E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Systemic Sclerosis-Related Interstitial Lung Disease |
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E.1.1.1 | Medical condition in easily understood language |
Systemic Sclerosis-Related Interstitial Lung Disease |
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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 safety and tolerability of pirfenidone at 2403 mg/d when administered to patients with systemic sclerosis-related interstitial lung disease (SSc-ILD)
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E.2.2 | Secondary objectives of the trial |
To assess the safety and tolerability of two pirfenidone dose-titration schedules |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Eligible patients are to fulfill the preliminary criteria of the American College of Rheumatology for the classification of SSc (Masi 1980) and have a confirmed diagnosis of SSc-ILD based on pulmonary function testing and radiologic data.
Patients who meet all of the following criteria are eligible to participate in the study:
Demographic Characteristics:
1. Male and female patients, aged 18−70 years (inclusive) on Day 1
SSc− and SSc-ILD−Related Criteria:
2. Diagnosis of SSc confirmed by the investigator using the preliminary criteria of the American College of Rheumatology for the classification of systemic sclerosis (Masi 1980, Appendix B)
a. Duration of diagnosis <7 years (dated from the onset of the first non-Raynaud’s phenomenon manifestation, to Day 1 of the study)
3. Diagnosis of SSc-ILD based on an HRCT scan (obtained in the 2 years before the date of written informed consent) that demonstrates findings consistent with ILD, as assessed by the investigator
4. Screening FVC ≥50% of the predicted value, and screening DLCO ≥40% of the predicted value
5. At study entry, the patient either is not taking SSc-ILD medication or is taking cyclophosphamide or MMF, as described below:
a. Not on SSc-ILD medication: Has not taken SSc-ILD medication in the 3 months before Day 1, or will complete appropriate washout of SSc-ILD medication by Day 1; for such patients, there must be no plan to start another SSc-ILD medication during the study
b. Taking cyclophosphamide or MMF: Is on an oral formulation of cyclophosphamide (≤2 mg/kg/d) or MMF (≤1.5 g two times daily [BID]), and the dose has been stable in the 3 months before Day 1; for such patients, there must be no plan to change that SSc-ILD medication or its dose during the study
Informed Consent and Protocol Adherence:
6. Able to understand and sign a written informed consent form
7. Able to understand the importance of adhering to study treatment and the study protocol, and willing to follow all study requirements, including the concomitant medication restrictions, throughout the study
8. Use of effective contraception: Women of childbearing potential are required to have a negative pregnancy test before treatment and must agree to maintain highly effective 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, one of the two methods of birth control must be an oral contraceptive (e.g., oral contraceptive and spermicide). |
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E.4 | Principal exclusion criteria |
1. Clinically significant pulmonary hypertension, based on any of the following criteria:
a. Receiving treatment for pulmonary hypertension
b. Or, if available, a previous right heart catheterization that demonstrates mean pulmonary artery pressure at rest of ≥25 mm Hg with concurrent wedge pressure of ≤15 mm Hg and pulmonary vascular resistance of >3 Wood units
c. Or, Doppler echocardiography in the 6 months before D1 with an estimated systolic pulmonary arterial pressure (Ppa) of >36 mm Hg corresponding to a tricuspid regurgitant jet velocity of >2.8 m/sec
2. Evidence of right atrial or ventricular enlargement or significant left ventricular dysfunction
3. Known underlying liver disease (e.g., hepatitis or cirrhosis)
4. Clinical evidence of significant aspiration or uncontrolled gastroesophageal reflux (UCLA SCTC GIT 2.0 reflux score >1.00), as assessed by the investigator
5. Known achalasia, esophageal stricture, or esophageal dysfunction sufficient to limit the ability to swallow oral medication
6. Tobacco smoking within 3 months of screening or unwillingness to avoid smoking throughout the study
7. History of a clinically significant environmental exposure that is known to cause PF including, but not limited to, drugs (e.g., amiodarone), asbestos, beryllium, radiation, or domestic birds or other factors associated with hypersensitivity pneumonitis
8. History of clinically significant asthma as an adult or clinically significant chronic obstructive pulmonary disease, as assessed by the investigator
9. Clinical evidence of active infection including, but not limited to, bronchitis, pneumonia, sinusitis, or UTI.
10. Features supporting diagnosis of another connective-tissue disorder (e.g., RA or SLE) or another pulmonary disorder (e.g., emphysema, asthma, cancer)
11. Expected to have study participation interrupted for a foreseeable medical or surgical event (e.g., organ, stem cell, or bone marrow transplant).
