of GSK189075 and its active entity, GSK189074 as well as metabolites (GSK279782, and GSK333081) in subjects with type 2 diabetes mellitus.
• To determine the effects of repeated dosing of GSK189075 on pharmacodynamic endpoints including fluid/electrolyte balance, urinary glucose excretion and circulating glucose concentrations in subjects with type 2 diabetes mellitus.
• To ascertain dose-response and exposure-response relationships of GSK189075, GSK189074 and metabolites with pharmacodynamic endpoints.
• To determine if there are changes in lipomics, the fatty acid composition in the non-polar lipid classes (provided that there are changes in plasma glucose and urine glucose which indicate that it is appropriate to explore this objective). |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Subjects with documented type 2 diabetes mellitus diagnosis
- whose HbA1c levels are between 7.0 to 9.0, inclusive, on monotherapy with at least 1,000mg per day of metformin. These subjects must be both willing and medically able to discontinue their diabetic medications from at least 2 weeks prior to the first dose of study medication until the last assessment of the last dosing period of this study, OR
- whose HbA1c levels are between 7.5 to 9.0, inclusive, and who are drug naïve or controlled by diet.
2. Adult men and women between 30 – 70 years of age, inclusive. No attempt will be made to balance the number of men and women enrolled in the study.
3. Enrollment of women will be restricted to those who are post-menopausal or surgically sterile, ie women of non-childbearing potential. Non-childbearing potential is defined as:
- Post-menopausal females defined as being amenorrhoeic for greater than one year with an appropriate clinical profile. However if indicated, this should be confirmed by estradiol and FSH levels consistent with menopause (according to local laboratory ranges)
- Pre-menopausal females with a documented (medical report verification) hysterectomy or tubal ligation.
4. Body weight >=50kg for men and >=45kg for women and BMI within the range 20-35kg/m2, inclusive.
5. Negative pre-study urine drug screen.
6. Negative test results for hepatitis C antibodies or hepatitis B surface antigen or HIV at screening
7. No significant concomitant health problems other than type 2 diabetes mellitus and otherwise healthy as judged by a responsible physician. No clinically significant abnormality identified on the medical or laboratory evaluation, including 12-lead ECG. A subject with a clinically significant abnormality or laboratory parameters outside the reference range for this age group may be included only if the Investigator and Sponsor’s Medical Monitor consider that the finding will not introduce additional risk factors and will not interfere with the study procedures.
8. Subjects taking stable regimens of aspirin, ACE inhibitors, beta-blockers, calcium channel blockers and HMG-CoA reductase inhibitors (statins) will be allowed if their dose regimen(s) remain constant throughout the study period. Concurrent usage of prescribed medications other than the medications listed above may be allowed to continue only with Sponsor’s consent. Stable regimens are those that have not required dosage adjustments within 30 days prior to screening and which remain the same throughout the end of the trial. Concomitant meds must be withheld on PK sampling days.
9. Signed and dated written informed consent prior to enrollment into the study.
10. The subject is able to understand and comply with protocol requirements, instructions, and protocol-stated restrictions. |
|
| E.4 | Principal exclusion criteria |
1. Requiring insulin therapy or oral antidiabetic medications other than metformin during the 3 months prior to the screening examination.
2. Medically unable or unwilling to discontinue their metformin therapy for up to 4 weeks (starting 2 weeks before administration of study drug and until after the last study assessment for each treatment period). If an average fasting blood glucose concentration below 8mmol/L (144mg/dL) or above 13.3mmol/L (240mg/dL) is confirmed during the washout period, the subject will be excluded from participation in the study.
3. Past or present disease (other than type 2 diabetes mellitus) as judged by the Investigator, which may affect the outcome of this study. These diseases include, but are not limited to, cardiovascular disease, malignancy, hepatic disease, renal disease, haematological disease, neurological disease and endocrine disease.
4. As a result of the medical interview, physical examination for screening investigations, the primary investigator considers the volunteer inappropriate for inclusion in the study.
5. History or presence of allergy to the study drug or drugs of this class or a history of drug or other allergy that, in the opinion of the physician responsible, contraindicates their participation.
6. History or presence of gastro-intestinal, hepatic or renal disease, or other condition known to interfere with the absorption, distribution, metabolism or excretion of drugs. Any acute gastrointestinal illness within 2 weeks prior to dosing.
7. Use of diuretics, systemic corticosteroids, or any other medication that may result in electrolyte depletion, within 3 weeks of any scheduled dose.
8. Blood electrolyte (K, Na, Cl, Mg, Ca or bicarbonate) values outside of the reference range at screening and admission. No deviation will be permitted unless there has been discussion on an individual basis between sponsor and investigator for these parameters.
9. If participation in the study will result in the subject having donated more than 1,500mL blood (males) or 1,000mL (females) in the previous 12 months and where participation in study would result in donation of blood in excess of 580mL within a 56-day period.
10. Systolic/Diastolic blood pressure: < 80/60mmHg or > 160/95mmHg at screening.
11. Abuse of alcohol defined, for males, as an average weekly intake of greater than 21 units or an average daily intake of greater than 3 units or defined for females, as an average weekly intake of greater than 14 units or an average daily intake of greater than 2 units. One unit is equivalent to a half-pint (220mL) of beer or 1 (25mL) measure of spirits or 1 glass (125mL) of wine.
12. They have suffered a urinary tract or bladder infection within 4 weeks of the start of the study that has not resolved after treatment with antibiotics. (Subjects with a urinary tract infection diagnosed at screening and documented by urine culture can be enrolled if they have culture-documented resolution of infection one week after completing a standard course of oral antibiotics.)
13. Significant renal disease as manifested by one of the following:
- Creatinine clearance <60mL/min
- Urine protein/creatinine (mg/mg) ratio >2.5; or urine albumin concentration >=300ug/mg of creatinine.
- Known loss of a kidney, either by surgical ablation, injury, or disease.
14. Subjects with the following clinical laboratory values:
- ALT and AST > 2 times the upper limit of normal at screening and prior to the first dose
- Bilirubin > 1.5 times the upper limit of normal at screening and prior to the first dose (total; subjects above this limit may only be included if direct bilirubin is within normal limits).
- Fasting triglycerides > 600mg/dL at screening and prior to first dose
- Fasting LDL cholesterol > 160mg/dL
15. Participation in a study trial with any investigational new drug (new chemical entity) within 90 days prior to the start of the study.
16. Male subject, from administration of study medication until completion of follow-up procedures, unwilling to abstain from, or use a condom during sexual intercourse with a pregnant or lactating female; or male subject unwilling to use a condom plus another form of contraception (e.g., spermicide, IUD, birth control pills taken by female partner, diaphragm with spermicide) during sexual intercourse with a female who could become pregnant.
16. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless it is in the opinion of the investigator and sponsor that the medication will not interfere with the study procedures or compromise subject safety. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Safety and tolerability: Adverse events and clinically relevant changes in vital signs (blood pressure, heart rate), ECG parameters, clinical laboratory data (blood and urine electrolytes, fluid balance, and creatinine clearance). |
|
| 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 | No |
| 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 | Information not present in EudraCT |
| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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