Clinical trial NCT01725126: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Obesity
Keywords: metformin
diabetes
obesity
liraglutide
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2012-11-12
Enrollment: 53
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Number of Participants With Any Adverse Event (AE), Serious Adverse Event (SAE) or Death During Part A
timeFrame: Up to Follow-up (8 weeks)
measure: Number of Participants With Any AE, SAE or Death During Part B and Part C
timeFrame: Up to Follow-up (8 weeks)
measure: Number of Participants With Any Hypoglycemic Events During Part A
timeFrame: Up to Follow-up (8 weeks)
measure: Number of Participants With Any Hypoglycemic Events During Part B and Part C
timeFrame: Up to Follow-up (8 weeks)
measure: Change From Baseline in Clinical Chemistry Parameters of Alkaline Phosphatase (ALP), ALT, Aspartate Aminotransferase (AST) and Gamma Glutamyltransferase (GGT) During Double-blind Treatment Period of Part A
timeFrame: Baseline (Day 1, Randomization) up to Day 42
measure: Change From Baseline in Clinical Chemistry Parameters of ALP, ALT, AST and GGT During the Double-blind Treatment Period of Part B and C
timeFrame: Baseline (Day -1) up to Day 42
measure: Change From Baseline in Clinical Chemistry Parameters of Electrolytes, Glucose Phosphorus Inorganic and Urea/Blood Urea Nitrogen (BUN) During the Double-blind Treatment Period of Part A
timeFrame: Baseline (Day 1, Randomization) up to Day 42
measure: Change From Baseline in Clinical Chemistry Parameters of Electrolytes, Glucose Phosphorus Inorganic, BUN and Cholesterol During the Double-blind Treatment Period of Part B and C
timeFrame: Baseline (Day -1) up to Day 42
measure: Change From Baseline in Clinical Chemistry Parameters of Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid During the Double-blind Treatment Period of Part A
timeFrame: Baseline (Day 1, Randomization) up to Day 42
measure: Change From Baseline in Clinical Chemistry Parameters of Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid During the Double-blind Treatment Period of Part B and C
timeFrame: Baseline (Day -1) up to Day 42
measure: Change From Baseline in Clinical Chemistry Parameters of Albumin and Total Protein During the Double-blind Treatment Period of Part A
timeFrame: Baseline (Day 1, Randomization) up to Day 42
measure: Change From Baseline in Clinical Chemistry Parameters of Albumin and Total Protein During the Double-blind Treatment Period of Part B and C
timeFrame: Baseline (Day -1) up to Day 42
measure: Change From Baseline in Clinical Chemistry Parameters of Insulin During the Double-blind Treatment Period of Part A
timeFrame: Baseline (Day 1, Randomization) up to Day 42
measure: Change From Baseline in Clinical Chemistry Parameters of Insulin During the Double-blind Treatment Period of Part B and C
timeFrame: Baseline (Day -1) up to Day 42
measure: Change From Baseline in Clinical Chemistry Parameters of Amylase and Lipase the Double-blind Treatment Period of Part B of Study
timeFrame: Baseline (Day -1) and Day 42
measure: Change From Baseline in Clinical Chemistry Parameter of Triiodothyronine (T3) Uptake During the Double-blind Treatment Period of Part B and C
timeFrame: Baseline (Day -1) and Day 42
measure: Change From Baseline in Clinical Chemistry Parameters of Total Thyroxine and Total T3 During the Double-blind Treatment Period of Part B and C
timeFrame: Baseline (Day -1) and Day 42
measure: Change From Baseline in Clinical Chemistry Parameters of Thyroid Stimulating Hormone During the Double-blind Treatment Period of Part B and C
timeFrame: Baseline (Day -1) up to Day 42
measure: Change From Baseline in Hematology Parameters of Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, White Blood Cell (WBC) Count During the Double-blind Treatment Period of Part A
timeFrame: Baseline (Day 1, Randomization) up to Day 42
measure: Change From Baseline in Hematology Parameters of Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, WBC Count During the Double-blind Treatment Period of Part B and C
timeFrame: Baseline (Day -1) up to Day 42
measure: Change From Baseline in Hematology Parameters of Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) During the Double-blind Treatment Period of Part A
