E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Idiopathic Pulmonary Fibrosis (IPF) |
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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 | 10021240 |
E.1.2 | Term | Idiopathic pulmonary fibrosis |
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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 assess the efficacy of treatment with pirfenidone 2403 mg/d compared with placebo in patients with idiopathic pulmonary fibrosis (IPF) •To assess the safety of treatment with pirfenidone (1197 and 2403 mg/d) compared with placebo in patients with IPF •To characterize the pharmacokinetic disposition of pirfenidone in patients with IPF
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E.2.2 | Secondary objectives of the trial | |
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Clinical symptoms consistent with IPF, including the insidious onset of otherwise unexplained dyspnea on exertion, of ≥3 months duration 2. Diagnosis of IPF, defined as first instance in which a patient was informed of having IPF, within 48 months of randomization 3. Age 40 through 80 years, inclusive 4. High-resolution computed tomographic (HRCT) scan showing a pattern of disease consistent with a confident (definite) radiographic diagnosis of usual interstitial pneumonia (UIP)/IPF. For patients with surgical lung biopsy showing definite or probable UIP, the HRCT criterion of probable (UIP)/IPF is sufficient. 5. For patients aged <50 years: open or video-assisted thoracoscopic (VATS) lung biopsy showing definite or probable UIP within 48 months of randomization. In addition, there are no features supporting an alternative diagnosis on transbronchial biopsy or bronchoalveolar lavage (BAL), if performed (see Table 3–1). 6. For patients aged more/equal to 50 years: At least one of the following diagnostic findings, as well as the absence of any features on specimens resulting from any of these procedures that support an alternative diagnosis, within 48 months of randomization (see Table 3–1): a. Open or VATS lung biopsy showing definite or probable UIP (see Appendix C of protocol) b. Transbronchial biopsy showing no features to support an alternative diagnosis. These alternative diagnoses include but are not limited to granulomatous disease, sarcoidosis, and hypersensitivity pneumonitis. c. BAL showing no features to support an alternative diagnosis Summary of Select Criteria for Diagnosis of IPF
Patient age ≥50 Years <50 Years
HRCT findings Definitive IPF Probable IPF Definitive IPF Probable IPF Pathologic Nondiagnostic Surgical* lung Surgical* lung Surgical* lung findings transbronchial biopsy with biopsy with biopsy with biopsy or BAL, UIP UIP UIP or surgicala lung biopsy with UIP *VATS or open lung.
7. Percent predicted FVC ≥50% at the Screen Visit and Day 1 (before randomisation). The change in FVC (measured in liters) between the Screen Visit and Day 1 must be ≤10% relative difference 8. Hemoglobin (Hb)-corrected carbon monoxide diffusing capacity/carbon monoxide transfer capacity (DLco) ≥35% of predicted value at the Screen Visit only 9. Either FVC or Hb-corrected DLco less/equivalent to 90% of predicted value at the Screen Visit 10. No evidence of improvement in measures of IPF disease severity over the preceding year 11. Distance walked ≥150 meters (492 feet) with O2 saturation ≥83% on less/equal to 6 L/min of O2 during the 6-Minute Walk Test (6MWT) oxygen titration procedure performed during screening (see Study Reference Guide). 12. Able to understand and sign a written informed consent form 13. Able to understand the importance of adherence to study treatment and the study protocol, including the concomitant medication restrictions throughout the Study Period
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E.4 | Principal exclusion criteria |
1.Not a suitable candidate for enrolment or unlikely to comply with the requirements of this study 2.Premature withdrawal from a randomized IPF clinical trial in the previous 2 years for any reason other than Sponsor decision or current participation in a clinical drug trial 3.FEV in the first second (FEV1)/FVC ratio <0.7 after administration of bronchodilator at the Screen Visit and Day 1 before randomisation 4.Bronchodilator Response defined by an absolute increase of ≥12% and an increase of 200 mL in the predicted FEV1 or FVC or both after bronchodilator use compared to the values seen before bronchodilator at the Screen Visit and Day 1 before randomisation 5 RV >120% of predicted (before administration of bronchodilator) 6.History of clinically significant environmental exposure known to cause PF (including drugs, asbestos, beryllium, radiation, domestic birds) 7.Known explanation for interstitial lung disease 8.Diagnosis of any connective tissue disease including scleroderma, systemic lupus erythematosus, and rheumatoid arthritis 9.Clinical evidence of active infection, including bronchitis, pneumonia, sinusitis, urinary tract infection, or cellulitis 10.In the clinical opinion of the investigator, the patient is expected to need and be eligible for a lung transplant within 72 weeks after randomisation. 