A Study in Type 2 Diabetics of Single and Multiple Doses of Orally Administered GSK1292263 to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics
Condition: Diabetes Mellitus, Type 2
MeSH terms: Diabetes Mellitus, Type 2
Intervention: GSK1292263; GSK1292263 matching placebo; Sitagliptin
Intervention description: GSK1292263 is an immediate-release round, white, film-coated tablet provided in 3 strengths, 25mg, 75mg and 200mg being developed for the treatment of type 2 diabetes.; Matching placebo to active drug GSK1292263; Sitagliptin (Januvia) 100mg tablets are beige, round, film-coated tablets with "277" on one side.
Intervention MeSH terms: Sitagliptin Phosphate
Phase: Phase 2
Study type: Interventional
Primary purpose: Other
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Enrollment: 100.0
Sex: All
Minimum age: 18 Years
Maximum age: 60 Years
Healthy volunteers: No
Keywords: Tolerability; Pharmacokinetics; Safety; Pharmacodynamics; Glucose

Summary:

      The purpose of this study is to see if GSK1292263 is safe and well-tolerated when
      administered to type 2 diabetics, and to get preliminary information about whether it may be
      effective in the treatment of type 2 diabetes.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male or female subjects, 18 - 60 years of age, inclusive, at the time of signing the
             informed consent.

          -  A female subject is eligible to participate if she is of non-childbearing potential,
             defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or
             postmenopausal defined as 12 months of spontaneous amenorrhea. FSH and estradiol
             levels will be checked at Screening for postmenopausal women. Simultaneous follicle
             stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40pg/ml (<140pmol/L) is
             confirmatory.

          -  Except as noted elsewhere, subjects should have no significant known medical
             conditions other than T2DM, as determined by a responsible physician, based on a
             medical evaluation including medical history, physical examination, laboratory tests
             and ECGs. A subject with a clinical abnormality or laboratory parameters that meets
             exclusion criteria but is outside the reference range for the population being studied
             may be included only if the Investigator and the GSK Medical Monitor agree that the
             finding is unlikely to introduce additional risk factors and will not interfere with
             the study procedures.

          -  BMI (body mass index) within the range 22-35 kg/m2, inclusive.

          -  Part A - T2DM diagnosed by American Diabetes Association criteria at least 3 months
             prior to Screening with:

          -  Currently controlled by diet and exercise.

          -  Fasting plasma glucose (FPG) level <= 250mg/dL at the Screening visit

          -  FPG level <= 250mg/dL on Day -1

          -  HbA1c between 6.5 and 11%, inclusive, at Screening visit

          -  For Parts B and C, T2DM diagnosed by American Diabetes Association criteria at least 3
             months prior to Screening with:

          -  T2DM currently controlled by diet and exercise, or, if on medication, subjects must be
             treating their T2DM using one of the following regimens:

          -  Metformin as monotherapy

          -  Sulfonylurea as monotherapy

          -  Metformin and sulfonylurea in combination, if both components are being administered
             at doses that are half their maximum dose or less

          -  DPP-IV inhibitors, either as monotherapy or in combination with other agent(s) on this
             list at half maximal dose or less

          -  Exenatide, either as monotherapy or in combination with other agent(s) on this list at
             half maximal dose or less

          -  For subjects that are being screened for Parts B and C, all doses of anti-diabetic
             medication must have been stable for at least 3 months prior to Screening, and the
             subject must be willing to wash out from their anti-diabetic medications from Day -7
             through post-last-dose of Period 2 (Part B) or Day -7 through Day 15 (Part C).

          -  Fasting plasma glucose (FPG) level <= 220mg/dL at the Screening visit

          -  FPG level <= 250mg/dL on Day -1

          -  HbA1c between 7 and 11%, inclusive, at Screening visit

          -  Capable of giving written informed consent, which includes compliance with the
             requirements and restrictions listed in the consent form.

        Exclusion Criteria:

          -  Has any of the following laboratory abnormalities:

          -  Positive pre-study Hepatitis B surface antigen or positive Hepatitis C, result within
             3 months of screening.

          -  Positive test for HIV antibody.

          -  History of uncorrected thyroid dysfunction or an abnormal thyroid function test
             assessed by TSH at Screening. (NOTE: subjects with hypothyroidism on a stable dose of
             thyroid replacement therapy for at least 3 months prior to Screening and who have a
             screening thyroid stimulating hormone (TSH) within the normal range may participate.)

          -  ALT and/or AST > 2 times the upper limit of normal at screening.

          -  Fasting triglycerides > 450mg/dL at screening.

          -  Total Bilirubin > 1.5 times the upper limit of normal at screening.

          -  For females a haemoglobin < 11.5 g/dL, and for males a hemoglobin < 12.5 g/dL.
             Hemoglobin < 11g/dL(A female subject with haemoglobin between 10g/dL and 11.5 g/dL, or
             a male subject with haemoglobin between 10g/dL and 12.5 g/dLmay be enrolled only if
             the Investigator and the GSK Medical Monitor agree that the finding is unlikely to
             introduce additional risk to the subject and will not interfere with the study
             procedures).

          -  A positive pre-study drug/urine screen. A minimum list of drugs that will be screened
             for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and
             benzodiazepines.

