A 2-Part, Phase 2 Open-label and Crossover Study of Belumosudil for Treatment of Idiopathic Pulmonary Fibrosis
Condition: Idiopathic Pulmonary Fibrosis
MeSH terms: Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Fibrosis
Intervention: Belumosudil; BSC
Intervention description: Treatment/drug as determined by each subject's prescribing physician
Intervention MeSH terms: Belumosudil
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: In Part 1: Subjects are randomized to treatment with either Belumosudil 400 mg PO QD (Belumosudil-R) or to BSC (BSC-R).
In Part 2: Subjects who are randomized and receive Belumosudil 400 mg PO QD during Part 1 have the option to continue treatment with Belumosudil 400 mg PO QD and subjects randomized to BSC have the option to cross over to treatment with Belumosudil 400 mg PO QD.
No subject is permitted > 96 weeks of treatment with belumosudil
Masking: None (Open Label)
Enrollment: 76.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Pulmonary Fibrosis; Fibrosis; Idiopathic Interstitial Pneumonias; Lung Diseases

Summary:

      This Phase 2 study is to be conducted to evaluate the safety, tolerability, and activity of
      400 mg of belumosudil orally (PO) once-daily (QD) compared to Best Supportive Care (BSC) in
      male and postmenopausal/surgically sterilized female subjects with Idiopathic Pulmonary
      Fibrosis (IPF). The primary objectives are to evaluate the:

        -  Change in Forced Vital Capacity (FVC) from baseline to 24 weeks after dosing with
           belumosudil 400 mg PO QD in subjects with IPF compared to BSC

        -  Safety and tolerability of belumosudil 400 mg PO QD when administered for 24 weeks to
           subjects with IPF compared to BSC
    

Eligibility criteria:

        Inclusion Criteria:

        A subject had to meet all of the following criteria to be eligible for the study:

          1. Adult male and postmenopausal/surgically sterilized female subjects at least 18 years
             of age (if female, was surgically sterilized [i.e., total hysterectomy, or bilateral
             salpingo-oophorectomy]).

          2. Able to provide written informed consent before the performance of any study specific
             procedures.

          3. IPF diagnosis within 5 years before study entry, proven according to the American
             Thoracic Society/European Respiratory Society consensus conference criteria, with
             surgical lung biopsy. In the absence of a surgical lung biopsy, high-resolution
             computerized tomography (HRCT) consistent with usual interstitial pneumonitis.

          4. Resting state pulse oximeter oxygen saturation (SpO2) ≥ 88% with or without
             supplemental oxygen, Forced Vital Capacity % (FVC%) ≥ 50% normal predicted value, and
             diffusing capcity (in the lung) of carbon monoxide (DLCO) ≥ 30% normal predicted value
             at baseline.

          5. Men with partners of childbearing potential willing to use 2 medically acceptable
             methods of contraception during the trial and for 3 months after the last dose of
             study drug. Effective birth control includes:

               1. Intrauterine device plus 1 barrier method

               2. Stable doses of hormonal contraception for ≥ 3 months (e.g., oral, injectible,
                  implant, transdermal) plus 1 barrier method

               3. 2 barrier methods. Effective barrier methods were male or female condoms,
                  diaphragms, and spermicides (creams or gels containing a chemical to kill sperm)

               4. Vasectomy.

          6. Have adequate bone marrow function:

               1. Absolute neutrophil count > 1500/mm^3

               2. Hemoglobin (Hb) > 9.0 g/L

               3. Platelets > 100,000/mm^3

          7. Willing to complete all study measurements and assessments in compliance with protocol

          8. Had either received pirfenidone and/or nintedanib or offered both treatments (with
             last dose administered at least 1 month before the expected start of study drug
             dosing). If either or both pirfenidone and nintedanib treatment had not been given,
             then documentation that the subject was offered both treatments must have been
             documented.

        Exclusion Criteria:

        A subject who met any of the following criteria was ineligible for the study:

          1. Interstitial lung disease caused by conditions other than IPF

          2. Severe concomitant illness limiting life expectancy (< 1 year)

          3. DLCO < 30% predicted

          4. Residual volume (RV) ≥ 120% predicted

          5. Obstructive lung disease: Forced Expiratory Volume in 1 Second (FEV1/FVC ratio < 0.70)

          6. Documented sustained improvement of the subject's IPF condition up to 12 months before
             study entry with or without IPF-specific therapy

          7. Pulmonary infection or upper respiratory tract infection (URTI) within 4 weeks before
             study entry

          8. Acute or chronic impairment (other than dyspnea) limiting the ability to comply with
             study requirements (e.g., pulmonary function tests [PFTs])

          9. Chronic heart failure with New York Heart Association Class III/IV or known left
             ventricular ejection fraction < 25%

         10. Moderate to severe hepatic impairment (i.e., Child-Pugh Class B or C)

         11. Estimated creatinine clearance < 30 mL/min

         12. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 2.0 * upper
             limit of normal (ULN)

         13. Hb < 75% of the lower limit of normal

         14. Systolic blood pressure < 100 mmHg

         15. Pregnant or breastfeeding female subject

         16. Men whose partner is pregnant or breastfeeding

         17. Current drug or alcohol dependence

         18. Chronic treatment with the following drugs within 4 weeks of study entry and during
             the study:

               1. Immunosuppressive or cytotoxic drugs including cyclophosphamide and azathioprine

               2. Antifibrotic drugs including pirfenidone, nintedanib, D-penicillamine,
                  colchicine, tumor necrosis factor-alpha blockers, imatinib, and interferon-γ

               3. Chronic use of N-acetylcysteine prescribed for IPF (> 600 mg/day)

               4. Oral anticoagulants prescribed for IPF

         19. Treatment with endothelin receptor antagonists within 4 weeks before study entry

         20. Systemic treatment within 4 weeks before study entry with cyclosporine A or
             tacrolimus, everolimus, or sirolimus (calcineurin or mammalian target of rapamycin
             inhibitors)

         21. Previous exposure to belumosudil or known allergy/sensitivity to belumosudil or any
             other Rho-associated protein kinase 2 (ROCK2) inhibitor

         22. Planned treatment or treatment with another investigational drug within 4 weeks before
             study entry

         23. Taking a medication with the potential for QTc prolongation

         24. Taking a drug sensitive substrate of CYP enzymes

         25. Taking a strong inducer of CYP3A4

         26. Had consumed an herbal medication (e.g., St. John's Wort) or grapefruit/grapefruit
             juice within 14 days prior to the Week 1 Day 1 visit