A Phase 2 interventional study of GSK189075 and pioglitazone in Diabetes Mellitus, Type 2, sponsored by GlaxoSmithKline. Completed at 136 sites in 19 countries. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2017-12-06.
Sponsored by GlaxoSmithKline · Phase 2, Interventional, and Treatment
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
10,925 studies on the registry are indexed under Diabetes Mellitus; 1,318 are open to participants now.
This study's enrollment of 334 is above the median of 80 across 8,367 interventional studies indexed under Diabetes Mellitus.
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Of its 258 completed or terminated interventional studies of FDA-regulated products, 232 (90%) have results posted.
Counted across the registry records on this site, refreshed daily.
Females of non-childbearing and childbearing potential are eligible to participate as follows:
(Post-menopausal is defined as after one year without menses with an appropriate clinical profile, e.g. age appropriate, >45 years, in the absence of hormone replacement therapy. In addition to the above criteria, if the post-menopausal status is still questionable, a blood sample should be drawn for simultaneous measurement of follicle stimulating hormone and estradiol; values considered to confirm the post-menopausal state are respectively: FSH >40 MIU/mL and estradiol \<40pg/mL (\<140 pmol/L)).
Exclusion Criteria:
Metabolic Disease
Diabetic Medication
Cardiovascular Disease
Recent history or presence of clinically significant acute cardiovascular disease including:
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.
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.
history of chronic or acute pancreatitis
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
A positive qualitative urinary dipstick for leukocytes, red blood cells (RBC) or nitrites at Screening.
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
Is currently taking or has taken any of the following medications in the 8 weeks prior to Screening:
Oral chromium
Is currently lactating or pregnant
GSK189075
Drug: GSK189075
Placebo
Other: Placebo
pioglitazone (active control)
Drug: pioglitazone
Experimental Drug
Active Control
Placebo Comparator
Change From Baseline (Week 0) in Glycosylated Hemoglobin (HbA1c) (%) at 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.
Time frame: Baseline (Week 0) and Week 12
Change From Baseline in HbA1c (%) at Weeks 4 and 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.
Time frame: Baseline (Week 0) and Week 4 and Week 8
Change From Baseline to Week 12 in Fasting Plasma Glucose (FPG) at Weeks 4, 8 and 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.
Time frame: Baseline (Week 0) and Week 4, Week 8 and Week 12
Change From Baseline to Week 12 in Fructosamine
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.
Time frame: Baseline (Week 0) to Week 12
Change From Baseline to Week 12 in Fasting Insulin
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.
Time frame: Baseline (Week 0) to Week 12
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
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.
Time frame: Week 12
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])
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)
Time frame: Baseline (Week 0) and Week 4, Week 8 and Week 12
Change From Baseline to Week 12 in Body Weight
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.
Time frame: Baseline (Week 0) to Week 12
Change From Baseline to Week 12 in Waist Circumference
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.
Time frame: Baseline (Week 0) to Week 12
Change From Baseline in 24-hour Percent of Filtered Glucose Excreted in Urine
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.
Time frame: Baseline (Week 0) and Week 12 (24-hour urine collection)
Change From Baseline in Plasma Glucose Area Under the Curve (AUC) During a 2-hour Oral Glucose Tolerance Test (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.
Time frame: Baseline (Week 0) and Week 12 (0 to 2 hour OGTT)
Change From Baseline in Insulin AUC During a 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.
Time frame: Baseline (Week 0) and Week 12 (0 to 2-hour OGTT)
Change From Baseline in C-peptide AUC During a 2-hr 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.
Time frame: Baseline (Week 0) and Week 12 (0 to 2 hour OGTT)
Number of Participants With On-therapy Adverse Events (AE) and Serious Adverse Events (SAE)
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.
Time frame: Up to 12 weeks
Number of Participants With On-therapy Hypoglycemia
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.
Time frame: Up to 14 weeks
Number of Participants With Change From Baseline Vital Signs of Potential Clinical Concern
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.
Time frame: Up to 14 weeks
Number of Participants With Electrocardiogram (ECG) Values of Potential Clinical Concern
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.
