To Investigate the Safety, Tolerability and Pharmacodynamics of GSK2890457 in Healthy Volunteers and Subjects With Type 2 Diabetes | RxWiki

To Investigate the Safety, Tolerability and Pharmacodynamics of GSK2890457 in Healthy Volunteers and Subjects With Type 2 Diabetes

Overview[ - collapse ][ - ]

Purpose	This study is the first administration of GSK2890457 in humans. The study will be conducted in 3 parts: - Part A (conducted at a single investigative site) will determine the safety and tolerability of GSK2890457 alone in healthy subjects during six weeks of dosing, as well as evaluating the potential for a pharmacokinetic interaction with metformin. Part A consists of Screening, Treatment (6 weeks) and Follow-up periods. - Part B (conducted at multiple sites) will determine safety, tolerability, and pharmacodynamics (PD) in subjects with Type 2 diabetes (T2D) when co-dosed for six weeks with liraglutide (Victoza). Part B consists of Screening, Run-in (1 week), Stabilization (12 weeks), Treatment (6 weeks) and Follow-up periods. - Part C (conducted at multiple sites) will determine safety, tolerability, and PD in subjects with T2D when co-dosed for 6 weeks with metformin. Part C consists of Screening, Run-in (1 week), Stabilization (12 weeks), Treatment (6 weeks) and Follow-up periods.
Condition	Obesity
Intervention	Drug: GSK2890457 Drug: Metformin Drug: Placebo Drug: Liraglutide
Phase	Phase 2
Sponsor	GlaxoSmithKline
Responsible Party	GlaxoSmithKline
ClinicalTrials.gov Identifier	NCT01725126
First Received	November 8, 2012
Last Updated	February 14, 2014
Last verified	November 2013

Tracking Information[ + expand ][ + ]

First Received Date	November 8, 2012
Last Updated Date	February 14, 2014
Start Date	February 2013
Estimated Primary Completion Date	September 2013
Current Primary Outcome Measures	Safety and tolerability of GSK2890457 as assessed by number of adverse events (AE)s [Time Frame: Part A - 8 Weeks. Part B - 20 Weeks. Part C - 12 Weeks] [Designated as safety issue: No]Safety and tolerability parameters will include recording of AEs. In Part A, AEs will be collected from the start of dosing until the Follow-up Visit. In Parts B and C, AEs will be collected from the start of the Stabilization Period until the Follow-up Visit Safety and tolerability of GSK2890457 as assessed by change from Baseline in laboratory values [Time Frame: Part A - Day 1, Day 7, Day 14, Day 28, Day 42. Part B & Part C - Days 1, 7, 14, 28 and 42] [Designated as safety issue: No]Safety and tolerability parameters will include determination of laboratory (clinical chemistry, urinalysis, fasting blood glucose and hematological parameters) values Safety and tolerability of GSK2890457 as assessed by change from Baseline in ECG readings [Time Frame: Part A, Baseline (Day 1) and Day 42 . For Parts B and C, Screening, Baseline (Day 1), Day 42 and Follow-up] [Designated as safety issue: No]ECGs Tolerability of GSK2890457 as assessed by change in gastrointestinal (GI) Symptoms Rating Scale (GSRS) [Time Frame: Part A - Day 1 (Baseline) and Day 7 and Day14 and Day 42. Parts B: Stabilization Period (SP) Weeks 1 and 7, Treatment Period (TP) Days -2, 7, 14, 28 and 41. Part C: SP Weeks 1 and 3, TP Days -2, 7, 14, 28 and 41.] [Designated as safety issue: No]A rating scale for gastrointestinal symptoms in patients Change in body weight from baseline to end of treatment [Time Frame: Part A - Screening (S), Day 1, Day 7, Day 14, Day 28, Day 42 and Day 56. Part B - S, Day -1, Day 1, Day 7, Day 14, Day 28, Day 42, Day 43 and Day 56 of Treatment Period (TP). Part C - Day -1, Day 1, Day 7, Day 14, Day 28, Day 42, Day 43 of TP & Followup] [Designated as safety issue: No]Change from baseline body weight will be analyzed using appropriate repeated measures analysis of covariance models. Differences in least squares means between the GSK2890457 treated groups and placebo will be calculated Percentage change in body weight from baseline to end of treatment [Time Frame: Part A - Screening (S), Day 1, Day 7, Day 14, Day 28, Day 42 and Day 56 Part B - S, Day -1, Day 1, Day 7, Day 14, Day 28, Day 42, Day 43 and Day 56 of Treatment Period (TP) Part C - Day -1, Day 1, Day 7, Day 14, Day 28, Day 42, Day 43 of TP and Follow-up] [Designated as safety issue: No]Change from baseline and % change from baseline body weight will be analyzed using appropriate repeated measures analysis of covariance models Differences in least squares means between the GSK2890457 treated groups and placebo will be calculated Rate of weight change [Time Frame: Part A - Screening, Day 1, Day 7, Day 14, Day 28, Day 42 and Day 56 Part B & Part C - Day -1 through Day 56] [Designated as safety issue: No]The rate of weight change (slope) will be compared between the GSK2890457 treated subjects and the placebo treated subjects Area under the curve weighted mean AUCs (0 to 24 hours) for glucose [Time Frame: Part B and Part C - Day -1 and Day 42.] [Designated as safety issue: No]On Days -1 and 42, in subjects with T2D (Parts B and C) Fasting plasma glucose [Time Frame: Part A - Day 1 (predose), Days 7, 14, 28 and 42. Part B & C - Day -2 through Day 56] [Designated as safety issue: No] Fasting plasma glucose and insulin [Time Frame: Part B and Part C - from Day -1 through Day 56 (Follow-up)] [Designated as safety issue: No] Insulin resistance/sensitivity [Time Frame: Part B and Part C - from Day -1 through Day 56 (Follow-up)] [Designated as safety issue: No]HOMA and Matsuda index measures Area under the curve weighted mean AUCs (0 to 4 hours) for glucose and insulin [Time Frame: Parts B and Part C - Day - 1 and Day 42] [Designated as safety issue: No]On Days -1 and 42 in subjects with T2D (Parts B and C). Change form Baseline in HbA1c [Time Frame: Parts B & C - Day -1 and Day 42] [Designated as safety issue: No]Change from baseline HbA1c will be analyzed using an ANCOVA model. Differences in least squares means between the GSK2890457 treated groups and placebo will be reported
Current Secondary Outcome Measures	Area under the curve at steady state (AUCss) of liraglutide (Part B) and metformin (Parts A and C) [Time Frame: Parts A, B and C - Days 1 and Day 42] [Designated as safety issue: No] Maximum concentration (Cmax) of liraglutide (Part B) and metformin (Parts A and C) [Time Frame: Parts A, B and C - Days 1 and Day 42] [Designated as safety issue: No] Time of occurrence of Cmax of liraglutide (Part B) and metformin (Parts A and C) [Time Frame: Parts A, B and C - Days 1 and Day 42] [Designated as safety issue: No]

