| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Obstructive Pulmonary Disease (COPD) |
|
| E.1.1.1 | Medical condition in easily understood language |
| COPD describes a group of lung conditions that make it difficult to empty air out of the lungs because your airways have been narrowed. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010952 |
| E.1.2 | Term | COPD |
| E.1.2 | System Organ Class | 100000004855 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- Assess the safety and tolerability of approximately 13 weeks of dosing of GSK2881078.
- Assess the effect of approximately 13 weeks of doing of GSK2281078 on leg strength in older mean and postmenopausal women with COPD and muscle weakness, participating in home exercise. |
|
| E.2.2 | Secondary objectives of the trial |
- Assess the effect of approximately 13 weeks of dosing of GSK2281078 on lean soft tissue mass.
- Assess the effect of approximately 13 weeks of dosing of GSK2881078 on exercise capacity.
- Assess the effect of approximately 13 weeks of dosing of GSK2881078 on patient reported outcomes, levels or physical activity, activities of daily living and the patient perspective of efficacy.
- Assess the effect of approximately 13 weeks of dosing on GSK2881078 on respiratory function.
- Characterise the population pharmacokinetic (PK) profile of approximately 13 weeks of dosing of GSK2881078 in older men and post menopausal women with COPD and muscle weakness. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Participants must be 50 to 75 years of age inclusive, at the time of signing the informed consent.
2. Male and/or female:
a. Male participants: A male participant with a partner who is a woman of child bearing potential (WOCPB) must agree to use contraception as detailed below during the treatment period and for 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.
- Male participants with female partners of child-bearing potential are eligible to participate if they agree to ONE of the following during the protocol-defined time frame described above:
- Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception.
- Agree to use a male condom plus an additional method of contraception with a failure rate of <1% per year when having penilevaginal intercourse with a woman of childbearing potential
- Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile penetration during the protocol-defined time frame
- Refrain from donating sperm for duration of study and for 4 months from last dose
b. Female participants: A female participant is eligible to participate if she is post-menopausal and not a woman of childbearing potential (WOCBP) as defined below.
Woman of Childbearing Potential (WOCBP) A woman is considered fertile following menarche and until becoming post-menopausal unless permanently sterile.
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with ONE of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
3. Postmenopausal female
- A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
- Females on HRT and whose menopausal status is in doubt will be required to use one of the non-hormonal highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status before study enrollment.
. Note: Postmenopausal is defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) levels consistent with menopause (refer to laboratory reference ranges for confirmatory levels), or be >60 years of age].
3. Confirmed diagnosis of COPD in accordance with the ATS/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.
4. Short Physical Performance Battery (SPPB) with ALL of the following:
- Timed chair stand score ≥1 AND ≤3
- No score of “0” on any component of the SPPB (i.e., gait speed, balance, or timed chair stand)
5. Body Mass Index (BMI) within the range 18 - 32kg/ m2 (inclusive), where BMI =(weight in kg) / (height in meters)2
6. 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.
7. Participants 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.
8. Participants participating in a structured exercise program must be willing to convert their current exercise program to the home exercise program used in this study.
9. Capable of giving signed informed consent as described in Appendix 3 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. |
|
| E.4 | Principal exclusion criteria |
1. Participants with a history of myocardial infarction, angina, congestive heart failure exacerbation, hospitalization for cardiac aetiology, stroke or transient ischemic attack in the past 12 months.
2. Neurologic, musculoskeletal, osteoarthritis, or any other condition that in the opinion of the investigator limits participant’s ability to complete study physical assessments.
3. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
4. Participants with a history of cholecystectomy.
5. Participants with a history of malignancy that is not in complete remission for at least 2 years or 1 year for non-melanoma skin carcinoma.
6. Participants with a family history of early onset prostate cancer or familial prostate cancer (multiple family members).
7. Diseases known to cause malabsorption of protein or energy, such as inflammatory
bowel disease, celiac disease, pancreatic insufficiency, etc.
8. Current or planned administration of cholestyramine or strong oral or injectable cytochrome P-450 isoenzyme 3A4 (CYP3A4) inducers.
9. Current or planned use of any prescription drugs known to affect muscle mass, including androgen supplements, anti-androgens (such as LHRH agonists), antiestrogens (tamoxifen, etc.), recombinant growth hormone, megesterol, etc.
10. Use of oral steroids concurrently or within 4 weeks preceding the screening visit.
11. The participant 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).
12. Participants with values outside the specified ranges for the following Key Clinical Laboratory Tests must be excluded from the study:
•Renal function: Glomerular Filtration Rate (GFR) <30 (mL/min/1.73 m2 ) using formulae provided in the Study Reference Manual (SRM). Note: Participants receiving dialysis are excluded from this study.
•Metabolic – HbA1c >7.5%.
•ALT >2xULN and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is
acceptable if bilirubin is fractionated and direct bilirubin <35%).
•Haematology – Haemoglobin <10.0 g/dL at screening
•Prostate Specific Antigen >4.0 ng/mL
13. Presence of hepatitis B surface antigen, positive hepatitis C antibody test
result at screening or within 3 months prior to first dose of study treatment. NOTE: Participants with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C RNA PCR test is obtained.
14. QT interval corrected for heart rate by Bazett's formula or QT interval corrected for heart rate by Fridericia’s formula >450 msec or QT interval corrected for heart rate >480 msec in participants with Bundle Branch Block based on a single ECG.
15. A positive test for HIV antibody.
16. 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: dyspnoea, 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 >37.5oC 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.
17. Any moderate/severe COPD exacerbation in the 4 weeks preceding the screening visit.
18. Participants on long term oxygen therapy, defined as prescribed continuous oxygen use for >14 hours/day.
19. Clinically diagnosed history of drug or alcohol abuse within 5 years prior to randomization.
20. 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 GSK Medical Monitor, contraindicates their participation.
21. Participation in a formal pulmonary rehabilitation exercise program outside or inside the home,either currently or completed within the previous 6 months.
22. For participants who opt to have 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Safety and tolerability of GSK2881078 as assessed by clinical monitoring of blood pressure (BP), heart rate, electrocardiogram (ECG) and laboratory safety data, as well as reporting of adverse events (AEs).
- % change from baseline and change from baseline in maximum leg press strength following 1 repetition maximum (1- RM).
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
-Throughout the duration of the study
- At the end of the study |
|
| E.5.2 | Secondary end point(s) |
- Change from baseline in appendicular, and total lean mass as assessed by Dual-energy X-ray Absorptiometry (DXA)
- Change from baseline in total Short Physical Performance Battery (SPPB) score and times for chair and 4 m gait speed.
- Change from baseline in Constant Work Rate (CWR) duration from endurance shuttle walking test
- Change from baseline in peak performance from incremental shuttle walking test
- Change from baseline in COPD Assessment Test (CAT)
- Change in PROactive endpoints (individual components and total score)
- Change in physical activity measures as assessed via an accelerometer
- Patient Global Impression of Change
- Patient Global Rating of Severity
- Change in St George Respiratory Questionnaire-COPD (SGRQ-c) total score and domains
- Change from baseline in forced expiratory volume in 1 second (FEV1)
- Change from baseline in Inspiratory capacity (IC)
- Change from baseline in Sniff nasal inspiratory pressure (SnIP)
- Model specific PK parameters of GSK2881078 (e.g., oral clearance, oral steady-state volume of distribution). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| -Throughout the duration of the study |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Germany |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last participant's last visit |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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