E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Obstructive Pulmonary Disease (COPD) |
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E.1.1.1 | Medical condition in easily understood language |
Chronic Obstructive Pulmonary Disease (COPD) |
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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 | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10010952 |
E.1.2 | Term | COPD |
E.1.2 | System Organ Class | 100000004855 |
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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 characterize the dose response relationship of PH-797804 on change from baseline in trough (pre-treatment and pre-bronchodilator) FEV1 at Week 12 compared to placebo in COPD patients on a background of tiotropium. |
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E.2.2 | Secondary objectives of the trial |
• To determine the safety and toleration of PH-797804 in COPD patients on a background of tiotropium bromide.
• To characterize the effect of all doses of PH-797804 on various spirometry endpoints:
• Effect on change from baseline in trough (pre-treatment and pre-bronchodilator) FVC, IC and FEV6 at Week 12.
• Time-course of effect over 12 weeks on change from baseline in trough FEV1, forced vital capacity (FVC), inspiratory capacity (IC) and FEV6.
• Effect of single (Week 0) and 12 weeks multiple dosing on post-dose, pre-bronchodilator FEV1, FVC, IC and FEV6.
• Effect of single (Week 0) and 12 weeks multiple dosing on change from baseline in post- bronchodilator FEV1, FVC, IC and FEV6.
Please refer to the Protocol for the full list of objectives |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subject eligibility should be reviewed and documented by an appropriately qualified member of the investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Male or female subjects between, and including, the ages of 40 and 80 years.
Female subjects of non-childbearing potential must meet at least one of the following criteria:
1. postmenopausal females, defined as:
- Females over the age of 60 years.
- Females between the ages of 45 to 60 who have been amenorrheic for at least 2 years PLUS have a serum FSH level within the laboratory's reference range for postmenopausal females.
2. Females who have a documented hysterectomy and/or bilateral
oophorectomy.
All other female subjects (including females with tubal ligations and
females that do NOT have a documented hysterectomy and/or bilateral oophorectomy) will be considered to be of childbearing potential.
2. Subjects with a diagnosis, for at least 6 months, of moderate to severe COPD (GOLD) and who meet the criteria for Stage II-III disease:
• Subjects must have a post-bronchodilator FEV1/FVC ratio <0.7 and a post- bronchodilator FEV1 of 30 - 80% (inclusive) of the predicted value for age, height, race and sex using European Community for Coal and Steel ECCS standards or NHANES III standards. To qualify for randomization, these criteria must be met at Screening and replicated during run-in phase (see Randomization Criteria for details).
3. Subjects must have a smoking history of at least 10 pack-years* and meet one of the following criteria:
• They are current smokers, or
• They are ex-smokers who have abstained from smoking for at least 6 months.
*Formula for pack-years: cigarettes = (average number of cigarettes/day ÷ 20) x years of smoking, tobacco = ounces per week x 2/7 x years of smoking.
4. Subjects treated with tiotropium bromide (SPIRIVA® HandiHaler®) 18 µg daily for at least 1 month prior to screening.
5. Subjects must have had stable disease for at least 1 month prior to screening. During the screening and run-in phase subjects must be able to manage disease symptoms adequately with tiotropium bromide ±salbutamol (albuterol) rescue medication (subjects should not use >10 actuations [100 µg/actuations] daily for more than 2 consecutive days), without reliance on other therapies including oral or inhaled corticosteroids, other long-acting bronchodilators, nebulizer therapy, theophylline, roflumilast or regular oxygen.
6. Body Mass Index (BMI) <35 kg/m2 and a total body weight >40 kg.
7. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legal acceptable representative) has been informed of all pertinent aspects of the study).Subjects must be able to give informed, written consent prior to entering the study.
8. Subjects who are willing and able to comply with schedules visits, treatment plan, laboratory tests, and other study procedures.Subjects must be willing and able to comply with scheduled visit and all study-related procedures. |
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E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the study:
1. A COPD exacerbation requiring treatment with oral steroids or hospitalization for the treatment of COPD within 3 months of screening.
2. History of a lower respiratory tract infection or significant disease instability during the month preceding screening or during the time between screening and randomization.
3. History or presence of respiratory failure, cor pulmonale or right ventricular failure.
4. Subjects with home oxygen therapy (either PRN or long-term oxygen therapy).
5. Any clearly documented history of adult asthma or other chronic respiratory disorders (eg, bronchiectasis, pulmonary fibrosis, pneumoconiosis).
6. Known previous diagnosis of Hepatitis B or C or HIV infection (specific screening is not required).
7. History of cancer (other than cutaneous basal cell) in the previous 5 years.
8. Active or past history of GI hemorrhage of any etiology, peptic ulceration, erosive esophagitis, gastric outlet obstruction or inflammatory bowel disease.
9. Regular use of aspirin at a dose greater than 325 mg/day.
10. History within the previous 6 months of: myocardial infarction, cardiac arrhythmia (eg, atrial fibrillation, paroxysmal atrial fibrillation, atrial flutter, supraventricular tachycardia, ventricular tachycardia), left ventricular failure, unstable angina, coronary angioplasty, coronary artery bypass grafting (CABG) or cerebrovascular accident (including transient ischemic attacks).
