A Study Investigating Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GSK2330672 Administered With Metformin to Type 2 Diabetes Patients

NCT02202161 | Completed Phase 2 Results

• 1 other identifier: 201351
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 4

Brief Summary

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.

Conditions

Diabetes Mellitus, Type 2

Keywords

pharmacokinetic; intestinal bile acid transporter inhibitor; metformin; sitagliptin; GSK2330672; pharmacodynamic

Outcome Measures

Primary Outcomes (15)

• 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.

  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.

  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.

  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).

  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.

  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.

  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).

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  Up to Day 15

Secondary Outcomes (8)

• PK Parameters for Metformin Steady State PK Parameters When Co-dosed With GSK2330672, Sitagliptin or Placebo-maximum Observed Concentration (Cmax)

  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)

  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])

  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

  Baseline (pre-dose Day -1) and Day 7, 14

• Ratio to Baseline in Fasting Apolipoprotein B

  Baseline (pre-dose Day -1) and Day 7, 14

Study Arms (6)

GSK2330672 10 mg

EXPERIMENTAL

Subjects will receive metformin 850 mg BID for 13-15 days during the run in period followed by GSK2330672 10 mg BID for 14 days.

Drug: GSK2330672; Drug: Metformin

GSK2330672 20 mg

EXPERIMENTAL

Subjects will receive metformin 850 mg BID for 13-15 days during the run in period followed by GSK2330672 20 mg BID for 14 days.

Drug: GSK2330672; Drug: Metformin

GSK2330672 30 mg

EXPERIMENTAL

Subjects will receive metformin 850 mg BID for 13-15 days during the run in period followed by GSK2330672 30 mg BID for 14 days.

Drug: GSK2330672; Drug: Metformin

GSK2330672 90 mg

EXPERIMENTAL

Subjects will receive metformin 850 mg BID for 13-15 days during the run in period followed by GSK2330672 90 mg BID for 14 days.

Drug: GSK2330672; Drug: Metformin

GSK2330672-matched placebo

PLACEBO COMPARATOR

Subjects will receive metformin 850 mg BID for 13-15 days during the run in period followed by matching placebo (of GSK2330672) BID for 14 days.

Drug: Placebo; Drug: Metformin

Sitagliptin 50 mg

ACTIVE COMPARATOR

Subjects will receive metformin 850 mg BID for 13-15 days during the run in period followed by Sitagliptin 50 mg BID for 14 days. In this study, sitagliptin 50 mg BID will be provided as open-label (unblinded) study treatment.

Drug: Sitagliptin; Drug: Metformin

Interventions

GSK2330672 DRUG

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

GSK2330672 10 mg; GSK2330672 20 mg; GSK2330672 30 mg; GSK2330672 90 mg

Placebo DRUG

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

GSK2330672-matched placebo

Sitagliptin DRUG

Sitagliptin will be available as film-coated tablets Tablet of 50 mg to be administered orally, BID, for 14 days

Sitagliptin 50 mg

Metformin DRUG

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

GSK2330672 10 mg; GSK2330672 20 mg; GSK2330672 30 mg; GSK2330672 90 mg; GSK2330672-matched placebo; Sitagliptin 50 mg

Eligibility Criteria

• Age: 30 Years - 64 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Male or female between 30 and 64 years of age inclusive, at the time of signing the informed consent
• Subjects with a diagnosis of T2DM for at least 3 months prior to screening, taking metformin for at least 4 weeks prior to screening, taking a metformin daily dose of\>= 1000 mg and having an Glycosolated haemoglobin A1c (HbA1c) value of 7-11% inclusive at screening. The investigator should make an effort to obtain documentation of medical history or prescription of metformin to substantiate the diagnosis of T2DM
• Fasting plasma glucose \<280 milligram per deciliter (mg/dl) at screening. A subject with a fasting plasma glucose at Day 1 that is more than 100 mg/dl lower than the screening value must not be randomized
• All T2DM subjects must meet the label recommendations for metformin and sitagliptin, including: Adequate renal function, as evidenced by an estimated glomerular filtration rate \>= 80 milliliter per minute (mL/min) using the modification of diet in renal disease (MDRD) equation or chronic kidney disease epidemiology collaboration (CKD-EPI) formula in the study procedures manual (SPM); No conditions which make hypoxia, dehydration, or sepsis likely; No cardiac disease (including no history of myocardial infarction, stroke, hospitalization for acute coronary syndrome, or heart failure)
• Body mass index (BMI) within the range 24 - 40 kilogram per meter square (kg/m\^2) (inclusive)
• Other than T2DM, subjects should be 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
• A female subject is eligible to participate if she is of non-childbearing potential defined as: Pre-menopausal females with a documented tubal ligation, bilateral oophorectomy, or hysterectomy \[for this definition, "documented" refers to the outcome of the investigator's/designee's review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records\]; OR Postmenopausal defined as 12 months of spontaneous amenorrhea. In questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 million international units (MlU)/mL and estradiol \< 40 picogram (pg)/mL (\<147 picomol per liter) is confirmatory. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods as described by the Investigator/designee, 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 2-4 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 contraception methods as described by the Investigator/designee. This criterion must be followed from the time of the first dose of study medication until the follow-up visit
• Subjects must be willing to discontinue their usual dose of metformin and take the study dose of 850 mg immediate release formulation metformin BID for the 13-15 day run-in period and the 2-week treatment period
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form