Descriptive Information[ + expand ][ + ]

Brief Title	To Investigate the Safety, Tolerability and Pharmacodynamics of GSK2890457 in Healthy Volunteers and Subjects With Type 2 Diabetes
Official Title	A Double-blind [Sponsor Unblinded], Randomized, Placebo-controlled, Staggered-parallel Study to Investigate the Safety, Tolerability, and Pharmacodynamics of GSK2890457 in Healthy Volunteers and Subjects With Type 2 Diabetes
Brief Summary	This study is the first administration of GSK2890457 in humans. The study will be conducted in 3 parts: - Part A (conducted at a single investigative site) will determine the safety and tolerability of GSK2890457 alone in healthy subjects during six weeks of dosing, as well as evaluating the potential for a pharmacokinetic interaction with metformin. Part A consists of Screening, Treatment (6 weeks) and Follow-up periods. - Part B (conducted at multiple sites) will determine safety, tolerability, and pharmacodynamics (PD) in subjects with Type 2 diabetes (T2D) when co-dosed for six weeks with liraglutide (Victoza). Part B consists of Screening, Run-in (1 week), Stabilization (12 weeks), Treatment (6 weeks) and Follow-up periods. - Part C (conducted at multiple sites) will determine safety, tolerability, and PD in subjects with T2D when co-dosed for 6 weeks with metformin. Part C consists of Screening, Run-in (1 week), Stabilization (12 weeks), Treatment (6 weeks) and Follow-up periods.
Detailed Description	Not Provided
Study Type	Interventional
Study Phase	Phase 2
Study Design	Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment
Condition	Obesity
Intervention	Drug: GSK2890457 Provided as powder and capsule. Drug: Metformin Tablet Part A: Single doses on Day 1 and Day 42 orally Part B: Subject continues usual metformin dose through Run-in, and resumes after Treatment Period completed Part C: Subject continues usual metformin dose throughout study Drug: Placebo Provided as powder and Capsule. Drug: Liraglutide Provided as Injection. 6mg/mL, 3mL injector pen that permits doses of 0.6mg, 1.2mg, and 1.8mg Subcutaneous injection 18 weeks dosing (Stabilization and Treatment Periods, Part B only Other Names: Victoza
Study Arm (s)	Experimental: Part A - GSK2890457 Subjects will titrate up from a maximially tolerated dose over a 7-day period. Treatment Period is 6 weeks Experimental: Part B - GSK2890457 + Liraglutide Subjects will titrate up from a maximially tolerated dose over a 7-day period. Treatment Period is 6 weeks Experimental: Part C - GSK2890457 + Metformin Subjects will titrate up from a maximially tolerated dose over a 7-day period. Treatment Period is 6 weeks Placebo Comparator: Part A - Placebo Subjects will titrate up from a maximially tolerated dose over a 7-day period. Treatment Period is 6 weeks Placebo Comparator: Part B - Placebo Subjects will titrate up from a maximially tolerated dose over a 7-day period. Treatment Period is 6 weeks Placebo Comparator: Part C - Placebo Subjects will titrate up from a maximially tolerated dose over a 7-day period. Treatment Period is 6 weeks

