Clinical trial NCT03359473: Study to Evaluate the Safety and Efficacy of 13 Weeks of the Selective Androgen Receptor Modulator (SARM) GSK2881078 in Chronic Obstructive Pulmonary Disease (COPD)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cachexia
Keywords: GSK2881078
COPD
muscle weakness
post-menopausal
selective androgen receptor modulator
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2017-12-02
Enrollment: 97
Sex: ALL
Minimum age (years): 50
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Study treatment will consist of two dosing cohorts: Cohort 1 will comprise of male subjects randomized to receive either placebo or 2 milligrams (mg) of GSK2881078 and Cohort 2 will comprise of post-menopausal female subjects randomized to receive either placebo or 1 mg of GSK2881078.
Primary purpose: TREATMENT

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.


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.
* The subject has participated in a clinical trial and has received an investigational product within the following time-period prior to randomization in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
* Subjects with values outside the specified ranges for the following Key Clinical Laboratory Tests must be excluded from the study: a) Renal function: Glomerular Filtration Rate (GFR) \<30 milliliter per minute per 1.73 meter square (mL/min/1.73 m\^2). Subjects receiving dialysis are excluded from this study. b) Metabolic-glycated hemoglobin (HbA1c) \>7.5%. c) ALT \>2 times upper limit of normal (ULN) and bilirubin \>1.5 times ULN (isolated bilirubin \>1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%). d) Hematology - Hemoglobin \<10.0 grams per deciliter (g/dL) at screening. e) Prostate Specific Antigen (PSA) \>4.0 nanograms per milliliter (ng/mL).
* Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment.
* QT interval corrected for heart rate by Bazett's formula (QTcB) or QT interval corrected for heart rate by Fridericia's formula (QTcF) \>450 milliseconds (msec) or QT interval corrected for heart rate (QTc) \>480 msec in subjects with Bundle Branch Block based on a single ECG.
* A positive test for human immunodeficiency virus (HIV) antibody.
* More than two moderate/severe COPD exacerbations within the past year. Exacerbation is defined as worsening of two or more of the following major symptoms: dyspnea, sputum volume, sputum purulence OR worsening of any one major symptom together with at least one of the following additional symptoms: sore throat, colds (nasal discharge and/or nasal congestion), fever \>37.5 degree Celsius without any explained cause, increased cough, increased wheeze. A moderate exacerbation is defined as an exacerbation that requires treatment with antibiotics and/or oral steroids. A severe exacerbation is defined as an event that is additionally associated with hospitalization or emergency room visit.
* Any moderate/severe COPD exacerbation in the 4 weeks preceding the screening visit.
* Subjects on long-term oxygen therapy (LTOT), defined as prescribed continuous oxygen use for \>14 hours/day.
* Clinically diagnosed history of drug or alcohol abuse within 5 years prior to randomization.
* 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 investigator or GlaxoSmithKline (GSK) Medical Monitor, contraindicates their participation.
* Participation in a formal pulmonary rehabilitation exercise program outside or inside the home, either currently or completed within the previous 6 months.
* For subjects who opt to have magnetic resonance imaging (MRI) at participating study sites, there must be no contraindications to MRI, for example known claustrophobia or a pacemaker. Specific MRI contraindications will be determined by the type of MRI scanner available at each site and study personnel should confirm local eligibility requirements.

Primary outcomes:
measure: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Baseline (Day 1, Pre-dose), Days 14, 28, 56 and 90
measure: Change From Baseline in Heart Rate
timeFrame: Baseline (Day 1, Pre-dose), Days 14, 28, 56 and 90
measure: 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)
timeFrame: Baseline (Day 1, Pre-dose), Days 14, 28, 56 and 90
measure: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Hematology Parameters
timeFrame: Baseline (Day 1, Pre-dose) and up to Day 132
measure: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Clinical Chemistry Parameters
timeFrame: Baseline (Day 1, Pre-dose) and up to Day 132
measure: Change From Baseline in Urinalysis Parameter; Specific Gravity: Placebo-Female Participants
timeFrame: Baseline (Day 1, Pre-dose), Days 28, 56 and 90
measure: Change From Baseline in Urinalysis Parameter; Specific Gravity: GSK2881078 1.0 mg- Female Participants
timeFrame: Baseline (Day 1, Pre-dose), Days 14 and 90
measure: Change From Baseline in Urinalysis Parameter; Specific Gravity: Male Participants
timeFrame: Baseline (Day 1, Pre-dose), Days 28 and 90
measure: Change From Baseline in Urinalysis Parameter; Potential of Hydrogen (pH): Placebo- Female Participants
timeFrame: Baseline (Day 1, Pre-dose), Days 28, 56 and 90
measure: Change From Baseline in Urinalysis Parameter; pH: GSK2881078 1.0 mg- Female Participants
timeFrame: Baseline (Day 1, Pre-dose), Days 14 and 90
measure: Change From Baseline in Urinalysis Parameter; pH: Male Participants
timeFrame: Baseline (Day 1, Pre-dose), Days 28 and 90
measure: Number of Participants With Urinalysis Dipstick Results Post-Baseline Relative to Baseline
timeFrame: Baseline (Day 1, Pre-dose) and up to Day 132
measure: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events
timeFrame: Up to Day 132
measure: Percentage Change From Baseline in Maximum Leg Press Strength Following 1 Repetition Maximum (1-RM) at Day 28
timeFrame: Baseline (Day 1, Pre-dose), Day 28
measure: Percentage Change From Baseline in Maximum Leg Press Strength Following 1 Repetition Maximum (1-RM) at Day 56
timeFrame: Baseline (Day 1, Pre-dose), Day 56
measure: Percentage Change From Baseline in Maximum Leg Press Strength Following 1 Repetition Maximum (1-RM) at Day 90
timeFrame: Baseline (Day 1, Pre-dose), Day 90
measure: Change From Baseline in Maximum Leg Press Strength Following 1 Repetition Maximum (1-RM) at Day 28
timeFrame: Baseline (Day 1, Pre-dose), Day 28
measure: Change From Baseline in Maximum Leg Press Strength Following 1 Repetition Maximum (1-RM) at Day 56
timeFrame: Baseline (Day 1, Pre-dose), Day 56
measure: Change From Baseline in Maximum Leg Press Strength Following 1 Repetition Maximum (1-RM) at Day 90
timeFrame: Baseline (Day 1, Pre-dose), Day 90
Secondary outcomes:
measure: Change From Baseline in Appendicular Lean Mass as Assessed by Dual-energy X-ray Absorptiometry (DXA) at Day 28
timeFrame: Baseline (Day 1, Pre-dose), Day 28
measure: Change From Baseline in Appendicular Lean Mass as Assessed by Dual-energy X-ray Absorptiometry (DXA) at Day 56
timeFrame: Baseline (Day 1, Pre-dose), Day 56
measure: Change From Baseline in Appendicular Lean Mass as Assessed by Dual-energy X-ray Absorptiometry (DXA) at Day 90
timeFrame: Baseline (Day 1, Pre-dose), Day 90
measure: Change From Baseline in Total Lean Mass as Assessed by Dual-energy X-ray Absorptiometry (DXA) at Day 28
timeFrame: Baseline (Day 1, Pre-dose), Day 28
measure: Change From Baseline in Total Lean Mass as Assessed by Dual-energy X-ray Absorptiometry (DXA) at Day 56
timeFrame: Baseline (Day 1, Pre-dose), Day 56
measure: Change From Baseline in Total Lean Mass as Assessed by Dual-energy X-ray Absorptiometry (DXA) at Day 90
timeFrame: Baseline (Day 1, Pre-dose), Day 90
measure: Change From Baseline in Total Short Physical Performance Battery (SPPB) Score at Day 28
timeFrame: Baseline (Day 1, Pre-dose), Day 28
measure: Change From Baseline in Total Short Physical Performance Battery (SPPB) Score at Day 56
timeFrame: Baseline (Day 1, Pre-dose), Day 56
measure: Change From Baseline in Total Short Physical Performance Battery (SPPB) Score at Day 90
timeFrame: Baseline (Day 1, Pre-dose), Day 90
measure: Change From Baseline in 'Time for Chair Rise' as Assessed by SPPB at Day 28
timeFrame: Baseline (Day 1, Pre-dose), Day 28
measure: Change From Baseline in 'Time for Chair Rise' as Assessed by SPPB at Day 56
timeFrame: Baseline (Day 1, Pre-dose), Day 56
measure: Change From Baseline in 'Time for Chair Rise' as Assessed by SPPB at Day 90
timeFrame: Baseline (Day 1, Pre-dose), Day 90
measure: Change From Baseline in 'Time for Fastest Walk for 4 Meter' as Assessed by SPPB at Day 28
timeFrame: Baseline (Day 1, Pre-dose), Day 28
measure: Change From Baseline in 'Time for Fastest Walk for 4 Meter' as Assessed by SPPB at Day 56
timeFrame: Baseline (Day 1, Pre-dose), Day 56
measure: Change From Baseline in 'Time for Fastest Walk for 4 Meter' as Assessed by SPPB at Day 90
timeFrame: Baseline (Day 1, Pre-dose), Day 90
measure: Change From Baseline in Constant Work Rate (CWR) Duration From Endurance Shuttle Walking Test
timeFrame: Baseline (Day 1, Pre-dose), Day 90
measure: Change From Baseline in Peak Performance From Incremental Shuttle Walking Test
timeFrame: Baseline (Highest non-missing pre-dose assessment from Day-9 and Day 1), Day 90
measure: Change From Baseline in Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) Score at Day 56
timeFrame: Baseline (Day 1, Pre-dose), Day 56
measure: Change From Baseline in Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) Score at Day 90
timeFrame: Baseline (Day 1, Pre-dose), Day 90
measure: Change From Baseline in Participant Reported Outcome (PRO)Active Individual Component: Difficulty Score at Day 56
timeFrame: Baseline (Day -9), Day 56
measure: Change From Baseline in Participant Reported Outcome (PRO)Active Individual Component: Difficulty Score at Day 90
timeFrame: Baseline (Day -9), Day 90
measure: Change From Baseline in Participant Reported Outcome (PRO)Active Individual Component: Amount Score at Day 56
timeFrame: Baseline (Day -9), Day 56
measure: Change From Baseline in Participant Reported Outcome (PRO)Active Individual Component: Amount Score at Day 90
timeFrame: Baseline (Day -9), Day 90
measure: Change From Baseline in Participant Reported Outcome (PRO)Active Total Score at Day 56
timeFrame: Baseline (Day -9), Day 56
measure: Change From Baseline in Participant Reported Outcome (PRO)Active Total Score at Day 90
timeFrame: Baseline (Day -9), Day 90
measure: Change From Baseline in Steps Per Day (Physical Activity Measure) as Assessed Via an Accelerometer
timeFrame: Baseline (Day -9), Days 56 and 90
measure: Change From Baseline in Vector Magnitude Unit Per Wear Time (Physical Activity Measure) as Assessed Via an Accelerometer
timeFrame: Baseline (Day -9), Days 56 and 90
measure: Number of Participants With Participant Global Impression of Change (PGIC) Score Over Time
timeFrame: Days 14, 28, 56 and 90
measure: Number of Participants With Participant Global Rating of Severity (PGRS) Score Over Time
timeFrame: Days 1 and 90
measure: Change From Baseline in St. George Respiratory Questionnaire (SGRQ) for COPD (SGRQ-c) Total Score
timeFrame: Baseline (Day 1, Pre-dose), Day 90
measure: Change From Baseline in SGRQ-c Symptoms Score
timeFrame: Baseline (Day 1, Pre-dose), Day 90
measure: Change From Baseline in SGRQ-c Activity Score
timeFrame: Baseline (Day 1, Pre-dose), Day 90
measure: Change From Baseline in SGRQ-c Impact Score
timeFrame: Baseline (Day 1, Pre-dose), Day 90
measure: Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1)
timeFrame: Baseline (Day 1, Pre-dose), Days 56 and 90
measure: Change From Baseline in Sniff Nasal Inspiratory Pressure (SnIP)
timeFrame: Baseline (Day 1, Pre-dose), Days 56 and 90
measure: Clearance (CL) of GSK2881078 Following Oral Dose in Participants
timeFrame: 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)
measure: Volume of Distribution at Steady State (Vss) of GSK2881078 Following Oral Dose in Participants
timeFrame: 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)
Other outcomes:
Locations:
city: Torrance
country: United States
facility: GSK Investigational Site
state: California
city: Jacksonville
country: United States
facility: GSK Investigational Site
state: Florida
city: High Point
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Spartanburg
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Frankfurt
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Grosshansdorf
country: Germany
facility: GSK Investigational Site
state: Schleswig-Holstein
city: Leicester
country: United Kingdom
facility: GSK Investigational Site
state: Leicestershire
city: Harefield
country: United Kingdom
facility: GSK Investigational Site
state: Middlesex
city: London, Greater London
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Mohan D, Rossiter H, Watz H, Fogarty C, Evans RA, Man W, Tabberer M, Beerahee M, Kumar S, Millns H, Thomas S, Tal-Singer R, Russell AJ, Holland MC, Akinseye C, Neil D, Polkey MI. Selective androgen receptor modulation for muscle weakness in chronic obstructive pulmonary disease: a randomised control trial. Thorax. 2023 Mar;78(3):258-266. doi: 10.1136/thorax-2021-218360. Epub 2022 Oct 25.