Dose-Ranging Study In Subjects With Type 2 Diabetes Mellitus Who Are Treatment-Naive

Study Overview
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Brief Summary
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This is a dose-ranging study to evaluate the efficacy, safety and tolerability of a range of doses of GSK189075 (an SGLT2 inhibitor) compared to placebo, administered over 12 weeks in treatment-naive subjects with type 2 diabetes mellitus

Official Title
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A Once-Daily Dose-Ranging Study of GSK189075 Versus Placebo In The Treatment of Type 2 Diabetes Mellitus in Treatment-Naïve Subjects

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: GSK189075
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with a documented diagnosis of T2DM and HbA1c ≥7.0% and ≤9.5% measured by the central laboratory at Visit 1. Note: Subjects with HbA1c <7.5% must have a fasting fingerstick glucose ≥7 mmol/L (126 mg/dL) at Week 0, prior to randomization. Note: The proportion of subjects who are randomized with an HbA1c <7.5% will be limited to be no more than 20% (approximately 51 subjects) Subjects who are treatment-naïve, and have not taken insulin, or any oral or injectable anti-diabetic medication in the past 3 months and have not taken a glucose lowering agent for ≥4 weeks at any time in the past, or subjects who are newly diagnosed and treated with diet and exercise for a minimum of 6 weeks Subjects who are 18 to 70 years of age inclusive at the time of Screening. Females of childbearing and non-childbearing and potential are eligible to participate as follows: Women of childbearing potential must be willing to use one of the following contraception methods: intrauterine device, condom or occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent for at least 30 days prior to the start of study medication, throughout the study and the follow-up visit. Note: use of oral contraceptives is not permitted. Women of non-child bearing potential are defined as follows: females regardless of age, with functioning ovaries who have a current documented tubal ligation, or who are surgically sterile (i.e. documented total hysterectomy or bilateral oophorectomy), or females who are post-menopausal. All females must have a negative urine pregnancy test on the day of, and prior to randomization. Informed Consent: a signed and dated written consent must be obtained from the subject before any procedures are performed. Exclusion Criteria: Metabolic Disease Diagnosis of Type 1 diabetes mellitus History of ketoacidosis which has required hospitalization Thyroid disorder TSH <0.4 MIU/L (<0.4 MCIU/mL) or >5.5 mIU/L (>5.5 MCIU/mL) at Screening BMI of <22 kg/m2 or >43 kg/m2 Significant weight gain or loss (as defined as >5% of total body weight) in the 3 months prior to Screening Diabetic Medication Has taken insulin, or any oral or injectable anti-diabetic medication within 3 months of screening Has taken insulin or any oral or injectable anti-diabetic medication ≥4 weeks at any time in the past Cardiovascular Disease Recent history or presence of clinically significant acute cardiovascular disease including: Documented myocardial infarction in the 6 months prior to Screening. Coronary revascularization including percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft (CABG) surgery either planned and/or occurred in the 6 months prior to Screening. Unstable angina in the 6 months prior to Screening. Clinically significant supraventricular arrhythmias requiring medical therapy, or history of nonsustained or sustained ventricular tachycardia. Symptomatic valvular heart disease or valvular heart disease requiring therapy other than endocarditis prophylaxis. Congestive heart failure (CHF, New York Heart Association (NYHA) Class II to IV) requiring pharmacologic treatment or the NYHA Class criteria in accordance with the local prescribing information for pioglitazone. Blood pressure (BP) >150/100mmHg. If a subject is receiving permitted antihypertensive therapy, then they must be on stable dose(s) of therapy for at least 4 weeks prior to Screening. Based on local readings, the subject has an initial QTc interval (Bazett's)≥450msec at Screening, and after two additional ECGs taken 5 minutes apart, the average of the QTC interval from the three ECGs is ≥450msec. Other clinically significant ECG abnormalities which, in the opinion of the Investigator, may affect the interpretation of efficacy or safety data, or which otherwise contraindicates participation in a clinical trial with a new chemical entity. Fasting triglycerides ≥400mg/dL (4.56mmol/L) at Screening. If a subject is receiving permitted lipid-lowering therapy, then they must be on a stable dose(s) of therapy for at least 6 weeks prior to Screening. Niacin and bile acid sequestrants are prohibited. Hepatic Disease Has a diagnosis of active hepatitis (hepatitis B surface antigen or hepatitis C antibody), or clinically significant hepatic enzyme elevation including: Any one of the following enzymes greater than 2 times the upper limit of the reference range (ULRR) value at Screening. alanine aminotransferase (ALT) aspartate aminotransferase (AST) alkaline phosphatase (AP) Has a total bilirubin level that is >1.5 times the ULRR at Screening with the exception of suspected or confirmed Gilbert's disease. Pancreatic Disease Secondary causes of diabetes: history of chronic or acute pancreatitis Renal Disease Significant renal disease at Screening as manifested by: Glomerular filtration rate (GFR) <60mL/min (as calculated by Quest at Visit using the Modification of Diet in Renal Disease (MDRD) equation •≥1+ protein on urine dipstick Trace or ≥1+ leukocyte esterase on urine dipstick Trace or ≥1+ blood on urine dipstick Positive nitrite on urine dipstick Recurrent genitourinary tract infections defined as ≥2 episodes of complicated or uncomplicated cystitis or pyelonephritis in the 6 months prior to Screening. Concurrent Disease Has any concurrent condition or any clinically significant abnormality identified on the screening physical examination, laboratory tests (including blood electrolytes), ECG, including pulmonary, neurological or inflammatory diseases, which, in the opinion of the investigator, may affect the interpretation of efficacy and safety data, or which otherwise contraindicates participation in a clinical trial with a new chemical entity. History of significant co-morbid diseases active in the 6 months prior to Screening (e.g., cholecystitis, acute pancreatitis, gastrointestinal disease, chronic diarrhea, etc.). History of malignancy within the past 5 years other than superficial squamous cell carcinoma (non-invasive on pathology) or basal cell carcinoma (successfully treated with local excision). History of cervical cancer in situ treated definitively at least 6 months prior to Screening. Concurrent Medication Is currently taking or has taken any of the following medications in the 8 weeks prior to Screening: Digoxin Warfarin and other oral anticoagulants (aspirin and non-steroidal anti-inflammatory drugs are permitted) Bile acid sequestrants Niacin (excluding routine vitamin supplementation) Antiobesity agents (including fat absorption blocking agents) Oral or injectable corticosteroids (inhaled, topical and intranasal corticosteroids are permitted) Loop diuretics Monoamine oxidase inhibitors and tricyclic amines Antiretroviral drugs St John's Wort Oral chromium 9.Breast Feeding 10.Other Current smoker who is unable to abstain from smoking while in the clinic at each visit Has a history of alcohol or substance abuse within the past year at Screening or alcohol or substance abuse during treatment, as determined by the investigator: Unwilling to refrain from the use of illicit drugs and adhere to other protocol-stated restrictions while participating in the study Has an average weekly intake of alcohol of >21 units or an average daily intake of >3 units (males) or an average weekly intake of >14 units or an average daily intake of >2 units (females). One unit is equivalent to a half pint of beer or 1 measure of spirits or 1 glass of wine Has participated in any study with an investigational or marketed drug in the 3 months prior to Screening. In the opinion of the investigator has a risk of non-compliance with study procedures, or cannot read, understand, or complete study related materials, particularly the informed consent. Known allergy to any of the tablet or capsule excipients, or history of drug or other allergy, which, in the opinion of the responsible study physician, contraindicates participation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK189075<br>Participants will receive GSK189075 for 12 weeks | Drug: GSK189075<br>* GSK189075 is available as a white, capsule-shaped tablet dosage form containing 50mg, 125mg, 250mg or 500mg of GSK189075 per tablet<br>|
| Placebo Comparator: Placebo<br>Participants will receive GSK189075 matching Placebo for 12 weeks | Drug: Placebo<br>* Available as Placebo matching tablet to GSK189075<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Hemoglobin A1c (Glycosylated Hemoglobin) (HbA1c) at Week 12 | The blood samples were collected at Baseline, Week 4, Week 8 and at Week 12 (or early withdrawal). Baseline was defined as the period immediately preceding treatment with study medication (Week 0). For participants with missing Baseline assessment, the last pre-therapy value prior to the Baseline visit was used as the Baseline value. Change from Baseline was the value at Week 12 minus Baseline value. The primary analysis was performed on the Intent-to-Treat (ITT) Population with Last observation carried forward (LOCF). Adjusted mean is presented as least square (LS) mean. | Baseline (Week 0) and at Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in HbA1c at Weeks 4 and 8 | The blood samples were collected at Baseline, Week 4, Week 8 and at Week 12 (or early withdrawal). Baseline was defined as the period immediately preceding treatment with study medication (Week 0). For participants with missing Baseline assessment, the last pre-therapy value prior to the Baseline visit was used as the Baseline value. Change from Baseline was the value at Week 4 and 8 minus Baseline value. The primary analysis was performed on the ITT Population with LOCF. | Baseline (Week 0) and at Week 4 nad 8 | 
| Mean Change From Baseline to Week 12 in Fasting Plasma Glucose (FPG) | The samples were collected at Baseline, Week 2, Week 4, Week 8, Week 12 and Week 14 (follow up). Participants were asked to be on fast for at least 8 hours prior to each study visits and collection of lab samples. Baseline was defined as the period immediately preceding treatment with study medication (Week 0). For participants with missing Baseline assessment, the last pre-therapy value prior to the Baseline visit was used as the Baseline value. Change from Baseline was the value at Week 12 minus Baseline value. The primary analysis was performed on the ITT Population with LOCF. Adjusted mean is presented as LS mean. | Baseline (Week 0) and at Week 12 | 
| Mean Change From Baseline to Week 12 in Fructosamine (Corrected) | The blood samples were collected at Baseline, Week 2, Week 4, Week 8, Week 12 and Week 14 (follow up). Participants were asked to be on fast for at least 8 hours prior to each study visits and collection of lab samples. Baseline was defined as the period immediately preceding treatment with study medication (Week 0). For participants with missing Baseline assessment, the last pre-therapy value prior to the Baseline visit was used as the Baseline value. Change from Baseline was the value at Week 12 minus Baseline value. The primary analysis was performed on the ITT Population with LOCF. Adjusted mean is presented as LS mean. | Baseline (Week 0) and at Week 12 | 
| Number of Participants Who Were HbA1c Responders at Week 12 | Differences between treatment groups in the proportion of participants who achieved HbA1c targets of <=6.5% and <7% at Week 12 in the ITT population with LOCF were assessed based on a logistic regression model with terms included for treatment and Baseline HbA1c. Differences between treatment groups in the proportion of participants who achieved a clinically meaningful decreases from Baseline in HbA1c (>=0.7%) at Week 12 were assessed in the same manner. | Week 12 | 
| Number of Participants Who Were Fasting Plasma Glucose (FPG) Responders at Week 12 | Differences between treatment groups in the proportion of participants who achieved FPG targets of <7.0 millimoles per liter (mmol/L) (126 milligrams per deciliter [mg/dL]) and <7.8 mmol/L (140 mg/dL) at Week 12 in the ITT population with LOCF were assessed based on a logistic regression model with terms included for treatment and Baseline FPG. The proportion of participants who achieved the target of <5.5 mmol/L (100 mg/dL) at Week 12 within each treatment group were summarized only. Differences between treatment groups in the proportion of participants who achieved a clinically meaningful decreases from Baseline in FPG (1.7 mmol/L [>=30 mg/dL]) at Week 12 were assessed in the same manner. | Week 12 | 
| Mean Change From Baseline to Week 12 in Triglycerides | Samples were collected at Baseline and at Week 12 (or early withdrawal). Baseline was defined as the period immediately preceding treatment with study medication (Week 0). For participants with missing Baseline assessment, the last pre-therapy value prior to the Baseline visit was used as the Baseline value. Change from Baseline was the value at Week 12 minus Baseline value. Adjusted mean is presented as LS mean. | Baseline (Week 0) and at Week 12 | 
| Mean Change From Baseline to Week 12 in Total Cholesterol | Samples were collected at Baseline and at Week 12 (or early withdrawal). Baseline was defined as the period immediately preceding treatment with study medication (Week 0). For participants with missing Baseline assessment, the last pre-therapy value prior to the Baseline visit was used as the Baseline value. Change from Baseline was the value at Week 12 minus Baseline value. Adjusted mean is presented as LS mean. | Baseline (Week 0) and at Week 12 | 
| Mean Change From Baseline to Week 12 in Low Density Lipoprotein Cholesterol (LDL-c) | Blood samples were collected at Baseline and at Week 12 (or early withdrawal). Baseline was defined as the period immediately preceding treatment with study medication (Week 0). For participants with missing Baseline assessment, the last pre-therapy value prior to the Baseline visit was used as the Baseline value. Change from Baseline was the value at Week 12 minus Baseline value. Adjusted mean is presented as LS mean. | Baseline (Week 0) and Week 12 | 
| Mean Change From Baseline to Week 12 in High Density Lipoprotein Cholesterol (HDL-c) | Blood samples were collected at Baseline and at Week 12 (or early withdrawal). Baseline was defined as the period immediately preceding treatment with study medication (Week 0). For participants with missing Baseline assessment, the last pre-therapy value prior to the Baseline visit was used as the Baseline value. Change from Baseline was the value at Week 12 minus Baseline value. Adjusted mean is presented as LS mean. | Baseline (Week 0) and Week 12 | 
| Mean Change From Baseline to Week 12 in LDL-c/HDL-c Ratio | Blood samples were collected at Baseline and at Week 12 (or early withdrawal). Baseline was defined as the period immediately preceding treatment with study medication (Week 0). For participants with missing Baseline assessment, the last pre-therapy value prior to the Baseline visit was used as the Baseline value. Change from Baseline was the value at Week 12 minus Baseline value. Adjusted mean is presented as LS mean. | Baseline (Week 0) and Week 12 | 
| Mean Change From Baseline to Week 12 in Total Cholesterol/HDL-c Ratio | Blood samples were collected at Baseline and at Week 12 (or early withdrawal). Baseline was defined as the period immediately preceding treatment with study medication (Week 0). For participants with missing Baseline assessment, the last pre-therapy value prior to the Baseline visit was used as the Baseline value. Change from Baseline was the value at Week 12 minus Baseline value. Adjusted mean is presented as LS mean. | Baseline (Week 0) and Week 12 | 
| Mean Change From Baseline to Week 12 in Body Weight | Body weight measurement was taken at Baseline, Week 2, Week 4, Week 8, Week 12 and at Week 14 (follow up). Baseline was defined as the period immediately preceding treatment with study medication (Week 0). For participants with missing Baseline assessment, the last pre-therapy value prior to the Baseline visit was used as the Baseline value. Change from Baseline was the value at Week 12 minus Baseline value. Adjusted mean is presented as LS mean. | Baseline (Week 0) and Week 12 | 
| Number of Participants With Any On-therapy Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE was defined as any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE was defined as any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment. | Up to Week 12 | 
| Number of Participants With On-therapy Hypoglycemia | Participants were provided with a Daily Glucose Monitoring Log to record glucose meter readings and to record symptoms of hypoglycemia. A separate electronic case report form (eCRF) page was provided to capture events of hypoglycemia. | Up to Week 12 | 
| Number of Participants With Vital Signs of Potential Clinical Importance (PCI) at Any Time on Therapy | Systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR) were measured pre-dose in duplicate, after the participant has been lying quietly for 5 minutes, and then in duplicate 3 minutes after standing up. Participants were asked to refrain from smoking for at least 30 minutes prior to vital sign measurements. | Up to Week 12 | 
| Number of Participants With Abnormal Electrocardiogram (ECG) Findings at Any Time Post-Baseline | Full 12-lead ECGs were recorded at Randomization (Week 0), Week 4, and Week 12 or early withdrawal. If the QTc was >500 milliseconds on the locally read ECG recording, an additional 2 ECG recordings at 10 minute intervals were made at that visit. If the average QTc for the 3 recordings was >500 milliseconds, the participant was withdrawn from the study. | Up to Week 12 | 
| Number of Participants With Abnormal Chemistry Value of PCI at Any Time on Therapy | Chemistry parameters: Albumin, Alkaline phosphatase, Alanine animotransferase, Aspartate aminotransferase, Total billirubin, Calcium, Carbon dioxide/Bicarbonate, Glucose, Potassium, Sodium, Phosphorus and Total protein were assessed for abnormal PCI values. Participants were instructed to fast for at least 8 hours prior to all study visits for the collection of laboratory samples. Samples were collected at Baseline, Week 2, Week 4, Week 8, Week 12 and at Week 14 (follow up). | Up to Week 12 | 
| Number of Participants With Abnormal Hematology Value of PCI at Any Time on Therapy | Hematology parameters: Hemoglobin, Hematocrit, Platelet count and White blood cells were assessed for abnormal PCI values. Participants were instructed to fast for at least 8 hours prior to all study visits for the collection of laboratory samples. Samples were collected at Baseline, Week 2, Week 4, Week 8, Week 12 and at Week 14 (follow up). | Up to Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes mellitus HbA1c