Efficacy, Safety, and Tolerability Study of Pirfenidone in Combination With Sildenafil in Participants With Advanced Idiopathic Pulmonary Fibrosis (IPF) and Intermediate or High Probability of Group 3 Pulmonary Hypertension

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02951429
• Collaborator: (none)
• Enrollment: 177
• Locations: 56
• Arms: 2
• Actual Duration (Months): 43.7
• Patients Per Site: 3.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This Phase IIb, randomized, placebo-controlled, multicenter, international study will evaluate the efficacy, safety, and tolerability of sildenafil or placebo added to pirfenidone (Esbriet) treatment in participants with advanced IPF and intermediate or high probability of Group 3 pulmonary hypertension (PH) who are on a stable dose of pirfenidone with demonstrated tolerability. Participants will be randomized to receive 1 year of treatment with either oral sildenafil or matching placebo while continuing to take pirfenidone.

Condition or Disease	Intervention/Treatment	Phase
Idiopathic Pulmonary Fibrosis	Drug: Pirfenidone; Drug: Placebo; Drug: Sildenafil	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 177 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase IIb, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Sildenafil Added to Pirfenidone in Patients With Advanced Idiopathic Pulmonary Fibrosis and Intermediate or High Probability of Group 3 Pulmonary Hypertension
• Actual Study Start Date: Dec 31, 2016
• Actual Primary Completion Date: Sep 26, 2019
• Actual Study Completion Date: Aug 22, 2020

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Pirfenidone + Placebo Participants will receive pirfenidone along with placebo matched to sildenafil, orally, three times a day (TID) for 52 weeks.	Drug: Pirfenidone; Pirfenidone will be given in the range of 1602 to 2403 milligram per day (mg/day), as 3 divided doses.; Other Names: Esbriet, RO0220912 ; Drug: Placebo; Placebo matched with sildenafil.
Experimental: Pirfenidone + Sildenafil Participants will receive pirfenidone along with sildenafil, orally, TID for 52 weeks.	Drug: Pirfenidone; Pirfenidone will be given in the range of 1602 to 2403 milligram per day (mg/day), as 3 divided doses.; Other Names: Esbriet, RO0220912 ; Drug: Sildenafil; Sildenafil will be given as 20 mg, TID.; Other Names: RO0280296

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Disease Progression, as Determined by Relevant Decline in 6 Minute Walk Distance (6MWD) of At Least (>=) 15 Percent (%) From Baseline, Respiratory-Related Non-Elective Hospitalization, or Death From Any Cause [Baseline up to Week 52]

   Disease Progression defined as relative decline in 6-minute walking distance (6MWD) from baseline (defined as >25% from baseline or 15-25% from baseline associated with worsening oxygen saturation, worsening Borg score, or increased oxygen requirements), respiratory-related non-elective hospitalizations, or all-cause mortality.

Secondary Outcome Measures

1. Time to First Occurrence of Disease Progression [Baseline up to Week 52]

   Disease Progression defined as relative decline in 6MWD from baseline (defined as >25% from baseline or 15-25% from baseline associated with worsening oxygen saturation, worsening Borg score, or increased oxygen requirements), respiratory-related non-elective hospitalizations, or all-cause mortality.

2. Time to Multiple Occurrence of Disease Progression Events [Baseline up to Week 52]

   Disease Progression defined as relative decline in 6MWD from baseline (defined as >25% from baseline or 15-25% from baseline associated with worsening oxygen saturation, worsening Borg score, or increased oxygen requirements), respiratory-related non-elective hospitalizations, or all-cause mortality. In case participant had more than one event as described in the endpoint definition the second, third etc event was counted as well for the calculation of the endpoint.

3. Percentage of Participants With Decline From Baseline in 6-minute Walking Distance (6MWD) of >= 15% [Baseline up to Week 52]

4. Time to First Occurrence of Relevant ≥15% Decline From Baseline in 6-minute Walking Distance (6MWD) [Baseline up to Week 52]

5. Time to Respiratory-Related Non-Elective Hospitalization From Baseline to Week 52 [Baseline up to Week 52]

   N.A. = non-calculable

6. Time to All-Cause Non-Elective Hospitalization [Baseline up to Week 52]

   N.A. = non-calculable

7. Time to Death From Any Cause [Baseline up to Week 52]

8. Percentage of Participants With Lung Transplantation [Baseline up to Week 52]

9. Time to Respiratory-Related Death [Baseline up to Week 52]

10. Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Peak Tricuspid Regurgitation Velocity [Baseline, Week 52]

11. Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Pulmonary Artery Pressure (PAPs) [Baseline, Week 52]

12. Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Tricuspid Annular Plane Systolic Excursion (TAPSE) [Baseline, Week 52]

13. Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Right Ventricle Basal Diameter [Baseline, Week 52]

14. Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Inferior Vena Cava Diameter [Baseline, Week 52]

15. Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Left Ventricular Ejection Fraction (LVEF) [Baseline, Week 52]

16. Change From Baseline to Week 52 in Carbon Monoxide Diffusing Capacity/ Pulmonary Diffusing Capacity (DLCO) [Baseline, Week 52]

17. Change From Baseline to Week 52 in Forced Vital Capacity (FVC) [Baseline, Week 52]

18. Percentage of Participants by World Health Organization (WHO) Functional Class at Week 52 [Week 52]

    The World Health Organisation (WHO) functional class system defines the severity of an participant's symptoms. Class II - Participants with Pulmonary Hypertension resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue breathlessness, fatigue (tiredness), or activities that can cause chest pain, dizziness or even black outs. Class III - Participants with Pulmonary Hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue breathlessness, fatigue (tiredness), or activities that can cause chest pain, dizziness or even black outs. Class IV - participants with pulmonary hypertension with inability to carry out any physical activity without symptoms. These participants manifest signs of right heart failure, breathlessness and /or fatigue, which may even be present at rest. Discomfort is increased by any physical activity.