12. Any clinical evidence of a malignancy that is likely to result in significant disability or likely to require significant medical or surgical intervention within the next 6 months (relative to D1). Excluded: minor surgical procedures for localized cancer (basal cell carcinoma).
13. Any condition (other than SSc-ILD) likely to result in the death of the patient within 12 months, as assessed by the investigator
14. History of unstable or deteriorating cardiac or pulmonary disease (other than SSc-ILD) within the previous 6 months (relative to D1) including, but not limited to unstable angina pectoris, myocardial infarction, congestive heart failure requiring hospitalization, uncontrolled clinically significant arrhythmia, pulmonary hypertension (see Exclusion Criterion 1)
15. Any condition that, as assessed by the investigator, might be significantly exacerbated by the known side effects associated with pirfenidone
16. Known or suspected peptic ulcer
17. Pregnancy or lactation: Positive pregnancy test; currently lactating; or for women of childbearing potential, an unwillingness to maintain highly effective contraception, as described in Inclusion Criterion 8
18. History of alcohol or substance abuse in the previous 2 years (relative to D1)
19. Family or personal history of long QT syndrome
20. Any of the following liver test criteria above the specified limit:
a. Total bilirubin above ULN, except in patients with predominantly unconjugated hyperbilirubinemia (Gilbert’s syndrome)
b. AST or ALT >2 × ULN
c. Alkaline phosphatase >2 × ULN
d. Creatinine clearance <40 mL/min, calculated using the Cockcroft-Gault formula
21. Any prior use of pirfenidone
22. Suspected intolerance, allergy, or hypersensitivity to pirfenidone or any of its excipients
23. Use of any investigational drug in the 28 days before screening (an investigational drug is defined as any drug that has not been approved for marketing for any indication in the country of the participating site)
24. Ongoing use or expected use of any of the following therapies:
a. Investigational therapy
b. Strong inhibitors of CYP1A2
c. Moderate inhibitors of CYP1A2 (ciprofloxacin allowed only at doses ≤500 mg BID)
d. Moderate inducers of CYP1A2
e. Methotrexate
f. Cyclosporine
g. Azathioprine
h. Rapamycin
i. Oral corticosteroids at a dose >10 mg/d prednisone equivalent
j. d-penicillamine
k. Minocycline
l. r-relaxin
m. Interferon-γ
n. Endothelin-1 receptor antagonists
o. Phosphodiesterase inhibitors for the treatment of SSc-ILD (e.g., sildenafil or tadalafil), unless used for other indications
p. TNF-α neutralizing drugs or other biologics used to treat connective-tissue disorders
q. Treatment with any UV spectrum-containing light, including lasers, and recreational use of any UV spectrum-containing light (e.g., tanning bed)
Exception: Therapeutic use of non-UV lasers (e.g., IR spectrum lasers)
25. Unsuitable for enrollment or unlikely to comply with study requirements, as assessed by the investigator |
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E.5 End points |
E.5.1 | Primary end point(s) |
- Evaluation of AEs and SAEs
- Study treatment discontinuations
- Treatment-emergent changes in clinical laboratory measures
- Treatment emergent changes in ECGs
- Patient responses on the UCLA SCTC GIT 2.0 questionnaire
- Spirometry
- DLCO
- Disease status scales
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- AE and SAE monitoring through directed medical history: D-21 to 1, D1, D7, D14, D28, D42, D56, D70, D84, D98, D112 and 28-35 d post dosing
- Study treatment discontinuations: D7, D14, D28, D42, D56, D70, D84, D98, D112
- Clinical lab measures (hematology, serum chemistry): D-21 to 1, D1, D14, D28, D56, D84, D112
- 12-lead ECG: D-21 to 1, D1, D14, D56, D112
- UCLA SCTC GIT 2.0: D-21 to 1, D1, D28, D56, D84, D112
- Spirometry: D-21 to 1, D112
- DLCO: D-21 to 1, D112
- Disease status scales: D1, D112
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E.5.2 | Secondary end point(s) |
- Dose modifications and associated AE and SAEs |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Dose modifications: D7, D14, D28, D42, D56, D70, D84, D98, D112 |
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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 | 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 | No |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
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 | Yes |
E.8.1.7.1 | Other trial design description |
Two dose titration schedules in parallel groups |
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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 | No |
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 | No |
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 |
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E.8.7 | Trial has a data monitoring committee | No |
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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |