Clinical trial NCT02202161: A Study Investigating Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GSK2330672 Administered With Metformin to Type 2 Diabetes Patients
Official title: A Randomized, Placebo Controlled, Repeat Dose, Double Blind (Sponsor Unblind) Study Investigating Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GSK2330672 Administered With Metformin to Type 2 Diabetes Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diabetes Mellitus, Type 2
Keywords: pharmacokinetic
intestinal bile acid transporter inhibitor
metformin
sitagliptin
GSK2330672
pharmacodynamic
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2014-07-28
Enrollment: 70
Sex: ALL
Minimum age (years): 30
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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
* 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
* Alanine aminotransferase (ALT)\>2xULN and bilirubin \>1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%)
* Fasting triglycerides \>= 400 mg/dl for subjects without a history of pancreatitis or \>250 mg/dl for subjects with a history of 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). Subjects taking statins, ezetimibe, or Vytorin are permitted in the study. Subjects taking other lipid therapies, including but not limited to niacin, bile acid sequestrants and/or fibrates are not eligible
* C-peptide of \<0.8 nanogram (ng)/mL at screening
* Urine albumin-to-creatinine ratio \>0.3 mg albumin/mg creatinine
* Positive fecal occult blood test at screening or during the run-in period
* Significant ECG abnormalities, defined as follows: Heart Rate (resting) was \<50 and \>100 beats per minute (bpm); PR Interval between \<120 and \>220 millisecond (msec); QRS duration between \<70 and \>120 msec
* Based on averaged QTcF of triplicate ECGs obtained at least 1 minute apart within approximately 15 minutes: QT duration corrected for heart rate by Fridericia's formula (QTcF) \>= 450 msec; OR QTcF \>= 480 msec in subjects with right 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 HIV antibody
* A positive urine drug screen or alcohol breath test at screening or during the run-in or treatment periods
* 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-clinic treatment period of the study
* 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
* Subjects who have participated in a previous study with GSK2330672 are excluded
* Because of the potential impact on bile acid synthesis and secretion in the liver, use of rifampicin and/or other pregnane X receptor (PXR) inducers, including but not limited to St. John's Wort, is cause for subject exclusion

Primary outcomes:
measure: 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])
timeFrame: 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)
measure: Number of Participants With Incidence and Nature of Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to 14 days (treatment period)
measure: Number of Participants With Abnormal Hematology With Potential Clinical Concern (PCI)
timeFrame: Up to Day 15
measure: Number of Participants With Abnormal Clinical Chemistry With PCI
timeFrame: Up to Day 15
measure: Number of Participants With Abnormal Urinalysis Data
timeFrame: Baseline (pre-dose Day -1), Day 7 and 15
measure: Summary of Urinalysis Data-mean Specific Gravity
timeFrame: Baseline (pre-dose Day -1), Day 7 and 15
measure: Summary of Urinalysis Data-mean pH
timeFrame: Baseline (pre-dose Day -1), Day 7 and 15
measure: Number of Participants With Abnormal Electrocardiogram (ECG) Findings Any Time Post-Baseline
timeFrame: Up to Day 15
measure: Change From Baseline in Vital Signs Assessments-temperature
timeFrame: Baseline (pre-dose Day -1) and, Day 7, 15
measure: Change From Baseline in Vital Signs Assessments-systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Baseline (pre-dose Day -1) and Day 7, 15
measure: Change From Baseline in Vital Signs Assessments-heart Rate
timeFrame: Baseline (pre-dose Day -1) and Day 7, 15
measure: Number of Bowel Movements (Stool Frequency) as Rated Using the Bristol Stool Form Scale (BSFS) Across Days 1 to 14
timeFrame: Up to Day 15 (administered after every in-house bowel movement)
measure: Number of Events With the Rating on Quality of Stools as Rated Using the BSFS Across Days 1 to 14
timeFrame: Up to Day 15 (administered after every in-house bowel movement)
measure: Number of Participants With Gastrointestinal Tolerability Assessments as Rated Using the Gastrointestinal Symptom Rating Scale (GSRS; With Worsening Symptoms >=2 Levels)
timeFrame: Day 7 and 14
measure: Number of Participants With Fecal Occult Blood Monitoring for Symptomatic or Visible Gastrointestinal Bleeding or Asymptomatic Occult Bleeding
timeFrame: Up to Day 15
Secondary outcomes:
measure: PK Parameters for Metformin Steady State PK Parameters When Co-dosed With GSK2330672, Sitagliptin or Placebo-maximum Observed Concentration (Cmax)
timeFrame: 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
measure: PK Parameters for Metformin Steady State PK Parameters When Co-dosed With GSK2330672, Sitagliptin or Placebo-time of Occurrence of Cmax (Tmax)
timeFrame: 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
measure: 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])
timeFrame: 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
measure: Ratio to Baseline in Fasting Low-density Cholesterol (LDL) Cholesterol, High-density Cholesterol (HDL) Cholesterol, Total Cholesterol, Non-HDL Cholesterol and Triglycerides
timeFrame: Baseline (pre-dose Day -1) and Day 7, 14
measure: Ratio to Baseline in Fasting Apolipoprotein B
timeFrame: Baseline (pre-dose Day -1) and Day 7, 14
measure: Sitagliptin Steady State PK Parameters When Co-dosed With Metformin-Cmax Following the First and Second Sitagliptin Doses
timeFrame: 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
measure: Sitagliptin Steady State PK Parameters When Co-dosed With Metformin-Tmax Following the First and Second Sitagliptin Doses
timeFrame: 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
measure: Sitagliptin Steady State PK Parameters When Co-dosed With Metformin-AUC(0-10)
timeFrame: Fasting pre-dose (within 15 minutes of dose), 1, 2, 3, 4 (pre-lunch), 10 (pre-dinner) on Day 14
Other outcomes:
Locations:
city: Chula Vista
country: United States
facility: GSK Investigational Site
state: California
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Baltimore
country: United States
facility: GSK Investigational Site
state: Maryland
city: San Antonio
country: United States
facility: GSK Investigational Site
state: Texas
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: