A Study Investigating Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GSK2330672 Administered With Metformin to Type 2 Diabetes Patients
Condition: Diabetes Mellitus, Type 2
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: GSK2330672; Placebo; Sitagliptin; Metformin
Intervention description: 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
Intervention MeSH terms: Metformin; Sitagliptin Phosphate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 70.0
Sex: All
Minimum age: 30 Years
Maximum age: 64 Years
Healthy volunteers: No
Keywords: pharmacokinetic; intestinal bile acid transporter inhibitor; metformin; sitagliptin; GSK2330672; pharmacodynamic

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