| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| 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 | 10003553 |
| E.1.2 | Term | Asthma |
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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 test all doses of PF-610,355 for superiority of trough (24 hour post-dose) FEV1 versus placebo.
To characterize the relationship of PF-610,355 dose to peak and trough FEV1
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| E.2.2 | Secondary objectives of the trial |
• To characterize the relationship of PF-610,355 dose to peak and trough peak expiratory flow rate (PEFR).
• To test all doses of PF-610,355 for superiority of trough (24 hour post-dose) PEFR versus placebo.
• To ‘bench-mark’ the efficacy (FEV1 peak effect) of PF-610,355 against salmeterol 50 microgram.
• To investigate the pharmacokinetics of PF-610,355 delivered via CRC749 in asthmatic subjects.
• To investigate the safety and toleration of PF-610,355 delivered via CRC749 in asthmatic subjects.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female subjects aged 18 to 65 years inclusive. Females may be of either child-bearing or non-child bearing potential.
2. All females of childbearing potential may be included provided they are not pregnant (negative urinary pregnancy test) or nursing, and are practicing acceptable contraception methods.
3. Subjects with a physician documented history or diagnosis of persistent asthma (according to Global Initiative in Asthma, GINA, 2006) definition of asthma, for at least 6 months prior to Screening 1.
4. Subjects who have been maintained on a stable dose of ICS over the previous month prior to Screening 1.
5. Screening FEV1 measure of >60% of predicted value for age, height and sex (using Community for Coal and Steel (ECCS) standards), following withdrawal of long-acting beta-agonist for a minimum of 72 hours and short-acting beta-agonist for a minimum of 8 hours. Measurement and reproducibility should conform to current ATS guidelines.
6. Subjects must demonstrate ≥15% improvement in FEV1 (and ≥ 200mL increase) within 15-45 minutes following 200 microgram salbutamol administered from a metered-dose inhaler (MDI) using a spacer.
7. Subjects with stable disease for at least the previous 3 months (i.e. no exacerbations requiring treatment with oral corticosteroids and no asthma-related hospital admissions). Subjects should have had no more than 1 exacerbation in the previous year prior to Screening 1.
8. Subjects with rescue medication use not exceeding 5 occasions per week over the 3 weeks prior to Screening 1.
9. Subjects who do not use short-acting bronchodilators at rest.
10. Body mass index (BMI) of approximately 18 to 33kg/m2 and a body weight of >50kg (110lbs). On a case-by-case basis (after discussion with the Pfizer Clinician), subjects with a BMI <18 or >33kg/m2 may be allowed in the study provided that BMI is proportionate to physical build, weight is stable and the subject is not morbidly obese, anorexic, bulimic or cachectic.
11. Subjects must be able to use the inhalation devices.
12. Subjects must be able to give informed written consent prior to entering the study.
13. Subjects must be willing and able to comply with scheduled visits and all study related procedures
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| E.4 | Principal exclusion criteria |
1. History or evidence, based on complete medical history, full physical examination, 12-lead ECG, or clinical laboratory test results, of any significant concomitant clinical disease (excluding asthma) including haematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease that may adversely affect the safety of the subject or the interpretation of the results of the study. Inclusion of subjects with significant disease (other than asthma) will need to be reviewed on an individual basis with the Pfizer Clinician.
2. Subjects with seasonal or perennial allergy may be included provided they are either asymptomatic or are willing to be maintained throughout the study using a regular dose of intranasal corticosteroids and/or intranasal anti-histamines only and the allergy is known not to cause a worsening of asthma symptoms.
3. Stable, well-controlled conditions such as controlled hypertension [but excluding those on beta-blockers and calcium channel blockers (Class I and II)], thyroid disease, well-controlled Type 1 and Type 2 diabetes, hypercholesterolaemia and gastroesophageal reflux are acceptable provided the symptoms and medication would not be predicted to compromise safety or interfere with the tests and interpretation of the study.
4. Subjects currently maintained on antimuscarinic agents, leukotriene receptor antagonists, theophylline, oral corticosteroids, Xolair, nedocromil or cromolyn are excluded. Subjects who have withdrawn from treatment with antimuscarinic agents, leukotriene receptor antagonists or theophylline, for greater than 2 weeks prior to Screening 1 are allowed.
5. Subjects requiring rescue medication on greater than 2 occasions in the 72 hours prior to Screening 2 (Visit 2) or any use of rescue medication at rest in the 72 hours prior to Screening 2.
6. Subjects who have evidence of drug or alcohol abuse.
7. Subjects who are current smokers. Ex smokers who have given up smoking for < 6 months and/or have a smoking pack history of ≥10 pack years (1 pack year = 20 cigarettes per day for 1 year or 5 cigarettes per day for 4 years).
8. Treatment with an investigational drug within 3 months preceding the first dose of study medication.
9. Subjects with evidence or history of cardiovascular disease including angina, myocardial infarction, clinically significant cardiac arrhythmia (e.g. atrial fibrillation, atrial flutter, superventricular tachycardia, ventricular tachycardia), systemic hypertension (SBP >160mmHg or DBP >100mmHg, resting hypotension (SBP<90mmHg) or resting bradycardia (heart rate <40bpm), pulmonary hypertension or cerebrovascular disease (including transient ischaemic attacks).
10. Screening 12-lead ECG demonstrating any of the following: heart rate >100bpm, QRS duration >120msec, QTcB >450msec, PR interval >220msec, any clinically significant rhythm abnormality or evidence of myocardial injury or ischemia. The assessment of QTc should be made by Principal Investigator.
11. Subjects with seasonally unstable asthma where the season will coincide with the subject’s participation in the study.
12. Subjects with a history of pulmonary disease other than asthma.
13. Respiratory tract infection in the 4 weeks prior to dosing.
14. Female subjects of child-bearing potential who are unwilling, or unable to use an acceptable method of contraception from screening until completion of follow-up procedures.
15. Use of prescription or non-prescription drugs as follows:
•Medication having a significant effect on cardiac rate, conduction system (including QT interval) or myocardial function.
•Medication known to be Cytochrome P-450 3A4 inhibitors or Cytochrome P-450 3A4 inducers are excluded within 28 days of the 1st dose of study medication.
•Medication contraindicated in the salmeterol and salbutamol labels
The following drugs are allowed:
•Protocol-specified asthma medication
•Occasional use of common non-prescription medication
•HRT, contraceptive pill, proton pump inhibitors, topical eczema treatments, thyroxin, Fosamax, ACE-inhibitors and diuretics are allowed.
Inclusion of subjects maintained on other drugs must be with the prior agreement of a Pfizer clinician.
16. Blood donation of approximately 1 pint (500mL) within 56 days prior to dosing and throughout the study.
17. Subjects with a history of significant drug allergies or hypersensitivity to lactose, or inhaled Beta2 agonists.
18. 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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Peak and trough (24 hour post-dose) FEV1. |
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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 | Yes |
| 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 |
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| 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 | 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| 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 |
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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 | 0 |
| E.8.9.1 | In the Member State concerned months | 8 |
| 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 | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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