| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Obstructive Pulmonary Disease |
|
| 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 | 18.1 |
| 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 |
To evaluate the dose response, efficacy and safety of five dosage
regimens of batefenterol delivered via the DPI in subjects with COPD. |
|
| E.2.2 | Secondary objectives of the trial |
To investigate the PK and PD of batefenterol in subjects with COPD
Exploratory:
To evaluate treatment effect of batefenterol on Patient Reported Outcomes in subjects with COPD |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Type of subject: Outpatient.
2. Informed Consent: A signed and dated written informed consent prior to study participation.
3. Age: 40 years of age or older at Visit 1.
4. Gender: Male and female subjects are eligible to participate in the study.
Female subjects are eligible to participate if not pregnant (as confirmed by a negative urine human chorionic gonadotrophin (hCG) test), not lactating, and at least one of the following conditions applies:
a. Non-reproductive potential defined as:
- Pre-menopausal females with one of the following:
- Documented tubal ligation
- Documented hysteroscopic tubal occlusion procedure with follow-up
confirmation of bilateral tubal occlusion
- Hysterectomy
- Documented Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea.
Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the 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 prior to study enrolment.
b. Reproductive potential and agrees to follow one of the options listed below 30 days prior to the first dose of study medication and until at least five terminal half-lives OR until any continuing pharmacologic effect has ended, whichever is longer after the last dose of study medication and completion of the follow-up visit. This list does not apply to females of reproductive potential with same sex
partners, when this is their preferred and usual lifestyle or for subjects who are and will continue to be abstinent from penile-vaginal intercourse on a long term and persistent basis.
- Contraceptive subdermal implant that meets <1% rate of failure per year, as stated in the product label
- Intrauterine device or intrauterine system that meets <1% rate of failure per year, as stated in the product label [Hatcher, 2007a]
- Oral Contraceptive, either combined or progestogen alone [Hatcher, 2007a]
- Injectable progestogen [Hatcher, 2007a]
- Contraceptive vaginal ring [Hatcher, 2007a]
- Percutaneous contraceptive patches [Hatcher, 2007a]
- Male partner sterilization with documentation of azoospermia prior to the female subject’s entry into the study, and this male is the sole partner for that subject [Hatcher, 2007a].
These allowed methods of contraception are only effective when used
consistently, correctly and in accordance with the product label. The
investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.
5. Diagnosis: An established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society [Celli, 2004] as follows:
“Chronic obstructive pulmonary disease is a preventable and treatable disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking.”
6. Smoking History: Current or former cigarette smokers with a history of cigarette smoking of => 10 pack-years. Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1. Number of pack years = (number of cigarettes per day / 20) x number of years smoked (e.g. 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years both equal 10 pack-years)
Note: pipe and cigar cannot be used to calculate pack-year history.
7. Severity of Disease: A post-albuterol/salbutamol FEV1/FVC ratio of ≤0.70 and a post-albuterol/salbutamol FEV1 =>30 and ≤ 70% of predicted normal at Visit 1.
Note: Percent predicted will be calculated using the European Respiratory Society Global Lung Function Initiative reference equations [Quanjer, 2012]. |
|
| E.4 | Principal exclusion criteria |
1. Asthma: Subjects with a current diagnosis of asthma. (Subjects with a prior history of asthma are eligible if they have a current diagnosis of COPD).
2. Other Respiratory Disorders: Known respiratory disorders other than COPDPlease view protocol for further information.
3. Other Diseases/Abnormalities: Any significant diseases (including uncontrolled hypertension, diabetes and thyroid disease) please view protocol for further information
4. Hepatitis: Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at Screening Visit 1 or within 3 months prior to first dose of study treatment. Please view protocol for further information.
5. Liver Disease: Current or chronic history of liver disease, known hepatic or biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones).
6. Cancer: A current malignancy or previous history of cancer in remission for < 5 years prior to Visit 1, please view protocol for further information. Any current or previous history of throat cancer.
7. Chest X-Ray: A chest X-ray or computed tomography (CT) scan that reveals evidence of clinically significant abnormalities not believed to be due to the presence of COPD. Please view protocol for further information.
8. Drug Allergy: A history of hypersensitivity or allergy to any beta adrenergic receptor-agonist, sympathomimetic, anticholinergic/anti-muscarinic receptor antagonist, or lactose/milk protein, which in the opinion of the investigator or GSK medical monitor contraindicates study participation.
9. Diseases Preventing Use of Anticholinergic: Medical diagnosis of narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that in the opinion of the study investigator would prevent use of an inhaled anticholinergic.