timeFrame: Baseline (Day 1, Randomization) up to Day 42
measure: Change From Baseline in Hematology Parameters of Hemoglobin and MCHC During the Double-blind Treatment Period of Part B and C
timeFrame: Baseline (Day -1) up to Day 42
measure: Change From Baseline in Hematology Parameters of Red Blood Cell (RBC) Count and Reticulocytes During the Double-blind Treatment Period of Part A
timeFrame: Baseline (Day 1, Randomization) up to Day 42
measure: Change From Baseline in Hematology Parameters of RBC Count and Reticulocytes During the Double-blind Treatment Period of Part B and C
timeFrame: Baseline (Day -1) up to Day 42
measure: Change From Baseline in Hematology Parameter of Hematocrit During the Double-blind Treatment Period of Part A
timeFrame: Baseline (Day 1, Randomization) up to Day 42
measure: Change From Baseline in Hematology Parameter of Hematocrit During the Double-blind Treatment Period of Part B and C
timeFrame: Baseline (Day -1) up to Day 42
measure: Change From Baseline in Hematology Parameter of Mean Corpuscle Hemoglobin (MCH) During the Double-blind Treatment Period of Part A
timeFrame: Baseline (Day 1, Randomization) up to Day 42
measure: Change From Baseline in Hematology Parameter of MCH During the Double-blind Treatment Period of Part B and C
timeFrame: Baseline (Day -1) up to Day 42
measure: Change From Baseline in Hematology Parameter of Mean Corpuscle Volume (MCV) During the Double-blind Treatment Period of Part A
timeFrame: Baseline (Day 1, Randomization) up to Day 42
measure: Change From Baseline in Hematology Parameter of MCV During the Double-blind Treatment Period of Part B and C
timeFrame: Baseline (Day -1) up to Day 42
measure: Number of Participants With Abnormal Urinalyisis Dipstick and Microscopic Results During the Double-blind Treatment Period of Part A
timeFrame: Up to Day 42
measure: Number of Participants With Abnormal Urinalyisis Dipstick and Microscopic Results During the Double-blind Treatment Period of Part B
timeFrame: Up to Day 42
measure: Number of Participants With Abnormal Urinalyisis Dipstick and Microscopic Results During the Double-blind Treatment Period of Part C
timeFrame: Up to Day 42
measure: Mean Specific Gravity Values of Urine During the Double-blind Treatment Period of Part A
timeFrame: Up to Day 42
measure: Mean Specific Gravity Values of Urine During the Double-blind Treatment Period of Part B and C
timeFrame: Up to Day 42
measure: Mean pH Values of Urine During the Double-blind Treatment Period of Part A
timeFrame: up to Day 42
measure: Mean pH Values of Urine During the Double-blind Treatment Period of Part B and C
timeFrame: Up to Day 42
measure: Change From Baseline in Vital Sign Parameter of Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) During the Double-blind Treatment Period of Part A
timeFrame: Baseline (Day 1, Randomization) up to Day 42
measure: Change From Baseline in Vital Sign Parameter of SBP and DBP During the Double-blind Treatment Period of Part B and C
timeFrame: Baseline (Day -1) up to Day 42
measure: Change From Baseline in Vital Sign Parameter of Heart Rate (HR) During the Double-blind Treatment Period of Part A
timeFrame: Baseline (Day 1, Randomization) up to Day 42
measure: Change From Baseline in Vital Sign Parameter of HR During the Double-blind Treatment Period of Part B and C
timeFrame: Baseline (Day -1) up to Day 42
measure: Change From Baseline in Electrocardiogram (ECG) Intervals During Part A
timeFrame: Baseline (Day 1, Randomization) up to Follow-up (Day 56)
measure: Change From Baseline in ECG Intervals During Part B and C
timeFrame: Baseline (Day -1) up to Follow-up (Day 56)
measure: Change From Baseline in the Overall Gastrointestinal (GI) Symptoms Rating Scale (GSRS) Score During the Double-blind Treatment Period of Part A
timeFrame: Baseline (Day 1, Randomization) up to Day 42
measure: Change From Baseline in the Overall GSRS Score During the Double-blind Treatment Period of Part B and C
timeFrame: Baseline (Day -2) up to Day 41
measure: Change From Baseline in In-clinic Body Weight During the Double-blind Treatment Period of Part B and C
timeFrame: Baseline (Day -1 and Day 1) up to Day 42
measure: Percent Change From Baseline in In-clinic Body Weight During the Double-blind Treatment Period of Part B and C
timeFrame: Baseline (Day -1 and Day 1) up to Day 42
measure: Change From Baseline in Weighted Mean Glucose Area Under the Curves From Time 0 to 24 Hours (AUC [0-24 Hours]) During the Double-blind Treatment Period of Part B and C
timeFrame: Baseline (Day -1) and Day 42
measure: Change From Baseline in Fasting Glucose During the Double-blind Treatment Period of Part B and C
timeFrame: Baseline (Day -1) and Day 42 of Part B and C
measure: Change From Baseline in Fasting Insulin and Weighted Mean Insulin AUC (0-4 Hour) and AUC (0-24 Hour) During the Double-blind Treatment Period of Part B and C
timeFrame: Baseline (Day -1) and Day 42
measure: Change From Baseline in Glycated Hemoglobin (HbA1c) During the Double-blind Treatment Period of Part B and C
timeFrame: Baseline (Day -1) and Day 42
measure: Change From Baseline in Homeostasis Model of Assessment-Insulin Resistance (HOMA-IR]) During the Double-blind Treatment Period of Part B and C
timeFrame: Baseline (Day -1) and Day 42
measure: Change From Baseline in Matsuda Index During the Double Blind-treatment Period of Part B and C
timeFrame: Baseline (Day -1) and Day 42
measure: Change From Baseline in Fasting Plasma Glucose (Safety Laboratory) Values During the Double-blind Treatment Period of Part B and C
timeFrame: Baseline (Day -1) up to Follow-up (Day 56)
Secondary outcomes:
measure: Area Under Plasma Concentration From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC [0-t]) of Liraglutide During the Double-blind Treatment Period of Part B
timeFrame: Day -1 and 42 at pre-dose (0 hour), 15 minutes, 30 minutes, 1, 1.5, 2, 4, 5.5, 6, 8, 10, 11.5, 12, 14 and 24 hours post-dose
measure: Maximum Observed Concentration (Cmax) of Liraglutide During the Double-blind Treatment Period of Part B
timeFrame: Day -1 and 42 at pre-dose (0 hour), 15 minutes, 30 minutes, 1, 1.5, 2, 4, 5.5, 6, 8, 10, 11.5, 12, 14 and 24 hours post-dose
measure: Time of Occurrence of Cmax (Tmax) of Liraglutide During the Double-blind Treatment Period of Part B
timeFrame: Day -1 and 42 at pre-dose (0 hour), 15 minutes, 30 minutes, 1, 1.5, 2, 4, 5.5, 6, 8, 10, 11.5, 12, 14 and 24 hours post-dose
measure: AUC of Metformin From Time 0 to 10 Hours Post-dose (AUC [0-10 Hour]) During the Double-blind Treatment Period of Part A
timeFrame: Day 1 and Day 42 at pre-dose (0 hour), 15 minutes, 30 minutes, 1, 1.5, 2, 4, 5.5, 6, 8 and 10 hours post-dose
measure: Cmax of Metformin During the Double-blind Treatment Period of Part A
timeFrame: Day 1 and Day 42 at pre-dose (0 hour), 15 minutes, 30 minutes, 1, 1.5, 2, 4, 5.5, 6, 8 and 10 hours post-dose
measure: Tmax of Metformin During the Double-blind Treatment Period of Part A
timeFrame: Day 1 and 42 at pre-dose (0 hour), 15 minutes, 30 minutes, 1, 1.5, 2, 4, 5.5, 6, 8 and 10 hours post-dose
measure: AUC From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC [0-t]) of Metformin During the Double-blind Treatment Period of Part C
timeFrame: Day -1 and 42 at pre-dose (0 hour), 15 minutes, 30 minutes, 1, 1.5, 2, 4 (pre-lunch), 5.5, 6, 8, 10 (pre-dinner), 11.5, 12, 14 and 24 hours post-dose
measure: Cmax of Metformin During the Double-blind Treatment Period of Part C
timeFrame: Day -1 and 42 at pre-dose (0 hour), 15 minutes, 30 minutes, 1, 1.5, 2, 4 (pre-lunch), 5.5, 6, 8, 10 (pre-dinner), 11.5, 12, 14 and 24 hours post-dose
measure: Tmax of Metformin During the Double-blind Treatment Period of Part C
timeFrame: Day -1 and 42 at pre-dose (0 hour), 15 minutes, 30 minutes, 1, 1.5, 2, 4 (pre-lunch), 5.5, 6, 8, 10 (pre-dinner), 11.5, 12, 14 and 24 hours post-dose
Other outcomes:
Locations:
city: Chula Vista
country: United States
facility: GSK Investigational Site
state: California
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Overland Park
country: United States
facility: GSK Investigational Site
state: Kansas
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Hodge RJ, Paulik MA, Walker A, Boucheron JA, McMullen SL, Gillmor DS, Nunez DJ. Weight and Glucose Reduction Observed with a Combination of Nutritional Agents in Rodent Models Does Not Translate to Humans in a Randomized Clinical Trial with Healthy Volunteers and Subjects with Type 2 Diabetes. PLoS One. 2016 Apr 19;11(4):e0153151. doi: 10.1371/journal.pone.0153151. eCollection 2016.