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Study to Evaluate the Safety and Efficacy of 13 Weeks of the Selective Androgen Receptor Modulator (SARM) GSK2881078 in Chronic Obstructive Pulmonary Disease (COPD)

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ClinicalTrials.gov Identifier: NCT03359473
Recruitment Status : Active, not recruiting
First Posted : December 2, 2017
Last Update Posted : July 22, 2019
Sponsor:
Collaborator:
Parexel
Information provided by (Responsible Party):
GlaxoSmithKline

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.

Condition or disease Intervention/treatment Phase
Cachexia Drug: GSK2881078 Drug: Matching Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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.
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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
Actual Study Start Date : February 28, 2018
Estimated Primary Completion Date : December 5, 2019
Estimated Study Completion Date : December 5, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 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.
Drug: GSK2881078
GSK2881078 will be available as capsules for oral administration. GSK2881078 will be administered once daily by the oral route at a dose of 1 mg and 2mg to post-menopausal female subjects and male subjects, respectively.

Placebo Comparator: 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.
Drug: Matching Placebo
Subjects will be administered two capsules of GSK2881078 matching placebo once daily by the oral route.

Experimental: 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.
Drug: GSK2881078
GSK2881078 will be available as capsules for oral administration. GSK2881078 will be administered once daily by the oral route at a dose of 1 mg and 2mg to post-menopausal female subjects and male subjects, respectively.

Placebo Comparator: 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.
Drug: Matching Placebo
Subjects will be administered two capsules of GSK2881078 matching placebo once daily by the oral route.




Primary Outcome Measures :
  1. Change in blood pressure from Baseline [ Time Frame: Baseline and up to Day 140 ]
    Blood pressure will be measured in a seated position after 5 minutes of rest for the subject in a quiet setting without distractions.

  2. Change in heart rate from Baseline [ Time Frame: Baseline and up to Day 140 ]
    Heart rate will be measured in a seated position after 5 minutes of rest for the subject in a quiet setting without distractions.

  3. Change in electrocardiogram (ECG) from Baseline [ Time Frame: Baseline and up to Day 140 ]
    12-lead ECG will be obtained in triplicate using an automated ECG machine.

  4. Number of subjects with abnormal hematology parameters [ Time Frame: Up to Day 140 ]
    Blood samples will be collected to assess the following hematology parameters: platelet count, red blood cell (RBC) count, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), percentage reticulocytes, neutrophils, lymphocytes, monocytes, eosinophils and basophils.

  5. Number of subjects with abnormal clinical chemistry parameters [ Time Frame: Up to Day 140 ]
    Blood samples will be collected to assess the following clinical chemistry parameters: blood urea nitrogen (BUN), creatinine, fasting glucose, phosphorus, potassium, sodium, calcium, bicarbonate, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total and direct bilirubin, total protein and albumin.

  6. Number of subjects with abnormal urine parameters [ Time Frame: Up to Day 140 ]
    Urine samples will be assessed for the following parameters: specific gravity; potential of hydrogen (pH), glucose, protein, blood and ketones by dipstick method. Microscopic examination of urine will be performed if blood or protein is abnormal.

  7. Number of subjects with adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: Up to Day 140 ]
    An AE is any untoward medical occurrence in a clinical study subject, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as any untoward medical occurrence that, at any dose results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect; other important medical events which may require medical or surgical intervention;is associated with liver injury and impaired liver function.

  8. Percentage change from Baseline in maximum leg press strength following 1 repetition maximum (1-RM) [ Time Frame: Baseline and up to Day 140 ]
    Lower extremity strength will be measured as 1-RM on a leg press device. Subjects will have a warm up followed by one set of 5-10 repetitions using 40-60% of estimated maximum. Subjects will then lift progressively heavier weights in steps, with each step separated by an appropriate rest period, until the subject cannot complete the lift. The last successfully completed lift will be recorded as the 1-RM.

