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A Study of GSK256073 in Subjects With Type 2 Diabetes Mellitus Who Are Being Treated With Metformin

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01376323
First Posted: June 20, 2011
Last Update Posted: October 11, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
GlaxoSmithKline
  Purpose
The aim of this combined, two part study is to evaluate the safety and glucose lowering effects of GSK256073 when administered to diabetic subjects for 12 weeks.

Condition Intervention Phase
Diabetes Mellitus, Type 2 Drug: GSK256073 1mg Drug: GSK256073 5mg Drug: GSK256073 10mg Drug: GSK256073 25mg Drug: Placebo Drug: Sitagliptin 100mg Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Multicenter, Two Part, Randomized, Parallel Group, Placebo and Sitagliptin Controlled Study to Evaluate the Safety and Efficacy of GSK256073 Administered Once or Twice Daily for 12 Weeks in Subjects With Type 2 Diabetes Mellitus Who Are Being Treated With Metformin

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) [ Time Frame: Up to Week 12 ]
    An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, may jeopardize the participant or require medical or surgical intervention to prevent one of the other outcomes listed in the definition above, or is an event of possible drug-induced liver injury.

  • Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) [ Time Frame: Baseline (pre-dose Day 1) and up to Week 12 ]
    Mean of triplicate measurements at each time point was considered for the summary. Baseline was defined as pre-dose of Day 1 visit. Change from Baseline was calculated by subtracting the Baseline values from the corresponding post-treatment values. It was assessed on Baseline, Day 1 (12 hours), Day 2 (pre-dose and 12 hours), Week 3, 6 (pre-dose and 12 hours), 9 and 12.

  • Change From Baseline in Heart Rate [ Time Frame: Baseline (pre-dose Day 1) and up to Week 12 ]
    Mean of triplicate measurements at each time point was considered for the summary. Baseline was defined as pre-dose of Day 1 visit. Change from Baseline was calculated by subtracting the Baseline values from the corresponding post-treatment values. It was assessed on Baseline (pre-dose Day 1), Day 1 (12 hours), Day 2, Week 3, 6, 9 and 12.

  • Number of Participants With Abnormal Electrocardiograms (ECGs) Findings [ Time Frame: Up to Week 20 ]
    Single 12-lead ECGs were obtained at each time point during the study using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and QTc intervals. It was assessed at Baseline (pre-dose Day 1), Day 2, Week 3, Week 6 and 12. Participants with normal, abnormal not clinically significant and abnormal clinically significant ECG were presented.

  • Number of Participants With Clinical Chemistry Abnormalities of Potential Clinical Importance (PCI) [ Time Frame: Up to Week 12 ]
    Clinical chemistry parameters included blood urea nitrogen (BUN), potassium, aspartate aminotransferase (AST), total bilirubin, direct bilirubin, creatinine, chloride, alanine aminotransferase (ALT), uric acid, fasting glucose, total carbon dioxide, gamma glutamyltransferase (GGT), albumin, sodium, calcium, alkaline phosphatase (ALP), total protein, creatine phosphokinase (CPK) and fasting lipid panel including total cholesterol, triglycerides, high density lipoprotein (HDL) cholesterol and low density lipoprotein (LDL) cholesterol. It was assessed on Baseline (pre-dose Day 1), Week 3 and 12. Data for parameters with high and low of PCI is provided.

  • Number of Participants With Hematology Abnormalities of Potential Clinical Importance (PCI) [ Time Frame: Up to Week 12 ]
    Hematology parameters included platelet, red blood cell (RBC) count, mean corpuscular volume (MCV), neutrophils, white blood cell (WBC) count (absolute), mean corpuscular hemoglobin (MCH), lymphocytes, reticulocyte count, mean corpuscular hemoglobin concentration (MCHC), monocytes, hemoglobin, eosinophils, hematocrit and basophils. It was assessed on Baseline (pre-dose Day 1) and 12. Data for parameters with high and low of PCI is provided.

  • Number of Participants With Abnormal Urinalysis: Glucose, Protein, Blood and Ketones by Dipstick [ Time Frame: Up to Week 12 ]
    Urinalysis parameters included glucose, protein, blood and ketones by dipstick. It was assessed on Baseline (Day -1) and 12. Urine glucose was measured as grams per deciliter (G/dL).