19. Change From Baseline in N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) Level (pg/mL) at Week 52 [Baseline, Week 52]

20. St. George's Respiratory Questionnaire (SGRQ) Changes From Baseline at Week 52 [Baseline, Week 52]

    The SGRQ is a 50-item questionnaire developed to measure health status (quality of life) in participants with diseases of airways obstruction. Three component scores are calculated, where the higher the component result the worse the condition: Symptoms concerned with the effect of respiratory symptoms, their frequency and severity (range: 0-16.61) Activity concerned with activities that cause or are limited by breathlessness (range: 0-30.31) Impacts covers a range of aspects concerned with social functioning and psychological disturbances resulting from airway disease (range: 0- 53.08) Total score summaries the impact of disease on overall health status. Scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status.

21. University of California, San Diego-Shortness of Breath Questionnaire (UCSD-SOBQ) Changes From Baseline at Week 52 [Baseline, Week 52]

    The UCSD-SOBQ is a respiratory questionnaire and it assesses dyspnea associated with activities of daily living (ADL). Participants indicate severity of SOB on a 6-point scale in 21 ADL. Three additional questions ask about fear of harm from overexertion, limitations and fear caused by SOB. A total score ranges from 0 to 120, with higher scores indicating greater impairment.

22. Change From Baseline in Distance Walked, 6-minute Walking Distance (6MWD) Test at Week 52 [Baseline up to Week 52]

23. Change From Baseline in Oxygen Requirements, 6-minute Walking Distance (6MWD) Test at Week 52 [Baseline up to Week 52]

24. Change From Baseline in Other 6-minute Walking Distance (6MWD) Parameters at Week 52 [Baseline up to Week 52]

25. Percentage of Participants With Adverse Events [Baseline up to Week 52 + 28 days]

26. Borg Scale Result at the End of the Test at Week 52 [Week 52]

    The Borg Scale rates participant's level of perceived exertion during any activity from 0-10, with 0 being no effort at all and 10 being maximal exertion.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 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 (defined as a measurable carbon monoxide diffusing capacity [DLCO] less than or equal to (<=)40% of predicted value at Screening) and intermediate or high probability of group 3 pulmonary hypertension (PH)

• Participants receiving pirfenidone for at least 12 weeks, at a dose in the range of 1602 to 2403 mg/day for at least 4 weeks prior to Screening and must not have experienced either a new or ongoing adverse event of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (version 4.03) Grade 2 or higher and considered by the investigator to be related to pirfenidone, or an interruption of pirfenidone treatment of greater than (>)7 days for any reason

• WHO Functional Class II or III at Screening

• 6MWD of 100 to 450 meters at screening

• Women of childbearing potential and for men who are not surgically sterile agreement to remain abstinent or use of contraceptive measures

Exclusion Criteria:

• History of any of the following types of PH: Group 1 (PAH); Group 1 (pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis); Group 2 (left-heart disease); Group 3 (due to conditions other than interstitial lung disease, including chronic obstructive pulmonary disease [COPD], sleep-disordered breathing, alveolar hypoventilation, high altitude, or developmental abnormalities); Group 4 (chronic thromboembolic pulmonary hypertension); Group 5 (other disorders)

• History of clinically significant cardiac disease

• History of coexistent and clinically significant COPD, bronchiectasis, asthma, inadequately treated sleep-disordered breathing, or any clinically significant pulmonary diseases or disorders other than IPF or PH secondary to IPF

• History of use of drugs and toxins known to cause PAH, including aminorex, fenfluramine, dexenfluramine, and amphetamines

• FEV1/FVC ratio less than (<) 0.70 post bronchodilator; SpO2 saturation at rest <92% with >= 6 liters (L) of supplemental oxygen at Screening

• Extent of emphysema greater than the extent of fibrotic changes (honeycombing and reticular changes) on any previous high-resolution computed tomography (HRCT) scan, in the opinion of the Investigator

• Smoked tobacco within 3 months prior to screening or is unwilling to avoid tobacco products (cigarettes, pipe, cigars) throughout the study

• Illicit drug or significant alcohol abuse

• Electrocardiogram (ECG) with a heart-rate corrected QT interval (corrected using Fridericia's formula [QTcF]) >=500 milliseconds (ms) at screening, or a family or personal history of long QT syndrome

• Exclusion criteria based on pirfenidone reference safety information: 1. participants with a history of angioedema due to pirfenidone; 2. concomitant use of fluvoxamine

• Exclusion criteria based on sildenafil reference safety information: 1. co-administration with nitric oxide donors or organic nitrates, phosphodiesterase-5 (PDE5) inhibitors, guanylate cyclase stimulators, and most potent of the Cytochrome P450 3A4 (CYP3A4) inhibitors; 2. loss of vision in one eye because of non-arteritic anterior ischemic optic neuropathy (NAION); 3. use of an alpha-blocker; 4. participants with bleeding disorders or active peptic ulceration; 5. known hereditary degenerative retinal disorders such as retinitis pigmentosa; 6. galactose intolerance