11.Unable to undergo pulmonary function testing, which includes meeting the following reproducibility standards: At Screening, the 2 highest acceptable FVC values must be within 0.10 liter; At Day 1 the 2 highest acceptable FVC values must be within 0.10 liter; At Screening 2 of the 3 acceptable DLco values must be within 2 units (for TLco, within 0.67 SI units) of each other. 12.Any history of malignancy likely to result in death or significant disability or likely to require significant medical or surgical intervention within the next 2 years. This does not include minor surgical procedures for localized carcinoma (e.g., basal cell carcinoma) 13.Any condition other than IPF which, in the opinion of the investigator, is likely to result in the death of the patient within the next 2 years 14.History of advanced cirrhosis or clinically significant liver disease 15.History of unstable or deteriorating cardiac or pulmonary disease (other than IPF) within the previous 6 months, including: Myocardial infarction, unstable angina pectoris, coronary artery bypass surgery, or coronary angioplasty; Congestive heart failure requiring hospitalization; Uncontrolled arrhythmias; Asthma or chronic bronchitis requiring hospitalization in the last 6 months 16.Any condition, which, in the opinion of the investigator, might be significantly exacerbated by the known side effects associated with the administration of pirfenidone 17.Poorly controlled diabetes (defined by glycosylated hemoglobin [HbA1C] >10) 18.Pregnancy or lactation. Women of childbearing capacity are required to have a negative serum pregnancy test before treatment and must agree to maintain highly effective methods of contraception by practicing abstinence or by using at least two methods of birth control from the date of consent through the end of the study. If abstinence is not practiced then one of the two methods of birth control should be an oral contraceptive (i.e., oral contraception and a spermicide). 19.History of alcohol or substance abuse in the past 2 years 20.History of any condition or habit associated with altered consciousness and a risk of aspiration in the past 2 years 21.Family or personal history of long QT Syndrome 22.Liver function test criteria above specified limits: total bilirubin >2.5 ´ upper limit of normal (ULN); aspartate or alanine aminotransferase (AST/SGOT or ALT/SGPT) >2.5 x ULN; alkaline phosphatase >2.5 x ULN 23.Screening or Day 1 ECG with a QTcB interval >500 msec 24. Prior use of pirfenidone or known hypersensitivity to any of the components of study treatment 25.Patients are excluded if they require the following therapies within 28 days prior to screening: a.Investigational therapy defined as any drug is not approved for marketing for any indication on the country of the participating site; b.Any cytotoxic, immunosuppressive, cytokine modulating or endothelin receptor antagonist agents including: azathioprine, bosentan, cyclophosphamide, corticosteroids, cyclosporine, etanercept, iloprost, infliximab, leukotrienes, methotraxate, mycophenolate mofetil, sildenafil (daily), tetrathiomolybdate, TNF α inhibitors, N-acetyl-cysteine (NAC), imatinib mesylate, Interferon gamma-1b (IFN-γ 1b and tyrosine kinase inhibitors; c.Concomitant medications being used for the treatment of IPF including:ACE-inhibitors, colchicines, warfarin, heparin, sildenafil and HMC-CoA reductase inhibitors. These drugs may be used if given for a non-IPF indication if there is no clinically acceptable alternative therapy for the same indication |
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E.5 End points |
E.5.1 | Primary end point(s) |
The absolute change in percent predicted FVC from Baseline to Week 72. |
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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 | Yes |
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 | Information not present in EudraCT |
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 | 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 | Yes |
E.8.1.7.1 | Other trial design description |
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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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
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 | 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 | 10 |
E.8.9.1 | In the Member State concerned days | |
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 | 10 |