          -  A pre-study urine cotinine screen indicating use of tobacco/ nicotine containing
             products.

          -  If female is pregnant or has a positive pregnancy test

          -  Significant renal disease as manifested by one or more of the following:

          -  Creatinine clearance <60mL/min. (estimated from serum creatinine (SCr) and demographic
             data using the MDRD calculation):

          -  To calculate estimated GFR (mL/min/1.73m2) manually:

        =186 x (SCr in mg/dL)-1.154 x (age)-0.203 x (0.742 if female) x (1.210 if African-American)
        =exp (5.228-1.154 x ln (SCr)-0.203x ln(age)-(0.299 if female) + (0.192 if African
        American)) (A link to a validated MDRD calculator on the internet is provided in the SRM.)

          -  Urine protein/creatinine (mg of protein/mg of creatinine) ratio >2.5; or urine albumin
             concentration >300mg/g of creatinine).

          -  Known loss of a kidney either by surgical ablation, injury, or disease.

          -  Significant ECG abnormalities, defined as follows:

        Heart Rate < 50 and >100bpm PR Interval <120 and > 220ms QRS duration < 70 and >120ms QTC
        Interval (Bazett)* > 450ms

        Or, has clinically significant rhythm abnormalities identified during 24-hour Screening
        Holter assessment. Subjects with Left Bundle Branch Block are excluded from the study.
        Subjects with partial Right Bundle Branch Block may be considered for inclusion following
        consultation with the GSK Medical Monitor. Subjects with WPW syndrome are excluded from the
        study.

        *Note that if ECG abnormalities are identified, the ECG should be repeated two more times
        (with 5 minutes between ECG readings) and the average of the 3 values used to determine
        eligibility.

          -  Systolic pressure > 150mmHg or <80mmHg or diastolic blood pressure > 95mmHg or <60mmHg
             at screening. Blood pressure assessments may be repeated once if needed, allowing
             adequate time for subject to rest.

          -  Previous use of insulin as a treatment within 3 months of Screening, or for >2 weeks
             when used for acute illness in the last 12 months prior to Screening, or if used for
             more than 1 year when associated with gestational diabetes mellitus.

          -  Has a history of any of the following conditions:

          -  Clinically significant symptoms of gastroparesis

          -  Cholelithiasis or obstructive or inflammatory gallbladder disease within 3 months
             prior to Screening

          -  Gastrointestinal disease that could affect fat or bile acid absorption, including
             inflammatory bowel disease, chronic diarrhea, Crohn's or malabsorption syndromes
             within the past year

          -  Gastrointestinal surgery

          -  Chronic or acute pancreatitis

          -  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 (360mL) of beer, 5 ounces (150mL) of wine
             or 1.5 ounces (45mL) of 80 proof distilled spirits.

          -  Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or
             nicotine-containing products within 6 months prior to screening.

          -  Has participated in a clinical trial and has received a drug or a new chemical entity
             within 30 days or 5 half-lives, or twice the duration of the biological effect of any
             drug (whichever is longer) prior to the first dose of current study medication.

          -  Exposure to more than four new chemical entities within 12 months prior to the first
             dosing day.

          -  Is taking prohibited medications. See Section 9.3 for a detailed list of prohibited
             medications. Note also:

          -  The use of anti-diabetic agents other than those listed in Inclusion #7 is reason for
             exclusion and subjects will not be allowed to wash off of unapproved anti-diabetic
             medications in order to qualify for participation in this study.

          -  Subjects must wash out from the following medications during the 7-day period prior to
             first dose, and must remain off these medications through discharge on post-last-dose
             of Period 2 (Part B) or Day 15 (Part C): all anti-diabetic medications specified in
             Inclusion #7, all statin agents, fat absorption blocking agents, bile acid
             sequestrants. Fibrates must be washed out for a 14-day period prior to first dose.

          -  Vitamins, herbal and dietary supplements (including St John's Wort) are prohibited
             within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study
             medication and through discharge.

          -  Unwilling to abstain from

          -  Caffeine-or xanthine-containing products for 24 hours prior to dosing until
             post-last-dose of Period 5 (Part A), post-last-dose of Period 2 (Part B) or Day -7
             through Day 15 (Part C).

          -  Use of illicit drugs or nicotine-containing products

          -  Alcohol for 24 hours prior to dosing until post-last-dose of Period 5 (Part A),
             post-last-dose of Period 2 (Part B) or Day -7 through Day 15 (Part C).

          -  Consumption of red wine, Seville oranges, grapefruit or grapefruit juice from 7 days
             prior to the first dose of study medication until collection of the final
             pharmacokinetic blood samples.

          -  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 physician responsible,
             contraindicates their participation. This includes sensitivity to heparin or
             heparin-induced thrombocytopenia, if heparin will be used to maintain catheter
             patency.

          -  Where participation in the study would result in donation of blood in excess of
             approximately 500mL within a 56 day period.

          -  Subject is either an immediate family member of a participating investigator, study
             coordinator, employee of an investigator; or is a member of the staff conducting the
             study.

          -  Unwillingness or inability to follow the procedures outlined in the protocol.

          -  Subject is mentally or legally incapacitated.