Clinical trial NCT01119846: A Study in Type 2 Diabetics of Single and Multiple Doses of Orally Administered GSK1292263 to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics
Official title: A Study in Type II Diabetic Subjects of Single and Multiple Doses of Orally Administered GSK1292263 to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the Compound Alone and When Co-administered With Sitagliptin or Metformin
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diabetes Mellitus, Type 2
Keywords: Tolerability
Pharmacokinetics
Safety
Pharmacodynamics
Glucose
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2010-05-10
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: OTHER

Brief 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.

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 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.

Primary outcomes:
measure: Part A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to Week 10
measure: Part A: Number of Participants With Abnormal Hematology Parameters of Potential Clinical Importance (PCI)
timeFrame: Up to Week 10
measure: Part A: Number of Participants With Abnormal Clinical Chemistry Parameters of PCI
timeFrame: Up to Week 10
measure: Part A: Number of Participants With Abnormal Electrocardiogram (ECG) Findings
timeFrame: Up to Week 10
measure: Part A: Number of Participants With Abnormal Vital Signs of PCI
timeFrame: Up to Week 10.
measure: Part A: Summary of Maximum Plasma Concentration (Cmax)
timeFrame: Pre-dose (time 0) and at 0.5, 1, 2, 3, 4, 6, 8, 14 and 24 hours on Day 1 of each treatment period
measure: Part A: Summary of Time to Maximum Concentration (T-max) and Lag Time Before Observation of Drug Concentration in Sampled Matrix (T-lag)
timeFrame: Pre-dose (time 0) and at 0.5, 1, 2, 3, 4, 6, 8, 14 and 24 hours on Day 1 of each treatment period
measure: Part A: Summary of Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC0-t) and Area Under the Concentration-time Curve From Zero (Pre-dose) to 24 Hours (AUC0-24)
timeFrame: Pre-dose (time 0) and at 0.5, 1, 2, 3, 4, 6, 8, 14 and 24 hours on Day 1 of each treatment period
measure: Part C: Number of Participants With AEs and SAEs
timeFrame: Up to Week 7
measure: Part C: Number of Participants With Abnormal Hematology Parameters of PCI
timeFrame: Up to Week 7
measure: Part C: Number of Participants With Abnormal Clinical Chemistry Parameters of PCI
timeFrame: Up to Week 7
measure: Part C: Number of Participants With Significant ECG Abnormalities
timeFrame: Up to Week 7
measure: Part C: Number of Participants With Abnormal Vital Signs of PCI
timeFrame: Up to Week 7
measure: Part C: Summary of Plasma Cmax
timeFrame: Days 1, 7, 13 and 14
measure: Part C: Summary of T-max and T-lag
timeFrame: Days 1, 7, 13 and 14
measure: Part C: Summary of AUC0-10, AUC0-12 and AUC0-24
timeFrame: Days 1, 7, 13 and 14
measure: Part C: Summary of Accumulation Ratio (Ro)
timeFrame: Days 1, 7, 13 and 14
measure: Part C: Summary of Time Invariance Ratio (Rs) of AUC0-10 for BID Dose of GSK1292263
timeFrame: Days 1, 7, 13 and 14
measure: Part C: Summary of Time Invariance Ratio (Rs) of AUC0-24 for Once Daily Dose of GSK1292263
timeFrame: Days 1, 7, 13 and 14
measure: Part C: Summary of Time Invariance Ratio (Rs) of Cmax
timeFrame: Days 1, 7, 13 and 14
measure: Part A: Relationships Between GSK1292263 Drug Exposures and Insulin Sensitivity
timeFrame: Day 1 of each treatment period
measure: Part C: Relationships Between GSK1292263 Drug Exposures and Insulin Sensitivity
timeFrame: Day -1, 13 and 14
measure: Part A: Summary of Change From Baseline in Fasted Glucose
timeFrame: Baseline (Day 1 pre-dose) and Day 1 (24 hours)
measure: Part A: Summary of the AUC 0-13, AUC 0-24, Incremental AUC (iAUC) 0-13 and iAUC 0-24 of Glucose
timeFrame: Up to Day 1 (24 hours)
measure: Part A: Summary of the AUC 0-12 and iAUC 0-12 of Glucagon, Glucagon-like Peptide (GLP; Active and Total)-1, C-peptide, Total Glucose-dependent Insulinotropic Peptide (GIP) and Total Peptide Tyrosine-tyrosine (PYY) and AUC 0-13 and iAUC 0-13 of Insulin
timeFrame: Up to Day 1 (24 hours)
measure: Part A: Summary of the OGTT AUC (0-3) and iAUC(0-3)-Glucose
timeFrame: Up to Day 1 (24 hours)
measure: Part A: Summary of the OGTT AUC (0-2) and iAUC(0-2)- C-peptide, Total GIP, GLP-1 (Active and Total), Glucagon and Total PYY and AUC 0-3 and iAUC 0-3 of Insulin
timeFrame: Up to Day 1 (24 hours)
measure: Part A: Summary of the OGTT Derived Parameters: Disposition Index
timeFrame: Up to Day 1 (24 hours)
measure: Part A: Summary of the OGTT Derived Parameters: Glucose/Insulin and Insulin/Glucose Ratio
timeFrame: Up to Day 1 (24 hours)
measure: Part A: Summary of the OGTT Derived Parameters: Insulin Glucose Index
timeFrame: Up to Day 1 (24 hours)
measure: Part A: Summary of the OGTT Derived Parameters: Insulin Sensitivity Index
timeFrame: Up to Day 1 (24 hours)
measure: Part C: Summary of Change From Baseline in Fasted Glucose
timeFrame: Baseline (Day 1 pre-dose) and Day -1, 13 and 14.
measure: Part C: Summary of Change From Baseline in Fasted Insulin
timeFrame: Baseline (Day 1 pre-dose) and Day -1, 13 and 14
Secondary outcomes:
measure: Part B: Number of Participants With AEs and SAEs
timeFrame: Up to Week 7
measure: Part B: Number of Participants With Abnormal Hematology Parameters of PCI
timeFrame: Up to Week 7
measure: Part B: Number of Participants With Abnormal Clinical Chemistry Parameters of PCI
timeFrame: Up to Week 7
measure: Part B: Number of Participants With Significant ECG Abnormalities
timeFrame: Up to Week 7
measure: Part B: Number of Participants With Abnormal Vital Signs of PCI
timeFrame: Up to Week 7
measure: Part B: Summary of Plasma Cmax
timeFrame: Pre-dose (time 0) and at 0.5, 1, 2, 3, 4, 6, 8, 13 and 24 hours on Day 1 of each treatment period.
measure: Part B: Summary of T-max and T-lag
timeFrame: Pre-dose (time 0) and at 0.5, 1, 2, 3, 4, 6, 8, 13 and 24 hours on Day 1 of each treatment period
measure: Part B: Summary of AUC0-t and AUC0-24
timeFrame: Pre-dose (time 0) and at 0.5, 1, 2, 3, 4, 6, 8, 13 and 24 hours on Day 1 of each treatment period
measure: Part B: Summary of Change From Baseline in Fasted Glucose
timeFrame: Baseline (Day 1 pre-dose) and Day 1 (24 hours)
measure: Part B: Summary of Change From Baseline in Fasted Glucagon, GLP-1, C-peptide, Total GIP, Total PYY and Insulin
timeFrame: Baseline (Day 1 pre-dose) and Day 1 (24 hours)
measure: Part C: Summary of Cmax of GSK1292263 and Sitagliptin When Co-administered
timeFrame: Days 1, 7, 13 and 14
measure: Part C: Summary of T-half and Tmax of GSK1292263 and Sitagliptin When Co-administered
timeFrame: Days 1, 7, 13 and 14
measure: Part C: Summary of AUC0-24, AUC0-t of GSK1292263 and Sitagliptin When Co-administered
timeFrame: Days 1, 7, 13 and 14
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: GSK Investigational Site
state: Arizona
city: Chula Vista
country: United States
facility: GSK Investigational Site
state: California
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Durham
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Columbus
country: United States
facility: GSK Investigational Site
state: Ohio
city: San Antonio
country: United States
facility: GSK Investigational Site
state: Texas
city: Tacoma
country: United States
facility: GSK Investigational Site
state: Washington
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Nunez DJ, Bush MA, Collins DA, McMullen SL, Gillmor D, Apseloff G, Atiee G, Corsino L, Morrow L, Feldman PL. Gut hormone pharmacology of a novel GPR119 agonist (GSK1292263), metformin, and sitagliptin in type 2 diabetes mellitus: results from two randomized studies. PLoS One. 2014 Apr 3;9(4):e92494. doi: 10.1371/journal.pone.0092494. eCollection 2014.