  9. Change from Baseline in maximum leg press strength following 1-RM [ Time Frame: Baseline and up to Day 140 ]
    Lower extremity strength will be measured as 1-RM on a leg press device. Subjects will have a warm up followed by one set of 5-10 repetitions using 40-60% of estimated maximum. Subjects will then lift progressively heavier weights in steps, with each step separated by an appropriate rest period, until the subject cannot complete the lift. The last successfully completed lift will be recorded as the 1-RM.


Secondary Outcome Measures :
  1. Change from Baseline in appendicular lean mass as assessed by Dual-energy X-ray Absorptiometry (DXA) [ Time Frame: Baseline and up to Day 140 ]
    Appendicular lean mass will be calculated from the regional lean mass measurements of the arms and legs using DXA.

  2. Change from Baseline in total lean mass as assessed by DXA [ Time Frame: Baseline and up to Day 140 ]
    Subjects will be required to lie on a padded platform while a mechanical arm passes over their body. Outputs from the scans will measure the body composition including total body mass, total lean mass and fat mass.

  3. Change from Baseline in total Short Physical Performance Battery (SPPB) score [ Time Frame: Baseline and up to Day 140 ]
    The SPPB has three components: balance, gait speed, and timed chair stand. The scores for each component and the time in seconds for each component will be scored from 0 to 4 to obtain a total score ranging from 0 (worst performance) to 12 (best performance).

  4. Change from Baseline in time for chair rise as assessed by SPPB [ Time Frame: Baseline and up to Day 140 ]
    The SPPB has three components: balance, gait speed, and timed chair stand. The scores for each component and the time in seconds for each component will be scored from 0 to 4.

  5. Change from Baseline in 4 meter gait speed as assessed by SPPB [ Time Frame: Baseline and up to Day 140 ]
    The SPPB has three components: balance, gait speed, and timed chair stand. The scores for each component and the time in seconds for each component will be scored from 0 to 4.

  6. Change from Baseline in Constant Work Rate (CWR) duration from endurance shuttle walking test [ Time Frame: Baseline and up to Day 90 ]
    An incremental shuttle walk will be performed to determine peak work rate. Subjects will perform CWR testing at 85% peak work rate determined from the incremental walk test conducted at the Baseline visit.

  7. Change from Baseline in peak performance from incremental shuttle walking test [ Time Frame: Baseline and up to Day 90 ]
    An incremental shuttle walk will be performed to determine peak work rate.

  8. Change from Baseline in COPD Assessment Test (CAT) score [ Time Frame: Baseline and up to Day 90 ]
    CAT is a validated, eight item questionnaire developed to assess the general health status of subjects with COPD. Subjects will be required to complete the questionnaire by rating their experience on a 6 point scale ranging from 0 (no impairment) to 5 (maximum impairment) with a total scoring range of 0-40.

  9. Change in PROactive individual component score [ Time Frame: Up to Day 80 ]
    Physical activity will be measured by the Daily PROactive Physical Activity in COPD instrument (D-PPAC). The Daily PROactive instrument comprises of an electronic diary (eDiary) and outputs from physical activity monitor. The eDiary consists of 7 questions to be completed each day. The output from the eDiary is combined with two summary outputs from the activity monitor to produce the PROactive score.

  10. Change in PROactive total score [ Time Frame: Up to Day 80 ]
    Physical activity will be measured by the D-PPAC. The Daily PROactive instrument comprises of an eDiary and outputs from physical activity monitor. The eDiary consists of 7 questions to be completed each day. The output from the eDiary is combined with two summary outputs from the activity monitor to produce the PROactive score.

  11. Change in physical activity measures as assessed via an accelerometer [ Time Frame: Up to Day 80 ]
    Accelerometer is a clinically validated physical activity monitor which will be used to measure the levels of activity. Subjects will be required to wear the physical activity monitor for 7 days during which they will rate their physical activity on a daily basis by completing the PROactive eDiary.

  12. Change in Patient Global Impression of Change (PGIC) score from Baseline [ Time Frame: Baseline and up to Day 140 ]
    Subjects will be required to provide responses to the PGIC question on a seven-point Likert scale ranging from much better to much worse.

  13. Change in Patient Global Rating of Severity (PGRS) score from Baseline [ Time Frame: Baseline and up to Day 90 ]
    The PGRS is a single global question that asks subjects to rate how their condition impacts their ability to perform physical activity on a five-point scale (none, mildly, moderately, severely, very severely).

  14. Change in St George Respiratory Questionnaire-COPD (SGRQ-c) total score [ Time Frame: Up to Day 90 ]
    SGRQ-c is a validated questionnaire for COPD. It consists of 40 items in total, corresponding to 3 individual domains: symptoms, activity and impact, with different components carrying a different weighting. The score range is from 0 (no impairment) to a theoretical maximum of 3201.9 for the worst possible state of the subject.

  15. Change in SGRQ-c domain score [ Time Frame: Up to Day 90 ]
    SGRQ-c is a validated questionnaire for COPD. It consists of 40 items in total, corresponding to 3 individual domains: symptoms, activity and impact.

  16. Change from Baseline in forced expiratory volume in 1 second (FEV1) [ Time Frame: Baseline and up to Day 90 ]
    FEV1 will be measured by spirometer.

  17. Change from Baseline in Sniff nasal inspiratory pressure (SnIP) [ Time Frame: Baseline and up to Day 90 ]
    Inspiratory muscle strength will be assessed by measuring the maximal SNIP. A bung size-specific to the subject is placed in the nostril deemed to be most patent by the investigator. The subject will be asked to make a maximum voluntary sniff effort via a SnIP meter and the greatest effort from 10 repeat measurements will be recorded.

  18. Oral clearance of GSK2881078 [ Time Frame: Day 14 (pre-dose), Day 28 (pre-dose, 1 to 4 hours post-dose), Day 56 (5 to 8 hours post-dose), Day 90 (pre-dose) ]
    Blood samples will be collected at the indicated time points and concentration of GSK2881078 will be determined in plasma.

  19. Oral steady-state volume of distribution of GSK2881078 [ Time Frame: Day 14 (pre-dose), Day 28 (pre-dose, 1 to 4 hours post-dose), Day 56 (5 to 8 hours post-dose), Day 90 (pre-dose) ]
    Blood samples will be collected at the indicated time points and concentration of GSK2881078 will be determined in plasma.



Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

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): NCT03359473


Locations
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United States, California
GSK Investigational Site
Torrance, California, United States, 90502
United States, Florida
GSK Investigational Site
Jacksonville, Florida, United States, 32216
United States, North Carolina
GSK Investigational Site
Durham, North Carolina, United States, 27701
GSK Investigational Site
High Point, North Carolina, United States, 27262
United States, Pennsylvania
GSK Investigational Site
Philadelphia, Pennsylvania, United States, 19140
United States, South Carolina
GSK Investigational Site
Spartanburg, South Carolina, United States, 29303
Germany
GSK Investigational Site
Frankfurt, Hessen, Germany, 60596
GSK Investigational Site
Grosshansdorf, Schleswig-Holstein, Germany, 22927
United Kingdom
GSK Investigational Site
Leicester, Leicestershire, United Kingdom, LE3 9QP
GSK Investigational Site
Harefield, Middlesex, United Kingdom, UB9 6JH
GSK Investigational Site
London, Greater London, United Kingdom, SE1 7EH
GSK Investigational Site
London, United Kingdom, SW3 6HP
Sponsors and Collaborators
GlaxoSmithKline
Parexel
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline

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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT03359473     History of Changes
Other Study ID Numbers: 200182
2017-001148-37 ( EudraCT Number )
First Posted: December 2, 2017    Key Record Dates
Last Update Posted: July 22, 2019
Last Verified: July 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by GlaxoSmithKline:
GSK2881078
COPD
muscle weakness
post-menopausal
selective androgen receptor modulator

Additional relevant MeSH terms:
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Pulmonary Disease, Chronic Obstructive
Cachexia
Muscle Weakness
Lung Diseases, Obstructive
Lung Diseases
Respiratory Tract Diseases
Emaciation
Weight Loss
Body Weight Changes
Body Weight
Signs and Symptoms
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Pathologic Processes
Androgens
GSK2881078
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Anabolic Agents