| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| patients aged 4 to <12 years with persistent asthma |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| 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 demonstrate the efficacy of ciclesonide, compared to placebo, at 80 μg BID or 40 μg BID for 12 weeks in patients aged 4 to <12 years with persistent asthma. |
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| E.2.2 | Secondary objectives of the trial |
| To assess the safety of ciclesonide. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Informed consent must be obtained from the parent/legal guardian in writing for all patients at screening visit (Visit 1) for enrollment into the study. If a patient is capable of signing a minors assent then the patient must sign a minor’s assent prior to any study procedures.
Patients meeting all of the following criteria at Visit 2 are eligible for enrollment into the study:
1. Males or females aged ≥4 to <12 years of age at the time of randomization;
2. History of persistent bronchial asthma for at least 3 months prior to screening;
3. For patients with persistent bronchial asthma and being treated with a ICS therapy (Previous therapy stratum: ICS): Documented (i.e., as verified in source documents) use of ICS monotherapy (i.e., ≤200 or ≤220 μg/day fluticasone propionate DPI or MDI or equivalent) for at least 30 days prior to screening;
4. For patients with persistent bronchial asthma and not being treated with ICS therapy (Previous therapy stratum: no ICS): No use of an inhaled corticosteroid steroid (ICS) within 30 days prior to screening. Patients may have documented (i.e., as verified in source documents) use of Singulair 5 mg QD or a reliever therapy (SABA) or may be untreated;
5. All patients aged (4 to <12 years of age) with morning Peak Expiratory Flow (AM PEF) of ≤90% of predicted values from the in-clinic spirometry after a 6 hour withhold of albuterol/salbutamol;
6. Only patients aged between 6 to <12 years must have a forced expiratory volume in one second (FEV1) of ≥50% to ≤85% of predicted normal after a 6 hour withhold of albuterol/salbutamol. FEV1 at randomization is required to be within 15% range (ie. relative change to screening value) of FEV1 at screening.
7. Reversibility:
For patients aged between 4 to <6 years: At screening or immediately prior to randomization, reversibility of in-clinic spirometer A.M. PEF after inhalation of 180 μg albuterol/salbutamol or documented history (i.e., as verified in source documents) of reversibility of PEF. Reversibility for such patients will be any improvement in spirometry PEF (L/min).
For patients aged between 6 to <12 years: Reversibility of FEV1 by at least 12% (relative to the pre-bronchodilator value in liters) and ≥200 mL after inhalation of 180 μg albuterol/salbutamol or documented history (i.e., as verified in source documents) of reversibility of FEV1 by at least 12% (relative to the pre-bronchodilator value in liters) and ≥ 200 mL within one year prior to screening.
At Visit 3: Prior to randomization
For all patients
8. Age >4 to <12 years;
9. After an albuterol/salbutamol withhold of at least 6 hours, AM PEF ≤90% of predicted value from the sponsor provided in-clinic spirometry;
10. Daytime asthma symptoms >1 for at least 3 days out of the last 7 days (with non-missing data).
For patients aged between 6 to <12 years only:
11. After an albuterol/salbutamol withhold of at least 6 hours, FEV1 of ≥50% to ≤85% of predicted normal.
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| E.4 | Principal exclusion criteria |
Patients presenting with any of the following will not be included in the study:
1. Nocturnal awakenings for asthma which require treatment with albuterol/salbutamol for 4 or more nights out of the last 7 days of the screening period (with non-missing data);
2. Use of more than 8 puffs/day of albuterol/salbutamol on 3 or more consecutive days within the last 7 days (with non-missing data);
3. Use of β2-adrenergic blocking agents for any reason;
4. Upper or lower respiratory tract infection within 4 weeks prior to screening and duringscreening period;
5. History of cystic fibrosis;
6. History of life-threatening asthma, including a history of significant hypercarbia (pCO2 >45 mmHg), prior intubation, respiratory arrest, or seizures as a result of an exacerbation of asthma;
7. More than 3 in-patient hospitalization or emergency care visits due to asthma exacerbations in the year prior to screening;
8. Use of injectable or oral corticosteroids within one month prior to screening, or more than 3 bursts (ie. oral prednisone tablets/syrup for 3 days or more or an injection of hydrocortisone constitutes a burst) within 6 months prior to screening;
9. Patients on maintenance immunotherapy who either began their immunotherapy regimen or had a clinically relevant change in their immunotherapy regimen within 30 days prior to screening;
10. Patients requiring potent inhibitors of cytochrome P450 3A4 (e.g. ritonavir, ketoconazole. See Appendix F);
11. Clinically relevant cardiovascular, hepatic, neurologic, endocrine, or other major systemic disease making implementation of the protocol or interpretation of the study results difficult;
12. Any clinically relevant deviation from normal in laboratory parameters that would limit participation in the study or interfere with interpretation of study results;
13. Female patients of childbearing potential (i.e., ovulating, pre-menopausal, not surgically sterile) unless practicing an adequate method of birth control, or unless sexual abstinence is confirmed at informed consent, or unless premenarchal and prepared to accept counseling on reproductive issues in case of becoming menarchal;
14. Likelihood of requiring treatment during the study period with medications not permitted by the study protocol;
15. Treatment with any Investigational Product within 30 days prior to screening;
16. Previous randomization in this study;
17. History of hypersensitivity to the study medication(s) or to drugs with a similar chemical structure;
18. Intolerance to albuterol/salbutamol and/or excipients in the MDI (HFA-134a propellant and ethanol excipient);
19. History of substance abuse;
20. Parent(s)/legal guardian(s) is (are), in the opinion of the Investigator, mentally or legally incapacitated preventing informed consent from being obtained;
21. Patient/parent unlikely to comply with protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study, and for 6 to <12 years only inability to perform spirometric measurements according to the ATS criteria;
22. Patient is the relative of the Investigator or sub-Investigator, research assistant, pharmacist, study coordinator or other staff and thereof directly involved in the conduct of the protocol;
23. Not able to demonstrate acceptable oral inhaler technique with the MDI (see Appendix B)and optional attached AeroChamber Z-Stat Plus® holding chamber, (see Appendix C).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy analysis variable will be the change from baseline (Day 1) to end of study (Week 12 or early termination) in FEV1 percent predicted for patients of 6 to <12 years only (FEV1 measurement for patients less than 6 years old is considered not reliable). FEV1 percent predicted will be based on the FEV1 predicted normal calculated using the Polgar predicted standards using the corresponding height measurements.
• The end-of-study FEV1 percent predicted will be based on a valid FEV1 value and height measured at Week 12 (Visit 8). However, if a valid Week 12 value for a particular patient is not available, the patient’s last valid FEV1 measurement closest to the last dose of study medication value will be used as the end-of-study FEV1 value to calculate the end-of-study FEV1 percent predicted (the last observation carried forward (LOCF) approach).
• Baseline FEV1 percent predicted value will be based on the FEV1 value and height recorded on Day 1 (Week 0, Visit 3), prior to the administration of double-blind study medication. The FEV1 measurement should be collected prior to the reversibility test if performed, otherwise, it should be the latest measurement prior to the first administration of double-blind study medication.
In addition, the change from baseline to the average of the Week 8 (Visit 7) and Week 12 (Visit 8) FEV1 percent predicted values will be used as a supportive efficacy variable to the primary efficacy endpoint. In case of discontinuation before Week 12, the LOCF procedures described below will be used to determine the end of study FEV1 value: for patients who discontinue between Weeks 8 and 12, the average of the Week 8 and the end-of-study FEV1 percent predicted will be used; for patients who discontinue before Week 8, the end-of-study FEV1 percent predicted will be used.
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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 | 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 | Information not present in EudraCT |
| 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) | Yes |
| 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 | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Single-blind placebo run in followed by double-blind treatment phase |
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| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| 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 | |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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