E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Bronchiolitis Obliterans Syndrome (BOS) in patients following lung transplantation. This syndrome occurs due to rejection of the transplanted organ (s). |
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E.1.1.1 | Medical condition in easily understood language |
A lung disease in which the small airway branches (bronchioles) are compressed and narrowed by scar tissue (fibrosis) and/or inflammation. This leads to partial or complete blockage of the airways.
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10049202 |
E.1.2 | Term | Bronchiolitis obliterans |
E.1.2 | System Organ Class | 100000004855 |
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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 evaluate the effect of Pirfenidone on the change in FEV1 over 6 months in lung transplant recipients with bronchiolitis obliterans syndrome, who are treated with Azithromycin. |
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E.2.2 | Secondary objectives of the trial |
• Categorical percentage change in FEV1 [Categorical percentage change in FEV1 ≥ 10 % (increase or decrease) relative to FEV1 (ml) at baseline]
• Change of FVC in liters
• Change in TLC in liters
• FEV1/FVC ratio change
• Number of patients with treatment failure
• Change in BOS grade
• Change in percent predicted DLco.
• Change in functional level as assessed by the 6MWT
• Hospital admission for any reason
• Death or re-transplantation rates
• Change in EQ5D scale
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients >18 years of age
2. Azithromycin therapy for at least 4 weeks prior to study start, with an Azithromycin dose of minimum 250mg /day at least 3 times per week
3. Double lung transplantation is required;
4. Patients must be at least 6 months after transplantation and must have documented post-transplant, base-line value of FEV1 (mean of the 2 highest values measured at least 3 weeks apart according to ISHLT criteria)
5. Patients must have BOS grade 1 - 3.
6. Patients must have documented progressive disease as demonstrated by:
• At least 3 FEV1 measurements in the last 6 months each at least 3 weeks apart
• a total decline of at least 200mL in FEV1 in the last 6 months
• a mean decline of at least 50 mL in the last two measurements
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E.4 | Principal exclusion criteria |
1. Patients with redo lung transplantation or combined transplantation (including heart and lung transplantation) Or Single lung recipients
2. Patients with any severe comorbidity complicating BOS which might determine the prognosis and functional level of the patient (e.g. invasive aspergillosis, active malignant disease within last 12 months (i.e. disease free since at least 12 months))
3. FEV1 decline related to other non BOS causes (eg pneumothorax, bronchial stenosis, effusion, etc.)
4. Screening ECG shows QTc > 500 ms
5. Patients who on Thorax CT at entry demonstrate new significant findings which are not compatible with BOS like interstitial fibrosis, consolidation, appearances suggesting restrictive Allograft Syndrome (RAS) and acute pulmonary infection as cause of decline in lung function
6. Documented acute perivascular rejection higher than grade A1 or findings compatible with antibody mediated rejection at the last trans bronchial biopsy performed.
7. Pregnancy or lactation.
8. Renal insufficiency (Creatinine clearance <30 ml/min calculated by the CKD-Epi formula).
9. Any of the following liver test criteria above the specified limit:
• Total bilirubin above the upper limit of the normal range (ULN), except in patients with predominantly unconjugated hyperbilirubinemia (e.g., Gilbert’s syndrome)
• Aspartate or alanine aminotransferase (AST or ALT) >3 × ULN
• Subjects with severe liver impairment (Child Pugh C )
10. Known allergy or hypersensitivity to Pirfenidone
11. Ongoing use or expected use of any of the following therapies:
- Strong inhibitors of CYP1A2 (e.g. fluvoxamine or enoxacin)
- Moderate inhibitors of CYP1A2 (e.g. mexiletine, thiabendazole, oral contraceptives or phenylpropanolamine [Note: ciprofloxacin will be allowed only at doses ≤500 mg BID])
- Moderate inducers (Montelukast, phenytoin)
- Cimetidine
- Previous treatment with Pirfenidone after transplantation
12. Patients who have resumed smoking after transplantation
13. Initiation of a new bronchodilator therapy or treatment with Montelukast within 4 weeks prior to randomization |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of the study is the change in FEV1 (ml) from baseline to 6 months. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
This endpoint will be evaluated at the end of the study (the 6 month visit for each patient). |
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E.5.2 | Secondary end point(s) |
• Categorical percentage change in FEV1 [Categorical percentage change in FEV1 ≥ 10 % (increase or decrease) relative to FEV1 (ml) at baseline]
• Change of FVC in liters
• Change in TLC in liters
• FEV1/FVC ratio change
• Number of patients with treatment failure
• Change in BOS grade
• Change in percent predicted DLco.
• Change in functional level as assessed by the 6MWT
• Hospital admission for any reason
• Death or re-transplantation rates
• Change in EQ5D scale
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
All secondary endpoints will be evaluated at the end of the study (the 6 month visit for each patient). |
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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) | 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 | 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 | 2 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 11 |
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 | 1 |
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 years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 9 |