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

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ClinicalTrials.gov Identifier: NCT02951429
Recruitment Status : Active, not recruiting
First Posted : November 1, 2016
Last Update Posted : September 18, 2018
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

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 risk 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 Type : Interventional  (Clinical Trial)
Estimated Enrollment : 176 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 Risk of Group 3 Pulmonary Hypertension
Actual Study Start Date : January 13, 2017
Estimated Primary Completion Date : April 1, 2019
Estimated Study Completion Date : August 29, 2020


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 Name: 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 Name: Esbriet, RO0220912

Drug: Sildenafil
Sildenafil will be given as 20 mg, TID.
Other Name: RO0280296




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 [ Time Frame: Baseline up to Week 52 ]

Secondary Outcome Measures :
  1. Progression-Free Survival (PFS), Defined as Time to Decline in 6MWD of >=15% From Baseline, Respiratory-Related Non-Elective Hospitalization, or Death From Any Cause [ Time Frame: Baseline up to Week 52 ]
  2. Percentage of Participants With Decline From Baseline in 6MWD of >= 15% [ Time Frame: Baseline up to Week 52 ]
  3. Time to Respiratory-Related Non-Elective Hospitalization [ Time Frame: Baseline up to Week 52 ]
  4. Time to All-Cause Non-Elective Hospitalization [ Time Frame: Baseline up to Week 52 ]
  5. Time to Death From Any Cause [ Time Frame: Baseline up to Week 52 ]
  6. Time to Respiratory-Related Death [ Time Frame: Baseline up to Week 52 ]
  7. Percentage of Participants With Lung Transplantation [ Time Frame: Baseline up to Week 52 ]
  8. Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Peak Tricuspid Regurgitation Velocity [ Time Frame: Baseline, Week 52 ]
  9. Change From Baseline to Week 52 in ECHO Parameter: Pulmonary Artery Pressure (PAPs) [ Time Frame: Baseline, Week 52 ]
  10. Change From Baseline to Week 52 in Forced Vital Capacity (FVC) [ Time Frame: Baseline, Week 52 ]
  11. Change From Baseline to Week 52 in Forced Expiratory Volume in 1 Second (FEV1) [ Time Frame: Baseline, Week 52 ]
  12. Change From Baseline to Week 52 in FEV1/FVC Ratio [ Time Frame: Baseline, Week 52 ]
  13. Change From Baseline to Week 52 in Carbon Monoxide Diffusing Capacity/ Pulmonary Diffusing Capacity (DLCO) [ Time Frame: Baseline, Week 52 ]
  14. Change From Baseline to Weeks 6, 12, 26, 39, and 52 in Oxyhemoglobin Saturation (SpO2) at Rest and During the 6MWT [ Time Frame: Baseline, Weeks 6, 12, 26, 39, and 52 ]
  15. Perceived Exertion, as Assessed by Borg Rating of Perceived Exertion Scale [ Time Frame: Baseline, Weeks 6, 12, 26, 39, and 52 ]
  16. Percentage of Participants by World Health Organization (WHO) Functional Class [ Time Frame: Baseline, Weeks 3, 6, 12, 19, 26, 32, 39, 45, and 52 ]
  17. Change From Baseline to Weeks 12, 26, 39, and 52 in Dyspnea, as Assessed by the University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ) [ Time Frame: Baseline, Weeks 12, 26, 39, and 52 ]
  18. Change From Baseline to Weeks 12, 26, 39, and 52 in Health-Related Quality of Life (HRQoL), as Assessed by the Saint George's Respiratory Questionnaire (SGRQ) [ Time Frame: Baseline, Weeks 12, 26, 39, and 52 ]
  19. Change From Baseline to Weeks 12, 26, and 52 in N-Terminal pro-Brain Natriuretic Peptide (NT-proBNP) Level [ Time Frame: Baseline, Weeks 12, 26, and 52 ]
  20. Percentage of Participants With Adverse Events and Serious Adverse Events [ Time Frame: Baseline up to 108 weeks ]


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Ages Eligible for Study:   40 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 risk 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. participants with bleeding disorders or active peptic ulceration; 4. known hereditary degenerative retinal disorders such as retinitis pigmentosa; 5. galactose intolerance

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02951429


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Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT02951429     History of Changes
Other Study ID Numbers: MA29957
2015-005131-40 ( EudraCT Number )
First Posted: November 1, 2016    Key Record Dates
Last Update Posted: September 18, 2018
Last Verified: September 2018

Additional relevant MeSH terms:
Hypertension
Fibrosis
Hypertension, Pulmonary
Pulmonary Fibrosis
Idiopathic Pulmonary Fibrosis
Idiopathic Interstitial Pneumonias
Vascular Diseases
Cardiovascular Diseases
Pathologic Processes
Lung Diseases
Respiratory Tract Diseases
Lung Diseases, Interstitial
Sildenafil Citrate
Pirfenidone
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Anti-Inflammatory Agents
Antirheumatic Agents
Antineoplastic Agents