This study is being conducted to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of GSK2330672 compared to sitagliptin when administered with metformin for 14 days to subjects with type 2 diabetes mellitus (T2DM). Approximately 72 male and female subjects aged 30-64 years with T2DM and currently taking metformin will be recruited for this study. Eligible subjects will begin a run-in period of 13-15 days to stabilize on metformin 850 milligram (mg) twice a day (BID). Subjects will then be randomized to GSK2330672 10 mg, 20 mg, 30 mg, 90 mg, matching placebo or open-label sitagliptin 50 mg for 14 days BID. Subjects will return for a follow-up visit 7-10 days after discharge.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
70
GSK2330672 will be available in 10 mg, 20 mg, 30 mg, and 90 mg oral solution to be administered BID for 14 days. Subjects are to drink contents of dosing bottle (45 ml) followed by 2 x 50 ml rinses of bottle and then an additional 95 ml water for a total volume of 240 ml consumed
Matching placebo will be available as oral solution to be administered for 14 days, BID. Subjects are to drink contents of dosing bottle (45 ml) followed by 2 x 50 ml rinses of bottle and then an additional 95 ml water for a total volume of 240 ml consumed
Sitagliptin will be available as film-coated tablets Tablet of 50 mg to be administered orally, BID, for 14 days
Metformin will be available as 850 mg white to off-white, film-coated tablets; to be administered BID orally during run-in through Day 14
GSK Investigational Site
Chula Vista, California, United States
GSK Investigational Site
Miami, Florida, United States
GSK Investigational Site
Baltimore, Maryland, United States
GSK Investigational Site
San Antonio, Texas, United States
Change From Baseline in Derived Plasma Glucose Parameter Over a 24-hour Period-fasting and Weighted Mean Glucose Area Under Curve (AUC[0-24 Hour])
The change from Baseline was calculated by subtracting the Baseline values from the individual post-Baseline values. Baseline was defined as pre-dose Day -1 value. It was assessed on Baseline, Day 7 and 14. Data for fasting and weighted mean (WM) AUC(0-24 hour) glucose is provided. Statistics for least square mean is provided and participants withdrawing early were excluded. Results were based on an analysis of covariance (ANCOVA) model: change from Baseline = Baseline + treatment.
Time frame: Baseline (Day -1) and Day 14 (Fasting Pre-dose [within 15 minutes of dose], 30 minutes, 1, 1.5, 2, 4 [pre-lunch], 5.5, 10 [pre-dinner], 11.5, 14 [bed time] and 24 hours) and Day 7 (30 minutes, 2, 4 [pre-lunch], 5.5, 10 [pre-dinner], 11.5, and 24 hours)
Number of Participants With Incidence and Nature of Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE was defined as any untoward medical occurrence (MO) in a participant temporally associated with the use of a medicinal product (MP), whether or not considered related to the MP and can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with its use. The SAE was any untoward MO that, at any dose, results in death, life threatening, persistent or significant disability/incapacity, results in or prolongs inpatient hospitalization, congenital abnormality or birth defect, that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition and alanine aminotransferase (ALT) \>= 3× upper limit of normal (ULN) and total bilirubin \>=2 × ULN (\>35% direct) or ALT \>=3 × ULN and international normalized ratio \>1.5.
Time frame: Up to 14 days (treatment period)
Number of Participants With Abnormal Hematology With Potential Clinical Concern (PCI)
Hematology parameters included platelet, red blood cell (RBC) count, mean corpuscular volume (MCV), neutrophils, white blood cell (WBC) count (absolute), mean corpuscular hemoglobin (MCH), lymphocytes, mean corpuscular hemoglobin concentration (MCHC), monocytes, hemoglobin, eosinophils, hematocrit and basophils. It was assessed on Baseline (pre-dose Day -1), Day 7 and 15. Data for parameters with above and below the PCI is provided.
Time frame: Up to Day 15
Number of Participants With Abnormal Clinical Chemistry With PCI
Clinical chemistry parameters included blood urea nitrogen (BUN), potassium, aspartate aminotransferase (AST), total bilirubin, direct bilirubin, creatinine, chloride, alanine aminotransferase (ALT), uric acid, fasting glucose, total carbon dioxide, gamma glutamyltransferase (GGT), albumin, sodium, calcium, alkaline phosphatase (ALP), total protein, total carbon dioxide and triglycerides. It was assessed on Baseline (pre-dose Day -1), Day 7 and 15. Data for parameters with above and below the PCI is provided. The normal range (NR) and PCI definition for abnormal parameters are: ALT (NR: 0-44, 0-32, 2-33; PCI: \>=2×upper limit of normal \[ULN\]); AST (NR: 0-40; PCI: \>=2× ULN) and total bilirubin (NR: 0.00-20.52; PCI: \>=1.5× ULN).
