E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Bronchiolitis Obliterans Syndrome in Patients post Single Lung Transplantation |
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E.1.1.1 | Medical condition in easily understood language |
Bronchiolitis Obliterans Syndrome in Patients post Single Lung 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 |
To assess the efficacy and safety of add-on aerosolized L-CsA to Standard of Care therapy as compared to SoC therapy alone in the treatment of BOS in single lung transplant recipients. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Adult patients of ≥ 18 years.
2. Patients with diagnosis of BOS Grade 0-p with screening FEV1 between 85-81% of personal best FEV1 value post transplant plus risk factors as defined below, OR BOS Grade 1 with screening FEV1 between 80-66% of personal best FEV1 value post-transplant. Patients with a diagnosis of BOS Grade 0-p must have ≥ 2 of these risk factors for BOS:
- Primary graft dysfunction (PGD)
- Acute cellular rejection
- Lymphocytic bronchiolitis
- Humoral rejection (e.g. de novo anti-human leukocyte antigen antibodies)
- Gastro-oesophageal reflux and microaspiration
- Infection (Viral, Bacterial, Fungal)
- Persistent neutrophil influx and sequestration (bronchoalveolar lavage neutrophilia)
- Autoimmunity (collagen V sensitization).
3. Patients with an FEV1/FVC ratio of < 0.8.
4. Patients in whom the diagnosis of BOS has been confirmed by the elimination of other possible causes of obstructive lung disease.
5. Patients with a diagnosis of BOS 0-p or BOS 1 made at least 1 year after transplant surgery and within 6 months prior to the Screening Visit.
6. Patients receiving a tacrolimus-based basic immunosuppression regimen in combination with MMF (or equivalent) and corticosteroids. This basic immunosuppression regimen must be stable (without changes to doses) for at least 4-weeks prior to Randomization.
7. Patients must consent to retrieve prespecified data from the historic medical record (e.g., information related to the transplant surgery; spirometry data; medication use).
8. Patients must be receiving prophylaxis against Cytomegalovirus (CMV) and Pneumocystis pneumonia.
9. Patients capable of understanding the purposes and risks of the clinical trial, who have given written informed consent and agree to comply with the clinical trial requirements/visit schedules, and who are capable of aerosol inhalation.
10. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to randomization and must agree to use one of the methods of contraception listed in Appendix II for their duration of clinical trial participation.
11. Patients have no concomitant diagnoses that are considered fatal within one year (12 months). |
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E.4 | Principal exclusion criteria |
1. Patients with confirmed other causes for loss of lung function, such as infection, acute rejection, restrictive allograft syndrome (RAS), etc.
2. Patients with Cystic Fibrosis.
3. Patients with donor-specific antibody (DSA) positivity at the Screening Visit.
4. Active bacterial, viral, or fungal infection not successfully resolved at least 4 weeks prior to the Screening Visit.
5. Mechanical ventilation within 12 weeks prior to Randomization.
6. Patient has baseline resting oxygen saturation of < 89% on room air or use of supplemental oxygen.
7. History or presence of bronchial strictures or airway stents or airways requiring balloon dilatations to maintain patency.
8. Known hypersensitivity to L-CsA or to cyclosporine A.
9. Patients with chronic renal failure defined as serum creatinine > 2.5 mg/dL or requiring chronic dialysis.
10. Patients with liver disease and serum bilirubin > 3-fold upper normal value or transaminases > 2.5 upper normal value.
11. Patients with a history of malignancy, including post-transplant lymphoproliferative disorder, with the exception of treated, localized basal and squamous cell carcinomas.
12. Pregnant women or women who are unwilling to use appropriate birth control to avoid pregnancy over the course of the clinical trial.
13. Women who are currently breastfeeding.
14. Receipt of an investigational drug as part of a clinical trial within 4 weeks prior to the Screening Visit. This is defined as any treatment that is implemented under an Investigational New Drug (IND) or compassionate use.
15. Patients who have received extracorporeal photophoresis (ECP) for treatment of BOS within 2 months prior to Randomization.
16. Patients who are currently participating in an interventional clinical trial.
17. Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary procedures.
18. 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Mean change in FEV1 (mL) from baseline. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• Mean change in FEV1/FVC from baseline;
• Time to Progression of BOS, defined as the earliest of the following:
- Absolute decrease from baseline in FEV1 ³ 10% or ³ 200 mL and absolute decrease in FEV1/FVC of > 5%, OR
- Change in BOS Grade, OR
- Re-transplantation, OR
- Death from respiratory failure
This endpoint will be assessed in a combined analysis with a similar Phase III clinical trial, BT – L-CsA – 302 – DLT (BOSTON-2) which will be conducted in the same investigational centers in patients who have undergone double-lung transplantations.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Week 48
• Time to Progression |
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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 | 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) | 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 | No |
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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
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 | No |
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 |
France |
Germany |
Israel |
Spain |
United Kingdom |
United States |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 2 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 2 |