A Study in Type 2 Diabetics of Single and Multiple Doses of Orally Administered GSK1292263 to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01119846
First received: November 12, 2009
Last updated: March 22, 2012
Last verified: March 2012
  Purpose

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.


Condition Intervention Phase
Diabetes Mellitus, Type 2
Drug: GSK1292263
Drug: GSK1292263 matching placebo
Drug: Sitagliptin
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Official Title: A Study in Type 2 Diabetic Subjects of Single and Multiple Doses of Orally Administered GSK1292263 to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the Compound

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • To investigate in subjects with T2DM the safety and tolerability of GSK1292263 administered as single ascending (Part A) and repeat oral doses (Part C). [ Time Frame: Part A: 5 single-day doses Part C: 14-days repeat dosing ] [ Designated as safety issue: Yes ]
  • To determine the pharmacokinetic parameters of GSK1292263 in subjects with T2DM following single ascending (Part A) and repeat oral doses (Part C). [ Time Frame: Part A: 5 single-day doses Part C: 14-days repeat dosing ] [ Designated as safety issue: Yes ]
  • To evaluate in T2DM subjects the pharmacodynamic effects of GSK1292263 following single ascending doses (Part A) and repeated doses (Part C), and the pharmacokinetic/pharmacodynamic relationships. [ Time Frame: Part A: 5 single-day doses Part C: 14-days repeat dosing ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To investigate in subjects with T2DM the safety and tolerability of GSK1292263 when administered as a single dose with food (Part B). [ Time Frame: Part B: 2 single-day doses ] [ Designated as safety issue: Yes ]
  • To determine the pharmacokinetic parameters of GSK1292263 in subjects with T2DM when administered as a single dose with food (Part B). [ Time Frame: Part B: 2 single-day doses ] [ Designated as safety issue: Yes ]
  • To establish the pharmacodynamic effects of GSK1292263 in subjects with T2DM when administered as a single dose with food (Part B). [ Time Frame: Part B: 2 single-day doses ] [ Designated as safety issue: Yes ]

Enrollment: 100
Study Start Date: June 2009
Study Completion Date: March 2010
Primary Completion Date: March 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part A
Part A (Cohort 1) is a single-blind, randomized, placebo-controlled, 5-period crossover in which drug naïve T2DM subjects will receive escalating doses of GSK1292263 in each of 3 periods and placebo and open-label sitagliptin in the other 2 periods. The sequence will be randomized, but will maintain the low, medium and high dose order for GSK1292263.
Drug: GSK1292263
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.
Drug: GSK1292263 matching placebo
Matching placebo to active drug GSK1292263
Drug: Sitagliptin
Sitagliptin (Januvia) 100mg tablets are beige, round, film-coated tablets with "277" on one side.
Other Name: Januvia
Experimental: Part B
Part B (Cohort 2) is a single-blind, randomized, 2-period study in which T2DM subjects will receive a single dose of GSK1292263, fasted or fed.
Drug: GSK1292263
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.
Experimental: Part C
Part C (Cohort 3, optional Cohort 4) is a single-blind, randomized, placebo-controlled, 5-arm study of 14 days of dosing with GSK1292263, placebo or open-label sitagliptin. An optional Cohort 4 may be enrolled to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of GSK1292263 when dosed in a BID regimen.
Drug: GSK1292263
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.
Drug: GSK1292263 matching placebo
Matching placebo to active drug GSK1292263
Drug: Sitagliptin
Sitagliptin (Januvia) 100mg tablets are beige, round, film-coated tablets with "277" on one side.
Other Name: Januvia

Detailed Description:

Data from this study will be used to assess the potential of GSK1292263 as a treatment for T2DM, and will aid the design and dose selection of future studies of longer duration in T2DM subjects that will evaluate GSK1292263 alone or in combination with other anti-diabetic drugs.

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01119846

Locations
United States, Arizona
GSK Investigational Site
Phoenix, Arizona, United States, 85013
United States, California
GSK Investigational Site
Chula Vista, California, United States, 91910
United States, Florida
GSK Investigational Site
Miami, Florida, United States, 33169
United States, North Carolina
GSK Investigational Site
Durham, North Carolina, United States, 27705
United States, Ohio
GSK Investigational Site
Columbus, Ohio, United States, 43212
United States, Texas
GSK Investigational Site
San Antonio, Texas, United States, 78209
United States, Washington
GSK Investigational Site
Tacoma, Washington, United States, 98418
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided by GlaxoSmithKline

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01119846     History of Changes
Other Study ID Numbers: 111598
Study First Received: November 12, 2009
Last Updated: March 22, 2012
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
Tolerability
Pharmacokinetics
Safety
Pharmacodynamics
Glucose

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Sitagliptin
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 01, 2014