Recruitment Information[ + expand ][ + ]

Recruitment Status	Completed
Estimated Enrollment	53
Estimated Completion Date	September 2013
Estimated Primary Completion Date	September 2013
Eligibility Criteria	Inclusion Criteria:Part A (Healthy Subjects) - Subject able to understand and voluntarily provide the consent to participate in the study - 18 - 70 years of age, inclusive, at the time of signing the informed consent and Body Mass Index (BMI) between 18.0 and 35.0 Kilogram (kg) per m^2, inclusive - Understands and is willing, able and likely to be compliant with taking study drug and comply with all study procedures and restrictions - Subject is willing to consume the foods that are part of the standardized breakfast, lunch, and dinner - In good general health with no clinically significant and relevant abnormalities of medical history or physical examination which includes adequate renal function, alanine transaminase (ALT), alkaline phosphatase and bilirubin <=1.5x Upper Limit of Normal (ULN ) - QTcF < 450 millisecond (msec); or QTcF < 480msec for subjects with right Bundle Branch Block - Females must be post-menopausal - Females on hormone replacement therapy (HRT) must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment - Females who are > 3 months postpartum and who have undergone a surgical sterilization procedure are eligible to participate in consultation with the GSK Medical Monitor Parts B and C (Type 2 Diabetic Subjects) - All the criteria mentioned in Part A except Body Mass Index (BMI) should be between 30.0 and 42.0 kg per m^2 - Diagnosis of T2D for at least 3 months, as defined by the American Diabetes Association - All T2D subjects must meet label recommendations for metformin - For Part B, subjects must be willing to discontinue metformin and replace it with daily liraglutide administered by subcutaneous injection and they must meet label recommendations - No personal history or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2 Exclusion Criteria: - History of gastrointestinal disease, current or chronic history of liver disease, history of serious, severe or unstable physical or psychiatric illness , significant cardiovascular disease, surgery for weight loss or gastrointestinal surgery within 3 months of screening, any documented or reported eating disorder, uncontrolled hypertension, as evidenced by systolic pressure>160 or diastolic pressure >90 mmHg - Positive test for HIV, Hepatitis B, or Hepatitis C at Screening - Subjects with significant ECG abnormalities - For subjects in Part C (continuing metformin), history of untreated pernicious anemia or who have laboratory parameters suggestive of subclinical megaloblastic anemia - Presence of or symptoms of an active infection - Uncorrected Thyroid Dysfunction - History of chronic or acute pancreatitis - Currently dieting to lose weight including, but not limited to, participation in a program designed to alter body weight within the last 60 days and unwilling to maintain relatively consistent exercise patterns throughout the study - Current or recent history (within one year of screening) of alcohol or other substance abuse - Unable to refrain from the use of non-prescription drugs - Current participation in another clinical study or participation in a clinical study involving an investigational drug within 30 days of the screening visit - History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy - An employee of the sponsor or the study site or members of their immediate family.
Gender	Both
Ages	18 Years
Accepts Healthy Volunteers	Accepts Healthy Volunteers
Contacts	Not Provided
Location Countries	United States

Administrative Information[ + expand ][ + ]

NCT Number	NCT01725126
Other Study ID Numbers	116623
Has Data Monitoring Committee	No
Information Provided By	GlaxoSmithKline
Study Sponsor	GlaxoSmithKline
Collaborators	Not Provided
Investigators	Study Director: GSK Clinical Trials GlaxoSmithKline
Verification Date	November 2013

Locations[ + expand ][ + ]