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
Condition: Idiopathic Pulmonary Fibrosis
MeSH terms: Hypertension, Pulmonary; Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Hypertension; Fibrosis
Intervention: Pirfenidone; Placebo; Sildenafil
Intervention description: Pirfenidone will be given in the range of 1602 to 2403 milligram per day (mg/day), as 3 divided doses.; Placebo matched with sildenafil.; Sildenafil will be given as 20 mg, TID.
Intervention MeSH terms: Pirfenidone; Sildenafil Citrate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 177.0
Sex: All
Minimum age: 40 Years
Maximum age: 80 Years
Healthy volunteers: No

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.
    

Eligibility 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 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