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	ULB Hôpital Erasme	Brussels		Belgium	1070
2	Cliniques Universitaires St-Luc	Bruxelles		Belgium	1200
3	UZ Antwerpen	Edegem		Belgium	2650
4	UZ Leuven Gasthuisberg	Leuven		Belgium	3000
5	CHU Sart-Tilman	Liège		Belgium	4000
6	CHU UCL Mont-Godinne	Mont-godinne		Belgium	5530
7	Hotel Dieu Hospital	Kingston	Ontario	Canada	K7L 2V7
8	CHUM Hôpital Notre-Dame	Montreal	Quebec	Canada	H2L 4M1
9	Institut universitaire de cardiologie et de pneumologie de Québec (Hôpital Laval)	Ste. Foy	Quebec	Canada	G1V 4G5
10	Thomayerova nemocnice; Pneumologicka klinika 1.LF UK TN	Praha 4 - Krc		Czechia	140 59
11	Clinical Research Center (CRC), Faculty of Medicine, Alexandria University	Alexandria		Egypt	21131
12	Kasr El-Aini-Chest Unit; Department 3-Chest Unit	Cairo		Egypt	11562
13	Ain Shams University Hospital-Chest unit; Chest unit	Cairo		Egypt	11566
14	Fachkrankenhaus Coswig GmbH Zentrum f.Pneumologie Beatmungsmedizin Thorax-u.Gefäßchirurgie	Coswig		Germany	01640
15	Klinik Donaustauf Zentrum für Pneumologie	Donaustauf		Germany	93093
16	Ruhrlandklinik Lungenzentrum der UNI Essen Abt.Pneumologie-Allergologie	Essen		Germany	45239
17	Klinikum Fulda gAG; Universitätsmedizin Marburg, Campus Fulda	Fulda		Germany	36043
18	Universitätsklinikum Standort Gießen Medizinische Klinik II u. Poliklinik Innere Med./Pneumologie	Gießen		Germany	35392
19	Thoraxklinik Heidelberg gGmbH	Heidelberg		Germany	69126
20	Fachklinik für Lungenerkrankungen	Immenhausen		Germany	34376
21	Klinikum der Universität München; Campus Großhadern; Med. Klinik und Poliklinik V	München		Germany	81377
22	Sotiria Hospital for Diseases of the Chest, Academic Department of Pneumonology	Athens		Greece	115 27
23	University General Hospital of Athens "Attikon", B' University Pulmonary Clinic	Chaidari		Greece	124 62
24	University General Hospital of Heraklio, Pulmonary Clinic	Heraklio		Greece	711 10
25	Semmelweis Egyetem X; Pulmonologiai Klinika	Budapest		Hungary	1083
26	Orszagos Koranyi TBC es Pulmonologiai Intezet	Budapest		Hungary	1121
27	Soroka; Pulmonary Clinic	Beer Sheba		Israel	8410101
28	Carmel Medical Center; Pulmonary Institute	Haifa		Israel	3436212
29	Shaare Zedek Medical Center; Pulmonary Inst.	Jerusalem		Israel	9103102
30	Hadassah Medical Center; Pulmonary Institute	Jerusalem		Israel	9112001
31	Meir Medical Center; Pulmonary Dept	Kfar Saba		Israel	4428164
32	Beilinson Medical Center; Pulmonary Inst.	Petach Tikva		Israel	4941492
33	Kaplan Medical Center	Rehovot		Israel	7610001
34	Ospedale Morgagni-Pierantoni; U.O. Pneumologia	Forlì	Emilia-Romagna	Italy	47121
35	A.O. Universitaria Policlinico Di Modena; DIP. Malattie Dell'apparato Respiratorio	Modena	Emilia-Romagna	Italy	41124
36	Ospedale San Giuseppe; U.O. di Pneumologia	Milano	Lombardia	Italy	20123
37	ASST DI MONZA; U O Clinica Pneumologica	Monza	Lombardia	Italy	20900
38	A.O.U. Ospedali Riuniti Di Foggia-Ospedale D'avanzo; Malattie Dell'apparato Respiratorio IV	Foggia	Puglia	Italy	71100
39	A.O.U. Policlinico Vittorio Emanuele; Centro per la cura delle Malattie Rare del Polmone	Catania	Sicilia	Italy	95123
40	A.O. Univ. Senese Policlinico S. Maria alle Scotte; UOC Malattie Resepiratorie e Trapianto Polmonare	Siena	Toscana	Italy	53100
41	Azienda Ospedaliera di Padova; Dip. Scienze Cardiologiche Toraciche Vascolari-UOC Pneumologia	Padova	Veneto	Italy	35128
42	Vu Medisch Centrum; Afdeling Longziekten	Amsterdam		Netherlands	1081 HV
43	Erasmus MC	Rotterdam		Netherlands	3015 GD
44	University of Cape Town Lung Institute; Lung Clinical Research	Cape Town		South Africa	7700
45	Milpark Hospital	Parktown West		South Africa	2196
46	University of Stellenbosch; Respiratory Research	Parow		South Africa	7505
47	Hospital Universitari de Bellvitge ; Servicio de Neumologia	Hospitalet de Llobregat	Barcelona	Spain	08097
48	Hospital Universitario Marques de Valdecilla; Servicio de neumologia	Santander	Cantabria	Spain	39008
49	Hospital Universitario Puerta de Hierro Majadahonda; Servicio de Neumología	Majadahonda	Madrid	Spain	28222
50	Hospital Clinic I provincial; Servicio de Neumologia	Barcelona		Spain	08036
51	Hospital Universitario la Fe; Servicio de Neumologia	Valencia		Spain	46009
52	Ankara Uni Faculty of Medicine; Chest Diseases	Ankara		Turkey	06100
53	Uludag University; Pulmonology and Allergy Department	Bursa		Turkey	16059
54	Yedikule Gogus Hastaliklari ve Gogus Cerrahisi EAH;Gogus Hastaliklari	Istanbul		Turkey	34020
55	Istanbul Universitesi Capa Tıp Fakültesi; Gogus Hastalıkları Anabilim dalı	Istanbul		Turkey	34093
56	Ege Universitesi Tıp Fakültesi; Gögüs Hastalıkları Bilim Dalı	İzmir		Turkey	35040

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

• Study Protocol - Dec 1, 2017
• Statistical Analysis Plan - Aug 21, 2019

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT02951429
• Other Study ID Numbers: MA29957; 2015-005131-40
• First Posted: Nov 1, 2016
• Last Update Posted: Nov 12, 2020
• Last Verified: Oct 1, 2020

• Additional relevant MeSH terms: Hypertension, Pulmonary; Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Hypertension; Fibrosis; Pirfenidone; Sildenafil Citrate

Study Results

Participant Flow

Pre-assignment Detail	Written informed consent for participation in the study was obtained before performing any study-specific screening tests or evaluations.

Arm/Group Title	Pirfenidone+Sildenafil	Pirfenidone+Placebo
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.	Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
Period Title: Overall Study
STARTED	88	89
COMPLETED	16	6
NOT COMPLETED	72	83

Baseline Characteristics

Arm/Group Title	Pirfenidone+Sildenafil	Pirfenidone+Placebo	Total
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.	Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.	Total of all reporting groups
Overall Participants	88	89	177
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	68.2 (7.7)	68.9 (7.1)	68.6 (7.4)
Sex: Female, Male (Count of Participants)
Female	19 21.6%	24 27%	43 24.3%
Male	69 78.4%	65 73%	134 75.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 2.3%	3 3.4%	5 2.8%
Not Hispanic or Latino	78 88.6%	79 88.8%	157 88.7%
Unknown or Not Reported	8 9.1%	7 7.9%	15 8.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 1.1%	0 0%	1 0.6%
Native Hawaiian or Other Pacific Islander	1 1.1%	0 0%	1 0.6%
Black or African American	0 0%	1 1.1%	1 0.6%
White	85 96.6%	88 98.9%	173 97.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 1.1%	0 0%	1 0.6%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Disease Progression, as Determined by Relevant Decline in 6 Minute Walk Distance (6MWD) of At Least (>=) 15 Percent (%) From Baseline, Respiratory-Related Non-Elective Hospitalization, or Death From Any Cause
Description	Disease Progression defined as relative decline in 6-minute walking distance (6MWD) from baseline (defined as >25% from baseline or 15-25% from baseline associated with worsening oxygen saturation, worsening Borg score, or increased oxygen requirements), respiratory-related non-elective hospitalizations, or all-cause mortality.
Time Frame	Baseline up to Week 52

Outcome Measure Data

Analysis Population Description

Participants with data available at week 52.

Arm/Group Title	Pirfenidone+Sildenafil	Pirfenidone+Placebo
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.	Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
Measure Participants	88	89
Number [Percentage of Participants]	72.7 82.6%	69.7 78.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pirfenidone+Sildenafil, Pirfenidone+Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6527
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Difference of percentage of participants
	Estimated Value	3.06
	Confidence Interval	(2-Sided) 95%; -11.30 to 17.97
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Time to First Occurrence of Disease Progression
Description	Disease Progression defined as relative decline in 6MWD from baseline (defined as >25% from baseline or 15-25% from baseline associated with worsening oxygen saturation, worsening Borg score, or increased oxygen requirements), respiratory-related non-elective hospitalizations, or all-cause mortality.
Time Frame	Baseline up to Week 52

Outcome Measure Data

Analysis Population Description

Participants with data available at week 52.

Arm/Group Title	Pirfenidone+Sildenafil	Pirfenidone+Placebo
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.	Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
Measure Participants	88	89
Median (95% Confidence Interval) [Weeks]	26.00	25.43

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pirfenidone+Sildenafil, Pirfenidone+Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7568
	Comments
	Method	Log Rank
	Comments	Log-rank test based on the time to the first event to compare the two treatment arms.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 95%; 0.67 to 1.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Time to Multiple Occurrence of Disease Progression Events
Description	Disease Progression defined as relative decline in 6MWD from baseline (defined as >25% from baseline or 15-25% from baseline associated with worsening oxygen saturation, worsening Borg score, or increased oxygen requirements), respiratory-related non-elective hospitalizations, or all-cause mortality. In case participant had more than one event as described in the endpoint definition the second, third etc event was counted as well for the calculation of the endpoint.
Time Frame	Baseline up to Week 52

Outcome Measure Data

Analysis Population Description

Participants with data available at week 52.

Arm/Group Title	Pirfenidone+Sildenafil	Pirfenidone+Placebo
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.	Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
Measure Participants	88	89
Median (95% Confidence Interval) [Weeks]	20.57	13.29

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pirfenidone+Sildenafil, Pirfenidone+Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3760
	Comments
	Method	Log Rank
	Comments	Log-rank test based on the time to the first event to compare the two treatment arms.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95%; 0.68 to 1.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percentage of Participants With Decline From Baseline in 6-minute Walking Distance (6MWD) of >= 15%
Time Frame	Baseline up to Week 52

Outcome Measure Data

Analysis Population Description

Participants with data available at week 52 to calculate a change from baseline.

