| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| 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 investigate whether regular treatment with salmeterol in combination with fluticasone propionate (FP) has an effect on blood markers of airway inflammation compared with FP alone or placebo in response to allergen challenge when treatment is administered over a period of 35 days. |
|
| E.2.2 | Secondary objectives of the trial |
| To investigate whether the time of dosing relative to the time of allergen challenge has an effect on blood markers of airway inflammation |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. A signed and dated written informed consent must be obtained from the subject and/or the subject’s legally acceptable representative prior to study participation.
2. Type of Subject: Outpatient
3. Gender: Male or female
Females are eligible to participate only if they are currently non-pregnant and non lactating.
A female is eligible to enter and participate in the study if she is of:
Non-child bearing potential (i.e., physiologically incapable of becoming pregnant), including any female who is post-menopausal.
Child bearing potential, has a negative pregnancy test (urine) at screening and all remaining visits throughout the study (as specified in Appendix 1), and agrees to one of the following acceptable contraceptive methods used consistently and correctly (i.e., in accordance with the approved product label and the instructions of the physician for the duration of the study – screening to follow-up telephone contact):
Acceptable methods of contraception are [Hatcher, 2004]:
• Abstinence
• oral contraceptive (either combined or progestogen only)
• injectable progestogen
• implants of levonorgestrel
• estrogenic vaginal ring
• percutaneous contraceptive devices
• intrauterine device (IUD) or intrauterine system (IUS) with published data showing that the failure rate is less than 1% per year
• male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study and is the sole sexual partner for that female subject
• double barrier method: condom or occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent
4. A subject must be ≥18 - 55 years of age at Visit 1a.
5. Asthma Diagnosis: A diagnosis of persistent asthma, for at least 3 months prior to Visit 1a, as defined by the National Institutes of Health [National Institute of Health, 2002; GINA, 2005].
6. Asthma Severity: A pre-albuterol (salbutamol) FEV1 of equal or greater than 75% of predicted normal value at screening (Visit 1a) based on the ECCS“Standardization of Lung Function Tests” [European Respiratory Journal, 1993] standards for 18 years and older and race adjusted for African-Americans [American Thoracic Society, 1991].
7. Concomitant Anti-Asthma Therapy: Subjects must have been using an as-needed short-acting beta2-agonist bronchodilator for 3 months preceding Visit 1a with no inhaled corticosteroid use for at least 4 weeks prior to Visit 1a.
8. Albuterol Use: All subjects must be able to replace their current short-acting beta2-agonist with study supplied albuterol/salbutamol MDI, to be used on an as-needed basis for the duration of the study. Each subject must be judged capable of withholding albuterol for at least 6 hours prior to performing spirometric evaluations.
9. Reversibility of Disease: Demonstrated ≥12% and 200mL reversibility of FEV1 within 30 minutes following 200mcg to 400mcg of albuterol/salbutamol inhalation aerosol (or one to two nebulized albuterol/salbutamol treatment) at Visit 1a.
Airway Hyperresponsiveness: If a subject fails to demonstrate reversibility of disease, the subject may then undergo a methacholine challenge 1 to 3 days after initial reversibility and must demonstrate bronchial hyperresponsiveness by a 20% decrease in FEV1 in response to a provocative concentration of inhaled methacholine (PC20) of <8mg/ml to be enrolled at Visit 1a. This procedure will be part of the visit 1a study assessments.
10. Demonstrated evidence of atopy with a positive skin prick test to allergens (US: cat, house dust mite or ragweed), and (UK: cat, house dust mite and grass pollens) at Visit 1a.
