E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Bronchiolitis Obliterans Syndrome in Patients Following Allogeneic Hematopoietic Stem Cell Transplantation
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E.1.1.1 | Medical condition in easily understood language |
Bronchiolitis Obliterans Syndrome in Patients Following Allogeneic Hematopoietic Stem Cell Transplantation
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
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 of this study is to assess the tolerability and safety, of two dose levels of aerosolized L-CsA vs placebo in addition to SoC therapy for the treatment of BOS in adult allo-HSCT recipients. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to assess PK and exploratory efficacy and quality of life of two dose levels of aerosolized L-CsA vs placebo in addition to SoC therapy for the treatment of BOS in adult allo-HSCT recipients. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Age ≥ 18 years.
2. Patient must have a history of allo-HSCT, regardless of source of stem cell or donor or indication for allo-HSCT
3. Documented diagnosis of cGvHD in any organ other than the lung. If BOS is the only manifestation of cGvHD, lung biopsy must have been performed before entering the trial to confirm BOS diagnosis.
4.Confirmed diagnosis of BOS Score 1 within > 6 months and < 3 years after allo-HSCT:
FEV1/FVC < 0.7 at Screening Visit AND
Post-bronchodilator FEV1 ≥ 60 and ≤ 79% predicted at Screening Visit AND
≥10% decline of FEV1 % predicted within 24 months prior to Screening Visit AND
Absence of acute infection in the respiratory tract.
5. Patient must be capable of understanding the purposes and risks of the study, has given written informed consent, and agrees to comply with the study requirements.
6. Patient is capable of aerosol inhalation.
7. Women of childbearing potential must have a negative serum or urine pregnancy test at screening and at randomization visit. |
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E.4 | Principal exclusion criteria |
1.Active bacterial, viral (as confirmed by multiplex PCR) or fungal infection not successfully resolved at least 4 weeks prior to the Screening Visit.
2.Chronic renal dysfunction with serum creatinine ≥ 2.5 mg/dL or need for renal dialysis.
3.Chronic hepatic dysfunction with serum total bilirubin > 5x upper limit of normal (ULN), transaminases > 5x ULN, or alkaline phosphatase > 5x ULN.
4. Evidence of relapse of the primary malignancy which warranted allogeneic bone marrow transplant.
5. Use of azithromycin within 4 weeks prior to Randomization (Visit 1).
6. Use of zafirlukast during the study period.
7. Chronic oxygen use or use of non-invasive ventilation.
8. Active smokers (i.e. any kind of inhaled nicotine consumption).
9. Pregnant women or women who are unwilling to use appropriate birth control to avoid pregnancy over the course of the clinical trial (for details see Appendix II).
10. Women who are currently breastfeeding.
11. Known hypersensitivity to L-CsA or to cyclosporine A.
12. Patients who do not tolerate administration of inhaled bronchodilators (e.g., salbutamol).
13. Patients with life-expectancy of less than 6 months.
14. Treatments with other Investigational Medicinal Products (IMPs) or previous therapies within four weeks or five times half-life of the drug, whichever is longer prior to screening and during the study. Participation in registries, considering the before, is allowed.
15. Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary procedures.
16. Any co-existing medical condition that in the Investigator’s judgment will substantially increase the risk associated with the patient’s participation in the clinical trial.
17. Pre-scheduled hospitalizations, surgeries or interventions planned to be performed after obtaining Informed Consent for this study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
IMP tolerability and safety during the first 4 weeks of treatment
IMP Tolerability Parameters:
• Local Tolerability:
o Cough
o Wheezing
o Bronchospasm
o Throat irritation
o Change in FEV1
•Overall Tolerability:
o Clinical Global Impressions (CGI) scale
o Investigator’s tolerability assessment at Visit 3
Safety Parameters:
• Adverse events (AEs)
• Serious adverse events (SAEs)
• Clinical laboratory values
• Vital signs
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
IMP tolerability and safety during the first 4 weeks of treatment
Please refer to 'Schedule of Activities' in the Protocol |
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E.5.2 | Secondary end point(s) |
IMP tolerability and safety during the first 12 weeks of treatment;
IMP Tolerability Parameters:
• Local Tolerability:
o Cough
o Wheezing
o Bronchospasm
o Throat irritation
o Change in FEV1
•Overall Tolerability:
o Clinical Global Impressions (CGI) scale
o Investigator’s tolerability assessment at Visit 3
Safety Parameters:
• Adverse events (AEs)
• Serious adverse events (SAEs)
• Clinical laboratory values
• Vital signs
CsA Pharmacokinetic Parameters:
o Cmax
o tmax
o AUC0-4h
• Whole blood trough levels |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
IMP tolerability and safety during the first 12 weeks of treatment;
Pharmacokinetic Parameters:
• PK: (Week 0) at pre-dose; directly after end of inhalation; 15, 30, and 45 minutes, and 1, 1.5, 2, and 4 hours after end of inhalation:
• Whole blood trough levels (at Weeks 2, 4, 8, and 12)
Please refer to 'Schedule of Activities' in the Protocol |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
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 |
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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 | 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 | Yes |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
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 | No |
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
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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 | 10 |
E.8.9.1 | In the Member State concerned days | 7 |
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 | 10 |
E.8.9.2 | In all countries concerned by the trial days | 7 |