Dose-Ranging Study in Treatment Naive Type 2 Diabetes Mellitus(T2DM)

Phase 2

Completed

Conditions: Diabetes Mellitus, Type 2

Interventions: Drug: GSK189075
Other: Placebo
Drug: pioglitazone

Registration Number: NCT00500331

Lead Sponsor: GlaxoSmithKline

Brief Summary: This is a dose-ranging study that will evaluate the efficacy, safety and tolerability of a range of doses of investigational product and pioglitazone, compared to placebo, administered as monotherapy over 12 weeks in treatment naive patients with T2DM

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 334

Inclusion Criteria

Not provided

Exclusion Criteria

Metabolic Disease
- Diagnosis of Type 1 diabetes mellitus.
- History of ketoacidosis which has required hospitalization.
- Thyroid disorder [TSH below the lower limit of the reference range (LLRR) of 0.4mIU/L or above the upper limit of the reference range (ULRR) of >5.5 mIU/L at Screening]. Hypothyroidism treated with the same dose and regimen of thyroid hormone replacement for at least 3 months prior to Screening is allowed.
- BMI of <22 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 ≥4 weeks at any time prior to screening.
- Has taken insulin or any oral or injectable anti-diabetic medication within 3 months of screening.
Cardiovascular Disease
- Recent history or presence of clinically significant acute cardiovascular disease including:
  1. Documented myocardial infarction in the 6 months prior to Screening.
  2. 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.
  3. Unstable angina in the 6 months prior to Screening.
  4. 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.
  5. Congestive heart failure (CHF, New York Heart Association (NYHA) Class II to IV) requiring pharmacologic treatment. NYHA Class I may be included in accordance with the local prescribing information for pioglitazone.
  6. 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.
  7. Has a QTc interval (Bazett's) ≥450msec at Screening on a single ECG or an average value from 3 ECGs taken 5 minutes apart (on local reading of ECG).
  8. Other clinically significant ECG abnormalities 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.
- 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 transaminase (ALT).
aspartate transaminase (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 estimated from serum creatinine at Visit 1 and demographic data using the MDRD equation).For the MDRD equation, please refer to the study procedures manual.

Proteinuria of ≥1+ by urinary dipstick

Recurrent genitourinary tract infections defined as ≥2 episodes of complicated or uncomplicated cystitis or pyelonephritis in the 6 months prior to Screening
A positive qualitative urinary dipstick for leukocytes, red blood cells (RBC) or nitrites at Screening.
- Concurrent Disease
Has any concurrent condition or any clinically significant abnormality identified on the screening physical examination, laboratory tests (including blood electrolytes), electrocardiogram, 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.)
Has a history of malignancy within the past five years [other than superficial squamous cell carcinoma which is non-invasive on pathology or basal cell carcinoma which is successfully treated with local excision] and 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:
1. Digoxin
2. Warfarin and other oral anticoagulants (aspirin and non-steroidal anti-inflammatory drugs are permitted)
3. Bile acid sequestrants
4. Niacin (excluding routine vitamin supplementation)
5. Antiobesity agents (including fat absorption blocking agents)
6. Oral or injectable corticosteroids (inhaled and intranasal corticosteroids are permitted)
7. Loop diuretics
8. Monoamine oxidase inhibitors and tricyclic amines
9. Antiretroviral drugs
10. St John's Wort
11. Oral chromium
  - Pregnancy & Breast Feeding
Is currently lactating or pregnant
- 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 greater than 21 units or an average daily intake of greater than 3 units (males) or an average weekly intake of greater than 14 units or an average daily intake of greater than 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 excipients, or history of drug or other allergy, which, in the opinion of the responsible study physician

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 1	GSK189075	GSK189075
Arm 2	Placebo	Placebo
Arm 3	pioglitazone	pioglitazone (active control)

Primary Outcome Measures

Name	Time	Method
Change From Baseline (Week 0) in Glycosylated Hemoglobin (HbA1c) (%) at Week 12	Baseline (Week 0) and Week 12	Fasted blood samples for HbA1c were collected at Baseline and Week 12. Participants were required to fast for at least 8 hours prior to laboratory samples and were told not to take the morning dose of study medication on these visit days and to refrain from eating until instructed to do so by study personnel in the clinic. When the participant had not fasted, the participant was rescheduled to return to the clinic to have a fasted sample taken. Baseline was Week 0. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values. Only those participants with a value at Baseline and at Week 12 (after Last Observation Carried Forward \[LOCF\]) were used for this analysis. Adjusted mean is presented as least square mean.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in 24-hour Percent of Filtered Glucose Excreted in Urine	Baseline (Week 0) and Week 12 (24-hour urine collection)	A 24-hour urine collection was obtained from all participants at Baseline (Week 0) and Week 12 to measure glucose. Participants were provided with urine collection bottles and cooler prior to these visits and instructed that the urine collections must be kept cold and dropped off at the clinic prior to or at the scheduled visits. Site staff queried participants to determine whether the sample represented a full 24-hour collection. The total volume and the sample date and time were recorded. The entire 24-hour urine collection was well mixed in one container and a urine aliquot obtained. Samples were assayed for glucose. The 24-hour collections were used to derive 24-hour urine glucose excretion corrected for filtered load. Baseline was Week 0. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values.
Change From Baseline in HbA1c (%) at Weeks 4 and 8	Baseline (Week 0) and Week 4 and Week 8	Fasted blood samples for HbA1c were collected at Baseline and Weeks 4 and 8. Participants were required to fast for at least 8 hours prior to laboratory samples and were told not to take the morning dose of study medication on these visit days and to refrain from eating until instructed to do so by study personnel in the clinic. When the participant had not fasted, the participant was rescheduled to return to the clinic to have a fasted sample taken. Baseline was Week 0. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values.
Number of Participants With On-therapy Hypoglycemia	Up to 14 weeks	Hypoglycemia is low blood glucose or low blood sugar. Hypoglycemic events were collected separately and reported separately from AE, including supplemental data which were not collected for AE. However, any hypoglycemic event which met the criteria for a SAE was included in the SAE summaries. The number of participants in each group that experienced a hypoglycemic event was summarized by frequency of the events.
Change From Baseline to Week 12 in Fasting Plasma Glucose (FPG) at Weeks 4, 8 and 12	Baseline (Week 0) and Week 4, Week 8 and Week 12	Fasted blood samples for FPG were collected up to Week 12. Participants were required to fast for at least 8 hours prior to laboratory samples and were told not to take the morning dose of study medication on these visit days and to refrain from eating until instructed to do so by study personnel in the clinic. When the participant had not fasted, the participant was rescheduled to return to the clinic to have a fasted sample taken. Baseline was Week 0. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values.
Change From Baseline to Week 12 in Fructosamine	Baseline (Week 0) to Week 12	Fasted blood samples for fructosamine were collected up to Week 12. Participants were required to fast for at least 8 hours prior to laboratory samples and were told not to take the morning dose of study medication on these visit days and to refrain from eating until instructed to do so by study personnel in the clinic. When the participant had not fasted, the participant was rescheduled to return to the clinic to have a fasted sample taken. Baseline was Week 0. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values.
Change From Baseline to Week 12 in Fasting Insulin	Baseline (Week 0) to Week 12	Fasted blood samples for insulin were collected up to Week 12. Participants were required to fast for at least 8 hours prior to laboratory samples and were told not to take the morning dose of study medication on these visit days and to refrain from eating until instructed to do so by study personnel in the clinic. When the participant had not fasted, the participant was rescheduled to return to the clinic to have a fasted sample taken. Baseline was Week 0. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values.
Number of Participants at Week 12 With: HbA1c <= 6.5%, HbA1c <7.0%; FPG <7 Mmo/L, FPG <7.8 mmol/L; FPG <5.5 mmol/L; a Decrease From Baseline of HbA1c >= 0.7%; a Decrease From Baseline of FPG ≥1.7 mmol/L	Week 12	Fasted blood samples for HbA1c were collected at Week 12. Participants were required to fast for at least 8 hours prior to laboratory samples and were told not to take the morning dose of study medication on these visit days and to refrain from eating until instructed to do so by study personnel in the clinic. When the participant had not fasted, the participant was rescheduled to return to the clinic to have a fasted sample taken. Number of participants at Week 12 with: HbA1c \<= 6.5%, HbA1c \<7.0%; FPG \<7 mmo/L (126 milligram/deciliter \[mg/dL\]), FPG \<7.8 mmol/L (140 mg/dL); FPG \<5.5 mmol/L (100 mg/dL); a decrease from Baseline of HbA1c \>= 0.7%; a decrease from Baseline of FPG ≥1.7 mmol/L (30 mg/dL) are presented.
Change From Baseline to Week 12 in Body Weight	Baseline (Week 0) to Week 12	Weight of participants was measured from Baseline (Week 0) to Week 12 and recorded in the case report form (CRF). Baseline was Week 0. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values.