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|
| E.4 | Principal exclusion criteria |
1. History of Life-threatening asthma: Defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest or hypoxic seizures.
2. Anti-Asthma Medications: Asthma medications listed below must not have been used prior to Visit 1a for the required interval listed below, and not taken during the study:
Within 2 weeks of Visit 1a:
• Oral short-acting beta2-agonists
• Slow-release bronchodilators (e.g., aminophylline, theophylline)
• Oral long-acting beta2-agonists
Within 4 weeks of Visit 1a:
• Inhaled corticosteriods
• Combination therapy containing inhaled beta2-agonists and ICS for asthma (e.g., fluticasone propionate/salmeterol combination, budesonide/formoterol combination)
• Anticholinergics
• Long-acting beta2-agonists (e.g., salmeterol, formoterol)
• Ketotifen
• Nedocromil sodium
• Sodium cromoglycate
• Anti-leukotrienes including suppressors of leukotriene production and antagonists
• Immunotherapy for the treatment of allergies is not allowed during the study. The subject must have stopped treatment within 4 weeks of Visit 1a to be eligible for enrolment into the study.
Within 12 weeks of Visit 1a:
• Systemic, oral, parenteral, or depot corticosteroids
• Anti-IgE (e.g., omalizumab)
3. Other Medications: The medications listed below must not have been used prior to Visit 1a for the required interval indicated below, and not taken during the study:
Within 1 week of Visit 1a:
• Antihistamines (including both short and long-acting)
Within 4 weeks of Visit 1a:
• Known potent inhibitors of CYP3A4 (e.g., ritonavir, ketoconazole)
4. Respiratory Infection: History of a respiratory tract infection within 4 weeks of Visit 1a.
5. Asthma Exacerbation: History of a an asthma exacerbation within 4 weeks of Visit 1a, any asthma exacerbation requiring oral corticosteroids within 3 months of Visit 1a, or any hospitalization due to asthma exacerbation within 6 months of Visit 1a.
6. Subjects with only exercise-induced asthma are excluded from participation in this study.
7. Concurrent Respiratory Disease: A subject must not have current evidence of pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic bronchitis, emphysema, chronic obstructive pulmomary disease, or other respiratory abnormalities other than asthma
8. Other Concurrent Diseases/Abnormalities: A subject must not have any clinically significant, uncontrolled condition or disease state that, in the opinion of the investigator, would put the safety of the patient at risk through study participation or would confound the interpretation of the efficacy results if the condition/disease exacerbated during the study.
9. Investigational Medications: A subject must not have used any investigational drug within 30 days prior to Visit 1a or within ten half-lives (t ½) of the prior investigational study (which ever is longer of the two) or concurrently during the study.
10. Drug Allergy: Any adverse reaction including immediate or delayed hypersensitivity to any beta2-agonist, sympathomimetic drug, or any intranasal, inhaled, or systemic corticosteroid therapy. Known or suspected sensitivity to the constituents of the powder inhaler (i.e., lactose).
11. Positive Pregnancy Test: A current positive pregnancy test.
12. Immunosuppressive Medications: Use of immunosuppressive medications is not allowed at any time during the study.
13. Milk Protein Allergy: History of severe milk protein allergy.
14. Attendance: A subject will not be eligible if he/she has any infirmity, disability, or geographical location which seems likely (in the opinion of the Investigator) to impair compliance with any aspect of this study protocol or scheduled visits to the study center and non-compliant with study medication or procedures (e.g. completion of daily diary). Neurological or psychiatric disease or history of drug or alcohol abuse which in the opinion of the investigator could interfere with the subject’s proper completion of the protocol requirements excludes study participation.
15. Tobacco Use: A subject may not have used tobacco products within the past one year (i.e., cigarettes, cigars, or pipe tobacco) or have historical use of >10 pack years (e.g., 20 cigarettes/day for 10 years).
16. Affiliation with Investigator’s Site: A subject will not be eligible for this study if he/she is an immediate family member of the participating Investigator, sub Investigator, study coordinator, or employee of the participating Investigator.
17. Concomitant Medications: Concomitant use of any of the following medications that may affect the course of asthma or interact with sympathomimetic amines will not be allowed. Specifically:
• beta blockers
• polycyclic antidepressants
• monoamine oxidase inhibitors
• phenobarbital
• ritonavir
• ketoconazole
• rifampin
• itraconzole
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Weighted mean change from baseline over 0-6 hours post allergen challenge in blood eosinophils between salmeterol/fluticasone propionate and placebo on Day 35 |
|
| 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 | No |
| E.6.5 | Efficacy | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Investigation of effect on blood markers of airway inflammation |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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) | 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
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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