| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Bronchiolitis Obliterans Syndrome | |
| 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 | 10049202 | | E.1.2 | Term | Bronchiolitis obliterans | |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | | The primary objective is to establish an IMP dosage with the most favourable risk-benefit ratio for the treatment of BOS in allogeneic HSCT patients. | |
| E.2.2 | Secondary objectives of the trial | | The secondary objectives are to compare efficacy and safety data from IMP versus placebo and to evaluate IMP PK data in whole blood and sputum samples. | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | 1. Subject’s written informed consent obtained prior to any screening procedure. For subjects below 18 years of age, the written informed consent is obtained from the subject’s legal representative
2.Received an allogeneic haematopoietic stem cell transplantation (HSCT)
3.Has a baseline FEV1 value available prior to HSCT according to Appendix III
4.Has a diagnosis of bronchiolitis obliterans (BOS) of grade 1, 2 or 3 and confirmation to initiate BOS-specific treatment based on declining FEV1 values according to Appendix III within 1 week prior to first IMP administration
5.Male or female, >/= 12 years of age
6.Capable of self-administration medications
7.Capable of understanding the purpose and risk of the clinical trial
8.Received at least 1 week prior to first IMP administration the following immunosuppressive agents and dosages for the treatment of chronic graft-versus-hostdisease (GVHD) including BOS:
a)Tacrolimus approximately 0.1 to 0.2 mg/kg/day adjusted to a target trough serum level (C0) of 5 to 15 µg/L
b)Prednisone 1 to 3 mg/kg/day for 2 to 6 weeks, tapered down subsequently
9.Female patients with reproductive potential must have a negative serum pregnancy test within 3 days prior to screening. Both women and men must agree to use a medically acceptable method of contraception throughout the IMP treatment period and for 3 months after IMP discontinuation. Acceptable methods of contraception are disclosed in Appendix II of the protocol
10.Estimated life expectancy > 6 months
| |
| E.4 | Principal exclusion criteria | 1. Received systemic or topical ciclosporin A within one week prior to IMP administration and during the clinical trial
2.Any active invasive bacterial, viral or fungal infection within one week prior to first IMP admiistration
3.Received systemic immunosuppressive therapy for chronic GVHD other than listed in the inclusion criteria within one week prior to first IMP administration
4.Has steroid-refractory or steroid-intolerant chronic GVHD due to insulin-dependent diabetes or symptomatic avascular necrosis
5.Current mechanical ventilation
6.Pregnant or breast-feeding woman
7.Has a known hypersensitivity to ciclosporin A
8.Has a serum creatinine value of more than 265 µmol/L (3 mg/dL) or chronic dialysis (haemodialysis)
9.Unlikely to comply with the visits, inhalation procedures or spirometric measurements scheduled in the protocol
10.Receipt of an investigational drug as part of a clinical trial within 4 weeks prior to first administration of IMP
11.Any co-existing medical condition that in the investigator’s judgement will substantially increase the risk associated with the subject’s participation in the clinical trial
12.Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary procedures
13.Subject was previously included in the present clinical trial
| |
| E.5 End points |
| E.5.1 | Primary end point(s) | Efficacy Endpoint
• Mean forced expiratory volume in one second (FEV1) at baseline, 3, 6, 9 and 12 month after first IMP administration
• Mean FEV1 slope from baseline to 3, 6, 9 and 12 months after first IMP administration
• Mean forced midexpiratory flow (FEF25-75), vital capacity (VC) and total lung capacity (TLC) at baseline, 3, 6, 9 and 12 months after first IMP administration
• Mean single breath diffusing capacity (DLCO) and capillary blood gases at baseline, 3, 6, 9 and 12 months after first IMP administration
• Cumulative mean incidence of invasive bacterial, viral or fungal infections 3, 6, 9 and 12 months after first IMP administration
• Cumulative mean incidence of acute GVHD at baseline, 3, 6, 9 and 12 months after first IMP administration
• Cumulative mean incidence of chronic GVHD other than BO at baseline, 3, 6, 9 and 12 months after first IMP administration
• Mean walking distance from 6 min walk test at baseline, 3, 6, 9 and 12 months after first IMP administration
• Mean cumulative dose of systemic immunosuppressants 3, 6, 9 and 12 months after first IMP administration
• Mean cumulative number of days without systemic immunosuppressants 3, 6, 9 and 12 months after first IMP administration
• Mean cumulative number of overnight hospital stays 3, 6, 9 and 12 months after first IMP administration
• Mean levels of inflammatory markers and L-CsA from sputum from at least two visits
during the clinical trial period
• Cumulative overall survival during the clinical trial period
Safety
• Incidence of AEs including clinically relevant laboratory findings until EoS
• Mean L-CsA blood levels at baseline and 3 months after first IMP administration
| |
| 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 | 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 | 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 | 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 | 8 |
| 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 | Yes |
| 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 | 18 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 18 |