10. Poorly controlled COPD: defined as the occurrence of ‘acute worsening of COPD that is managed with corticosteroid and/or antibiotics or that requires treatment prescribed by a physician in the 6 weeks prior to Screening (Visit 1)’, or ‘subjects who are hospitalized due to acute worsening of COPD within 12 weeks of Visit 1’.
11. History of COPD exacerbation: Subjects who have had more than one exacerbation (moderate or severe) within the 12 months prior to Visit 1. See protocol Section 7.4.7 for the protocol definition of moderate/severe COPD exacerbation.
12. Pneumonia and lower respiratory tract infection: Subjects with lower respiratory
tract infection that required the use of antibiotics within 6 weeks prior to Visit 1 or subjects hospitalized due to pneumonia within 12 weeks of Visit 1.
13. Lung Resection: Lung volume reduction surgery within the 12 months prior to Visit 1.
14. 12-lead ECG: An abnormal and clinically significant 12-lead electrocardiogram (ECG). Please view protocol for further information. For this study, an abnormal and clinically significant ECG that would preclude a subject from entering the trial is defined as a 12-lead tracing that is interpreted as, but not limited to, any of the following: please see protocol for further information.
16. Medication Prior to Spirometry: Unable to withhold albuterol/salbutamol for the 4 hour period required prior to spirometry testing at each study visit.
17. Excluded Medications: Use of the following medications please view protocol for further information, are not permitted within the defined time intervals prior to Visit 1 and throughout the study:
17. Oxygen: Use of long-term oxygen therapy (LTOT) described as oxygen therapy prescribed for greater than 12 hours a day. As-needed oxygen use (i.e. <=12 hours per day) is not exclusionary.
18. Nebulized Therapy: Regular use (prescribed for use every day, not for as-needed use) of short-acting bronchodilators (e.g. albuterol/salbutamol) via nebulized therapy.
19. Pulmonary Rehabilitation Program: Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Visit 1. Subjects who are in the maintenance phase of a pulmonary rehabilitation program are not excluded.
20. Drug or Alcohol Abuse: A known or suspected history of alcohol or drug abuse within 2 years prior to Visit 1.
21. Non-compliance: Subjects at risk of non-compliance, or unable to comply with the study procedures. Any infirmity, disability, or geographic location that would limit compliance for scheduled visits.
22. Questionable validity of consent: Subjects with a history of psychiatric disease, intellectual deficiency, poor motivation or other conditions that will limit the validity of informed consent to participate in the study
23. Affiliation with Investigator Site: Is an investigator, sub-investigator, study coordinator, employee of a participating investigator or study site, or immediate family member of the aforementioned that is involved in this study.
24. Inability to read: In the opinion of the investigator, any subject who is unable to read and/or would not be able to complete a diary. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Weighted-mean FEV1 over 0 to 6 hours post-dose at Day 42 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Day 1: -30minutes and 0 minutes pre-dose and post-dose at 5, 15, and 30 minutes and 1, 2, 4 and 6 hours; Day 42: trough 23rd and 24th hour assessments will be collected first. The 6 hr serial timepoints will then be performed following dosing at 5, 15, and 30 min and 1, 2, 4 and 6 hours. |
|
| E.5.2 | Secondary end point(s) |
Secondary Efficacy:
Trough FEV1 at Day 42
Other Efficacy:
-Time to onset (defined as an increase of 100mL above baseline in FEV1)
during 0-6 hours post-dose on Treatment Day 1
-Proportion of subjects achieving an increase of ≥ 100mL above baseline on Day1 and Day 42
- Trough FEV1 and weighted-mean FEV1 over 0-6 hours post-dose at other time points
- Serial FEV1 over 0 to 6 hours post-dose (at each time point) on Day 1 and Day 42
- Serial FVC over 0 to 6 hours post-dose (at each time point) on Day 1 and Day 42
- Albuterol/salbutamol use (occasions/day), averaged over each week of
treatment and over the 42-day treatment period.
- The percentage of albuterol/salbutamol rescue-free days (24 hours) during each week of treatment and over the 42-day treatment period.
Safety:
- Incidence of AEs
- Vital signs (pulse rate, systolic and diastolic blood pressure)
- 12-lead ECG assessments
- Clinical laboratory tests (haematology and chemistry)
- Fasting glucose and potassium assessments
- Incidence of COPD exacerbations
Secondary:
Plasma batefenterol concentrations and derived PK parameters.
Exploratory:
- COPD Assessment Test (CAT)
- Taste Questionnaire |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Performed at 23 and 24 hours at Days 7, 14, 28 and 42 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 | Yes |
| 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 | Yes |
| 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 | Yes |
| 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 | 7 |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
| South Africa |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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