Arm/Group Title	Pirfenidone+Sildenafil	Pirfenidone+Placebo
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.	Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
Measure Participants	88	89
Number [Percentage]	53.4	50.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pirfenidone+Sildenafil, Pirfenidone+Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7046
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Difference (95% CI)
	Estimated Value	2.85
	Confidence Interval	(2-Sided) 95%; -12.13 to 17.84
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Time to First Occurrence of Relevant ≥15% Decline From Baseline in 6-minute Walking Distance (6MWD)
Time Frame	Baseline up to Week 52

Outcome Measure Data

Analysis Population Description

Participants with data available at week 52 to calculate a change from baseline.

Arm/Group Title	Pirfenidone+Sildenafil	Pirfenidone+Placebo
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.	Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
Measure Participants	88	89
Median (95% Confidence Interval) [Weeks]	39.00	38.71

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pirfenidone+Sildenafil, Pirfenidone+Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7550
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Difference (95% CI)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.62 to 1.41
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Time to Respiratory-Related Non-Elective Hospitalization From Baseline to Week 52
Description	N.A. = non-calculable
Time Frame	Baseline up to Week 52

Outcome Measure Data

Analysis Population Description

Participants with data available at week 52.

Arm/Group Title	Pirfenidone+Sildenafil	Pirfenidone+Placebo
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.	Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
Measure Participants	88	89
Median (95% Confidence Interval) [Weeks]	54.29	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pirfenidone+Sildenafil, Pirfenidone+Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9174
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.02
	Confidence Interval	(2-Sided) 95%; 0.65 to 1.61
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Time to All-Cause Non-Elective Hospitalization
Description	N.A. = non-calculable
Time Frame	Baseline up to Week 52

Outcome Measure Data

Analysis Population Description

Participants with data available at week 52.

Arm/Group Title	Pirfenidone+Sildenafil	Pirfenidone+Placebo
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.	Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
Measure Participants	88	89
Median (95% Confidence Interval) [Weeks]	47.57	49.86

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pirfenidone+Sildenafil, Pirfenidone+Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7748
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95%; 0.70 to 1.62
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Time to Death From Any Cause
Time Frame	Baseline up to Week 52

Outcome Measure Data

Analysis Population Description

Participants with data available at week 52.

Arm/Group Title	Pirfenidone+Sildenafil	Pirfenidone+Placebo
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.	Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
Measure Participants	88	89
Median (95% Confidence Interval) [Weeks]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pirfenidone+Sildenafil, Pirfenidone+Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4258
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.38 to 1.50
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Percentage of Participants With Lung Transplantation
Time Frame	Baseline up to Week 52

Outcome Measure Data

Analysis Population Description

Participants with data available at week 52.

Arm/Group Title	Pirfenidone+Sildenafil	Pirfenidone+Placebo
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.	Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
Measure Participants	88	89
Number [Percentage]	10.2	6.7

10. Secondary Outcome

Title	Time to Respiratory-Related Death
Time Frame	Baseline up to Week 52

Outcome Measure Data

Analysis Population Description

Participants with data available at week 52.

Arm/Group Title	Pirfenidone+Sildenafil	Pirfenidone+Placebo
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.	Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
Measure Participants	88	89
Median (95% Confidence Interval) [Weeks]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pirfenidone+Sildenafil, Pirfenidone+Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3161
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95%; 0.31 to 1.47
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Peak Tricuspid Regurgitation Velocity
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

Participants with data available at week 52 to calculate a change from baseline.

Arm/Group Title	Pirfenidone+Sildenafil	Pirfenidone+Placebo
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.	Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
Measure Participants	38	29
Mean (Standard Deviation) [m/s]	-0.014 (0.6326)	0.103 (0.6699)

12. Secondary Outcome

Title	Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Pulmonary Artery Pressure (PAPs)
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

Participants with data available at week 52 to calculate a change from baseline.

Arm/Group Title	Pirfenidone+Sildenafil	Pirfenidone+Placebo
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.	Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
Measure Participants	41	30
Mean (Standard Deviation) [mmHg]	2.0 (15.65)	3.6 (22.38)

13. Secondary Outcome

Title	Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Tricuspid Annular Plane Systolic Excursion (TAPSE)
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

Participants with data available at week 52 to calculate a change from baseline.

Arm/Group Title	Pirfenidone+Sildenafil	Pirfenidone+Placebo
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.	Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
Measure Participants	30	27
Mean (Standard Deviation) [cm]	-0.204 (0.4170)	-0.146 (0.4453)

14. Secondary Outcome

Title	Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Right Ventricle Basal Diameter
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

Participants with data available at week 52 to calculate a change from baseline.

Arm/Group Title	Pirfenidone+Sildenafil	Pirfenidone+Placebo
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.	Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
Measure Participants	29	24
Mean (Standard Deviation) [cm]	0.462 (1.2305)	0.095 (1.2875)

15. Secondary Outcome

Title	Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Inferior Vena Cava Diameter
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

Participants with data available at week 52 to calculate a change from baseline.

Arm/Group Title	Pirfenidone+Sildenafil	Pirfenidone+Placebo
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.	Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
Measure Participants	24	22
Mean (Standard Deviation) [cm]	-0.05 (0.595)	-0.09 (0.540)

16. Secondary Outcome

Title	Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Left Ventricular Ejection Fraction (LVEF)
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

Participants with data available at week 52 to calculate a change from baseline.

Arm/Group Title	Pirfenidone+Sildenafil	Pirfenidone+Placebo
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.	Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
Measure Participants	43	30
Mean (Standard Deviation) [Percentage]	1.22 (9.166)	-0.85 (5.767)

17. Secondary Outcome

Title	Change From Baseline to Week 52 in Carbon Monoxide Diffusing Capacity/ Pulmonary Diffusing Capacity (DLCO)
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

Participants with data available at week 52 to calculate a change from baseline.

