| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Obstructive Pulmonary Disease (COPD) |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009033 |
| E.1.2 | Term | Chronic obstructive pulmonary disease |
|
| 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 estimate the bronchodilatory trough effect of 3 single dose levels of PF-03635659 delivered via the CRC749 inhaler device in moderate COPD subjects in order to select the lowest efficacious dose to study in Phase 2b.
To investigate the pharmacokinetics of 3 single dose levels of PF-03635659 delivered via the CRC749 inhaler device in moderate COPD subjects. |
|
| E.2.2 | Secondary objectives of the trial |
To ‘bench-mark’ the efficacy trough effect of single dose PF-03635659 against single dose Spiriva® (tiotropium bromide) 18 mcg.
To investigate the safety and toleration of 3 single dose levels of PF-03635659 delivered via the CRC749 inhaler device in moderate COPD subjects. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female (women of non-childbearing potential) subjects between the ages of 40 and 80 years, inclusive with a diagnosis of moderate COPD (GOLD, 2007 update) and who meet the following criteria for GOLD stage II disease:
•Post-bronchodilator FEV1/FVC ratio of <0.7, and a
•Post bronchodilator FEV1 of 50-80% (inclusive) of predicted for age, height, sex and race.
•Note: Subjects who are maintained on LABA, Spiriva® or ipratropium should have a washout period of at least 48, 72 and 24 hours respectively before undergoing the screening post-bronchodilator test.
2. Body Mass Index (BMI) of less than 35.5 kg/m2; and a total body weight >40 kg (88 lbs).
3. Subjects must have a smoking history of at least 10 pack-years (Formula for pack-years cigarettes = (average number of cigarettes/day ÷ 20) x years of smoking. Formula for pack-years tobacco = ounces per week x 2/7 x years of smoking) 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.
4. Subjects must have stable disease for at least 1 month prior to screening. Subjects must be able to manage their symptoms adequately with short-acting bronchodilators only. (Salbutamol as needed, maximum of 8 actuations (100 mcg/actuation) daily). Subjects currently maintained on LABA and/or Spiriva®, must agree to withdraw these drugs at least 2 weeks prior to study Period 1 and must be able to manage their symptoms with salbutamol as stated above. (During the LABA and/or Spiriva® wash out period subjects will be contacted by telephone to check their stability).
5. An informed consent document signed and dated by the subject or a legally acceptable representative.
6. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. |
|
| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the study:
1. Subjects having more than 2 exacerbation requiring treatment with oral steroids or hospitalization for the treatment of COPD in the previous year.
2. Use of prescription or non-prescription drugs as follows:
•Subjects on medication (other than salbutamol) having a significant effect on cardiac rate, conduction system (including QT interval) or myocardial function.
•Subjects on inhaled corticosteroids.
3. Subjects with uncontrolled hypertension. Stable hypertensive subjects are permitted but must remain on their anti-hypertensive medication through out the study and not change drug, regime or dose etc during the trial.
4. History of lower respiratory tract infection or significant disease instability during the month preceding screening or during the period between screening and randomization.
5. History or presence of respiratory failure, cor pulmonale or right ventricular failure.
6. Apart from COPD, any clearly documented history of adult asthma (onset of symptoms prior to the age of 40 years) or other chronic respiratory disorders (eg, bronchiectasis, pulmonary fibrosis, pneumoconiosis.
7. Abnormal 12-lead ECG including evidence of ischaemia, myocardial infarction, arrhythmia or QTc >450 msec. (If QTc exceeds these limits, the ECG should be repeated two more times and the average of the three QTc values should be used to determine the subject’s eligibility). Patients with familial long QT syndrome are also excluded.
8. A resting pulse rate >100 bpm or <50 bpm.
9. History within the previous year of: myocardial infarction, cardiac arrhythmia (eg, atrial fibrillation, paroxysmal atrial fibrillation, atrial flutter, supraventricular tachycardia, ventricular tachycardia), cardiac insufficiency NYHA II-IV, left ventricular failure, unstable angina, coronary angioplasty, or coronary artery bypass grafting (CABG).
10. Any of the following liver function test abnormalities that persist on retesting:
•Alanine amino transferase >1.5 x upper limit of normal (ULN).
•Aspartate amino transferase >1.5 x ULN.
•Alkaline phosphatase >1.2 x ULN.
•Total bilirubin >1.5 x ULN.
11. Use of any investigational drug within 6 weeks prior to dosing.
12. History of severe drug induced hypersensitivity (ie, anaphylaxis).
13. A positive urine drug screen.
14. History of regular alcohol consumption exceeding 14 drinks/week for females or 21 drinks/week for men (1 drink = 150 mL of wine or 360 mL of beer or 45 mL of spirits) within 6 months of screening.
15. Pregnant or nursing females and females of childbearing potential.
16. Subjects with a known intolerance to lactose, ipratropium, Spiriva® (tiotropium bromide) or any of the listed rescue medications.
17. Subjects in whom antimuscarinic agents are contraindicated or who suffer from hypersensitivity to Spiriva®, atropine or its derivatives, eg, ipratropium or oxitropium or to the excipient lactose monohydrate which contains milk protein.
18. Subjects suffering narrow-angle glaucoma, benign prostatic hyperplasia or bladder-neck obstruction.
19. Blood donation of approximately 1 pint (500 mL) within 56 days prior to dosing.
20. Unwilling or unable to comply with the Lifestyle guidelines described in this protocol.
21. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study, or a legally institutionalized subject. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy
Change from baseline in trough FEV1.
Pharmacokinetics
Cmax, CmaxDN, Tmax, AUClast, AUClastDN, AUCinf, AUCinfDN, T½. |
|
| 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 | 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 | No |
| 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 | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| 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 | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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
|
| LSLV is defined as the date the investigator reviews the last subject’s final safety data and determines that no further evaluation is required for the subject to complete 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 | 3 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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