You may not qualify if:

• The use of approved non-metformin anti-diabetic agents within 3 months of the screening visit
• Hypoglycemia unawareness. T2DM subjects are excluded if, in the opinion of the investigator, they have significant hypoglycemia unawareness (for example, no symptoms of hypoglycemia when the blood glucose level is \<70 mg/dl)
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome). Subjects with a history of cholelithiasis, biliary colic, inflammatory gall bladder disease and/or cholestatic liver disease are excluded, unless this results in curative cholecystectomy 3 months or more before screening and with the approval of the GlaxoSmithKline (GSK) Medical Monitor
• 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). NOTE: Subjects with a lipase value above the upper limit of normal (ULN) at screening are excluded. A single repeat assessment is allowed within 3 days of the original test
• History of Gastrointestinal (GI) disease (e.g., irritable bowel disease, chronic or current diarrhea, inflamed bowel, steatorrhoea/fat malabsorption, celiac disease, symptomatic lactose intolerance, small bowel resection). Subjects with gastroparesis requiring treatment are excluded. Subjects with history of prolapsed or bleeding haemorrhoids within 1 month of screening are excluded unless approved by the GSK Medical Monitor
• History of autonomic neuropathy
• History of epilepsy and/or use of anti-convulsants, including but not limited to phenobarbitone, phenytoin, carbamazepine, valproate
• History of serious, severe, or unstable physical or psychiatric illness including depression, suicidal thoughts, schizophrenia, bipolar disorder, or generalized anxiety disorder. In addition to elicited symptoms and signs, this should include specific questions relating to known psychiatric diagnoses and medications used
• History of significant cardiovascular disease not covered by the label recommendations for metformin, for example, ventricular tachyarrhythmias, peripheral arterial disease, and pulmonary embolism, within the previous 12 months
• Uncontrolled hypertension, as evidenced by systolic pressure \>160 millimeters of mercury (mmHg) or diastolic pressure \>90 mmHg on a single assessment. If systolic pressure \>140 mmHg or diastolic pressure \>90 mmHg, a single repeat is allowed within 1 hour. Subjects whose blood pressure is well-controlled by taking anti-hypertensive medications (e.g., beta blockers, angiotensin converting enzyme(ACE) inhibitors, angiotensin II receptor antagonists, calcium channel blockers, and thiazide diuretics) are permitted
• History of untreated pernicious anemia or who have laboratory parameters suggestive of subclinical megaloblastic anemia (e.g., increased mean corpuscular volume \[MCV\] with low red blood cells \[RBC\] count and/or haemoglobin \[Hb\] level).
• Thyroid disease: Uncorrected Thyroid Dysfunction as 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 gram (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 (including other Dipeptidyl Peptidase-IV \[DPP-IV\] inhibitors) that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (4)

GSK Investigational Site

Chula Vista, California, 91910, United States

Location

GSK Investigational Site

Miami, Florida, 33169, United States

Location

GSK Investigational Site

Baltimore, Maryland, 21225, United States

Location

GSK Investigational Site

San Antonio, Texas, 78209, United States

Location

Related Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

3-((((3R,5R)-3-butyl-3-ethyl-7-(methyloxy)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl)methyl)amino)pentanedioic acid; Sitagliptin Phosphate; Metformin

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrazines; Biguanides; Guanidines; Amidines; Organic Chemicals

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 24, 2014
• First Posted: July 28, 2014
• Study Start: August 27, 2014
• Primary Completion: January 30, 2015
• Study Completion: January 30, 2015
• Last Updated: November 6, 2017
• Results First Posted: November 6, 2017

Record last verified: 2017-08

Data Sharing

• IPD Sharing: Will share

Locations

US (4)