Arm/Group Title	Pirfenidone+Sildenafil	Pirfenidone+Placebo
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.	Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
Measure Participants	43	29
Mean (Standard Deviation) [Percentage Predicted]	-2.918 (6.2296)	-2.440 (8.2820)

18. Secondary Outcome

Title	Change From Baseline to Week 52 in Forced Vital Capacity (FVC)
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

Participants with data available at week 52 to calculate a change from baseline.

Arm/Group Title	Pirfenidone+Sildenafil	Pirfenidone+Placebo
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.	Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
Measure Participants	45	33
Mean (Standard Deviation) [Percentage Predicted]	-2.761 (7.8044)	-1.616 (11.1158)

19. Secondary Outcome

Title	Percentage of Participants by World Health Organization (WHO) Functional Class at Week 52
Description	The World Health Organisation (WHO) functional class system defines the severity of an participant's symptoms. Class II - Participants with Pulmonary Hypertension resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue breathlessness, fatigue (tiredness), or activities that can cause chest pain, dizziness or even black outs. Class III - Participants with Pulmonary Hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue breathlessness, fatigue (tiredness), or activities that can cause chest pain, dizziness or even black outs. Class IV - participants with pulmonary hypertension with inability to carry out any physical activity without symptoms. These participants manifest signs of right heart failure, breathlessness and /or fatigue, which may even be present at rest. Discomfort is increased by any physical activity.
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

Participants with data available at week 52.

Arm/Group Title	Pirfenidone+Sildenafil	Pirfenidone+Placebo
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.	Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
Measure Participants	49	36
Class II	19.3	13.5
Class III	33.0	24.7
Class IV	3.4	1.1
Missing	0	1.1

20. Secondary Outcome

Title	Change From Baseline in N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) Level (pg/mL) at Week 52
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

Participants with data available at week 52 to calculate a change from baseline.

Arm/Group Title	Pirfenidone+Sildenafil	Pirfenidone+Placebo
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.	Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
Measure Participants	44	28
Mean (Standard Deviation) [pg/mL)]	110.1 (612.98)	605.9 (1273.19)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pirfenidone+Sildenafil, Pirfenidone+Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5646
	Comments
	Method	Linear Mixed Effects Model
	Comments
Method of Estimation	Estimation Parameter	Difference in mean change from baseline
	Estimated Value	-206.59
	Confidence Interval	(2-Sided) 95%; -920.03 to 506.85
	Parameter Dispersion	Type: Value:
	Estimation Comments

21. Secondary Outcome

Title	St. George's Respiratory Questionnaire (SGRQ) Changes From Baseline at Week 52
Description	The SGRQ is a 50-item questionnaire developed to measure health status (quality of life) in participants with diseases of airways obstruction. Three component scores are calculated, where the higher the component result the worse the condition: Symptoms concerned with the effect of respiratory symptoms, their frequency and severity (range: 0-16.61) Activity concerned with activities that cause or are limited by breathlessness (range: 0-30.31) Impacts covers a range of aspects concerned with social functioning and psychological disturbances resulting from airway disease (range: 0- 53.08) Total score summaries the impact of disease on overall health status. Scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

Participants with data available at week 52 to calculate a change from baseline.

Arm/Group Title	Pirfenidone+Sildenafil	Pirfenidone+Placebo
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.	Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
Measure Participants	41	31
Total score	6.149 (12.3407)	11.437 (12.5187)
Symptoms component score	2.498 (19.6074)	8.261 (19.5558)
Activities component score	3.997 (15.4341)	10.871 (14.5246)
Impacts component score	8.417 (15.0040)	12.118 (15.3487)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pirfenidone+Sildenafil, Pirfenidone+Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5255
	Comments
	Method	ANCOVA
	Comments	Difference in mean change in total score: -4.22
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-3.33
	Confidence Interval	(2-Sided) 95%; -9.98 to 2.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

22. Secondary Outcome

Title	University of California, San Diego-Shortness of Breath Questionnaire (UCSD-SOBQ) Changes From Baseline at Week 52
Description	The UCSD-SOBQ is a respiratory questionnaire and it assesses dyspnea associated with activities of daily living (ADL). Participants indicate severity of SOB on a 6-point scale in 21 ADL. Three additional questions ask about fear of harm from overexertion, limitations and fear caused by SOB. A total score ranges from 0 to 120, with higher scores indicating greater impairment.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

Participants with data available at week 52 to calculate a change from baseline.

Arm/Group Title	Pirfenidone+Sildenafil	Pirfenidone+Placebo
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.	Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
Measure Participants	35	25
Mean (Standard Deviation) [Points on scale]	12.5 (20.93)	18.8 (19.68)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pirfenidone+Sildenafil, Pirfenidone+Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4263
	Comments
	Method	ANCOVA
	Comments	Difference in mean change in total score: -5.07
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-6.00
	Confidence Interval	(2-Sided) 95%; -18.00 to 6.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

23. Secondary Outcome

Title	Change From Baseline in Distance Walked, 6-minute Walking Distance (6MWD) Test at Week 52
Time Frame	Baseline up to Week 52

Outcome Measure Data

Analysis Population Description

Participants with data available at week 52 to calculate a change from baseline.

Arm/Group Title	Pirfenidone+Sildenafil	Pirfenidone+Placebo
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.	Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
Measure Participants	42	30
Mean (Standard Deviation) [meters]	-52.9 (121.07)	-40.8 (91.26)

24. Secondary Outcome

Title	Change From Baseline in Oxygen Requirements, 6-minute Walking Distance (6MWD) Test at Week 52
Time Frame	Baseline up to Week 52

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pirfenidone+Sildenafil	Pirfenidone+Placebo
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.	Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
Measure Participants	42	30
Mean (Standard Deviation) [L]	0.6 (1.27)	0.6 (1.43)

25. Secondary Outcome

Title	Change From Baseline in Other 6-minute Walking Distance (6MWD) Parameters at Week 52
Time Frame	Baseline up to Week 52

Outcome Measure Data

Analysis Population Description

Participants with data available at week 52 to calculate a change from baseline.

Arm/Group Title	Pirfenidone+Sildenafil	Pirfenidone+Placebo
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.	Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
Measure Participants	42	30
SpO2 before the test (at rest)	-0.5 (4.63)	-0.8 (3.77)
SpO2 lowest during the test	-3.4 (8.93)	0.3 (5.27)
SpO2 after the test	0.5 (9.97)	-2.3 (6.67)

26. Secondary Outcome

Title	Percentage of Participants With Adverse Events
Time Frame	Baseline up to Week 52 + 28 days

Outcome Measure Data

Analysis Population Description

Participants with AEs that started or worsened on or after first intake of randomized treatment until last positive dose + 28 days

Arm/Group Title	Pirfenidone+Sildenafil	Pirfenidone+Placebo
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.	Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
Measure Participants	88	89
Number [Percentage]	98.9	93.3

27. Secondary Outcome

Title	Borg Scale Result at the End of the Test at Week 52
Description	The Borg Scale rates participant's level of perceived exertion during any activity from 0-10, with 0 being no effort at all and 10 being maximal exertion.
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

Participants with data available at week 52.

Arm/Group Title	Pirfenidone+Sildenafil	Pirfenidone+Placebo
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.	Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
Measure Participants	42	30
Mean (Standard Deviation) [Points on Scale]	0.9 (3.00)	0.7 (3.24)