  • Change From Baseline in Glycated Hemoglobin (HbA1c) at Week 12 [ Time Frame: Baseline (Day -1) and up to Week 12 ]
    Blood samples for analysis of HbA1c were collected at Baseline (Day -1), Day 41, Week 9 and Week 12. Change from Baseline was calculated by subtracting the Baseline values from the corresponding post-treatment values. Baseline was defined as Day -1 visit. Statistics is provided for least square mean at Week 12.


Secondary Outcome Measures:
  • Change From Baseline in 12 Hour Non-esterified Fatty Acids (NEFA) and Glucose Weighted Mean Concentration Value at Day 2 and at Week 6 [ Time Frame: Baseline (Day 1) and up to Week 6 ]
    Change from Baseline was calculated by subtracting the Baseline values from the corresponding post-treatment values. Baseline was defined as weighted mean value at Day 1 visit. Statistics is provided for least square mean at Week 6. It was assessed on Baseline (Day 1), Day 2 and Week 6.

  • GSK256073 AUC and HbA1c at Week 12 Was Evaluated to Establish the Exposure-response Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship [ Time Frame: Up to Week 12 ]
    The relationships between drug exposure and HbA1c and relative PD endpoints of interest was planned to be plotted graphically. The data for this outcome measure was not collected.

  • Change From Baseline in Fasting Plasma Glucose at Week 12 [ Time Frame: Baseline (Day 1) and up to Week 12 ]
    Mean of triplicate measurements at pre-dose time point were considered for the summary. Change from Baseline was calculated by subtracting the Baseline values from the corresponding post-treatment values. Baseline was defined as mean of Day 1 pre-dose visit. Statistics is provided for least square mean at Week 12. It was assessed on Day 1 (pre-dose), 2 (pre-dose), Week 6 (pre-dose) and Week 12.

  • Change From Baseline in Fasting Insulin at Week 12 [ Time Frame: Baseline (Day 1) and up to Week 12 ]
    Mean of triplicate measurements at pre-dose time point were considered for the summary. Change from Baseline was calculated by subtracting the Baseline values from the corresponding post-treatment values. Baseline was defined as mean of Day 1 pre-dose visit. Statistics is provided for least square mean at Week 12. It was assessed on Day 1 (pre-dose), 2 (pre-dose), Week 6 (pre-dose) and Week 12.

  • Summary of Homeostatic Model Assessment (HOMA) Index Calculated From Change From Baseline in Fasting Insulin and Fasting Glucose at Week 12 [ Time Frame: Baseline (Day 1) and up to Week 12 ]
    Mean of triplicate measurements at pre-dose time point was considered for the summary. HOMA was calculated by multiplying insulin concentration with glucose concentration divided by 22.5. Change from Baseline for insulin and glucose was calculated by subtracting the Baseline values from the corresponding post-treatment values. Baseline was defined as mean of Day 1 pre-dose visit. Statistics is provided for least square mean. It was assessed on Day 1 (pre-dose), 2 (pre-dose), Week 6 (pre-dose) and Week 12.

  • Change From Baseline in Fructosamine at Week 6 and Week 12 [ Time Frame: Baseline (Day -1) and Week 12 ]
    Change from Baseline was calculated by subtracting the Baseline values from the corresponding post-treatment values. Baseline was defined as mean of Day -1 visit. Statistics is provided for least square mean. It was assessed on Baseline (Day -1), Day 41 and Week 12.

  • Number of Participants With HbA1c < 7.0% and < 6.5% [ Time Frame: Up to Week 12 ]
    Data has been presented for number of participants with their corresponding percentages with HbA1c <7.0% and <6.5%.


Enrollment: 92
Actual Study Start Date: July 13, 2011
Study Completion Date: September 17, 2012
Primary Completion Date: September 16, 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: GSK256073 1mg bid
GSK256073 1mg capsule taken orally twice a day
Drug: GSK256073 1mg
GSK256073 1mg capsule
Experimental: GSK256073 2mg qd
GSK256073 2 x 1mg capsule taken orally once a day
Drug: GSK256073 1mg
GSK256073 1mg capsule
Experimental: GSK256073 5mg bid
GSK256073 5mg capsule taken orally twice a day
Drug: GSK256073 5mg
GSK256073 5mg capsule
Experimental: GSK256073 10mg qd
GSK256073 2 x 5mg capsule taken orally once a day
Drug: GSK256073 5mg
GSK256073 5mg capsule
Experimental: GSK256073 10mg bid
GSK256073 10mg capsule taken orally twice a day
Drug: GSK256073 10mg
GSK256073 10mg capsule
Experimental: GSK256073 20mg qd
GSK256073 2x 10mg capsule taken orally once a day
Drug: GSK256073 10mg
GSK256073 10mg capsule
Experimental: GSK256073 25mg bid
GSK256073 25mg capsule taken orally twice a day
Drug: GSK256073 25mg
GSK256073 25mg capsule
Experimental: GSK256073 50mg qd
GSK256073 2x 25mg capsule taken orally once a day
Drug: GSK256073 25mg
GSK256073 25mg capsule
Placebo Comparator: Placebo
Matching placebo capsules taken orally either once a day or twice a day
Drug: Placebo
placebo capsule
Active Comparator: Sitagliptin 100mg qd
Commercially available Sitagliptin 100mg capsules taken once a day
Drug: Sitagliptin 100mg
Sitagliptin 100mg capsule

Detailed Description:

The study will be conducted at centers in Europe and the United States. The study is being conducted in two parts. Part A (n = 90 subjects) will provide a preliminary evaluation of 12 weeks of treatment. Initiation of part B (n = 210 additional subjects) will be dependent on the results observed in part A. The emerging data from part A will be used to guide selection of the doses in Part B. Up to 8 dose levels of GSK256073 may be included in part B. The emerging exposure response relationships from the part A interim analysis will be used to guide dose selection.

Each subject enrolled in the study will undergo screening procedures, a 2 week placebo run-in period, baseline assessments, randomization, a twelve week treatment period, and a 2 week follow-up period. Following completion of the baseline visit and randomization into the study, subjects will return to the clinic for safety and efficacy assessments at Weeks 3, 6, 9, and 12. A subject's total participation in the study will last up to approximately 20 weeks. Subjects will continue their current prescribed regimen of metformin (glucophage) monotherapy and will monitor fasting blood glucose levels daily using a glucometer.

  Eligibility

Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   20 Years to 70 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • A diagnosis of T2DM as determined by a responsible physician based on a medical evaluation including medical history, physical examination, and laboratory tests, with onset at least 6 months prior to Screening. Subjects may be entered if they have stable hypertension or dyslipidemia on therapy. Subjects with other conditions except as noted in the Exclusion criteria may be included only if the investigator and GSK medical monitor agree that the condition is unlikely to introduce additional risk factors and will not interfere with study procedures
  • HbA1c levels greater than or equal to 7.0 % and less than or equal to 9.5% at Screening
  • On monotherapy with metformin at the time of screening, and at a maximum tolerated dose greater than or equal to 1000 mg for at least 2 months prior to dosing.
  • Fasting plasma glucose level less than 13.3 mmol/L (240 mg/dL) at Screening
  • Male or female between 20 and 70 years of age, inclusive, at the time of signing the informed consent
  • Fasting Triglycerides lower than 4.52 mmol/L (400 mg/dL)
  • A female subject is able to participate is she if of non-child bearing potential
  • Male subjects must agree to use one of the contraception methods listed in the protocol. This criterion must be followed from the time of the first dose of study medication until 3 days after last dose of the study medication
  • Overweight with BMI greater than or equal to 25 kg/m2 for non-Asian Indians and greater than or equal to 24 kg/m2 for Asian-Indian, and less than 40 kg/m2
  • The subject is capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
  • Subjects in France will be eligible only if they are affiliated to or a beneficiary of a social security category
  • Subjects in other countries must meet all local and/or country-specific requirements for registration and reimbursement, as applicable

Exclusion Criteria:

  • Requiring insulin therapy or use of combination oral antidiabetic medications or use of monotherapy other than metformin within the 3 months prior to screening
  • Past or present disease (other than type 2 diabetes mellitus) that in the opinion of the Investigator may affect the outcome of this study
  • A positive pre-study Hepatitis B surface antigen, or positive Hepatitis C result within 3 months of screening
  • Renal impairment as defined by a calculated GFR less than 60 mL/min
  • Any concurrent serious illness (e.g., severe COPD, history of malignancy other than skin cancer within 5 years of initial diagnosis or with evidence of recurrence) that may interfere with a subject completing the study
  • Laboratory values as defined per protocol
  • ECG criteria as defined per protocol
  • Systolic blood pressure greater than 160 mmHg, or diastolic blood pressure greater than 100 mmHg at Screening
  • History of uric acid kidney stone, and being treated with drugs for hyperuricemia including Allopurinol or Probenecid
  • History of peptic ulcer disease (PUD) and/or other gastrointestinal bleeding within the 12 months prior to screening
  • Use of certain blood pressure medications or certain other medications that are renally excreted as defined per protocol
  • History of myopathy or CPK value greater than 3 times upper limit of normal at screening
  • The subject has participated in a clinical trial and has received an investigational product within 30 days or 5 half-lives or twice the biological effect (whichever is longer)
  • Exposure to more than four new chemical entities within 12 months prior to the first dosing day
  • Any change in diet, exercise habits or smoking status within six weeks prior to screening. Any subject that cannot refrain from smoking while in the unit must be excluded
  • History of sensitivity to any of the study medications, including sitagliptin or metformin, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation
  • The subject has a positive pre-study drug screen
  • History of regular alcohol consumption within 6 months of the study as defined per protocol
  • Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period
  • Pregnant females as determined by positive serum and/or urine hCG test at screening and prior to dosing
  • Lactating females
  • Subjects who are unwilling or unable to follow the procedures outlined in the protocol
  • Subject is mentally or legally incapacitated
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01376323


Locations
United States, Alabama
GSK Investigational Site
Anniston, Alabama, United States, 36207
United States, Florida
GSK Investigational Site
Miami, Florida, United States, 33169
GSK Investigational Site
Miramar, Florida, United States, 33025
France
GSK Investigational Site
Nantes cedex 01, France, 44093
GSK Investigational Site
Pierre-Bénite Cedex, France, 69495
GSK Investigational Site
Rennes Cedex, France, 35046
GSK Investigational Site
Rueil-Malmaison, France, 92502
Spain
GSK Investigational Site
Alicante, Spain, 03114
GSK Investigational Site
Badalona, Spain, 08916
GSK Investigational Site
Granada, Spain, 18004
GSK Investigational Site
Madrid, Spain, 28046
United Kingdom
GSK Investigational Site
Edinburgh, Midlothian, United Kingdom, EH4 2XU
GSK Investigational Site
Cambridge, United Kingdom, CB2 0GG
GSK Investigational Site
Coventry, United Kingdom, CV2 2DX
GSK Investigational Site
Newcastle upon Tyne, United Kingdom, NE1 4LP
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Additional Information:
Study Data/Documents: Statistical Analysis Plan  This link exits the ClinicalTrials.gov site
Identifier: 114728
For additional information about this study please refer to the GSK Clinical Study Register
Individual Participant Data Set  This link exits the ClinicalTrials.gov site
Identifier: 114728
For additional information about this study please refer to the GSK Clinical Study Register
Informed Consent Form  This link exits the ClinicalTrials.gov site
Identifier: 114728
For additional information about this study please refer to the GSK Clinical Study Register
Study Protocol  This link exits the ClinicalTrials.gov site
Identifier: 114728
For additional information about this study please refer to the GSK Clinical Study Register
Dataset Specification  This link exits the ClinicalTrials.gov site
Identifier: 114728
For additional information about this study please refer to the GSK Clinical Study Register
Annotated Case Report Form  This link exits the ClinicalTrials.gov site
Identifier: 114728
For additional information about this study please refer to the GSK Clinical Study Register
Clinical Study Report  This link exits the ClinicalTrials.gov site
Identifier: 114728
For additional information about this study please refer to the GSK Clinical Study Register

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01376323     History of Changes
Other Study ID Numbers: 114728
First Submitted: June 16, 2011
First Posted: June 20, 2011
Results First Submitted: August 10, 2017
Results First Posted: October 11, 2017
Last Update Posted: October 11, 2017
Last Verified: August 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
URL: http://

Keywords provided by GlaxoSmithKline:
Safety
Dose Ranging
Efficacy

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