| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Obstructive Pulmonary Disease |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010952 |
| E.1.2 | Term | COPD |
|
| 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 efficacy and safety/tolerability of PH-797804 in adults with moderate to severe COPD (GOLD stage II/III). |
|
| E.2.2 | Secondary objectives of the trial |
• To characterize the dose response of PH-797804 in COPD patients.
• To explore the efficacious dose range for PH-797804 in COPD patients.
• To evaluate the time course of response to PH-797804 in COPD patients.
• To explore the PK-PD relationship between dose and/or systemic PH-797804 exposure versus efficacy and/or safety/tolerability in COPD patients. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female subjects between, and including, the ages of 40 and 80 years. Females must be of non-childbearing potential. Females of non-child-bearing potential will be defined as:
• Females over the age of 60 years.
• Females who are 45-60 years of age who have been amenorrheic for at least 2 years and have a serum FSH level >30 IU/L in the absence of hormone replacement therapy or have a documented hysterectomy and/or bilateral oophrectomy.
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 postbronchodilator FEV1 of 30 - 80% (inclusive) of the predicted value for age, height, race and sex using European Community for Coal and Steel ECCS standards. To qualify for randomization, these criteria must be met at Screening and replicated during run-in phase.
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 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 short-acting bronchodilators only [i.e. inhaled ipratropium bromide 2 actuations (20µg /actuation) QID administered from a MDI +/- salbutamol (albuterol) rescue medication up to a maximum of 8 actuations (100µg /actuation) daily], without reliance on other therapies including oral or inhaled corticosteroids, long-acting bronchodilators, nebulizer therapy, theophylline or regular oxygen.
5. Body Mass Index (BMI) < 35 kg/m2 and a total body weight >40 kg.
6. Subjects must be able to give informed, written consent prior to entering the study.
7. Subjects must be willing and able to comply with scheduled visit and all study-related procedures. |
|
| E.4 | Principal exclusion criteria |
1.More than 2 exacerbations of COPD requiring treatment with oral steroids in the preceding year or hospitalization for the treatment of COPD within 3 months of screening or more than twice during the preceding year.
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 (e.g. bronchiectasis, pulmonary fibrosis, pneumoconiosis).
6.Known previous diagnosis of HIV infection.
7.History of cancer (other than cutaneous basal cell) in the previous 5 years.
8.History within the previous 2 years of: myocardial infarction, cardiac arrhythmia (e.g. atrial fibrillation, paroxysmal atrial fibrillation, atrial flutter, supraventricular tachycardia, ventricular tachycardia), left ventricular failure, congestive cardiac failure, unstable angina, coronary angioplasty, coronary artery bypass grafting (CABG) or cerebrovascular accident (including transient ischemic attacks).
9.Tuberculosis without treatment and/or positive tuberculin reaction to PPD (Purified Protein Deriviative) without known (documented) vaccination with the bacilli Calmette-Guerin vaccine (BCG). A positive approved immunoassay/ELIA blood test for TB (e.g. TB T-SPOT, QuantiFERON-Gold test) where used.
10.History within the previous 6 months of:
• An epileptic seizure.
• Poorly controlled Type 1 or Type 2 diabetes.
• Acute hepatitis of any aetiology.
11.Presenting with:
• Any condition possibly affecting oral drug absorption (e.g. 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 infection including herpetic lesions;
• Congestive heart failure requiring treatment New York Heart Association (NYHA) Class III-IV;
12.A major surgical operation within 1 month of screening.
13.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 QTc prolongation at screening or baseline Week 0 (defined as >450 ms) 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 e.g. 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 ischaemia.
14.History or evidence, based upon a complete medical history, full physical examination, posterior-anterior chest X-ray (within last 12 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.
15.Evidence of organ dysfunction or hematopoietic disorder based on any of the following assessments:
• Hgb <10 g/dL, Hct <32%;
• Absolute WBC count <3.0 x 109/L (<3000/mm3)
• Neutrophil count < 1.2 x 109/L (<1200/ mm3)
• Platelet count <100 x 109/L (<100,000/ mm3)
• AST or ALT >1.2 x ULN
• Total bilirubin >1.2 x ULN
• Alkaline phosphatase >1.2 x ULN
• Albumin <3.5 g/dL or 35 g/L due to known liver disease
• Serum creatinine >ULN
16.Positive HBsAg, HBcAb or anti-hepatitis C virus serology.
17.Use of any of the prohibited concomitant medications within the time frame prior to the start of screening or during the run-in period.
18.History of severe drug induced hypersensitivity (i.e. anaphylaxis).
19.Contraindication for rescue/maintenance medication i.e. salbutamol (albuterol) or ipratropium bromide.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Change from baseline in trough (prior to administration of study medication) forced
expiratory volume in one second (FEV1) at Week 6. |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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.8.3 |
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 | 20 |
| 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 | Information not present in EudraCT |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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