Time frame: Up to Day 15
Number of Participants With Abnormal Urinalysis Data
Urinalysis included urine occult blood: trace to 3+, glucose: negative to 3+, protein: negative to 2+ and ketones: trace to negative by dipstick and microscopic examination included cast, cellular cast, granular cast, hyaline cast (none seen to 1) and RBC: 0-2, 3-10, 11-30, \>30, WBC: none seen, 0-5, 1, 2, 4, \<5, 6-10, 11-30, 19, \>30). The plus sign increases with a higher level of occult blood, glucose, ketones, proteins, RBC, WBC in the urine: 1+: slightly positive, 2+: positive, 3+: high positive. Participants were categorized as none seen or 1 based on the absence or presence, respectively, of cast, cellular cast, granular cast and hyaline cast. Higher value indicates higher abnormality.
Time frame: Baseline (pre-dose Day -1), Day 7 and 15
Summary of Urinalysis Data-mean Specific Gravity
Data for mean specific gravity is provided. Specific gravity is a measure of the amount of material dissolved in the urine. Specific gravity is the ratio of the density (mass of a unit volume) of a substance to the density (mass of the same unit volume) of a reference substance. Normal urine has a specific gravity between 1.010 and 1.020.
Time frame: Baseline (pre-dose Day -1), Day 7 and 15
Summary of Urinalysis Data-mean pH
Urine pH is an acid-base measurement. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0).
Time frame: Baseline (pre-dose Day -1), Day 7 and 15
Number of Participants With Abnormal Electrocardiogram (ECG) Findings Any Time Post-Baseline
Single 12-lead ECGs was obtained at each time point during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. It was assessed on Baseline (pre-dose Day -1), Day 7 and 15. Participants with normal, abnormal not clinically significant and abnormal clinically significant ECG is presented.
Time frame: Up to Day 15
Change From Baseline in Vital Signs Assessments-temperature
The change from Baseline was calculated by subtracting the Baseline values from the individual post-Baseline values. Baseline was defined as pre-dose Day -1 value.
Time frame: Baseline (pre-dose Day -1) and, Day 7, 15
Change From Baseline in Vital Signs Assessments-systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
The change from Baseline was calculated by subtracting the Baseline values from the individual post-Baseline values. Baseline was defined as pre-dose Day -1 value.
Time frame: Baseline (pre-dose Day -1) and Day 7, 15
Change From Baseline in Vital Signs Assessments-heart Rate
The change from Baseline was calculated by subtracting the Baseline values from the individual post-Baseline values. Baseline was defined as pre-dose Day -1 value.
Time frame: Baseline (pre-dose Day -1) and Day 7, 15
Number of Bowel Movements (Stool Frequency) as Rated Using the Bristol Stool Form Scale (BSFS) Across Days 1 to 14
The site staff classified participant's stools and record the date and time of occurrence after any bowel movement that occurs while participants were in residence in the clinic. BSFS is scale between type 1-7, it measured the shape of the stool, type 1: separate hard lumps, like nuts; type 2: sausage shaped but lumpy; type 3: like a sausage or snake but with cracks on its surface; type 4: like a sausage or snake, smooth and soft; type 5: soft blobs with clear cut edges; type 6: fluffy pieces with ragged edges, a mushy stool and type 7: watery, no solid pieces. Participants were discharged after they have had at least one bowel movement after the Day 14 dosing and after the investigator/designee had reviewed the Day 15 end of study questions.
Time frame: Up to Day 15 (administered after every in-house bowel movement)
Number of Events With the Rating on Quality of Stools as Rated Using the BSFS Across Days 1 to 14
The site staff classified participant's stools and record the date and time of occurrence after any bowel movement that occurs while participants were in residence in the clinic. BSFS is scale between type 1-7, it measured the shape of the stool, type 1: separate hard lumps, like nuts; type 2: sausage shaped but lumpy; type 3: like a sausage or snake but with cracks on its surface; type 4: like a sausage or snake, smooth and soft; type 5: soft blobs with clear cut edges; type 6: fluffy pieces with ragged edges, a mushy stool and type 7: watery, no solid pieces. Participants were discharged after they have had at least one bowel movement after the Day 14 dosing and after the investigator/designee had reviewed the Day 15 end of study questions.
Time frame: Up to Day 15 (administered after every in-house bowel movement)
Number of Participants With Gastrointestinal Tolerability Assessments as Rated Using the Gastrointestinal Symptom Rating Scale (GSRS; With Worsening Symptoms >=2 Levels)
GSRS is a rating scale consisting of 15 items. Each item was scored from 1: no discomfort at all, 2: minor discomfort, 3: mild discomfort, 4: moderate discomfort, 5: moderately severe discomfort, 6: severe discomfort, 7: very severe discomfort. The overall GSRS score is the mean of these 15 items, varying from 1 to 7; a score of 1 indicates that no symptoms are present, and a score of 7 indicates the worst possible degree of all symptoms. A higher score relative to Baseline indicates worsening of severity. There were 5 defined syndrome scores and 1 overall score that was derived by computing the mean of the scores for specific subsets of questions as indicated below: abdominal pain (1, 4, 5); reflux syndrome (2, 3); diarrhea syndrome (11, 12, 14); indigestion syndrome (6, 7, 8, 9); constipation syndrome (10, 13, 15) and overall GSRS (1-15). The data is presented for participants with worsening of symptoms in \>=2 levels.
Time frame: Day 7 and 14
Number of Participants With Fecal Occult Blood Monitoring for Symptomatic or Visible Gastrointestinal Bleeding or Asymptomatic Occult Bleeding
Testing cards were provided to participants for assessments. Participants with abnormal not clinically significant and abnormal clinically significant is presented. The Day -1 sample was obtained any time starting Day -2 and prior to GSK2330672 dosing on Day 1. The Day 14 sample was collected any time after dosing on Day 14 and prior to discharge on Day 15.
Time frame: Up to Day 15
PK Parameters for Metformin Steady State PK Parameters When Co-dosed With GSK2330672, Sitagliptin or Placebo-maximum Observed Concentration (Cmax)
The first occurrence of the maximum observed plasma concentration determined directly from the raw concentration-time data. Statistics for geometric least square mean provided.
Time frame: Fasting pre-dose (within 15 minutes of dose), 30 minutes, 1, 1.5, 2, 3, 4 (pre-lunch), 5.5, 8, 10 hours (pre-dinner) on Day 14
PK Parameters for Metformin Steady State PK Parameters When Co-dosed With GSK2330672, Sitagliptin or Placebo-time of Occurrence of Cmax (Tmax)
The time at which Cmax observed was determined directly from the raw concentration-time data.
Time frame: Fasting pre-dose (within 15 minutes of dose), 30 minutes, 1, 1.5, 2, 3, 4 (pre-lunch), 5.5, 8, 10 hours (pre-dinner) on Day 14
PK Parameters for Metformin Steady State PK Parameters When Co-dosed With GSK2330672, Sitagliptin or Placebo-area Under the Concentration-time Curve Over the Dosing Interval of 10 Hours (AUC[0-10])
PK population. Only those participants available at the specified time points were analyzed.
Time frame: Fasting pre-dose (within 15 minutes of dose), 30 minutes, 1, 1.5, 2, 3, 4 (pre-lunch), 5.5, 8, 10 hours (pre-dinner) on Day 14
Ratio to Baseline in Fasting Low-density Cholesterol (LDL) Cholesterol, High-density Cholesterol (HDL) Cholesterol, Total Cholesterol, Non-HDL Cholesterol and Triglycerides
Data for fasting low-density cholesterol (LDL) cholesterol, high-density cholesterol (HDL) cholesterol, total cholesterol, non-HDL cholesterol and triglycerides is presented. Participants withdrawing early were excluded. Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.
Time frame: Baseline (pre-dose Day -1) and Day 7, 14
Ratio to Baseline in Fasting Apolipoprotein B
Data for fasting apolipoprotein B is presented. Participants withdrawing early were excluded. Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.
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Time frame: Baseline (pre-dose Day -1) and Day 7, 14
Sitagliptin Steady State PK Parameters When Co-dosed With Metformin-Cmax Following the First and Second Sitagliptin Doses
The first occurrence of the maximum observed plasma concentration determined directly from the raw concentration-time data following the first and second dose of sitagliptin on Day 14 (Cmax1 and Cmax2).
Time frame: Fasting pre-dose (within 15 minutes of dose), 1, 2, 3, 4 (pre-lunch), 10 (pre-dinner), 13 and 14 hours (bed time) on Day 14
Sitagliptin Steady State PK Parameters When Co-dosed With Metformin-Tmax Following the First and Second Sitagliptin Doses
The time at which Cmax was observed by determining directly from the raw concentration-time data following the first and second dose of sitagliptin on Day 14 (Tmax1 and Tmax2). If data permits, Tmax2 was defined as the time of Cmax following the second dose of sitagliptin.
Time frame: Fasting pre-dose (within 15 minutes of dose), 1, 2, 3, 4 (pre-lunch), 10 (pre-dinner), 13 and 14 hours (bed time) on Day 14
Sitagliptin Steady State PK Parameters When Co-dosed With Metformin-AUC(0-10)
The AUC(0-10) following the first dose and prior to the second dose of sitagliptin was determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations.
Time frame: Fasting pre-dose (within 15 minutes of dose), 1, 2, 3, 4 (pre-lunch), 10 (pre-dinner) on Day 14