Change From Baseline to Week 12 in Waist Circumference	Baseline (Week 0) to Week 12	Waist circumference of participants was measured from Baseline (Week 0) to Week 12 and recorded in the CRF. Baseline was Week 0. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values.
Change From Baseline in Insulin AUC During a 2-hour OGTT	Baseline (Week 0) and Week 12 (0 to 2-hour OGTT)	Post-prandial assessments of insulin were performed at Baseline (Week 0) and at Week 12 using a 2-hour OGTT in a subgroup of participants at selected sites who agreed to participate. Participants were required to fast for at least 8 hours prior to the test. Seventy-five (75) g of standard oral glucose solution was administered 15 minutes after the morning administration of study medication (Week 12) and in the place of breakfast at Week 0 (i.e., at Week 0 the OGTT was completed prior to administration of study medication). Time "0" started when the participants drank the glucose solution. Blood samples were collected at the following times relative to the administration of oral glucose: -30 min (pre-glucose), -20 min (pre-glucose), 20 min, 30 min, 1 hour, 1.5 hour and 2 hour post glucose administration. Baseline was Week 0. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values.
Percent Change From Baseline in Lipid Parameters at Weeks 4, 8 and 12(Triglycerides [TG], Total Cholesterol [TC], Low-density Lipoprotein Cholesterol [LDL-C] and High-density Lipoprotein Cholesterol [HDL-C])	Baseline (Week 0) and Week 4, Week 8 and Week 12	Fasted samples for TC, LDL-C, HDL-C and TG were collected at Week 12. When the participant had not fasted, the participant was rescheduled to return to the clinic to have a fasted sample taken. Baseline was Week 0. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values. Percent Change based on log-transformed data: 100\*(exponentiated(mean change on log scale)-1)
Number of Participants With Change From Baseline Vital Signs of Potential Clinical Concern	Up to 14 weeks	Vital signs included heart rate and blood pressure. Heart rate and blood pressure were taken before blood draws were performed. Participants were asked to refrain from smoking for at least 30 minutes prior to vital sign measurements. Heart rate and blood pressure was measured pre-dose in duplicate at the specified visits, after the participant had been lying quietly for 5 minutes, and then in duplicate 3 minutes after standing up. Heart rate was measured at the same time as blood pressure using the standardized blood pressure equipment that was provided. Baseline was Week 0. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values.
Number of Participants With Change From Baseline in Standard Laboratory Parameters of Potential Clinical Concern	Up to 14 weeks	Participants were instructed to fast for at least 8 hours prior to all study visits for the collection of laboratory samples. An additional fasting blood sample (serum and plasma) was drawn at Week 0, Week 4, Week 6 and Week 12 or at early withdrawal (up to 14 weeks) and kept in long-term storage for future testing of biomarkers for diabetes and complications of the disease. Baseline was Week 0. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values.
Change From Baseline in Plasma Glucose Area Under the Curve (AUC) During a 2-hour Oral Glucose Tolerance Test (OGTT)	Baseline (Week 0) and Week 12 (0 to 2 hour OGTT)	Post-prandial assessments of glucose were performed at Baseline (Week 0) and at Week 12 using a 2-hour OGTT in a subgroup of participants at selected sites who agreed to participate. Participants were required to fast for at least 8 hours prior to the test. Seventy-five (75) g of standard oral glucose solution was administered 15 minutes after the morning administration of study medication (Week 12) and in the place of breakfast at Week 0 (i.e., at Week 0 the OGTT was completed prior to administration of study medication). Time "0" started when the participants drank the glucose solution. Blood samples were collected at the following times relative to the administration of oral glucose: -30 min (pre-glucose), -20 min (pre-glucose), 20 min, 30 min, 1 hour, 1.5 hour and 2 hour post glucose administration. Baseline was Week 0. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values.
Change From Baseline in C-peptide AUC During a 2-hr OGTT	Baseline (Week 0) and Week 12 (0 to 2 hour OGTT)	Post-prandial assessments of C-peptide were performed at Baseline (Week 0) and at Week 12 using a 2-hour OGTT in a subgroup of participants at selected sites who agreed to participate. Participants were required to fast for at least 8 hours prior to the test. Seventy-five (75) g of standard oral glucose solution was administered 15 minutes after the morning administration of study medication (Week 12) and in the place of breakfast at Week 0 (i.e., at Week 0 the OGTT was completed prior to administration of study medication). Time "0" started when the participants drank the glucose solution. Blood samples were collected at the following times relative to the administration of oral glucose: -30 min (pre-glucose), -20 min (pre-glucose), 20 min, 30 min, 1 hour, 1.5 hour and 2 hour post glucose administration. Baseline was Week 0. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values.
Number of Participants With On-therapy Adverse Events (AE) and Serious Adverse Events (SAE)	Up to 12 weeks	AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant.
Number of Participants With Electrocardiogram (ECG) Values of Potential Clinical Concern	Up to Early withdrawal (Between Week 12 and Week 14)	Full 12-lead ECGs were recorded at screening, Baseline (Week 0), Week 4, Week 12 or early withdrawal, and Week 14 (Follow-up) using an ECG machine that automatically calculated the heart rate and measured the PR, QRS, QT and corrected QT (QTc) intervals. All 12-lead ECGs were read locally by the Investigator or his/her designate and were forwarded electronically to the central reader for interpretation. If the QTc was \>500 milliseconds (msec) 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 msec, the participant was withdrawn from the study.