E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pulmonary Hypertension in patients with Idiopathic pulmonary fibrosis (IPF) |
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E.1.1.1 | Medical condition in easily understood language |
Idiopathic pulmonary fibrosis leads to formation of scars in lungs due to unknown reason causing breathing problems. Pulmonary Hypertension is a disease adversely affecting blood flow in lungs. |
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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 | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10021240 |
E.1.2 | Term | Idiopathic pulmonary fibrosis |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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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 efficacy of adding sildenafil compared with placebo to pirfenidone treatment in patients with advanced IPF and intermediate or high probability of Group 3 pulmonary hypertension (PH) on the basis of relevant decline in 6-minute walk distance (6MWD) of at least 15% from baseline, respiratory-related non-elective hospitalizations, or all-cause mortality |
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E.2.2 | Secondary objectives of the trial |
•To evaluate the efficacy of adding sildenafil compared with placebo to pirfenidone treatment on the basis of
Progression-free survival (PFS)
Proportion of patients with decline in 6MWD of >=15% from baseline
Time to all-cause and respiratory-related non-elective hospitalization
Time to death from any cause and respiratory-related death
Lung transplantation
Change from baseline in transthoracic echocardiography (ECHO) parameters, pulmonary function tests (PFTs), and oxyhemoglobin saturation (SpO2) at rest and during the 6MWT
World Health Organization (WHO) Functional Class
Dyspnoea (assessed by the University of California San Diego Shortness of Breath questionnaire [UCSD SOBQ])
Health-related quality of life (HRQoL) (assessed by the Saint George’s Respiratory Questionnaire [SGRQ])
N-terminal pro-brain natriuretic peptide (NT-proBNP) level (assessed by a blood test)
•To evaluate the safety of adding sildenafil compared with placebo to pirfenidone treatment
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age 40-80 years (inclusive) at Screening
- Diagnosis of IPF for at least 3 months prior to screening
- Confirmation of IPF diagnosis by the Investigator, in accordance with the 2011 international consensus guidelines, at Screening
- Advanced IPF as defined by a measurable carbon monoxide diffusing capacity/pulmonary diffusing capacity [DLCO] <= 40% of predicted value at Screening and intermediate or high probability of Grade 3 PH (as defined in the protocol)
- Prior to the start of Screening, receiving pirfenidone for at least 12 weeks, and on a dose in the range of 1602 to 2403 mg/day for at least 4 weeks prior to the first Screening Visit.
- WHO Functional Class II or III at Screening
- 6MWD of 100 to 450 meters at Screening
- For women of childbearing potential: agreement to remain abstinent or use a non-hormonal contraceptive method with a failure rate of <1% per year during the treatment period and for at least 58 days after the last dose of study treatment
- For men who are not surgically sterile: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm for at least 118 days after the last dose of study treatment
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E.4 | Principal exclusion criteria |
- History of any of the following types of PH: Group 1 pulmonary arterial hypertension (PAH); Group 2 (left-heart disease); Group 3 (due to conditions other than interstitial lung disease; Group 4 (chronic thromboembolic pulmonary hypertension); Group 5 (other disorders)
- History of clinically significant cardiac disease in the opinion of the Investigator
- History of coexistent and clinically significant (in the opinion of the Investigator) COPD, bronchiectasis, asthma, inadequately treated sleep-disordered breathing, or any clinically significant pulmonary diseases or disorders other than IPF or PH secondary to IPF
- Hypotension, autonomic dysfunction, or conditions in which vasodilation may cause an unsafe drop in blood pressure (BP)
- History of use of drugs and toxins known to cause PAH
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint will be evaluated based on a comparison of the proportion of patients showing disease progression over 52 weeks of treatment period, as evidenced by reaching the following combined endpoint:
•Relative decline in 6MWD of at least 15% from baseline (as defined in the protocol), respiratory related non elective hospitalization, or all cause mortality
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
•The primary analysis of the study will be conducted when all patients completed the 52 weeks treatment phase and the mandatory 4 weeks follow-up visit. |
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E.5.2 | Secondary end point(s) |
Efficacy:
1.Progression-free survival (PFS)
2.Proportion of patients with decline in 6MWD of >=15% from baseline
3.Time to respiratory-related non-elective hospitalization
4.Time to death from any cause
5.Lung transplantation will be analysed descriptively
6.Time to all-cause non-elective hospitalization
7.Time to respiratory-related death
8.Change from baseline in transthoracic ECHO parameters
9.Change from baseline in PFTs (FVC, FEV1, FEV1/FVC, and DLCO)
10.Oxyhemoglobin saturation (SpO2) at rest and during the 6MWT will be summarized descriptively over time
11.Borg scale measurement of perceived exertion will be summarized descriptively over time
12.WHO Functional Class II or III over time
13.Dyspnea as assessed by UCSD SOBQ will be summarized descriptively over time
14.HRQoL (assessed by SGRQ) will be summarized descriptively over time
15.Changes from baseline in NT-proBNP levels
Safety:
16.Nature, frequency, severity, relationship and timing of treatment-emergent adverse events
17.Changes in vital signs, physical examination, clinical laboratory test results, 12-lead electrocardiograms (ECGs)
18.Proportion of patients with study discontinuation or study drug discontinuation
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-18. The primary analysis of the study will be conducted when all patients completed the 52 weeks treatment phase and the mandatory 4 weeks follow-up visit. |
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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 | 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 | 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 | 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 | 41 |
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 |
Belgium |
Canada |
Czech Republic |
Egypt |
Germany |
Greece |
Hungary |
Israel |
Italy |
Netherlands |
South Africa |
Spain |
Turkey |
United Arab Emirates |
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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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The end of the clinical trial is defined as the date when the last patient completes the last visit (LPLV) or the date at which the last data point which is required for the statistical analysis is received, whichever is the later date. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 3 |