| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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 |
|
| 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 assess the efficacy of PF-00610355 (‘once daily’ QD doses of 100 mcg, 300 mcg and 600 mcg) in the treatment of moderate asthma following 4 weeks treatment. |
|
| E.2.2 | Secondary objectives of the trial |
To assess the safety and toleration of PF-00610355 (QD) in subjects with moderate asthma.
To characterize the relationship of PF-00610355 dose (QD) to systemic pharmacodynamics (PD) (heart rate and potassium).
To characterize the dose response relationship of PF-00610355 (QD) to efficacy; (forced expiratory volume (FEV1)).
To assess the efficacy of PF-00610355 on quality of life (QOL), asthma symptoms, rescue medication usage, peak expiratory flow (PEF).
To investigate the pharmacokinetics of PF-00610355. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
Screening (Visit 1) Inclusion Criteria
1. Subjects who are willing and able to comply with scheduled visits, treatment plan,
laboratory tests, and other study procedures.
2. Male/Female between and including the ages of 18-65 years. Females may be of either childbearing or non-child bearing potential. See section 4.4.1 for full requirements.
3. Females must be postmenopausal (≥2 year), surgically sterilized or using adequate contraception (see section 4.4.1 for full requirements). All females must also have a negative urine pregnancy test.
4. Body Mass Index (BMI) of approximately 18 to 33 kg/m2 and a body weight of ≥50 kg (110 lbs). On a case-by-case basis (after discussion with Pfizer Clinician), subjects with a BMI <18 or >33 kg/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.
5. Subjects with a physician documented history or diagnosis of persistent asthma (according to GINA, 2007) definition of asthma, for at least 6 months prior to Screening Visit 1.
6. Subjects who have been maintained on a stable dose of ICS over the previous month prior to screening.
7. Subject selection is based on maintenance treatment prior to screening. The population most closely relates to the National Institute of Health Expert Panel Report 3 (NIH EPR 3) guidelines. Thus subjects are at Step 3 or 4 of treatment (or judged similar in severity to these subjects). Subjects must be maintained on one of the following treatments prior to screening:
Low dose ICS plus LABA
Medium dose ICS alone
Medium dose ICS plus LABA
8. Treatment judged to be equivalent to medium dose ICS plus LABA (eg, high dose ICS alone).
9. Trough FEV1 must be 50-100% of predicted (for age, height, sex, race) on current ICS treatment after abstaining from LABA (where applicable) for a minimum of 24 hours and after abstaining from short acting bronchodilator (SABA) for a minimum of 6 hours.
10. Subjects on prior treatment of low dose ICS alone may also be recruited provided they meet the NIH EPR 3 criteria for ‘not well controlled’ (specifically: symptoms >2 days/week and night-time awakenings 1-3 times/ week and/or use of SABA >2 days/ week. These subjects must have a trough FEV1 50-80% of predicted (for age, height, sex, race) on current ICS treatment after abstaining from SABA for a minimum of 6 hours.
11. Reversibility ≥15% and ≥200 ml (within 15-45 minutes following 200 mcg salbutamol, administered with spacer) on current ICS treatment and after abstaining from LABA (where applicable) for a minimum of 24 hours and after abstaining from SABA for a minimum of 6 hours.
12. Subjects with seasonal or perennial asthma (eg, to common aeroallergens) may be included provided they are either asymptomatic (and expect to remain so throughout the study) or are willing to be maintained throughout the study using a regular dose of intranasal corticosteroids and/ or intranasal antihistamines only, and the allergy is known not to cause a worsening of asthma symptoms.
13. Judged able to switch to Asmanex Twisthaler 200 or 400 mcg per day and as needed salbutamol (SABA) for the 5 week run-in period and 4 week treatment period.
Run-in Period (Visit 2) Inclusion Criteria
1. Trough FEV1 50-100% of predicted (age, height, sex, race) after abstaining from SABA for a minimum of 6 hours.
Run-in Period (Visit 3) Inclusion Criteria
1. Trough FEV1 of 50-90% of predicted (age, height, sex, race).
2. Reversibility ≥15% and ≥200 mL (within 15-45 minutes following 200 mcg salbutamol administered with spacer) after abstaining from SABA for a minimum of 6 hours.
Randomisation (Visit 4) Inclusion Criteria
1. Trough FEV1 must be 50-90% of predicted (age, height, sex, race) after abstaining from SABA for 6 hours.
2. FEV1 and PEF must be within plus/minus 15% of the values at Run-in (Visit 3). |
|
| E.4 | Principal exclusion criteria |
1. Subjects who have had a severe asthma exacerbation in the 2 months prior to screening defined as follows: a short temporary increase in corticosteroid therapy (inhaled, oral or IV) in response to worsening asthma control or a decrease in the morning PEF (if known).
2. 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 (eg, 1 pack year = 20 cigarettes per day for 1 year or 5 cigarettes per day for 4 years).
3. Evidence of airways infection in the 4 weeks prior to screening.
4. The subject is diagnosed with chronic obstructive pulmonary disease (COPD) and/or other chronic lung diseases (eg, pulmonary fibrosis, bronchiectasis, pneumoconiosis, sarcoidosis, tuberculosis).
5. FEV1 <50% predicted after abstaining from LABA (where applicable) for a minimum of 24 hours and SABA for a minimum of 6 hours.
6. Subjects meeting any of the criteria of ‘very poorly controlled’ according to the NIH EPR 3 guidelines (see Appendix 2). Specifically: symptoms throughout the day or night-time awakenings >4 times/ week or requirement for SABA several times/ day. (Note: eligibility based on FEV1 is wider than the NIH EPR 3 criteria as the lower limit of prebronchodilator FEV1 allowed in this study is 50%.
7. Evidence of unstable or poorly controlled asthma in the 2 weeks prior to screening, including but not limited FEV1 <50% or if known, PEF ≥30% below personal best for 2 or more consecutive days in the week before screening. Investigators should use their judgment regarding additional indicators of unstable or poorly controlled asthma.
8. Subjects unable to perform acceptable and repeatable spirometry according to the 2005 ATS/ERS guidelines.
9. Subjects with evidence or history of cardiovascular disease including angina, myocardial infarction, clinically significant cardiac arrhythmia (eg, atrial fibrillation, atrial flutter, supraventricular tachycardia, ventricular tachycardia), systemic hypertension (SBP > 160 mmHg or DBP >100 mmHg), pulmonary hypertension or cerebrovascular disease (including transient ischaemic attacks).
10. ECG evidence of QTc prolongation >450 msec.
11. Clinically relevant abnormal laboratory values suggesting an unknown disease and requiring further clinical evaluation (assessed by the investigator).
12. Hypokalaemia (below LLN for reference laboratory).
13. Liver function test abnormalities:
•Alanine amino transferase >3 x upper limit of normal (ULN).
•Aspartate amino transferase >3 x ULN.
•Alkaline phosphatase >1.5 x ULN.
•Total bilirubin >ULN.
14. Note, subjects otherwise eligible for the study but with alanine amino transferase or aspartate amino transferase levels up to 1.5x ULN may be included provided all other liver function parameters are normal. Subjects with levels >1.5x ULN < 3x ULN may be retested after approximately 1 week and included in the study if the above criteria are met.
15. Subjects with previous diagnosis of malignancy, HIV (specific screening is not required), hepatic insufficiency or severe renal insufficiency will be excluded. GFR will be calculated using plasma creatinine (determined for laboratory safety measurement at screening) according to the Cockcroft & Gault formula. Subjects with GFR<30mL/min/1.73E2 will be excluded.
16. History within the previous 6 months of an epileptic seizure, “poorly controlled” (HbAc1≥10%) Type 1 or Type 2 diabetes and or acute hepatitis of any etiology. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline trough (24 hours post-dose) FEV1 at week 4. |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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 | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 | 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
|
| Time at which it is deemed that sufficient subjects have been recruited and completed the study as stated in the regulatory application (eg, Clinical Study Application (CTA)) and ethics application in the Member State. End of Trial in all participating countries is defined as Last Subject Last Visit. |
|
| 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 | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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