Time frame: Up to Early withdrawal (Between Week 12 and Week 14)
Number of Participants With Change From Baseline in Standard Laboratory Parameters of Potential Clinical Concern
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.
Time frame: Up to 14 weeks
This study was conducted at 121 centers of which 95 randomized participants, in 18 countries (9 European, 8 International, and the United States) from 23 January 2007 to 14 February 2008.
| Milestone | Placebo | GSK189075 50 mg | GSK189075 100 mg | GSK189075 250 mg | GSK189075 500 mg | GSK189075 1000 mg | Pioglitazone 30 mg |
|---|---|---|---|---|---|---|---|
| Started | 48 | 47 | 48 | 48 | 48 | 47 | 48 |
| Completed | 33 | 42 | 43 | 38 | 44 | 42 | 46 |
| Not completed | 15 | 5 | 5 | 10 | 4 | 5 | 2 |
| Withdrew: Adverse event | 0 | 2 | 0 | 1 | 2 | 2 | 0 |
| Withdrew: Lost to follow-up | 1 | 1 | 1 | 2 | 1 | 0 | 0 |
| Withdrew: Protocol violation | 3 | 1 | 1 | 0 | 1 | 1 | 1 |
| Withdrew: Withdrawal by subject | 4 | 0 | 1 | 5 | 0 | 1 | 1 |
| Withdrew: Lack of efficacy | 3 | 1 | 0 | 0 | 0 | 0 | 0 |
| Withdrew: Liver function test abnormality | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Withdrew: Increased serum creatinine from baseline | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Withdrew: Didn't return for continuation of study | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Withdrew: Exclusion citeria not met on visit 4 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Withdrew: Sponsor decided to withdraw participant | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Withdrew: Participant was randomized by mistake | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Withdrew: Diabetologist nurse in the study | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Withdrew: State ban of biological samples export | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Withdrew: Protocol violated | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
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.
| Percentage of hemoglobin | Placebo | GSK189075 50 mg | GSK189075 100 mg | GSK189075 250 mg | GSK189075 500 mg | GSK189075 1000 mg | Pioglitazone 30 mg |
|---|---|---|---|---|---|---|---|
| Change From Baseline (Week 0) in Glycosylated Hemoglobin (HbA1c) (%) at Week 12 | -0.31 ± 0.107 | -1.04 ± 0.105 | -0.96 ± 0.107 | -1.05 ± 0.106 | -1.21 ± 0.102 | -1.38 ± 0.104 | -1.07 ± 0.102 |
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.
| Percentage of hemoglobin | Placebo | GSK189075 50 mg | GSK189075 100 mg | GSK189075 250 mg | GSK189075 500 mg | GSK189075 1000 mg | Pioglitazone 30 mg |
|---|---|---|---|---|---|---|---|
| Week 4 | -0.30 ± 0.535 | -0.77 ± 0.541 | -0.69 ± 0.583 | -0.64 ± 0.535 | -0.83 ± 0.639 | -0.84 ± 0.551 | -0.39 ± 0.557 |
| Week 8 | -0.41 ± 0.689 | -0.98 ± 0.712 | -0.96 ± 0.827 | -0.99 ± 0.751 | -1.07 ± 0.747 | -1.28 ± 0.636 | -0.88 ± 0.713 |
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.
| Millimoles per Liter (mmol/L) | Placebo | GSK189075 50 mg | GSK189075 100 mg | GSK189075 250 mg | GSK189075 500 mg | GSK189075 1000 mg | Pioglitazone 30 mg |
|---|---|---|---|---|---|---|---|
| Week 4 | -0.49 ± 1.991 | -0.56 ± 1.512 | -1.43 ± 2.005 | -1.49 ± 2.314 | -1.90 ± 2.232 | -2.48 ± 2.491 | -1.26 ± 1.294 |
| Week 8 | -0.62 ± 1.859 | -0.91 ± 2.073 | -1.30 ± 1.821 | -1.76 ± 2.137 | -2.14 ± 2.547 | -2.78 ± 2.531 | -1.73 ± 1.340 |
| Week 12 | -0.51 ± 1.700 | -0.89 ± 1.960 | -1.63 ± 2.145 | -1.80 ± 2.107 | -2.07 ± 2.459 | -2.76 ± 2.821 | -1.71 ± 1.978 |
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.
| Micromol per Liter (mcmol/L) | Placebo | GSK189075 50 mg | GSK189075 100 mg | GSK189075 250 mg | GSK189075 500 mg | GSK189075 1000 mg | Pioglitazone 30 mg |
|---|---|---|---|---|---|---|---|
| Change From Baseline to Week 12 in Fructosamine | 5.7 ± 51.24 | -33.8 ± 38.20 | -35.7 ± 41.69 | -38.9 ± 29.62 | -41.9 ± 35.54 | -55.2 ± 30.31 | -34.7 ± 38.84 |
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.
| Picomol per Liter (pmol/L) | Placebo | GSK189075 50 mg | GSK189075 100 mg | GSK189075 250 mg | GSK189075 500 mg | GSK189075 1000 mg | Pioglitazone 30 mg |
|---|---|---|---|---|---|---|---|
| Change From Baseline to Week 12 in Fasting Insulin | -30.6 ± 171.35 | 0.3 ± 58.69 | -20.7 ± 60.75 | -9.7 ± 43.95 | -25.8 ± 60.94 | -15.1 ± 57.59 | -2.1 ± 49.60 |
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.
| Participants | Placebo | GSK189075 50 mg | GSK189075 100 mg | GSK189075 250 mg | GSK189075 500 mg | GSK189075 1000 mg | Pioglitazone 30 mg |
|---|---|---|---|---|---|---|---|
| HbA1c <= 6.5% | 3 | 10 | 8 | 11 | 17 | 17 | 8 |
| HbA1c <7.0% | 9 | 20 | 18 | 22 | 28 | 29 | 21 |
| FPG <7 mmo/L | 4 | 16 | 20 | 18 | 22 | 22 | 21 |
| FPG <7.8 mmol/L | 13 | 24 | 26 | 27 | 33 | 34 | 31 |
| FPG <5.5 mmol/L | 0 | 4 | 2 | 5 | 4 | 3 | 2 |
| Decrease from Baseline of HbA1c >= 0.7% | 16 | 33 | 27 | 33 | 36 | 39 | 28 |
| Decrease from Baseline of FPG ≥1.7 mmol/L | 8 | 15 | 19 | 21 | 24 | 30 | 23 |
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)
| Percent change | Placebo | GSK189075 50 mg | GSK189075 100 mg | GSK189075 250 mg | GSK189075 500 mg | GSK189075 1000 mg | Pioglitazone 30mg |
|---|---|---|---|---|---|---|---|
| TG: Week 4 | -8.35 (-44.3 to 110.1) | -3.45 (-48.1 to 177.8) | 6.32 (-55.1 to 112.1) | -13.42 (-56.8 to 133.6) | -13.04 (-74.8 to 207.1) | -4.62 (-48.2 to 256.3) | -7.22 (-68.6 to 76.9) |
| TG: Week 8 | -1.66 (-67.2 to 135.2) | -9.09 (-61.3 to 88.8) | 0.59 (-47.4 to 122.5) | -10.01 (-57.9 to 100.0) | -13.35 (-51.9 to 207.1) | -7.30 (-60.9 to 121.6) | -0.79 (-71.1 to 82.5) |
| TG: Week 12 | 3.32 (-58.6 to 135.2) | -10.91 (-60.2 to 213.0) | 10.92 (-45.3 to 232.5) | -4.71 (-56.8 to 73.6) | -15.28 (-66.8 to 255.7) | -9.97 (-58.4 to 123.4) | -7.19 (-58.2 to 116.7) |
| TC: Week 4 | 0.47 (-57.4 to 25.8) | 1.85 (-22.9 to 65.0) | 1.62 (-17.6 to 34.8) | 4.13 (-40.1 to 63.9) | 4.43 (-37.9 to 36.6) | 2.39 (-22.7 to 54.4) | 2.29 (-42.0 to 29.5) |
| TC: Week 8 | 0.82 (-48.4 to 48.4) | 3.49 (-31.3 to 43.1) | 3.64 (-31.5 to 30.0) | 4.49 (-14.0 to 73.7) | 5.31 (-19.9 to 41.2) | 0.00 (-24.3 to 49.9) | 1.06 (-40.2 to 34.9) |
| TC: Week 12 | 4.75 (-46.5 to 76.6) | 3.39 (-28.1 to 43.4) | 5.45 (-19.0 to 84.6) | 3.97 (-16.8 to 67.1) | 9.82 (-16.3 to 43.3) | 2.77 (-17.5 to 52.5) | -2.05 (-48.3 to 31.4) |
| LDL-C: Week 4 | 0.82 (-75.6 to 68.5) | 0.83 (-27.3 to 117.0) | 0.37 (-30.9 to 75.0) | 6.91 (-52.9 to 84.1) | 10.03 (-39.0 to 59.6) | 7.02 (-37.0 to 130.3) | 0.00 (-54.0 to 50.0) |
| LDL-C: Week 8 | 3.17 (-63.0 to 56.4) | 8.67 (-38.7 to 53.1) | 3.62 (-32.6 to 125.0) | 8.96 (-37.9 to 118.8) | 7.57 (-24.8 to 67.2) | 4.44 (-39.5 to 119.5) | -2.24 (-47.8 to 55.2) |
| LDL-C: Week 12 | 3.17 (-60.4 to 56.4) | 6.69 (-39.4 to 90.2) | 3.57 (-29.7 to 355.0) | 3.93 (-23.0 to 102.9) | 11.43 (-36.7 to 92.0) | 14.89 (-23.7 to 125.6) | 1.18 (-61.9 to 51.8) |
| HDL-C: Week 4 | -1.97 (-23.5 to 23.5) | 5.43 (-11.5 to 45.8) | 3.69 (-31.3 to 54.2) | 5.13 (-29.3 to 93.3) | 5.69 (-17.0 to 56.2) | 0.00 (-33.0 to 32.9) | 9.18 (-17.6 to 57.5) |
| HDL-C: Week 8 | 0.00 (-31.6 to 19.1) | 6.20 (-20.6 to 40.6) | 5.00 (-20.7 to 58.3) | 3.09 (-41.4 to 93.5) | 7.14 (-15.8 to 59.2) | 0.00 (-42.7 to 52.2) | 8.20 (-13.2 to 48.1) |
| HDL-C: Week 12 | 0.00 (-31.6 to 32.6) | 5.56 (-28.6 to 42.2) | 4.96 (-16.7 to 70.8) | 6.70 (-14.4 to 90.3) | 11.93 (-15.8 to 51.7) | 4.27 (-50.2 to 36.4) | 10.00 (-12.6 to 46.2) |
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.
| Kilograms | Placebo | GSK189075 50 mg | GSK189075 100 mg | GSK189075 250 mg | GSK189075 500 mg | GSK189075 1000 mg | Pioglitazone 30 mg |
|---|---|---|---|---|---|---|---|
| Change From Baseline to Week 12 in Body Weight | -0.49 ± 1.719 | -1.78 ± 3.197 | -2.41 ± 2.850 | -2.38 ± 2.875 | -3.52 ± 2.874 | -4.00 ± 2.945 | 0.96 ± 2.425 |
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.
| Centimeters | Placebo | GSK189075 50 mg | GSK189075 100 mg | GSK189075 250 mg | GSK189075 500 mg | GSK189075 1000 mg | Pioglitazone 30 mg |
|---|---|---|---|---|---|---|---|
| Change From Baseline to Week 12 in Waist Circumference | -0.7 ± 2.92 | -1.2 ± 3.58 | -2.0 ± 4.51 | -2.2 ± 3.43 | -2.6 ± 3.31 | -2.4 ± 4.26 | 1.3 ± 4.82 |
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.
| Percentage of filtered glucose molecules | Placebo | GSK189075 50 mg | GSK189075 100 mg | GSK189075 250 mg | GSK189075 500 mg | GSK189075 1000 mg | Pioglitazone 30 mg |
|---|---|---|---|---|---|---|---|
| Change From Baseline in 24-hour Percent of Filtered Glucose Excreted in Urine | -1.09 ± 5.731 | 27.96 ± 15.693 | 40.43 ± 16.144 | 38.98 ± 19.006 | 42.41 ± 22.708 | 52.39 ± 15.264 | -0.99 ± 2.313 |
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.
| Millimol*hour per Liter (mmol*hr/L) | Placebo | GSK189075 50 mg | GSK189075 100 mg | GSK189075 250 mg | GSK189075 500 mg | GSK189075 1000 mg | Pioglitazone 30 mg |
|---|---|---|---|---|---|---|---|
| Change From Baseline in Plasma Glucose Area Under the Curve (AUC) During a 2-hour Oral Glucose Tolerance Test (OGTT) | -0.90 ± 5.739 | -6.31 ± 5.907 | -6.71 ± 7.326 | -7.69 ± 3.791 | -6.06 ± 2.837 | -7.59 ± 3.065 | -6.55 ± 3.841 |
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.
| Picomol*hour per Liter (pmol*hr/L) | Placebo | GSK189075 50 mg | GSK189075 100 mg | GSK189075 250 mg | GSK189075 500 mg | GSK189075 1000 mg | Pioglitazone 30 mg |
|---|---|---|---|---|---|---|---|
| Change From Baseline in Insulin AUC During a 2-hour OGTT | -5.3 ± 177.23 | 162.4 ± 362.82 | -70.9 ± 193.77 | 66.6 ± 213.07 | -173.9 ± 143.52 | -97.8 ± 224.24 | 10.0 ± 128.77 |
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.
| Nanomol*hour per Liter (nmol*hr/L) | Placebo | GSK189075 50 mg | GSK189075 100 mg | GSK189075 250 mg | GSK189075 500 mg | GSK189075 1000 mg | Pioglitazone 30 mg |
|---|---|---|---|---|---|---|---|
| Change From Baseline in C-peptide AUC During a 2-hr OGTT | -0.140 ± 0.7348 | 0.654 ± 1.4023 | -0.156 ± 1.0566 | -0.026 ± 0.9606 | -0.476 ± 0.4668 | -0.175 ± 0.8322 | -0.239 ± 0.6732 |
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.
| Participants | Placebo | GSK189075 50 mg | GSK189075 100 mg | GSK189075 250 mg | GSK189075 500 mg | GSK189075 1000 mg | Pioglitazone 30 mg |
|---|---|---|---|---|---|---|---|
| AE | 18 | 18 | 17 | 19 | 18 | 22 | 22 |
| SAE | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
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.
| Participants | Placebo | GSK189075 50 mg | GSK189075 100 mg | GSK189075 250 mg | GSK189075 500 mg | GSK189075 1000 mg | Pioglitazone 30 mg |
|---|---|---|---|---|---|---|---|
| Number of Participants With On-therapy Hypoglycemia | 1 | 1 | 0 | 0 | 1 | 0 | 0 |
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.
| Participants | Placebo | GSK189075 50 mg | GSK189075 100 mg | GSK189075 250 mg | GSK189075 500 mg | GSK189075 1000 mg | Pioglitazone 30 mg |
|---|---|---|---|---|---|---|---|
| High SBP | 3 | 0 | 2 | 0 | 0 | 1 | 0 |
| Low SBP | 0 | 0 | 1 | 2 | 2 | 2 | 0 |
| High DBP | 1 | 0 | 0 | 0 | 0 | 2 | 0 |
| Low DBP | 0 | 1 | 2 | 0 | 0 | 1 | 3 |
| High heart rate | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Low heart rate | 0 | 0 | 0 | 0 | 1 | 1 | 0 |
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.
| Participants | Placebo | GSK189075 50 mg | GSK189075 100 mg | GSK189075 250 mg | GSK189075 500 mg | GSK189075 1000 mg | Pioglitazone 30 mg |
|---|---|---|---|---|---|---|---|
| PR interval > 300 msec | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| QRS Duration > 200 msec | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| QTc(Bazett) > 500 msec | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| QTc(Fridericia) > 500 msec | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
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.
| Participants | Placebo | GSK189075 50 mg | GSK189075 100 mg | GSK189075 250 mg | GSK189075 500 mg | GSK189075 1000 mg | Pioglitazone 30 mg |
|---|---|---|---|---|---|---|---|
| Low Hemoglobin | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Low Hematocrit | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
Collected over Up to 12 weeks.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Placebo | 0/48 (0%) | 0/48 (0%) | 3/48 (6.3%) |
| GSK189075 50 mg | 0/47 (0%) | 0/47 (0%) | 5/47 (10.6%) |
| GSK189075 100 mg | 0/48 (0%) | 0/48 (0%) | 5/48 (10.4%) |
| GSK189075 250 mg | 0/48 (0%) | 0/48 (0%) | 4/48 (8.3%) |
| GSK189075 500 mg | 0/48 (0%) | 0/48 (0%) | 5/48 (10.4%) |
| GSK189075 1000 mg | 0/47 (0%) | 0/47 (0%) | 3/47 (6.4%) |
| Pioglitazone 30 mg | 0/48 (0%) | 0/48 (0%) | 12/48 (25%) |
| Event | Placebo | GSK189075 50 mg | GSK189075 100 mg | GSK189075 250 mg | GSK189075 500 mg | GSK189075 1000 mg | Pioglitazone 30 mg |
|---|---|---|---|---|---|---|---|
| HeadacheNervous system disorders | 0/48 | 1/47 | 2/48 | 1/48 | 2/48 | 1/47 | 5/48 |
| Urinary tract infectionInfections and infestations | 0/48 | 2/47 | 1/48 | 0/48 | 0/48 | 0/47 | 4/48 |
| DiarrhoeaGastrointestinal disorders | 3/48 | 1/47 | 1/48 | 1/48 | 0/48 | 2/47 | 3/48 |
| ConstipationGastrointestinal disorders | 0/48 | 1/47 | 1/48 | 2/48 | 3/48 | 0/47 | 0/48 |
| Age, Continuous(Years) | Placebo | GSK189075 50 mg | GSK189075 100 mg | GSK189075 250 mg | GSK189075 500 mg | GSK189075 1000 mg | Pioglitazone 30 mg | Total |
|---|---|---|---|---|---|---|---|---|
| Mean | 55.9 ± 9.67 | 54.3 ± 9.04 | 56.0 ± 8.11 | 55.7 ± 9.46 | 54.6 ± 9.33 | 52.4 ± 9.03 | 54.5 ± 9.45 | 54.8 ± 9.16 |
| Sex: Female, Male(Participants) | Placebo | GSK189075 50 mg | GSK189075 100 mg | GSK189075 250 mg | GSK189075 500 mg | GSK189075 1000 mg | Pioglitazone 30 mg | Total |
|---|---|---|---|---|---|---|---|---|
| Female | 18 | 23 | 17 | 19 | 20 | 20 | 24 | 141 |
| Male | 30 | 24 | 31 | 29 | 28 | 27 | 24 | 193 |
| Race (NIH/OMB)(Participants) | Placebo | GSK189075 50 mg | GSK189075 100 mg | GSK189075 250 mg | GSK189075 500 mg | GSK189075 1000 mg | Pioglitazone 30 mg | Total |
|---|---|---|---|---|---|---|---|---|
| American Indian or Alaska Native | 1 | 4 | 4 | 3 | 0 | 3 | 4 | 19 |
| Asian | 1 | 2 | 3 | 1 | 2 | 1 | 3 | 13 |
| Native Hawaiian or Other Pacific Islander | 1 | 1 | 2 | 0 | 0 | 0 | 0 | 4 |
| Black or African American | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 |
| White | 41 | 37 | 36 | 41 | 42 | 40 | 39 | 276 |
| More than one race | 1 | 0 | 1 | 1 | 1 | 1 | 0 | 5 |
| Unknown or Not Reported | 3 | 2 | 2 | 2 | 3 | 2 | 2 | 16 |
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