Adverse Events

Time Frame	From baseline to primary data cut-off (up to 2 years 7 months). The safety data includes DBP and SFU up to 11-Nov-2019.
Adverse Event Reporting Description	Total # of Deaths (all causes n= 64) represent deaths occurring during Double blind treatment period+4 week FU+additional safety follow up to the database snapshot of 11-Nov-2019.
Arm/Group Title	Pirfenidone+Sildenafil		Pirfenidone+Placebo
Arm/Group Description	Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.		Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
All Cause Mortality
	Pirfenidone+Sildenafil		Pirfenidone+Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/88 (31.8%)		36/89 (40.4%)
Serious Adverse Events
	Pirfenidone+Sildenafil		Pirfenidone+Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	54/88 (61.4%)		55/89 (61.8%)
Cardiac disorders
Angina pectoris	1/88 (1.1%)	1	0/89 (0%)	0
Cardiac arrest	1/88 (1.1%)	1	4/89 (4.5%)	4
Cardiac failure	2/88 (2.3%)	2	0/89 (0%)	0
Cardiac failure acute	1/88 (1.1%)	1	0/89 (0%)	0
Cardiac failure chronic	0/88 (0%)	0	1/89 (1.1%)	1
Cardiac failure congestive	1/88 (1.1%)	1	1/89 (1.1%)	1
Cardio-respiratory arrest	0/88 (0%)	0	2/89 (2.2%)	2
Coronary artery disease	1/88 (1.1%)	1	0/89 (0%)	0
Right ventricular failure	3/88 (3.4%)	4	1/89 (1.1%)	1
Supraventricular tachycardia	1/88 (1.1%)	1	0/89 (0%)	0
Endocrine disorders
Goitre	1/88 (1.1%)	1	0/89 (0%)	0
Eye disorders
Blindness transient	1/88 (1.1%)	1	0/89 (0%)	0
Gastrointestinal disorders
Inguinal hernia	1/88 (1.1%)	1	1/89 (1.1%)	1
Pancreatitis	1/88 (1.1%)	1	0/89 (0%)	0
Pancreatitis acute	1/88 (1.1%)	1	0/89 (0%)	0
General disorders
Death	3/88 (3.4%)	3	1/89 (1.1%)	1
Inflammation	1/88 (1.1%)	1	0/89 (0%)	0
Hepatobiliary disorders
Cholecystitis acute	1/88 (1.1%)	1	0/89 (0%)	0
Cholelithiasis	1/88 (1.1%)	1	0/89 (0%)	0
Cholestasis	0/88 (0%)	0	1/89 (1.1%)	1
Infections and infestations
Bronchitis	1/88 (1.1%)	1	1/89 (1.1%)	1
Influenza	1/88 (1.1%)	1	0/89 (0%)	0
Respiratory tract infection	2/88 (2.3%)	2	1/89 (1.1%)	1
Upper respiratory tract infection	1/88 (1.1%)	1	1/89 (1.1%)	1
Appendicitis	1/88 (1.1%)	1	0/89 (0%)	0
Atypical pneumonia	0/88 (0%)	0	1/89 (1.1%)	1
Clostridium difficile colitis	1/88 (1.1%)	1	0/89 (0%)	0
Herpes zoster disseminated	1/88 (1.1%)	1	0/89 (0%)	0
Lower respiratory tract infection	4/88 (4.5%)	4	1/89 (1.1%)	1
Pneumonia	7/88 (8%)	9	4/89 (4.5%)	4
Pneumonia bacterial	0/88 (0%)	0	1/89 (1.1%)	1
Pneumonia haemophilus	1/88 (1.1%)	1	1/89 (1.1%)	1
Pneumonia viral	0/88 (0%)	0	1/89 (1.1%)	1
Postoperative wound infection	1/88 (1.1%)	1	0/89 (0%)	0
Respiratory tract infection viral	0/88 (0%)	0	1/89 (1.1%)	1
Sepsis	0/88 (0%)	0	1/89 (1.1%)	1
Septic shock	0/88 (0%)	0	1/89 (1.1%)	1
Injury, poisoning and procedural complications
Postoperative respiratory failure	1/88 (1.1%)	1	0/89 (0%)	0
Spinal compression fracture	1/88 (1.1%)	1	0/89 (0%)	0
Tibia fracture	1/88 (1.1%)	1	0/89 (0%)	0
Metabolism and nutrition disorders
Cachexia	0/88 (0%)	0	1/89 (1.1%)	1
Fluid overload	1/88 (1.1%)	1	0/89 (0%)	0
Hyponatraemia	1/88 (1.1%)	1	0/89 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder neoplasm	1/88 (1.1%)	1	0/89 (0%)	0
Lung neoplasm malignant	0/88 (0%)	0	1/89 (1.1%)	1
Renal cancer metastatic	0/88 (0%)	0	1/89 (1.1%)	1
Squamous cell carcinoma of lung	0/88 (0%)	0	1/89 (1.1%)	1
Nervous system disorders
Dizziness	0/88 (0%)	0	1/89 (1.1%)	1
Brain stem infarction	0/88 (0%)	0	1/89 (1.1%)	3
Cerebral haemorrhage	0/88 (0%)	0	1/89 (1.1%)	1
Cerebral infarction	1/88 (1.1%)	1	0/89 (0%)	0
Seizure	0/88 (0%)	0	1/89 (1.1%)	1
Renal and urinary disorders
Urinary bladder polyp	0/88 (0%)	0	1/89 (1.1%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	7/88 (8%)	9	5/89 (5.6%)	5
Idiopathic pulmonary fibrosis	19/88 (21.6%)	23	21/89 (23.6%)	31
Acute respiratory failure	2/88 (2.3%)	2	1/89 (1.1%)	1
Chronic respiratory failure	0/88 (0%)	0	1/89 (1.1%)	1
Hypoxia	1/88 (1.1%)	1	0/89 (0%)	0
Interstitial lung disease	1/88 (1.1%)	1	0/89 (0%)	0
Pneumonitis	1/88 (1.1%)	1	0/89 (0%)	0
Pneumothorax	0/88 (0%)	0	1/89 (1.1%)	1
Pulmonary embolism	0/88 (0%)	0	2/89 (2.2%)	2
Pulmonary fibrosis	4/88 (4.5%)	4	2/89 (2.2%)	2
Pulmonary hypertension	1/88 (1.1%)	1	2/89 (2.2%)	2
Pulmonary oedema	0/88 (0%)	0	1/89 (1.1%)	1
Respiratory acidosis	1/88 (1.1%)	1	0/89 (0%)	0
Respiratory failure	5/88 (5.7%)	5	3/89 (3.4%)	5
Surgical and medical procedures
Lung transplant	1/88 (1.1%)	1	1/89 (1.1%)	1
Vascular disorders
Cryoglobulinaemia	0/88 (0%)	0	1/89 (1.1%)	1
Dry gangrene	1/88 (1.1%)	1	0/89 (0%)	0
Extremity necrosis	1/88 (1.1%)	1	0/89 (0%)	0
Peripheral ischaemia	1/88 (1.1%)	1	0/89 (0%)	0
Other (Not Including Serious) Adverse Events
	Pirfenidone+Sildenafil		Pirfenidone+Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	53/88 (60.2%)		58/89 (65.2%)
Gastrointestinal disorders
Diarrhoea	11/88 (12.5%)	15	2/89 (2.2%)	2
Vomiting	5/88 (5.7%)	5	3/89 (3.4%)	3
General disorders
Fatigue	8/88 (9.1%)	8	6/89 (6.7%)	6
Oedema peripheral	3/88 (3.4%)	4	5/89 (5.6%)	5
Infections and infestations
Bronchitis	6/88 (6.8%)	6	9/89 (10.1%)	15
Influenza	2/88 (2.3%)	2	5/89 (5.6%)	6
Respiratory tract infection	9/88 (10.2%)	11	4/89 (4.5%)	6
Upper respiratory tract infection	8/88 (9.1%)	9	2/89 (2.2%)	4
Investigations
Weight decreased	5/88 (5.7%)	5	3/89 (3.4%)	3
Metabolism and nutrition disorders
Decreased appetite	6/88 (6.8%)	6	9/89 (10.1%)	9
Nervous system disorders
Dizziness	5/88 (5.7%)	5	2/89 (2.2%)	2
Headache	6/88 (6.8%)	7	2/89 (2.2%)	3
Respiratory, thoracic and mediastinal disorders
Cough	7/88 (8%)	9	9/89 (10.1%)	9
Dyspnoea	22/88 (25%)	23	17/89 (19.1%)	18
Idiopathic pulmonary fibrosis	8/88 (9.1%)	8	7/89 (7.9%)	10
Skin and subcutaneous tissue disorders
Pruritus	3/88 (3.4%)	3	5/89 (5.6%)	6
Vascular disorders
Hypotension	6/88 (6.8%)	7	9/89 (10.1%)	10

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.