Diabetes Mellitus, Type 2
Conditions
Keywords
Metformin, Diabetes
Brief summary
Metformin may have complex interactions in the gut and is generally first line therapy for type 2 diabetes mellitus (T2DM). It is important to understand whether there are significant pharmacokinetic or pharmacodynamic interactions when GSK2330672 is co-administered with metformin in subjects with T2DM. The purpose of this study is to investigate the safety and tolerability of GSK2330672 administered for 7 days to subjects with T2DM taking metformin. This will be a two-period crossover study; subjects will receive either GSK2330672 or placebo for 7 days in each period separated by a washout period of 13 to 15 days. All subjects will receive metformin throughout the study
Interventions
DRUGGSK2330672
GSK2330672 will be supplied as oral solution, and will be administered BID \[45 mg (2 days repeat dose) and 90 mg (5 days repeat dose) in each period\]
DRUGPlacebo
GSK2330672 matching placebo will be supplied as oral solution, and will be administered BID (7 days of dosing in each period)
DRUGMetformin
Metformin 850 mg will be administered BID from Run-in period till Day 7 of period 2
Sponsors
Elite Research Institute
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
30 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
* Males and females aged between 30 and 64 years of age inclusive, at the time of signing the informed consent. * Subjects with documented T2DM diagnosis (diagnosed not less than 3 months prior to screening); AND one of the following: taking stable metformin 850 milligrams (mg) twice daily (BID) (or the equivalent of 1700 mg/day) for at least 4 weeks prior to screening and a glycosolated haemoglobin A1c (HbA1c) of \>=7.0% to \<=11% at screening; OR taking stable metformin of \>=1000 mg/day to \<1700 mg/day for at least 4 weeks prior to screening and a HbA1c of \>=7.5% to \<=11% at Screening; OR taking stable metformin of \>1700 to \<=2000 mg/day for at least 4 weeks prior to screening and a HbA1c of \>=7.0% to \<=10% at screening; not taking other anti-diabetic medications. * All T2DM subjects must meet label recommendations for metformin, including: Adequate renal function, as evidenced by the Modification of Diet in Renal Disease estimate of glomerular filtration rate \>=60 milliliters (mL)/minute (min); No conditions which make hypoxia, dehydration, or sepsis likely; No clinical or laboratory evidence of hepatic disease (including history of cholecystitis or symptomatic gallstones) and cardiac disease (including a history of myocardial infarction or heart failure). Subjects with a history of cholelithiasis and uncomplicated cholecystectomy more than 3 months before screening may be eligible if approved by the GlaxoSmithKline (GSK) Medical Monitor; No excessive alcohol intake. * C-peptide of \>0.8 nanogram (ng)/mL at screening visit. * Urine albumin-to-creatinine ratio \<30 mg/gram (g). * Fasting plasma glucose \<280 mg/decilitre (dL) * Body mass index (BMI) of 24 to 40 kilograms (kg)/square meter (m\^2), inclusive * In good general health with (in the opinion of the investigator) no clinically significant and relevant abnormalities of medical history or physical examination that would introduce additional risk factors or interfere with study procedures or objectives, based on a medical evaluation including medical history, physical examination, vital signs and laboratory tests. * Female subjects of non-childbearing potential. Non-childbearing potential is defined as: Pre-menopausal females with a documented tubal ligation or hysterectomy \[for this definition, documented refers to the outcome of the investigator's/designee's review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records\]. Postmenopausal defined as 12 months of spontaneous amenorrhea. In questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 milli international units (MIU)/mL and estradiol \< 40 picograms (pg)/mL (\<147 picomole \[pmol\]/liter \[L\]) is confirmatory. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the acceptable contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2 to 4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method. * Male subjects with female partners of child-bearing potential must agree to use one of the acceptable contraception methods. This criterion must be followed from the time of the first dose of study medication until follow up visit. * Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
Exclusion criteria
* CRITERIA BASED UPON MEDICAL HISTORIES: * Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome). * History of chronic or acute pancreatitis. Approval from the GSK Medical Monitor must be obtained for subjects with a past history of pancreatitis more than 12 months from the start of the treatment period (subjects with a history of pancreatitis within 12 months prior to the start of the treatment period are excluded). * History of gastrointestinal (GI) disease (e.g., irritable bowel disease, chronic or current diarrhea, inflamed bowel, steatorrhoea/fat malabsorption, celiac disease, symptomatic lactose intolerance). Subjects with gastroparesis requiring treatment are excluded. * History of significant cardiovascular disease including acute myocardial infarction, stroke, hospitalization for acute coronary syndrome, heart failure within the previous 12 months. * Uncontrolled hypertension, as evidenced by systolic pressure \>160 or diastolic pressure \>90. Subjects taking anti-hypertensive medications are permitted. * Significant ECG abnormalities, defined as follows: Heart rate (resting) \<50 and \>100 beats per minute (bpm); PR Interval \<120 and \>220 milliseconds (msec); QRS duration \<70 and \>120 msec * History of untreated pernicious anemia or who have laboratory parameters suggestive of subclinical megaloblastic anemia (e.g., increased mean corpuscular volume with low red blood cells count and/or haemoglobin level). * Current or relevant previous significant medical disorder that may require treatment or make the subject unlikely to fully complete the study, or any condition that, in the opinion of the investigator, presents undue risk from the study medication or procedures. * Thyroid Disease: Uncorrected Thyroid Dysfunction: Fasting plasma thyroid stimulating hormone (TSH) outside of the normal range, as determined at the screening visit; Subjects on stable thyroid replacement therapy and with TSH in the normal range are eligible if approved by the GSK Medical Monitor; Unevaluated thyroid nodule or goiter at Screening. * History of regular alcohol consumption within 6 months of the study defined as: An average weekly intake of \>14 drinks for males or \>7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits. * History of sensitivity to heparin or heparin-induced thrombocytopenia. * History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation * CRITERIA BASED UPON DIAGNOSTIC ASSESSMENTS: * Alanine transaminase, alkaline phosphatase and bilirubin \> 1.5x upper limit of normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%). * Based on averaged QTcF values of triplicate ECGs obtained at least 1 minute apart within approximately 15 minutes: QTcF \>=450 msec; or QTcF \>=480 msec in subjects with Bundle Branch Block (subjects with left bundle branch block are excluded) * A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening * A positive test for human immunodeficiency virus antibody * A positive pre-study drug/alcohol urine screen * A subject with a positive urine cotinine test result will be excluded from the study unless in the judgment of the Investigator the subject will be able to abstain from using tobacco for the duration of the in-house periods of the study. * OTHER CRITERIA * Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period. * The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). * Exposure to more than four new chemical entities within 12 months prior to the first dosing day. * A subject with a fasting plasma glucose at Day -1 that is more than 100 mg/dL lower than at screening must not be randomized, unless on a repeat test the value less than 100 mg/dL of the screening value.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Overall Gastrointestinal Symptom Rating Scale (GSRS) Scores | Baseline (Day -1) and Day 8 of each treatment period | The impact of gastrointestinal (GI) symptoms on health-related quality of life was assessed using the GSRS. The GSRS is a 15-item related to abdominal pain, reflux, indigestion, diarrhea and constipation syndromes, self-administered questionnaire that assesses the impact of gastrointestinal symptoms during the past week on a scale from 1 (no discomfort at all) to 7 (very severe discomfort). Overall GSRS is the mean of questions 1-15 and range from 1 to 7, with lower scores indicating a better quality of life with respect to gastrointestinal symptoms. Baseline was defined as the assessment done on Day -1. Change from baseline was calculated by subtracting the baseline (Day -1) values from the post-baseline value (Day 8). |
| Number of Participants With Vital Sign Values of PCI at Any Time Post Baseline | Up to Follow-up (up to 53 days) | Vital signs assessment included heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP). Assessments were completed at pre morning dose on Day 1 (Baseline), Day 3, Day 8 (before discharge) and Follow-up. Criteria for vital sign values meeting PCI for Type 2 diabetes mellitus (T2DM) included: SBP \<85 and \>160 millimeters of mercury (mmHg), DBP \<45 and \>100 mmHg and HR \<40 and \>110 beats per minute (bpm). Only those parameters for which at least one value of PCI was reported are summarized. |
| Number of Participants With Abnormal (Clinically Significant or Not Clinically Significant) Findings in 12-lead Electrocardiogram (ECG) at Any Time Post Baseline | Up to Follow-up (up to 53 days) | 12-lead ECG assessments were obtained pre-dose at Day 1, Day 3, Day 8 (before discharge) and Follow-up. The assessments were done using an ECG machine that automatically calculated the heart rate and measures PQ, QRS, QT, and QTc(B) intervals. Abnormal ECG findings (clinically significant or not clinically significant) were categorized. The abnormal PCI range for T2DM participants include QTc interval of \>450 to \<=480 milliseconds (msec) and increase from Baseline QTc interval of \> 30 to \<=60 msec, PR interval \<110 and \>220 msec and QRS interval \<75 and \>110 msec. ECG abnormalities were categorized as clinically significant or not clinically significant based on PCI criteria and judgment of the investigator. Baseline was defined as the mean of three replicate assessments at pre-dose on Day 1. |
| Number of Events of Stool or Bowel Movements of Participants Using Bristol Stool Form Rating (BSFR) Scale Across Day 1 to 7 | Day 1 to 7 of each treatment period | The BSFR Scale assessed stool quality using a 7-point scale, where 1=separate hard lumps like nuts (difficult to pass) and 7=watery, no solid pieces (entirely liquid). Bristol Stool Form Scale Rating: 1=separate hard lumps, like nuts, 2=sausage shaped but lumpy, 3=like a sausage or snake but with cracks on its surface, 4=like a sausage or snake, smooth and soft, 5=soft blobs with clear cut edges, 6=fluffy pieces with ragged edges, a mushy stool, 7=watery, no solid pieces. Data is reported for number of events in participants with each category of BSFR scale across Day 1 to 7 post morning dose. |
| Number of Participants in Each Category of BSFR Across Day 1 to 7 | Day 1 to 7 of each treatment period | The BSFR Scale assessed stool quality using a 7-point scale, where 1=separate hard lumps like nuts (difficult to pass) and 7 = watery, no solid pieces (entirely liquid). Bristol Stool Form Scale Rating: 1=separate hard lumps, like nuts, 2=sausage shaped but lumpy, 3=like a sausage or snake but with cracks on its surface, 4=like a sausage or snake, smooth and soft, 5=soft blobs with clear cut edges, 6=fluffy pieces with ragged edges, a mushy stool, 7=watery, no solid pieces. Data is reported for number of events in participants with each category of BSFR scale across Day 1 to 7 post morning dose. |
| Number of Participants With at Least One Adverse Event (AE), Serious Adverse Event (SAE) or Death | Up to Follow-up (up to 53 days) | An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as 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, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition, associated with liver injury and impaired liver function defined as alanine aminotransferase (ALT) \>=3 x upper limit of normal (ULN), and total bilirubin \>=2 x ULN or international normalized ratio \>1.5. |
| Number of Participants With the Indicated Clinical Chemistry Values of Potential Clinical Importance (PCI) at Any Time Post Baseline | Up to Follow-up (up to 53 days) | The assessments were done at Day -1, Day 3, Day 8 and Follow-up under fasting condition. The following laboratory parameters of clinical chemistry were analyzed: blood urea nitrogen (BUN), creatinine, fasting triglycerides (TGs), total cholesterol, low-density lipoprotein cholesterol (LDLc), high-density lipoprotein cholesterol (HDLc), sodium, potassium, chloride, total bicarbonate, calcium, aspartate aminotransferase (AST), ALT, gamma glutamyltransferase (GGT), alkaline phosphatase, total and direct bilirubin, uric acid, albumin and total protein. Baseline was the assessment done on Day -1 (pre dose). Only those parameters for which at least one value of PCI was reported are summarized. Data is reported for participants with high glucose PCI, where the PCI value for T2DM participants was ( low \< 3.8857 millimole per liter (mmol/L); high \> 15 mmol/L; normal range was 3.61 - 5.5 mmol/L). |
| Number of Participants With the Indicated Haematology Values of PCI at Any Time Post Baseline | Up to Follow-up (up to 53 days) | The assessments were done at Day -1, Day 3, Day 8 and Follow-up under fasting condition. The following laboratory parameters of clinical haematology were analyzed: platelet count, red blood cells (RBC) count, absolute white blood cells (WBC) count, reticulocyte count, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), neutrophils, lymphocytes, monocytes, eosinophils and basophils. Baseline was the assessment done on Day -1 (pre dose). Only those parameters for which at least one value of PCI was reported are summarized. Data is reported for participants with high WBC counts PCI, where the PCI value for T2DM participants was (relative low : 0.5 multiplier of lower limit of normal \[LLN\]; relative high : 1.82 multiplier of upper limit of normal \[LLN\]; where normal range was 3.8 - 10.8 giga cells per liter (GI/L). |
| Number of Participants With Abnormal Values of Urine Microscopic Analysis of Bacteria, Hyaline Casts (Semi-quantitive), RBC, Squamous Epithelial Cells and WBC at Any Time Post Baseline | Up to Follow-up (up to 53 days) | The assessments were done at Day -1, Day 3, Day 8 and Follow-up under fasting condition for microscopic analysis of bacteria, hyaline casts (semi-quantitive), RBC, squamous epithelial cells and WBC. Baseline was the assessment done on Day -1 (pre dose). The participants were categorized as 0-5, 6-10, 10-20, moderate, few and many. Only those parameters for which at least one value of these categories reported are summarized. |
| Number of Participants With Abnormal Values of Urine Dipstic Analysis of Occult Blood, Glucose, Ketones and Proteins at Any Visit Post Baseline | Up to Follow-up (up to 53 days) | The assessments were done at Day -1, Day 3, Day 8 and Follow-up under fasting condition for urine dipstic analysis of occult blood, glucose, ketones and proteins. Baseline was the assessment done on Day -1 (pre dose). The participants were categorized with results of 1+, 2+, 3+ and trace. Only those parameters for which at least one value of these categories reported are summarized. |
| Mean Specific Gravity of Urine at Any Visit Post Baseline | Up to Follow-up (up to 53 days) | Urine specific gravity is a laboratory test that shows the concentration of all chemical particles in the urine. The assessments were done at Day -1, Day 3, Day 8 and Follow-up under fasting condition. Baseline was the assessment done on Day -1 (pre dose). |
| Number of Participants With Abnormal Results for Fecal Occult Blood Test | Day 8 of both treatment periods | The assessment of fecal occult blood was done on Day 8. Stool sample was obtained any time after dosing on Day 7. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC From Time 0 to 10 h (AUC 0-10 h) of Metformin in Presence of GSK2330672 or Placebo on Day 7 | Pre-dose (0 h), 0.25 h, 0.50 h, 1 h, 2 h, 3 h, 4 h (pre-lunch), 5 h, 5.5 h, 6 h, 8 h and 10 h (pre-dinner) on Day 7 of each treatment period | AUC(0-10) for metformin when co-dosed with GSK2330672 or placebo is defined as the the area under the plasma concentration-time curve from time 0 to 10 h. It was determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations. Blood samples were collected at 0 h (pre-dose within 15 min of dose and began eating breakfast immediately after taking study drug and finished eating in 15 min), 0.25 h, 0.50 h, 1 h, 2 h, 3 h, 4 h (pre-lunch), 5 h, 5.5 h, 6 h, 8 h and 10 h (pre-dinner) on Day 7. Analysis was done using a mixed effects model with fixed effect terms for treatment, period, and sequence. Participant within sequence was fitted as a random effect in the model. |
| Maximum Plasma Concentration of Metformin (Cmax) in Presence of GSK2330672 or Placebo on Day 7 | Pre-dose (0 h), 0.25 h, 0.50 h, 1 h, 2 h, 3 h, 4 h (pre-lunch), 5 h, 5.5 h, 6 h, 8 h and 10 h (pre-dinner) on Day 7 of each treatment period | Cmax is defined as the first occurrence of the maximum observed plasma concentration determined directly from the raw concentration-time data Blood samples were collected at 0 h (pre-dose within 15 min of dose and began eating breakfast immediately after taking study drug and finished eating in 15 min), 0.25 h, 0.50 h, 1 h, 2 h, 3 h, 4 h (pre-lunch), 5 h, 5.5 h, 6 h, 8 h and 10 h (pre-dinner) on Day 7. Analysis was done using a mixed effects model with fixed effect terms for treatment, period, and sequence. Participant within sequence was fitted as a random effect in the model. |
| Median Time to Observed Peak Plasma Concentration (Tmax) When Co-dosed With GSK2330672 or Placebo on Day 7 | Pre-dose (0 h), 0.25 h, 0.50 h, 1 h, 2 h, 3 h, 4 h (pre-lunch), 5 h, 5.5 h, 6 h, 8 h and 10 h (pre-dinner) on Day 7 of each treatment period | Tmax is defined as the time at which Cmax is observed, determined directly from the raw concentration-time data. Blood samples were collected at 0 h (pre-dose within 15 min of dose and began eating breakfast immediately after taking study drug and finished eating in 15 min), 0.25 h, 0.50 h, 1 h, 2 h, 3 h, 4 h (pre-lunch), 5 h, 5.5 h, 6 h, 8 h and 10 h (pre-dinner) on Day 7. |
| Maximum and Weighted Mean Change From Baseline in Plasma Glucose Concentrations Over a 24 Hour (h) Period on Day 7 | Baseline (Day -1) and Day 7 of each treatment period | Baseline was defined as the time matched assessment done on Day -1. Change from baseline was calculated by subtracting the baseline (Day -1) time matched values from the post-baseline value (Day 8). Data is reported for fasting glucose level and for weighted mean and maximum values for fasting, 0-4 h, 4-10 h, 10-14 h and 0-24 h. Area under the curve (AUC) with respect to these time interval was calculated using the linear trapezoidal rule by the sum of the areas between each chronological pair of assessments (using observed times). The weighted mean was then determined by dividing the AUC by the observed length of the collection interval (time of last assessment - time of first assessment in h). Analysis was done using analysis of covariance (ANCOVA) model where, change from baseline was summation of baseline, period, sequence and treatment. Participants were fitted as a random effect. |
Countries
United States
Participant flow
Recruitment details
The study was planned on 16 participants with Type 2 diabetes mellitus (T2DM), aged 30 to 64 years, at a single center of United States from 22 August 2013 to 21 November 2013.
Pre-assignment details
A total of 15 participants were randomized in the study and entered a run-in period where participants were administered oral dose of metformin 850 milligram (mg) tablet twice daily (BID) for 14 days, after which they entered the 2 double blind treatment periods in a crossover manner.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants In each treatment period, participants received oral dose of treatment A-metformin 850 mg BID tablet for 7 days plus GSK2330672 45 mg tablet BID on Day 1 and 2 and GSK2330672 90 mg tablet BID on Day 3 to 7 or oral dose of treatment B-metformin 850 mg tablet BID plus matchig placebo to GSK2330672 tablet BID for 7 days according to a plan of randomization. The two treatment periods were separated by a washout period of 13 to 15 days in which participants continued metformin 850 mg tablet BID. After completion of the double blind treatment period 2 (after the last dose of period 2), participants received oral dose of metformin 850 mg tablet BID for 7-10 days of Follow-up. | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1:Intervention Period 1 (7 Days) | Adverse Event | 1 | 0 |
| Period 1:Intervention Period 1 (7 Days) | Withdrawal by Subject | 0 | 1 |
| Period 3:Intervention Period 2 (7 Days) | Adverse Event | 0 | 1 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 54.9 Years STANDARD_DEVIATION 7.06 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 12 Participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 14 |
| other Total, other adverse events | 12 / 14 | 9 / 14 |
| serious Total, serious adverse events | 1 / 14 | 0 / 14 |
Outcome results
Primary
Mean Change From Baseline in Overall Gastrointestinal Symptom Rating Scale (GSRS) Scores
The impact of gastrointestinal (GI) symptoms on health-related quality of life was assessed using the GSRS. The GSRS is a 15-item related to abdominal pain, reflux, indigestion, diarrhea and constipation syndromes, self-administered questionnaire that assesses the impact of gastrointestinal symptoms during the past week on a scale from 1 (no discomfort at all) to 7 (very severe discomfort). Overall GSRS is the mean of questions 1-15 and range from 1 to 7, with lower scores indicating a better quality of life with respect to gastrointestinal symptoms. Baseline was defined as the assessment done on Day -1. Change from baseline was calculated by subtracting the baseline (Day -1) values from the post-baseline value (Day 8).
Time frame: Baseline (Day -1) and Day 8 of each treatment period
Population: Safety Population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A-GSK2330672 + Metformin | Mean Change From Baseline in Overall Gastrointestinal Symptom Rating Scale (GSRS) Scores | 0.59 Score on scale | Standard Deviation 0.891 |
| Treatment B-Placebo + Metformin | Mean Change From Baseline in Overall Gastrointestinal Symptom Rating Scale (GSRS) Scores | 0.08 Score on scale | Standard Deviation 0.468 |
Primary
Mean Specific Gravity of Urine at Any Visit Post Baseline
Urine specific gravity is a laboratory test that shows the concentration of all chemical particles in the urine. The assessments were done at Day -1, Day 3, Day 8 and Follow-up under fasting condition. Baseline was the assessment done on Day -1 (pre dose).
Time frame: Up to Follow-up (up to 53 days)
Population: Safety Population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A-GSK2330672 + Metformin | Mean Specific Gravity of Urine at Any Visit Post Baseline | Day 3 | 1.0121 Ratio | Standard Deviation 0.00352 |
| Treatment A-GSK2330672 + Metformin | Mean Specific Gravity of Urine at Any Visit Post Baseline | Day 8 | 1.0125 Ratio | Standard Deviation 0.00654 |
| Treatment B-Placebo + Metformin | Mean Specific Gravity of Urine at Any Visit Post Baseline | Day 3 | 1.0110 Ratio | Standard Deviation 0.00335 |
| Treatment B-Placebo + Metformin | Mean Specific Gravity of Urine at Any Visit Post Baseline | Day 8 | 1.0109 Ratio | Standard Deviation 0.00386 |
| Follow-up-Metformin | Mean Specific Gravity of Urine at Any Visit Post Baseline | Follow-up | 1.0203 Ratio | Standard Deviation 0.00832 |
Primary
Number of Events of Stool or Bowel Movements of Participants Using Bristol Stool Form Rating (BSFR) Scale Across Day 1 to 7
The BSFR Scale assessed stool quality using a 7-point scale, where 1=separate hard lumps like nuts (difficult to pass) and 7=watery, no solid pieces (entirely liquid). Bristol Stool Form Scale Rating: 1=separate hard lumps, like nuts, 2=sausage shaped but lumpy, 3=like a sausage or snake but with cracks on its surface, 4=like a sausage or snake, smooth and soft, 5=soft blobs with clear cut edges, 6=fluffy pieces with ragged edges, a mushy stool, 7=watery, no solid pieces. Data is reported for number of events in participants with each category of BSFR scale across Day 1 to 7 post morning dose.
Time frame: Day 1 to 7 of each treatment period
Population: Safety Population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment A-GSK2330672 + Metformin | Number of Events of Stool or Bowel Movements of Participants Using Bristol Stool Form Rating (BSFR) Scale Across Day 1 to 7 | Participants with Rating 3 | 4 Number of events |
| Treatment A-GSK2330672 + Metformin | Number of Events of Stool or Bowel Movements of Participants Using Bristol Stool Form Rating (BSFR) Scale Across Day 1 to 7 | Participants with Rating 5 | 18 Number of events |
| Treatment A-GSK2330672 + Metformin | Number of Events of Stool or Bowel Movements of Participants Using Bristol Stool Form Rating (BSFR) Scale Across Day 1 to 7 | Participants with Rating 2 | 4 Number of events |
| Treatment A-GSK2330672 + Metformin | Number of Events of Stool or Bowel Movements of Participants Using Bristol Stool Form Rating (BSFR) Scale Across Day 1 to 7 | Participants with Rating 6 | 60 Number of events |
| Treatment A-GSK2330672 + Metformin | Number of Events of Stool or Bowel Movements of Participants Using Bristol Stool Form Rating (BSFR) Scale Across Day 1 to 7 | Participants with Rating 4 | 11 Number of events |
| Treatment A-GSK2330672 + Metformin | Number of Events of Stool or Bowel Movements of Participants Using Bristol Stool Form Rating (BSFR) Scale Across Day 1 to 7 | Participants with Rating 7 | 111 Number of events |
| Treatment A-GSK2330672 + Metformin | Number of Events of Stool or Bowel Movements of Participants Using Bristol Stool Form Rating (BSFR) Scale Across Day 1 to 7 | Participants with Rating 1 | 0 Number of events |
| Treatment B-Placebo + Metformin | Number of Events of Stool or Bowel Movements of Participants Using Bristol Stool Form Rating (BSFR) Scale Across Day 1 to 7 | Participants with Rating 7 | 16 Number of events |
| Treatment B-Placebo + Metformin | Number of Events of Stool or Bowel Movements of Participants Using Bristol Stool Form Rating (BSFR) Scale Across Day 1 to 7 | Participants with Rating 1 | 6 Number of events |
| Treatment B-Placebo + Metformin | Number of Events of Stool or Bowel Movements of Participants Using Bristol Stool Form Rating (BSFR) Scale Across Day 1 to 7 | Participants with Rating 2 | 4 Number of events |
| Treatment B-Placebo + Metformin | Number of Events of Stool or Bowel Movements of Participants Using Bristol Stool Form Rating (BSFR) Scale Across Day 1 to 7 | Participants with Rating 3 | 8 Number of events |
| Treatment B-Placebo + Metformin | Number of Events of Stool or Bowel Movements of Participants Using Bristol Stool Form Rating (BSFR) Scale Across Day 1 to 7 | Participants with Rating 4 | 20 Number of events |
| Treatment B-Placebo + Metformin | Number of Events of Stool or Bowel Movements of Participants Using Bristol Stool Form Rating (BSFR) Scale Across Day 1 to 7 | Participants with Rating 5 | 15 Number of events |
| Treatment B-Placebo + Metformin | Number of Events of Stool or Bowel Movements of Participants Using Bristol Stool Form Rating (BSFR) Scale Across Day 1 to 7 | Participants with Rating 6 | 17 Number of events |
Primary
Number of Participants in Each Category of BSFR Across Day 1 to 7
The BSFR Scale assessed stool quality using a 7-point scale, where 1=separate hard lumps like nuts (difficult to pass) and 7 = watery, no solid pieces (entirely liquid). Bristol Stool Form Scale Rating: 1=separate hard lumps, like nuts, 2=sausage shaped but lumpy, 3=like a sausage or snake but with cracks on its surface, 4=like a sausage or snake, smooth and soft, 5=soft blobs with clear cut edges, 6=fluffy pieces with ragged edges, a mushy stool, 7=watery, no solid pieces. Data is reported for number of events in participants with each category of BSFR scale across Day 1 to 7 post morning dose.
Time frame: Day 1 to 7 of each treatment period
Population: Safety Population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment A-GSK2330672 + Metformin | Number of Participants in Each Category of BSFR Across Day 1 to 7 | Rating 1 | 0 Participants |
| Treatment A-GSK2330672 + Metformin | Number of Participants in Each Category of BSFR Across Day 1 to 7 | Rating 5 | 8 Participants |
| Treatment A-GSK2330672 + Metformin | Number of Participants in Each Category of BSFR Across Day 1 to 7 | Rating 3 | 4 Participants |
| Treatment A-GSK2330672 + Metformin | Number of Participants in Each Category of BSFR Across Day 1 to 7 | Rating 6 | 12 Participants |
| Treatment A-GSK2330672 + Metformin | Number of Participants in Each Category of BSFR Across Day 1 to 7 | Rating 2 | 3 Participants |
| Treatment A-GSK2330672 + Metformin | Number of Participants in Each Category of BSFR Across Day 1 to 7 | Rating 7 | 14 Participants |
| Treatment A-GSK2330672 + Metformin | Number of Participants in Each Category of BSFR Across Day 1 to 7 | Rating 4 | 5 Participants |
| Treatment B-Placebo + Metformin | Number of Participants in Each Category of BSFR Across Day 1 to 7 | Rating 7 | 6 Participants |
| Treatment B-Placebo + Metformin | Number of Participants in Each Category of BSFR Across Day 1 to 7 | Rating 2 | 3 Participants |
| Treatment B-Placebo + Metformin | Number of Participants in Each Category of BSFR Across Day 1 to 7 | Rating 3 | 6 Participants |
| Treatment B-Placebo + Metformin | Number of Participants in Each Category of BSFR Across Day 1 to 7 | Rating 4 | 10 Participants |
| Treatment B-Placebo + Metformin | Number of Participants in Each Category of BSFR Across Day 1 to 7 | Rating 5 | 6 Participants |
| Treatment B-Placebo + Metformin | Number of Participants in Each Category of BSFR Across Day 1 to 7 | Rating 6 | 8 Participants |
| Treatment B-Placebo + Metformin | Number of Participants in Each Category of BSFR Across Day 1 to 7 | Rating 1 | 4 Participants |
Primary
Number of Participants With Abnormal (Clinically Significant or Not Clinically Significant) Findings in 12-lead Electrocardiogram (ECG) at Any Time Post Baseline
12-lead ECG assessments were obtained pre-dose at Day 1, Day 3, Day 8 (before discharge) and Follow-up. The assessments were done using an ECG machine that automatically calculated the heart rate and measures PQ, QRS, QT, and QTc(B) intervals. Abnormal ECG findings (clinically significant or not clinically significant) were categorized. The abnormal PCI range for T2DM participants include QTc interval of \>450 to \<=480 milliseconds (msec) and increase from Baseline QTc interval of \> 30 to \<=60 msec, PR interval \<110 and \>220 msec and QRS interval \<75 and \>110 msec. ECG abnormalities were categorized as clinically significant or not clinically significant based on PCI criteria and judgment of the investigator. Baseline was defined as the mean of three replicate assessments at pre-dose on Day 1.
Time frame: Up to Follow-up (up to 53 days)
Population: Safety Population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment A-GSK2330672 + Metformin | Number of Participants With Abnormal (Clinically Significant or Not Clinically Significant) Findings in 12-lead Electrocardiogram (ECG) at Any Time Post Baseline | Not-clinically Significant, Day 8 | 2 Participants |
| Treatment A-GSK2330672 + Metformin | Number of Participants With Abnormal (Clinically Significant or Not Clinically Significant) Findings in 12-lead Electrocardiogram (ECG) at Any Time Post Baseline | Not-clinically Significant, Day 3 | 3 Participants |
| Treatment A-GSK2330672 + Metformin | Number of Participants With Abnormal (Clinically Significant or Not Clinically Significant) Findings in 12-lead Electrocardiogram (ECG) at Any Time Post Baseline | Clinically Significant, Day 8 | 0 Participants |
| Treatment A-GSK2330672 + Metformin | Number of Participants With Abnormal (Clinically Significant or Not Clinically Significant) Findings in 12-lead Electrocardiogram (ECG) at Any Time Post Baseline | Clinically Significant, Day 3 | 0 Participants |
| Treatment B-Placebo + Metformin | Number of Participants With Abnormal (Clinically Significant or Not Clinically Significant) Findings in 12-lead Electrocardiogram (ECG) at Any Time Post Baseline | Not-clinically Significant, Day 8 | 4 Participants |
| Treatment B-Placebo + Metformin | Number of Participants With Abnormal (Clinically Significant or Not Clinically Significant) Findings in 12-lead Electrocardiogram (ECG) at Any Time Post Baseline | Not-clinically Significant, Day 3 | 2 Participants |
| Treatment B-Placebo + Metformin | Number of Participants With Abnormal (Clinically Significant or Not Clinically Significant) Findings in 12-lead Electrocardiogram (ECG) at Any Time Post Baseline | Clinically Significant, Day 3 | 0 Participants |
| Treatment B-Placebo + Metformin | Number of Participants With Abnormal (Clinically Significant or Not Clinically Significant) Findings in 12-lead Electrocardiogram (ECG) at Any Time Post Baseline | Clinically Significant, Day 8 | 0 Participants |
| Follow-up-Metformin | Number of Participants With Abnormal (Clinically Significant or Not Clinically Significant) Findings in 12-lead Electrocardiogram (ECG) at Any Time Post Baseline | Not-clinically Significant, Follow-up | 3 Participants |
| Follow-up-Metformin | Number of Participants With Abnormal (Clinically Significant or Not Clinically Significant) Findings in 12-lead Electrocardiogram (ECG) at Any Time Post Baseline | Clinically Significant, Follow-up | 0 Participants |
Primary
Number of Participants With Abnormal Results for Fecal Occult Blood Test
The assessment of fecal occult blood was done on Day 8. Stool sample was obtained any time after dosing on Day 7.
Time frame: Day 8 of both treatment periods
Population: Safety Population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment A-GSK2330672 + Metformin | Number of Participants With Abnormal Results for Fecal Occult Blood Test | 0 Participants |
| Treatment B-Placebo + Metformin | Number of Participants With Abnormal Results for Fecal Occult Blood Test | 0 Participants |
Primary
Number of Participants With Abnormal Values of Urine Dipstic Analysis of Occult Blood, Glucose, Ketones and Proteins at Any Visit Post Baseline
The assessments were done at Day -1, Day 3, Day 8 and Follow-up under fasting condition for urine dipstic analysis of occult blood, glucose, ketones and proteins. Baseline was the assessment done on Day -1 (pre dose). The participants were categorized with results of 1+, 2+, 3+ and trace. Only those parameters for which at least one value of these categories reported are summarized.
Time frame: Up to Follow-up (up to 53 days)
Population: Safety population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment A-GSK2330672 + Metformin | Number of Participants With Abnormal Values of Urine Dipstic Analysis of Occult Blood, Glucose, Ketones and Proteins at Any Visit Post Baseline | Urine Glucose, Day 3, 1+ | 1 Participants |
| Treatment A-GSK2330672 + Metformin | Number of Participants With Abnormal Values of Urine Dipstic Analysis of Occult Blood, Glucose, Ketones and Proteins at Any Visit Post Baseline | Urine Glucose, Day 3, 2+ | 1 Participants |
| Treatment A-GSK2330672 + Metformin | Number of Participants With Abnormal Values of Urine Dipstic Analysis of Occult Blood, Glucose, Ketones and Proteins at Any Visit Post Baseline | Urine Glucose, Day 3, Trace | 1 Participants |
| Treatment A-GSK2330672 + Metformin | Number of Participants With Abnormal Values of Urine Dipstic Analysis of Occult Blood, Glucose, Ketones and Proteins at Any Visit Post Baseline | Urine Glucose, Day 8, 2+ | 1 Participants |
| Treatment A-GSK2330672 + Metformin | Number of Participants With Abnormal Values of Urine Dipstic Analysis of Occult Blood, Glucose, Ketones and Proteins at Any Visit Post Baseline | Urine Glucose, Day 8, Trace | 2 Participants |
| Treatment A-GSK2330672 + Metformin | Number of Participants With Abnormal Values of Urine Dipstic Analysis of Occult Blood, Glucose, Ketones and Proteins at Any Visit Post Baseline | Urine Ketones, Day 3, Trace | 1 Participants |
| Treatment B-Placebo + Metformin | Number of Participants With Abnormal Values of Urine Dipstic Analysis of Occult Blood, Glucose, Ketones and Proteins at Any Visit Post Baseline | Urine Glucose, Day 3, Trace | 1 Participants |
| Treatment B-Placebo + Metformin | Number of Participants With Abnormal Values of Urine Dipstic Analysis of Occult Blood, Glucose, Ketones and Proteins at Any Visit Post Baseline | Urine Glucose, Day 8, 2+ | 3 Participants |
| Treatment B-Placebo + Metformin | Number of Participants With Abnormal Values of Urine Dipstic Analysis of Occult Blood, Glucose, Ketones and Proteins at Any Visit Post Baseline | Urine Glucose, Day 8, Trace | 5 Participants |
| Treatment B-Placebo + Metformin | Number of Participants With Abnormal Values of Urine Dipstic Analysis of Occult Blood, Glucose, Ketones and Proteins at Any Visit Post Baseline | Urine Glucose, Day 3, 1+ | 3 Participants |
| Treatment B-Placebo + Metformin | Number of Participants With Abnormal Values of Urine Dipstic Analysis of Occult Blood, Glucose, Ketones and Proteins at Any Visit Post Baseline | Urine Glucose, Day 3, 2+ | 0 Participants |
| Treatment B-Placebo + Metformin | Number of Participants With Abnormal Values of Urine Dipstic Analysis of Occult Blood, Glucose, Ketones and Proteins at Any Visit Post Baseline | Urine Ketones, Day 3, Trace | 0 Participants |
| Follow-up-Metformin | Number of Participants With Abnormal Values of Urine Dipstic Analysis of Occult Blood, Glucose, Ketones and Proteins at Any Visit Post Baseline | Urine Ketones, Follow-up, Trace | 2 Participants |
| Follow-up-Metformin | Number of Participants With Abnormal Values of Urine Dipstic Analysis of Occult Blood, Glucose, Ketones and Proteins at Any Visit Post Baseline | Urine Glucose, Follow-up, Trace | 3 Participants |
| Follow-up-Metformin | Number of Participants With Abnormal Values of Urine Dipstic Analysis of Occult Blood, Glucose, Ketones and Proteins at Any Visit Post Baseline | Urine Glucose, Follow-up, 3+ | 3 Participants |
| Follow-up-Metformin | Number of Participants With Abnormal Values of Urine Dipstic Analysis of Occult Blood, Glucose, Ketones and Proteins at Any Visit Post Baseline | Urine Protein, Follow-up, Trace | 1 Participants |
Primary
Number of Participants With Abnormal Values of Urine Microscopic Analysis of Bacteria, Hyaline Casts (Semi-quantitive), RBC, Squamous Epithelial Cells and WBC at Any Time Post Baseline
The assessments were done at Day -1, Day 3, Day 8 and Follow-up under fasting condition for microscopic analysis of bacteria, hyaline casts (semi-quantitive), RBC, squamous epithelial cells and WBC. Baseline was the assessment done on Day -1 (pre dose). The participants were categorized as 0-5, 6-10, 10-20, moderate, few and many. Only those parameters for which at least one value of these categories reported are summarized.
Time frame: Up to Follow-up (up to 53 days)
Population: Safety Population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment A-GSK2330672 + Metformin | Number of Participants With Abnormal Values of Urine Microscopic Analysis of Bacteria, Hyaline Casts (Semi-quantitive), RBC, Squamous Epithelial Cells and WBC at Any Time Post Baseline | Urine Microscopy, WBC's, Day 3, 10-20 | 0 Participants |
| Treatment A-GSK2330672 + Metformin | Number of Participants With Abnormal Values of Urine Microscopic Analysis of Bacteria, Hyaline Casts (Semi-quantitive), RBC, Squamous Epithelial Cells and WBC at Any Time Post Baseline | Urine Microscopy, SEC's, Day 3, 0-5 | 0 Participants |
| Treatment A-GSK2330672 + Metformin | Number of Participants With Abnormal Values of Urine Microscopic Analysis of Bacteria, Hyaline Casts (Semi-quantitive), RBC, Squamous Epithelial Cells and WBC at Any Time Post Baseline | Urine Microscopy, Bacteria, Day 3, Few | 0 Participants |
| Treatment A-GSK2330672 + Metformin | Number of Participants With Abnormal Values of Urine Microscopic Analysis of Bacteria, Hyaline Casts (Semi-quantitive), RBC, Squamous Epithelial Cells and WBC at Any Time Post Baseline | Urine Microscopy, SEC's, Day 8, 0-5 | 0 Participants |
| Treatment A-GSK2330672 + Metformin | Number of Participants With Abnormal Values of Urine Microscopic Analysis of Bacteria, Hyaline Casts (Semi-quantitive), RBC, Squamous Epithelial Cells and WBC at Any Time Post Baseline | Urine Microscopy, Bacteria, Day 8, Few | 1 Participants |
| Treatment A-GSK2330672 + Metformin | Number of Participants With Abnormal Values of Urine Microscopic Analysis of Bacteria, Hyaline Casts (Semi-quantitive), RBC, Squamous Epithelial Cells and WBC at Any Time Post Baseline | Urine Microscopy, Bacteria, Day 3, Many | 0 Participants |
| Treatment B-Placebo + Metformin | Number of Participants With Abnormal Values of Urine Microscopic Analysis of Bacteria, Hyaline Casts (Semi-quantitive), RBC, Squamous Epithelial Cells and WBC at Any Time Post Baseline | Urine Microscopy, SEC's, Day 3, 0-5 | 1 Participants |
| Treatment B-Placebo + Metformin | Number of Participants With Abnormal Values of Urine Microscopic Analysis of Bacteria, Hyaline Casts (Semi-quantitive), RBC, Squamous Epithelial Cells and WBC at Any Time Post Baseline | Urine Microscopy, Bacteria, Day 3, Few | 1 Participants |
| Treatment B-Placebo + Metformin | Number of Participants With Abnormal Values of Urine Microscopic Analysis of Bacteria, Hyaline Casts (Semi-quantitive), RBC, Squamous Epithelial Cells and WBC at Any Time Post Baseline | Urine Microscopy, Bacteria, Day 3, Many | 1 Participants |
| Treatment B-Placebo + Metformin | Number of Participants With Abnormal Values of Urine Microscopic Analysis of Bacteria, Hyaline Casts (Semi-quantitive), RBC, Squamous Epithelial Cells and WBC at Any Time Post Baseline | Urine Microscopy, Bacteria, Day 8, Few | 1 Participants |
| Treatment B-Placebo + Metformin | Number of Participants With Abnormal Values of Urine Microscopic Analysis of Bacteria, Hyaline Casts (Semi-quantitive), RBC, Squamous Epithelial Cells and WBC at Any Time Post Baseline | Urine Microscopy, SEC's, Day 8, 0-5 | 1 Participants |
| Treatment B-Placebo + Metformin | Number of Participants With Abnormal Values of Urine Microscopic Analysis of Bacteria, Hyaline Casts (Semi-quantitive), RBC, Squamous Epithelial Cells and WBC at Any Time Post Baseline | Urine Microscopy, WBC's, Day 3, 10-20 | 1 Participants |
| Follow-up-Metformin | Number of Participants With Abnormal Values of Urine Microscopic Analysis of Bacteria, Hyaline Casts (Semi-quantitive), RBC, Squamous Epithelial Cells and WBC at Any Time Post Baseline | Urine Microscopy, SEC's, Follow-up, 6-10 | 1 Participants |
| Follow-up-Metformin | Number of Participants With Abnormal Values of Urine Microscopic Analysis of Bacteria, Hyaline Casts (Semi-quantitive), RBC, Squamous Epithelial Cells and WBC at Any Time Post Baseline | Urine Microscopy, Bacteria, Follow-up, Many | 1 Participants |
| Follow-up-Metformin | Number of Participants With Abnormal Values of Urine Microscopic Analysis of Bacteria, Hyaline Casts (Semi-quantitive), RBC, Squamous Epithelial Cells and WBC at Any Time Post Baseline | Urine Microscopy, WBC's, Follow-up, 6-10 | 1 Participants |
| Follow-up-Metformin | Number of Participants With Abnormal Values of Urine Microscopic Analysis of Bacteria, Hyaline Casts (Semi-quantitive), RBC, Squamous Epithelial Cells and WBC at Any Time Post Baseline | Urine Microscopy, WBC's, Follow-up, 0-5 | 1 Participants |
| Follow-up-Metformin | Number of Participants With Abnormal Values of Urine Microscopic Analysis of Bacteria, Hyaline Casts (Semi-quantitive), RBC, Squamous Epithelial Cells and WBC at Any Time Post Baseline | Urine Microscopy, SEC's, Follow-up, 0-5 | 1 Participants |
Primary
Number of Participants With at Least One Adverse Event (AE), Serious Adverse Event (SAE) or Death
An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as 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, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition, associated with liver injury and impaired liver function defined as alanine aminotransferase (ALT) \>=3 x upper limit of normal (ULN), and total bilirubin \>=2 x ULN or international normalized ratio \>1.5.
Time frame: Up to Follow-up (up to 53 days)
Population: Safety Population was defined as all participants enrolled into the study who have received at least one dose of study drug (including metformin, GSK2330672, and matching placebo. One participant withdrew consent after taking period 1 study treatment of placebo + GSK2330672.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment A-GSK2330672 + Metformin | Number of Participants With at Least One Adverse Event (AE), Serious Adverse Event (SAE) or Death | Any AE | 12 Participants |
| Treatment A-GSK2330672 + Metformin | Number of Participants With at Least One Adverse Event (AE), Serious Adverse Event (SAE) or Death | Any SAE | 1 Participants |
| Treatment A-GSK2330672 + Metformin | Number of Participants With at Least One Adverse Event (AE), Serious Adverse Event (SAE) or Death | Any Death | 0 Participants |
| Treatment B-Placebo + Metformin | Number of Participants With at Least One Adverse Event (AE), Serious Adverse Event (SAE) or Death | Any AE | 9 Participants |
| Treatment B-Placebo + Metformin | Number of Participants With at Least One Adverse Event (AE), Serious Adverse Event (SAE) or Death | Any SAE | 0 Participants |
| Treatment B-Placebo + Metformin | Number of Participants With at Least One Adverse Event (AE), Serious Adverse Event (SAE) or Death | Any Death | 0 Participants |
Primary
Number of Participants With the Indicated Clinical Chemistry Values of Potential Clinical Importance (PCI) at Any Time Post Baseline
The assessments were done at Day -1, Day 3, Day 8 and Follow-up under fasting condition. The following laboratory parameters of clinical chemistry were analyzed: blood urea nitrogen (BUN), creatinine, fasting triglycerides (TGs), total cholesterol, low-density lipoprotein cholesterol (LDLc), high-density lipoprotein cholesterol (HDLc), sodium, potassium, chloride, total bicarbonate, calcium, aspartate aminotransferase (AST), ALT, gamma glutamyltransferase (GGT), alkaline phosphatase, total and direct bilirubin, uric acid, albumin and total protein. Baseline was the assessment done on Day -1 (pre dose). Only those parameters for which at least one value of PCI was reported are summarized. Data is reported for participants with high glucose PCI, where the PCI value for T2DM participants was ( low \< 3.8857 millimole per liter (mmol/L); high \> 15 mmol/L; normal range was 3.61 - 5.5 mmol/L).
Time frame: Up to Follow-up (up to 53 days)
Population: Safety Population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment A-GSK2330672 + Metformin | Number of Participants With the Indicated Clinical Chemistry Values of Potential Clinical Importance (PCI) at Any Time Post Baseline | 0 Participants |
| Treatment B-Placebo + Metformin | Number of Participants With the Indicated Clinical Chemistry Values of Potential Clinical Importance (PCI) at Any Time Post Baseline | 0 Participants |
| Follow-up-Metformin | Number of Participants With the Indicated Clinical Chemistry Values of Potential Clinical Importance (PCI) at Any Time Post Baseline | 2 Participants |
Primary
Number of Participants With the Indicated Haematology Values of PCI at Any Time Post Baseline
The assessments were done at Day -1, Day 3, Day 8 and Follow-up under fasting condition. The following laboratory parameters of clinical haematology were analyzed: platelet count, red blood cells (RBC) count, absolute white blood cells (WBC) count, reticulocyte count, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), neutrophils, lymphocytes, monocytes, eosinophils and basophils. Baseline was the assessment done on Day -1 (pre dose). Only those parameters for which at least one value of PCI was reported are summarized. Data is reported for participants with high WBC counts PCI, where the PCI value for T2DM participants was (relative low : 0.5 multiplier of lower limit of normal \[LLN\]; relative high : 1.82 multiplier of upper limit of normal \[LLN\]; where normal range was 3.8 - 10.8 giga cells per liter (GI/L).
Time frame: Up to Follow-up (up to 53 days)
Population: Safety Population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment A-GSK2330672 + Metformin | Number of Participants With the Indicated Haematology Values of PCI at Any Time Post Baseline | 1 Participants |
| Treatment B-Placebo + Metformin | Number of Participants With the Indicated Haematology Values of PCI at Any Time Post Baseline | 0 Participants |
| Follow-up-Metformin | Number of Participants With the Indicated Haematology Values of PCI at Any Time Post Baseline | 0 Participants |
Primary
Number of Participants With Vital Sign Values of PCI at Any Time Post Baseline
Vital signs assessment included heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP). Assessments were completed at pre morning dose on Day 1 (Baseline), Day 3, Day 8 (before discharge) and Follow-up. Criteria for vital sign values meeting PCI for Type 2 diabetes mellitus (T2DM) included: SBP \<85 and \>160 millimeters of mercury (mmHg), DBP \<45 and \>100 mmHg and HR \<40 and \>110 beats per minute (bpm). Only those parameters for which at least one value of PCI was reported are summarized.
Time frame: Up to Follow-up (up to 53 days)
Population: Safety Population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment A-GSK2330672 + Metformin | Number of Participants With Vital Sign Values of PCI at Any Time Post Baseline | SBP | 0 Participants |
| Treatment A-GSK2330672 + Metformin | Number of Participants With Vital Sign Values of PCI at Any Time Post Baseline | HR | 1 Participants |
| Treatment B-Placebo + Metformin | Number of Participants With Vital Sign Values of PCI at Any Time Post Baseline | SBP | 1 Participants |
| Treatment B-Placebo + Metformin | Number of Participants With Vital Sign Values of PCI at Any Time Post Baseline | HR | 0 Participants |
| Follow-up-Metformin | Number of Participants With Vital Sign Values of PCI at Any Time Post Baseline | SBP | 0 Participants |
| Follow-up-Metformin | Number of Participants With Vital Sign Values of PCI at Any Time Post Baseline | HR | 0 Participants |
Secondary
AUC From Time 0 to 10 h (AUC 0-10 h) of Metformin in Presence of GSK2330672 or Placebo on Day 7
AUC(0-10) for metformin when co-dosed with GSK2330672 or placebo is defined as the the area under the plasma concentration-time curve from time 0 to 10 h. It was determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations. Blood samples were collected at 0 h (pre-dose within 15 min of dose and began eating breakfast immediately after taking study drug and finished eating in 15 min), 0.25 h, 0.50 h, 1 h, 2 h, 3 h, 4 h (pre-lunch), 5 h, 5.5 h, 6 h, 8 h and 10 h (pre-dinner) on Day 7. Analysis was done using a mixed effects model with fixed effect terms for treatment, period, and sequence. Participant within sequence was fitted as a random effect in the model.
Time frame: Pre-dose (0 h), 0.25 h, 0.50 h, 1 h, 2 h, 3 h, 4 h (pre-lunch), 5 h, 5.5 h, 6 h, 8 h and 10 h (pre-dinner) on Day 7 of each treatment period
Population: Pharmacokinetic (PK) Population was defined as participants from the safety population who had plasma metformin and or GSK2330672 PK parameter estimates from any portion of the study. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A-GSK2330672 + Metformin | AUC From Time 0 to 10 h (AUC 0-10 h) of Metformin in Presence of GSK2330672 or Placebo on Day 7 | 9189.2649 Nanogram (ng)*h/mL | Geometric Coefficient of Variation 34.08 |
| Treatment B-Placebo + Metformin | AUC From Time 0 to 10 h (AUC 0-10 h) of Metformin in Presence of GSK2330672 or Placebo on Day 7 | 9232.5372 Nanogram (ng)*h/mL | Geometric Coefficient of Variation 24.404 |
90% CI: [0.912, 1.125]
Secondary
Maximum and Weighted Mean Change From Baseline in Plasma Glucose Concentrations Over a 24 Hour (h) Period on Day 7
Baseline was defined as the time matched assessment done on Day -1. Change from baseline was calculated by subtracting the baseline (Day -1) time matched values from the post-baseline value (Day 8). Data is reported for fasting glucose level and for weighted mean and maximum values for fasting, 0-4 h, 4-10 h, 10-14 h and 0-24 h. Area under the curve (AUC) with respect to these time interval was calculated using the linear trapezoidal rule by the sum of the areas between each chronological pair of assessments (using observed times). The weighted mean was then determined by dividing the AUC by the observed length of the collection interval (time of last assessment - time of first assessment in h). Analysis was done using analysis of covariance (ANCOVA) model where, change from baseline was summation of baseline, period, sequence and treatment. Participants were fitted as a random effect.
Time frame: Baseline (Day -1) and Day 7 of each treatment period
Population: Safety Population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A-GSK2330672 + Metformin | Maximum and Weighted Mean Change From Baseline in Plasma Glucose Concentrations Over a 24 Hour (h) Period on Day 7 | Maximum (0-4 h) | 6.250 mg/deciliter | Standard Deviation 45.227 |
| Treatment A-GSK2330672 + Metformin | Maximum and Weighted Mean Change From Baseline in Plasma Glucose Concentrations Over a 24 Hour (h) Period on Day 7 | AUC (0-4 h) Weighted Mean | 6.0737 mg/deciliter | Standard Deviation 43.37336 |
| Treatment A-GSK2330672 + Metformin | Maximum and Weighted Mean Change From Baseline in Plasma Glucose Concentrations Over a 24 Hour (h) Period on Day 7 | Maximum (10-14 h) | 2.500 mg/deciliter | Standard Deviation 51.34819 |
| Treatment A-GSK2330672 + Metformin | Maximum and Weighted Mean Change From Baseline in Plasma Glucose Concentrations Over a 24 Hour (h) Period on Day 7 | AUC (4-10 h) Weighted Mean | -4.6051 mg/deciliter | Standard Deviation 43.31083 |
| Treatment A-GSK2330672 + Metformin | Maximum and Weighted Mean Change From Baseline in Plasma Glucose Concentrations Over a 24 Hour (h) Period on Day 7 | Maximum (4-10 h) | -6.583 mg/deciliter | Standard Deviation 45.4402 |
| Treatment A-GSK2330672 + Metformin | Maximum and Weighted Mean Change From Baseline in Plasma Glucose Concentrations Over a 24 Hour (h) Period on Day 7 | AUC (10-14 h) Weighted Mean | 4.4221 mg/deciliter | Standard Deviation 55.00201 |
| Treatment A-GSK2330672 + Metformin | Maximum and Weighted Mean Change From Baseline in Plasma Glucose Concentrations Over a 24 Hour (h) Period on Day 7 | Maximum (0-24 h) | 4.583 mg/deciliter | Standard Deviation 45.902 |
| Treatment A-GSK2330672 + Metformin | Maximum and Weighted Mean Change From Baseline in Plasma Glucose Concentrations Over a 24 Hour (h) Period on Day 7 | AUC (0-24 h) Weighted Mean | -2.0829 mg/deciliter | Standard Deviation 44.76645 |
| Treatment A-GSK2330672 + Metformin | Maximum and Weighted Mean Change From Baseline in Plasma Glucose Concentrations Over a 24 Hour (h) Period on Day 7 | Fasting Value | -12.325 mg/deciliter | Standard Deviation 36.1277 |
| Treatment B-Placebo + Metformin | Maximum and Weighted Mean Change From Baseline in Plasma Glucose Concentrations Over a 24 Hour (h) Period on Day 7 | AUC (0-24 h) Weighted Mean | 26.0704 mg/deciliter | Standard Deviation 40.74711 |
| Treatment B-Placebo + Metformin | Maximum and Weighted Mean Change From Baseline in Plasma Glucose Concentrations Over a 24 Hour (h) Period on Day 7 | Fasting Value | 7.479 mg/deciliter | Standard Deviation 44.6181 |
| Treatment B-Placebo + Metformin | Maximum and Weighted Mean Change From Baseline in Plasma Glucose Concentrations Over a 24 Hour (h) Period on Day 7 | Maximum (0-4 h) | 22.857 mg/deciliter | Standard Deviation 49.1307 |
| Treatment B-Placebo + Metformin | Maximum and Weighted Mean Change From Baseline in Plasma Glucose Concentrations Over a 24 Hour (h) Period on Day 7 | Maximum (4-10 h) | 29.714 mg/deciliter | Standard Deviation 42.1251 |
| Treatment B-Placebo + Metformin | Maximum and Weighted Mean Change From Baseline in Plasma Glucose Concentrations Over a 24 Hour (h) Period on Day 7 | Maximum (10-14 h) | 40.307 mg/deciliter | Standard Deviation 56.18196 |
| Treatment B-Placebo + Metformin | Maximum and Weighted Mean Change From Baseline in Plasma Glucose Concentrations Over a 24 Hour (h) Period on Day 7 | Maximum (0-24 h) | 23.071 mg/deciliter | Standard Deviation 39.6959 |
| Treatment B-Placebo + Metformin | Maximum and Weighted Mean Change From Baseline in Plasma Glucose Concentrations Over a 24 Hour (h) Period on Day 7 | AUC (0-4 h) Weighted Mean | 22.0247 mg/deciliter | Standard Deviation 46.5498 |
| Treatment B-Placebo + Metformin | Maximum and Weighted Mean Change From Baseline in Plasma Glucose Concentrations Over a 24 Hour (h) Period on Day 7 | AUC (4-10 h) Weighted Mean | 24.7262 mg/deciliter | Standard Deviation 39.21502 |
| Treatment B-Placebo + Metformin | Maximum and Weighted Mean Change From Baseline in Plasma Glucose Concentrations Over a 24 Hour (h) Period on Day 7 | AUC (10-14 h) Weighted Mean | 38.2479 mg/deciliter | Standard Deviation 51.91011 |
Comparison: Treatment A-GSK2330672 + Metformin versus Treatment B-Placebo + Metformin for Fasting Value.95% CI: [-50.4, -5.86]
Comparison: Treatment A-GSK2330672 + Metformin versus Treatment B-Placebo + Metformin for Maximum (0-4 h) Value.95% CI: [-51.68, -6.64]
Comparison: Treatment A-GSK2330672 + Metformin versus Treatment B-Placebo + Metformin for Maximum (4-10 h) Value.95% CI: [-62.25, -10.9]
Comparison: Treatment A-GSK2330672 + Metformin versus Treatment B-Placebo + Metformin for Maximum (10-14 h) Value.95% CI: [-72.8, -18.03]
Comparison: Treatment A-GSK2330672 + Metformin versus Treatment B-Placebo + Metformin for Maximum (0-24 h) Value.95% CI: [-50.84, -7.86]
Comparison: Treatment A-GSK2330672 + Metformin versus Treatment B-Placebo + Metformin for AUC (0-4 h) Weighted Mean95% CI: [-45.8, -6.49]
Comparison: Treatment A-GSK2330672 + Metformin versus Treatment B-Placebo + Metformin for AUC (4-10 h) Weighted Mean.95% CI: [-55.41, -8.58]
Comparison: Treatment A-GSK2330672 + Metformin versus Treatment B-Placebo + Metformin for AUC (10-14 h) Weighted Mean.95% CI: [-66.64, -15.29]
Comparison: Treatment A-GSK2330672 + Metformin versus Treatment B-Placebo + Metformin for AUC (0-24 h) Weighted Mean.95% CI: [-54.67, -14.85]
Secondary
Maximum Plasma Concentration of Metformin (Cmax) in Presence of GSK2330672 or Placebo on Day 7
Cmax is defined as the first occurrence of the maximum observed plasma concentration determined directly from the raw concentration-time data Blood samples were collected at 0 h (pre-dose within 15 min of dose and began eating breakfast immediately after taking study drug and finished eating in 15 min), 0.25 h, 0.50 h, 1 h, 2 h, 3 h, 4 h (pre-lunch), 5 h, 5.5 h, 6 h, 8 h and 10 h (pre-dinner) on Day 7. Analysis was done using a mixed effects model with fixed effect terms for treatment, period, and sequence. Participant within sequence was fitted as a random effect in the model.
Time frame: Pre-dose (0 h), 0.25 h, 0.50 h, 1 h, 2 h, 3 h, 4 h (pre-lunch), 5 h, 5.5 h, 6 h, 8 h and 10 h (pre-dinner) on Day 7 of each treatment period
Population: PK Population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A-GSK2330672 + Metformin | Maximum Plasma Concentration of Metformin (Cmax) in Presence of GSK2330672 or Placebo on Day 7 | 1707.1 ng/mL | Geometric Coefficient of Variation 28 |
| Treatment B-Placebo + Metformin | Maximum Plasma Concentration of Metformin (Cmax) in Presence of GSK2330672 or Placebo on Day 7 | 1638.3 ng/mL | Geometric Coefficient of Variation 25 |
90% CI: [0.937, 1.145]
Secondary
Median Time to Observed Peak Plasma Concentration (Tmax) When Co-dosed With GSK2330672 or Placebo on Day 7
Tmax is defined as the time at which Cmax is observed, determined directly from the raw concentration-time data. Blood samples were collected at 0 h (pre-dose within 15 min of dose and began eating breakfast immediately after taking study drug and finished eating in 15 min), 0.25 h, 0.50 h, 1 h, 2 h, 3 h, 4 h (pre-lunch), 5 h, 5.5 h, 6 h, 8 h and 10 h (pre-dinner) on Day 7.
Time frame: Pre-dose (0 h), 0.25 h, 0.50 h, 1 h, 2 h, 3 h, 4 h (pre-lunch), 5 h, 5.5 h, 6 h, 8 h and 10 h (pre-dinner) on Day 7 of each treatment period
Population: PK Population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment A-GSK2330672 + Metformin | Median Time to Observed Peak Plasma Concentration (Tmax) When Co-dosed With GSK2330672 or Placebo on Day 7 | 1.4583 h |
| Treatment B-Placebo + Metformin | Median Time to Observed Peak Plasma Concentration (Tmax) When Co-dosed With GSK2330672 or Placebo on Day 7 | 1.0000 h |