11. A family history of long QT syndrome.
12. Tuberculosis (TB): In order to be enrolled in the study, subjects will be screened for TB. Presence of any of the following means that the subject will be excluded:
• Evidence or history of either untreated or inadequately treated latent or active tuberculosis infection.
• A subject who is currently being treated for active TB infection. Note: a subject currently being treated for latent TB infection may be enrolled if criteria described in the protocol are met.
• Positive reaction (≥5 mm induration) of the PPD tuberculin skin test unless there has been documented vaccination with the bacilli Calmette-Guerin vaccine (BCG).
• Chest X-ray (within last 3 months) with changes suggestive of active TB infection as determined by a qualified radiologist.
13. History within the previous 6 months of:
• An epileptic seizure.
• Poorly controlled Type 1 or Type 2 diabetes.
• Acute hepatitis of any aetiology.
14. Presenting with:
• Any condition possibly affecting oral drug absorption (eg, gastrectomy or clinically significant diabetic gastroenteropathy).
• Any clinically significant skin lesions as described in Common Terminology Criteria for Adverse Events for Dermatology (CTCAE) Version 3.0
• Any clinically significant active systemic or cutaneous infection including herpetic lesions.
• Congestive heart failure requiring treatment New York Heart Association (NYHA) Class III-IV.
15. A major surgical operation within 1 month of screening.
16. ECG abnormalities at screening or randomization, including those listed below. The investigator will decide whether ECG abnormalities other than those listed are clinically significant and should exclude the subject from enrolment if abnormality is considered to be clinically significant:
• Subjects with pre-randomization evidence of QTcF prolongation (defined as
>450 ms) at screening or baseline (Week 0) are not eligible for randomization. This assessment is based on a confirmed mean of the triplicate ECG recordings and is made by the investigator at the time of ECG collection.
• Predominant heart rhythm other than normal sinus rhythm eg, atrial fibrillation, atrial flutter, supraventricular tachycardia.
• Atrioventricular (AV) block greater than first degree.
• Resting heart rate >100 or <40 bpm.
• Evidence of previous myocardial infarction in the absence of clinical history consistent with these findings.
• Evidence of acute ischemia.
17. History or evidence, based upon a complete medical history, full physical examination, posterior-anterior chest X-ray (within last 3 months), 12-lead resting ECG or clinical laboratory test results, of any other significant concomitant clinical disease that, in the opinion of the investigator, could interfere with the conduct, safety or interpretation of results of this study. Subjects with certain chronic conditions such as hypertension, thyroid disease, Type 1 or Type 2 diabetes, hypercholesterolemia, gastroesophageal reflux, or depression may be included in the study providing the conditions are well controlled and medications prescribed to treat the condition are not prohibited, have been stable for the month prior to screening and would not be predicted to compromise safety or interfere with the tests and interpretations of this study.
Please refer to the Protocol for the full list of exclusion criteria |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in trough (pre-treatment and pre-bronchodilator) FEV1 at Week 12.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Spirometry endpoints:
• Change from baseline in trough, pre-bronchodilator FEV1 at Weeks 2, 6, and 10.
• Change from baseline in trough, pre-bronchodilator FEV6, FVC and IC at Weeks 2, 6, 10 and 12.
• Average change from baseline in trough, pre-bronchodilator FEV1,
FEV6, FVC and IC over 12 weeks treatment.
• Change from baseline in post-study drug, pre-bronchodilator FEV1, FEV6, FVC and IC at Weeks 0 and 12.
• Change from baseline in post-study drug, post-bronchodilator FEV1, FEV6, FVC and IC at Weeks 0 and 12.
Patient-reported endpoints:
• Change from baseline in COPD symptoms (EXACT-PRO Daily Diary)
over 12 weeks treatment.
• Change from baseline in Chronic Respiratory Questionnaire - Self
Administered Standard (CRQ-SAS) at Weeks 2, 6, 10 and 12.
• Patient Global Impression of Change at Week 12.
• Rescue bronchodilator use (per daily diary) over 12 weeks of therapy.
Clinician (or other Site Staff)-rated endpoints:
• Change from baseline (BDI) in dyspnea (TDI) at Weeks 2, 6, 10 and 12.
• Clinician Global Impression of Change at Week 12.
Other endpoints:
• Population pharmacokinetics.
Secondary Safety Endpoints
• Adverse event reporting.
• Laboratory safety data.
• Change in ECG measurements post-study medication.
• Change in pulse rate and blood pressure post-study medication. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
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 | 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 | 6 |
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 | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 60 |
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 |
Bulgaria |
Canada |
Japan |
Slovakia |
Sweden |
Argentina |
Chile |
Czech Republic |
Germany |
Hong Kong |
Hungary |
Spain |
Poland |
Serbia |
South Africa |
Taiwan |
Turkey |
United States |
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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
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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 | 1 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |