A Randomized, Double-blind (Sponsor Unblind), Placebo-controlled, Multi-centred Phase IIa Study to Evaluate the Safety and Efficacy of 13 Weeks of Once Daily Oral Dosing of the Selective Androgen Receptor Modulator (SARM) GSK2881078 in Older Men and Post Menopausal Women With COPD and Muscle Weakness, Participating in Home Exercise
Overview
- Phase
- Phase 2
- Intervention
- GSK2881078
- Conditions
- Cachexia
- Sponsor
- GlaxoSmithKline
- Enrollment
- 97
- Locations
- 1
- Primary Endpoint
- Change From Baseline in Heart Rate
- Status
- Completed
- Last Updated
- 5 years ago
Overview
Brief Summary
Impaired physical function and muscle dysfunction are a major consequence of COPD, which may be associated with increased mortality, poor quality of life and increased health care use. This is a randomized, placebo-controlled, double-blind, parallel group study to evaluate the safety and tolerability of GSK2881078, an SARM over 13 weeks of dosing in older male subjects and post-menopausal female subjects with COPD and muscle weakness. This study will also assess the effect of GSK2881078 on physical strength and function after 13 weeks of treatment. Approximately 100 subjects with COPD and muscle weakness will be randomized into two cohorts of 50 male subjects and 50 female subjects. Within each cohort, subjects will be randomized to receive GSK2881078 or placebo in a ratio of 1:1. All subjects will participate in a standardized home exercise program, which will consist of daily walking, along with several resistance or weight-bearing exercises, such as bicep curls, upright rows, step ups and a sit-to-stand maneuver. The study will consist of a screening/Baseline period of up to 30 days, a 13-week treatment period and a post-treatment follow-up period of 6 weeks.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Subject must be 50 to 75 years of age inclusive, at the time of signing the informed consent.
- •Male and/or female subjects will be included. a) A male subject with a partner who is a woman of child bearing potential (WOCPB) must agree to use contraception during the treatment period and until at least 5 half-lives of study medication have passed after the last ingested dose \[125 days, corresponding to time needed to eliminate study treatment for both genotoxic and teratogenic study treatments plus an additional 90 days (a spermatogenesis cycle) for study treatments with genotoxic potential\] after the last dose of study treatment and refrain from donating sperm during this period. b) A female subject is eligible to participate if she is post-menopausal and not a WOCBP.
- •Confirmed diagnosis of COPD in accordance with the American Thoracic Society (ATS)/European Respiratory Society (ERS) criteria with a post-bronchodilator FEV1/forced vital capacity (FVC) \<0.70 and 30% \<= FEV1% predicted \<=65% of predicted normal value calculated at Screen using the Quanjer reference equation.
- •SPPB with ALL of the following: Timed chair stand score \>=1 and \<=3; No score of "0" on any component of the SPPB (that is, gait speed, balance, or timed chair stand).
- •Body Mass Index (BMI) within the range 18-32 kilogram per meter square (kg/m\^2) (inclusive), where BMI = (weight in kg)/(height in meters)\^2
- •Current smokers or former smokers with a cigarette smoking history of \>=10 pack years (1 pack year =20 cigarettes smoked per day for 1 year or equivalent). Former smokers are defined as those who have stopped smoking for at least 6 months prior to Baseline.
- •Subjects must be able to read and write in the language used for the provided electronic diary and be able to operate an electronic device to a level that allows them to complete an electronic diary on a daily basis.
- •Subjects participating in a structured exercise program must be willing to convert their current exercise program to the home exercise program used in this study.
- •Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and protocol.
Exclusion Criteria
- •Subjects with a history of myocardial infarction, angina, congestive heart failure exacerbation, hospitalization for cardiac etiology, stroke or transient ischemic attack in the past 12 months.
- •Neurologic, musculoskeletal, osteoarthritis, or any other condition that in the opinion of the investigator limits subject's ability to complete study physical assessments.
- •Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
- •Subjects with a history of cholecystectomy.
- •Subjects with a history of malignancy that is not in complete remission for at least 2 years or 1 year for non-melanoma skin carcinoma.
- •Subjects with a family history of early onset prostate cancer or familial prostate cancer (multiple family members).
- •Diseases known to cause malabsorption of protein or energy, such as inflammatory bowel disease, celiac disease, pancreatic insufficiency, etc.
- •Current or planned administration of cholestyramine or strong oral or injectable cytochrome P-450 isoenzyme 3A4 (CYP3A4) inducers.
- •Current or planned use of any prescription drugs known to affect muscle mass, including androgen supplements, anti-androgens (such as luteinizing hormone-releasing hormone \[LHRH\] agonists), anti-estrogens (tamoxifen, etc.), recombinant growth hormone, megesterol, etc.
- •Use of oral steroids concurrently or within 4 weeks preceding the screening visit.
Arms & Interventions
Male subjects receiving GSK2881078-Cohort 1
Male subjects between the age of 50 and 75 years will be administered GSK2881078 at a dose of 2 mg once daily by the oral route.
Intervention: GSK2881078
Male subjects receiving Placebo-Cohort 1
Male subjects between the age of 50 and 75 years will be administered GSK2881078 matching placebo once daily by the oral route.
Intervention: Matching Placebo
Female subjects receiving GSK2881078-Cohort 2
Post-menopausal female subjects between the age of 50 and 75 years will be administered GSK2881078 at a dose of 1 mg once daily by the oral route.
Intervention: GSK2881078
Female subjects receiving Placebo-Cohort 2
Post-menopausal female subjects between the age of 50 and 75 years will be administered GSK2881078 matching placebo once daily by the oral route.
Intervention: Matching Placebo
Outcomes
Primary Outcomes
Change From Baseline in Heart Rate
Time Frame: Baseline (Day 1, Pre-dose), Days 14, 28, 56 and 90
Heart rate was measured in a seated position with a completely automated device. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as post-dose visit value minus the Baseline value.
Change From Baseline in PR Interval, QRS Duration, QT Interval, QT Interval Corrected for Heart Rate by Fridericia's Formula (QTcF) and QT Interval Corrected for Heart Rate by Bazett's Formula (QTcB)
Time Frame: Baseline (Day 1, Pre-dose), Days 14, 28, 56 and 90
Twelve-lead electrocardiograms (ECG) were obtained using an automated ECG machine to measure PR Interval, QRS Duration, QT Interval, QTcF Interval and QTcB Interval. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as post-dose visit value minus the Baseline value.
Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Clinical Chemistry Parameters
Time Frame: Baseline (Day 1, Pre-dose) and up to Day 132
Blood samples were collected for the analysis of following clinical chemistry parameters: alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), bilirubin (Bil),calcium (Ca), cholesterol (Chol), creatinine (Creat), glucose(Gl), phosphate (Phos), potassium (Pot) and sodium (Sod). The laboratory parameters were graded according to NCI-CTCAE version 4.03. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in CTCAE grade relative to Baseline grade. Values (Hyper and hypo) for Ca, Gl, Pot, Phos and Sod is presented. Only those participants with increase to grade 3 and increase to grade 4 are presented.
Change From Baseline in Urinalysis Parameter; Specific Gravity: Male Participants
Time Frame: Baseline (Day 1, Pre-dose), Days 28 and 90
Urine samples were collected to analyze the urinalysis parameter: specific gravity. Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine, indicated as ratio of urine density to water density. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as post-dose visit value minus the Baseline value.
Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Hematology Parameters
Time Frame: Baseline (Day 1, Pre-dose) and up to Day 132
Blood samples were collected for the analysis of following hematology parameters: hemoglobin (Hb), lymphocyte count (Lympho), neutrophil count (Neutro) and platelet count (PC). The laboratory parameters were graded according to National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in CTCAE grade relative to Baseline grade. Only those participants with increase to grade 3 and increase to grade 4 are presented.
Change From Baseline in Urinalysis Parameter; Specific Gravity: Placebo-Female Participants
Time Frame: Baseline (Day 1, Pre-dose), Days 28, 56 and 90
Urine samples were collected to analyze the urinalysis parameter: specific gravity. Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine, indicated as ratio of urine density to water density. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as post-dose visit value minus the Baseline value.
Number of Participants With Urinalysis Dipstick Results Post-Baseline Relative to Baseline
Time Frame: Baseline (Day 1, Pre-dose) and up to Day 132
Urine samples were collected to analyze parameters including glucose, occult blood (OB) and protein levels by dipstick. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameters can be read as increase to trace, increase to 1+ (low concentrations present), increase to 2+ (moderate concentrations present) and increase to 3+ (high concentrations present) indicating proportional concentrations in the urine sample. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Data for worst-case post-Baseline relative to Baseline is presented.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
Time Frame: Baseline (Day 1, Pre-dose), Days 14, 28, 56 and 90
SBP and DBP were measured in a seated position with a completely automated device. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as post-dose visit value minus the Baseline value. Safety Population comprised of all randomized participants who received at least one dose of study medication. This population was based on the treatment the participant received.
Change From Baseline in Urinalysis Parameter; Specific Gravity: GSK2881078 1.0 mg- Female Participants
Time Frame: Baseline (Day 1, Pre-dose), Days 14 and 90
Urine samples were collected to analyze the urinalysis parameter: specific gravity. Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine, indicated as ratio of urine density to water density. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as post-dose visit value minus the Baseline value.
Change From Baseline in Urinalysis Parameter; Potential of Hydrogen (pH): Placebo- Female Participants
Time Frame: Baseline (Day 1, Pre-dose), Days 28, 56 and 90
Urine samples were collected to analyze the urinalysis parameter: pH. Urine pH is an acid-base measurement. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acidic pH (5.0 - 6.0). Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as post-dose visit value minus the Baseline value.
Change From Baseline in Urinalysis Parameter; pH: GSK2881078 1.0 mg- Female Participants
Time Frame: Baseline (Day 1, Pre-dose), Days 14 and 90
Urine samples were collected to analyze the urinalysis parameter: pH. Urine pH is an acid-base measurement. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acidic pH (5.0 - 6.0). Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as post-dose visit value minus the Baseline value.
Change From Baseline in Urinalysis Parameter; pH: Male Participants
Time Frame: Baseline (Day 1, Pre-dose), Days 28 and 90
Urine samples were collected to analyze the urinalysis parameter: pH. Urine pH is an acid-base measurement. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acidic pH (5.0 - 6.0). Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as post-dose visit value minus the Baseline value.
Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events
Time Frame: Up to Day 132
An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that; results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other situations judged by physician, is associated with liver injury and impaired liver function. Number of participants who had SAEs and non-SAEs are presented.
Percentage Change From Baseline in Maximum Leg Press Strength Following 1 Repetition Maximum (1-RM) at Day 28
Time Frame: Baseline (Day 1, Pre-dose), Day 28
Lower extremity strength was measured as 1-RM on a leg press device. Participants continued with a one set of 5 to 10 repetitions of lifting weights using 40 to 60% of estimated maximum, after warm up. Participants, then lifted progressively heavier weights in steps, with each step separated by an appropriate rest period, until participant could not complete the lift. The last successfully completed lift was recorded as the 1-RM. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Percentage change from Baseline was calculated by 100\*\[(post-dose value minus Baseline value)/ Baseline value\]. Adjusted means and standard error (SE) are presented. Analysis Population comprised of the participants in the 'All Participants (all randomized participants who received at least one dose of study medication)' Population having Baseline and at least one post-Baseline assessment of the treatment the participant was randomized to.
Percentage Change From Baseline in Maximum Leg Press Strength Following 1 Repetition Maximum (1-RM) at Day 56
Time Frame: Baseline (Day 1, Pre-dose), Day 56
Lower extremity strength was measured as 1-RM on a leg press device. Participants continued with a one set of 5 to 10 repetitions of lifting weights using 40 to 60% of estimated maximum, after warm up. Participants, then lifted progressively heavier weights in steps, with each step separated by an appropriate rest period, until participant could not complete the lift. The last successfully completed lift was recorded as the 1-RM. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Percentage change from Baseline was calculated by 100\*\[(post-dose value minus Baseline value)/ Baseline value\]. Adjusted means and SE are presented.
Percentage Change From Baseline in Maximum Leg Press Strength Following 1 Repetition Maximum (1-RM) at Day 90
Time Frame: Baseline (Day 1, Pre-dose), Day 90
Lower extremity strength was measured as 1-RM on a leg press device. Participants continued with a one set of 5 to 10 repetitions of lifting weights using 40 to 60% of estimated maximum, after warm up. Participants, then lifted progressively heavier weights in steps, with each step separated by an appropriate rest period, until participant could not complete the lift. The last successfully completed lift was recorded as the 1-RM. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Percentage change from Baseline was calculated by 100\*\[(post-dose value minus Baseline value)/ Baseline value\]. Adjusted means and SE are presented.
Change From Baseline in Maximum Leg Press Strength Following 1 Repetition Maximum (1-RM) at Day 28
Time Frame: Baseline (Day 1, Pre-dose), Day 28
Lower extremity strength was measured as 1-RM on a leg press device. Participants continued with a one set of 5 to 10 repetitions of lifting weights using 40 to 60% of estimated maximum, after warm up. Participants, then lifted progressively heavier weights in steps, with each step separated by an appropriate rest period, until participant could not complete the lift. The last successfully completed lift was recorded as the 1-RM. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as post-dose visit value minus the Baseline value. Adjusted means and SE are presented.
Change From Baseline in Maximum Leg Press Strength Following 1 Repetition Maximum (1-RM) at Day 90
Time Frame: Baseline (Day 1, Pre-dose), Day 90
Lower extremity strength was measured as 1-RM on a leg press device. Participants continued with a one set of 5 to 10 repetitions of lifting weights using 40 to 60% of estimated maximum, after warm up. Participants, then lifted progressively heavier weights in steps, with each step separated by an appropriate rest period, until participant could not complete the lift. The last successfully completed lift was recorded as the 1-RM. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as post-dose visit value minus the Baseline value. Adjusted means and SE are presented.
Change From Baseline in Maximum Leg Press Strength Following 1 Repetition Maximum (1-RM) at Day 56
Time Frame: Baseline (Day 1, Pre-dose), Day 56
Lower extremity strength was measured as 1-RM on a leg press device. Participants continued with a one set of 5 to 10 repetitions of lifting weights using 40 to 60% of estimated maximum, after warm up. Participants, then lifted progressively heavier weights in steps, with each step separated by an appropriate rest period, until participant could not complete the lift. The last successfully completed lift was recorded as the 1-RM. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline was calculated as post-dose visit value minus the Baseline value. Adjusted means and SE are presented.
Secondary Outcomes
- Change From Baseline in Total Lean Mass as Assessed by Dual-energy X-ray Absorptiometry (DXA) at Day 90(Baseline (Day 1, Pre-dose), Day 90)
- Change From Baseline in Total Lean Mass as Assessed by Dual-energy X-ray Absorptiometry (DXA) at Day 28(Baseline (Day 1, Pre-dose), Day 28)
- Change From Baseline in Total Short Physical Performance Battery (SPPB) Score at Day 56(Baseline (Day 1, Pre-dose), Day 56)
- Change From Baseline in 'Time for Chair Rise' as Assessed by SPPB at Day 28(Baseline (Day 1, Pre-dose), Day 28)
- Change From Baseline in 'Time for Chair Rise' as Assessed by SPPB at Day 90(Baseline (Day 1, Pre-dose), Day 90)
- Change From Baseline in Appendicular Lean Mass as Assessed by Dual-energy X-ray Absorptiometry (DXA) at Day 28(Baseline (Day 1, Pre-dose), Day 28)
- Change From Baseline in Appendicular Lean Mass as Assessed by Dual-energy X-ray Absorptiometry (DXA) at Day 56(Baseline (Day 1, Pre-dose), Day 56)
- Change From Baseline in Appendicular Lean Mass as Assessed by Dual-energy X-ray Absorptiometry (DXA) at Day 90(Baseline (Day 1, Pre-dose), Day 90)
- Change From Baseline in Total Lean Mass as Assessed by Dual-energy X-ray Absorptiometry (DXA) at Day 56(Baseline (Day 1, Pre-dose), Day 56)
- Change From Baseline in Total Short Physical Performance Battery (SPPB) Score at Day 28(Baseline (Day 1, Pre-dose), Day 28)
- Change From Baseline in Total Short Physical Performance Battery (SPPB) Score at Day 90(Baseline (Day 1, Pre-dose), Day 90)
- Change From Baseline in 'Time for Fastest Walk for 4 Meter' as Assessed by SPPB at Day 28(Baseline (Day 1, Pre-dose), Day 28)
- Change From Baseline in 'Time for Fastest Walk for 4 Meter' as Assessed by SPPB at Day 56(Baseline (Day 1, Pre-dose), Day 56)
- Change From Baseline in 'Time for Fastest Walk for 4 Meter' as Assessed by SPPB at Day 90(Baseline (Day 1, Pre-dose), Day 90)
- Change From Baseline in Constant Work Rate (CWR) Duration From Endurance Shuttle Walking Test(Baseline (Day 1, Pre-dose), Day 90)
- Change From Baseline in 'Time for Chair Rise' as Assessed by SPPB at Day 56(Baseline (Day 1, Pre-dose), Day 56)
- Change From Baseline in Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) Score at Day 56(Baseline (Day 1, Pre-dose), Day 56)
- Change From Baseline in Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) Score at Day 90(Baseline (Day 1, Pre-dose), Day 90)
- Change From Baseline in Participant Reported Outcome (PRO)Active Individual Component: Difficulty Score at Day 56(Baseline (Day -9), Day 56)
- Change From Baseline in Peak Performance From Incremental Shuttle Walking Test(Baseline (Highest non-missing pre-dose assessment from Day-9 and Day 1), Day 90)
- Change From Baseline in Participant Reported Outcome (PRO)Active Total Score at Day 56(Baseline (Day -9), Day 56)
- Change From Baseline in SGRQ-c Impact Score(Baseline (Day 1, Pre-dose), Day 90)
- Change From Baseline in Participant Reported Outcome (PRO)Active Individual Component: Amount Score at Day 56(Baseline (Day -9), Day 56)
- Change From Baseline in Participant Reported Outcome (PRO)Active Individual Component: Amount Score at Day 90(Baseline (Day -9), Day 90)
- Change From Baseline in SGRQ-c Activity Score(Baseline (Day 1, Pre-dose), Day 90)
- Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1)(Baseline (Day 1, Pre-dose), Days 56 and 90)
- Change From Baseline in Sniff Nasal Inspiratory Pressure (SnIP)(Baseline (Day 1, Pre-dose), Days 56 and 90)
- Clearance (CL) of GSK2881078 Following Oral Dose in Participants(Day 14 (Pre-dose), Day 28 (Pre-dose and at 1 to 4 hours Post-dose), Day 56 (at 5 to 8 hours Post-dose), Day 90 (Pre-dose))
- Change From Baseline in Participant Reported Outcome (PRO)Active Individual Component: Difficulty Score at Day 90(Baseline (Day -9), Day 90)
- Change From Baseline in Participant Reported Outcome (PRO)Active Total Score at Day 90(Baseline (Day -9), Day 90)
- Change From Baseline in Steps Per Day (Physical Activity Measure) as Assessed Via an Accelerometer(Baseline (Day -9), Days 56 and 90)
- Change From Baseline in Vector Magnitude Unit Per Wear Time (Physical Activity Measure) as Assessed Via an Accelerometer(Baseline (Day -9), Days 56 and 90)
- Number of Participants With Participant Global Impression of Change (PGIC) Score Over Time(Days 14, 28, 56 and 90)
- Number of Participants With Participant Global Rating of Severity (PGRS) Score Over Time(Days 1 and 90)
- Change From Baseline in St. George Respiratory Questionnaire (SGRQ) for COPD (SGRQ-c) Total Score(Baseline (Day 1, Pre-dose), Day 90)
- Change From Baseline in SGRQ-c Symptoms Score(Baseline (Day 1, Pre-dose), Day 90)
- Volume of Distribution at Steady State (Vss) of GSK2881078 Following Oral Dose in Participants(Day 14 (Pre-dose), Day 28 (Pre-dose and at 1 to 4 hours Post-dose), Day 56 (at 5 to 8 hours Post-dose), Day 90 (Pre-dose))