A 2-Part, Phase 2 Open-label and Crossover Study of Belumosudil for Treatment of Idiopathic Pulmonary Fibrosis

Study Overview
=================
Brief 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

Detailed Description
-----------------
Study KD025-207 is a Phase 2, randomized, 2-part, open-label, crossover study in subjects with IPF. The purpose of the study is to evaluate the safety, tolerability, and activity of 400 mg of belumosudil administered orally (PO) every day (QD) compared to Best Standard of Care (BSC) in subjects with IPF who have previously been treated with or declined treatment with pirfenidone or nintedanib. The primary objectives are to evaluate the change in Forced Vital Capacity (FVC), and the safety and tolerability from baseline to 24 weeks in subjects with IPF after dosing with belumosudil 400 mg PO QD compared to BSC. Part 1: Randomized, Open-label for 24 Weeks Approximately 81 eligible subjects with IPF are to be enrolled, in 10 to 15 sites, and randomized in a 2:1 ratio (belumosudil:BSC) to 1 of the following 2 groups: Belumosudil-R (Investigational Group): Belumosudil 400 mg PO QD for 24 weeks BSC-R (Control Group): BSC for 24 weeks The study plan is for 54 subjects to be entered into the Belumosudil-R Treatment Group and 27 subjects into the BSC-R Treatment Group. This sample size provides over 90% power at the 2-sided 0.05 significance level to detect a 20% difference between treatment groups at 24 weeks in percentage change from baseline in FVC assuming a standard deviation (SD) in percentage change from baseline in FVC of 17%. The sample size of 54 subjects receiving belumosudil provides over 90% probability of ≥ 1 subject in the study experiencing an AE that had an underlying rate of ≥ 5%. Part 2: Continuation of Belumosudil Therapy or Crossover to Belumosudil Therapy Subjects in the Belumosudil-R group who complete 24 weeks of treatment with belumosudil 400 mg PO QD have the option of continuing therapy with belumosudil 400 mg PO QD up to an additional 72 weeks if there are no safety signals and if clinical progress continues. No subject in the Belumosudil-R group is to be permitted to receive therapy with belumosudil greater than a total of 96 weeks. Subjects in control group BSC-R who complete 24 weeks of BSC have the option of crossing over to therapy with belumosudil 400 mg PO QD for up to 96 weeks if there are no safety signals and if clinical progress continues. No subject in control group BSC-R is to be permitted to receive belumosudil 400 mg PO QD therapy greater than 96 weeks. Follow-up Period: Follow-up Visits are to occur 30 days (± 3 days) after the last dose of belumosudil during which subjects are to undergo safety assessments. (A Follow-up Visit is not necessary for subjects receiving BSC.) Duration of Study for Individual Subjects: Subjects randomized to belumosudil: total up to 104 weeks (4-week screening, 96-week treatment with belumosudil, and 4-week follow-up) Subject randomized to BSC: total up to 128 weeks (4-week screening; up to 24-week treatment with BSC, 96-week treatment with belumosudil, and 4-week follow-up) Efficacy Assessments FVC FVC% Predicted 6-minute Walking Distance (6MWD) Diffusing Capacity of Carbon Monoxide (DLCO) Lung Fibrosis (by HRCT and Radiologist's Visual Assessments) Time to Acute Exacerbation Time to Progression of IPF Time to Respiratory-related Hospitalization Time to Respiratory-related Death St. Georges Respiratory Questionnaire (SGRQ) Biomarker Assessments Matrix Metalloproteinase-7 (MMP7) Chemokine Ligand 18 (CCL18) Surfactant Protein-D (SPD) Safety Assessments Adverse event (AE) Serious adverse event (SAE) Physical examination (PE) Vital signs (VS) Clinical laboratory evaluations (hematology, chemistry, and urinalysis) Electrocardiogram (ECG) Reason for treatment discontinuation due to toxicity Analyses Efficacy and safety are to be analyzed at the end of Part 1 (Week 24) and for the Entire Treatment Period (Parts 1 and 2). Analyses of study subjects are to be grouped and defined as follows: Belumosudil-R: subjects randomized to belumosudil BSC-R: subjects randomized to BSC Belumosudil-WC: subjects randomized to belumosudil plus subjects randomized to BSC and who cross over to treatment with belumosudil BSC-NC: subjects randomized to BSC and who cross over to treatment with belumosudil but have data censored by the date of crossover

Official Title
-----------------
A Randomized, Phase 2, Open-Label, Multicenter Study to Evaluate the Safety, Tolerability, and Activity of Belumosudil in Subjects With Idiopathic Pulmonary Fibrosis (IPF)

Conditions
-----------------
Idiopathic Pulmonary Fibrosis

Intervention / Treatment
-----------------
* Drug: Belumosudil
* Other: BSC


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: A subject had to meet all of the following criteria to be eligible for the study: 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]). Able to provide written informed consent before the performance of any study specific procedures. 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. 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. 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: Intrauterine device plus 1 barrier method Stable doses of hormonal contraception for ≥ 3 months (e.g., oral, injectible, implant, transdermal) plus 1 barrier method 2 barrier methods. Effective barrier methods were male or female condoms, diaphragms, and spermicides (creams or gels containing a chemical to kill sperm) Vasectomy. Have adequate bone marrow function: Absolute neutrophil count > 1500/mm^3 Hemoglobin (Hb) > 9.0 g/L Platelets > 100,000/mm^3 Willing to complete all study measurements and assessments in compliance with protocol 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: Interstitial lung disease caused by conditions other than IPF Severe concomitant illness limiting life expectancy (< 1 year) DLCO < 30% predicted Residual volume (RV) ≥ 120% predicted Obstructive lung disease: Forced Expiratory Volume in 1 Second (FEV1/FVC ratio < 0.70) Documented sustained improvement of the subject's IPF condition up to 12 months before study entry with or without IPF-specific therapy Pulmonary infection or upper respiratory tract infection (URTI) within 4 weeks before study entry Acute or chronic impairment (other than dyspnea) limiting the ability to comply with study requirements (e.g., pulmonary function tests [PFTs]) Chronic heart failure with New York Heart Association Class III/IV or known left ventricular ejection fraction < 25% Moderate to severe hepatic impairment (i.e., Child-Pugh Class B or C) Estimated creatinine clearance < 30 mL/min Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 2.0 * upper limit of normal (ULN) Hb < 75% of the lower limit of normal Systolic blood pressure < 100 mmHg Pregnant or breastfeeding female subject Men whose partner is pregnant or breastfeeding Current drug or alcohol dependence Chronic treatment with the following drugs within 4 weeks of study entry and during the study: Immunosuppressive or cytotoxic drugs including cyclophosphamide and azathioprine Antifibrotic drugs including pirfenidone, nintedanib, D-penicillamine, colchicine, tumor necrosis factor-alpha blockers, imatinib, and interferon-γ Chronic use of N-acetylcysteine prescribed for IPF (> 600 mg/day) Oral anticoagulants prescribed for IPF Treatment with endothelin receptor antagonists within 4 weeks before study entry Systemic treatment within 4 weeks before study entry with cyclosporine A or tacrolimus, everolimus, or sirolimus (calcineurin or mammalian target of rapamycin inhibitors) Previous exposure to belumosudil or known allergy/sensitivity to belumosudil or any other Rho-associated protein kinase 2 (ROCK2) inhibitor Planned treatment or treatment with another investigational drug within 4 weeks before study entry Taking a medication with the potential for QTc prolongation Taking a drug sensitive substrate of CYP enzymes Taking a strong inducer of CYP3A4 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Belumosudil-R<br>Subjects receive two 200 mg tablets of belumosudil (400 mg) PO QD for 24 weeks. Subjects may also continue treatment with belumosudil 400 mg PO QD after 24 weeks. No subject may receive more than 96 weeks of treatment with belumosudil | Drug: Belumosudil<br> <br> * Other names: SLx-2119;|
| Active Comparator: BSC-R<br>Subjects receive best supportive care as determined by the physician. Subjects may later crossover to treatment with belumosudil 400 mg PO QD. No subject may receive more than 96 weeks of treatment with belumosudil. | Other: BSC<br>* Treatment/drug as determined by each subject's prescribing physician<br>* Other names: Best standard of care;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy: Mean Changes in FVC From Baseline to Week 24 | Changes in the mean Forced Vital Capacity (FVC) from baseline at Week 24. Normal FVC-- Healthy males 20 to 60 years: 4.75 to 5.5 L; healthy females 20 to 60 years: 3.25 to 3.75 L | 24 weeks | 
| Efficacy: Mean Changes in FVC% Predicted From Baseline at Week 24 | Changes in the mean Forced Vital Capacity (FVC)% Predicted from baseline at Week 24. Normal FVC%: 80% to 120% | 24 weeks | 
| Safety: Percentages of Subjects With Non-serious TEAEs and Relationship to Study Treatment | Percentage of subjects with non-serious TEAEs by relationship to treatment with belumosudil, BSC, or belumosudil and BSC. Severity of TEAEs were measured using the Common Terminology Criteria for Adverse Events (CTCAE) version 22.1 (Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = fatal). | Up to 96 weeks (Weeks 24, 48, and 96) of treatment with belumosudil. Subjects randomized to BSC had the option of crossing over at 24 weeks. | 
| Safety: Percentages of Subjects With SAEs Related to Study Treatment | Percentage of subjects with serious TEAEs by relationship to treatment with belumosudil and/or BSC. Investigators assessed whether events were related to treatment as possibly, probably, or definitely related. | Up to 96 weeks (Weeks 24, 48, and 96) of treatment with belumosudil. Subjects randomized to BSC and crossing over also up to 24 weeks of BSC. | 
| Safety: Percentages of Subjects With TEAEs Leading to Discontinuation of Treatment With Belumosudil | Percentage of subjects with treatment-emergent adverse events (TEAEs) leading to subjects discontinuing from treatment. Investigators assessed whether TEAEs leading to discontinuation were related to study drug (possibly, probably, or definitely), belumosudil 400 mg PO QD. | Up to 96 weeks (Weeks 24, 48, and 96) of treatment with belumosudil | 
| Safety: Percentages of Subjects With Deaths Related to Study Treatment | Percentage of subjects with deaths by relationship to treatment with belumosudil, BSC, or belumosudil and BSC. Investigators assessed whether events were related to treatment as possibly, probably, or definitely related. | Up to 96 weeks (Weeks 24, 8, and 96) of treatment with belumosudil. Subjects randomized to BSC also had the option of crossing over to treatment with belumosudil at 24 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy: Mean Changes in FVC From Baseline at Week 24 by GAP Stage and by Use of Pirfenidone or Nintedanib-- | Changes in the mean Forced Vital Capacities (FVC) at Week 24 by Gender/Age/Physiology (GAP) Stage and by the previous use of pirfenidone and/or nintedanib prior to the study for Belumosudil-WC compared to BSC-NC. Normal FVC--Healthy males 20 to 60 years: 4.75 to 5.5 L; healthy famles 20 to 60 years: 3.25 to 3.75 L GAP is measured by points as follows: (G) Gender: Female = 0 points; Male = 1 point (A) Age: ≤ 60 years = 0 points; 61-65 years = 1 point; > 65 years = 2 points (P) Physiology: FVC% Predicted: > 75% = 0 points; 50-75% = 1 point; ≤ 50% = 2 points DLCO% (diffusing lung capacity of carbon monoxide by % predicted) Predicted: > 55% = 0 points; 36-55% = 1 point, ≤ 35% = 2 points; cannot perform = 3 points GAP Stage: Stage I Index = 0 to 3 points Stage II Index= 4 to 5 points Stage III Index = 6 to 8 points | 24 weeks | 
| Efficacy: Mean Changes in FVC From Baseline at Week 48, Week 96, and EOT | Changes in the mean Forced Vital Capacity (FVC) from baseline at Weeks 48 and 96, and End-of-Treatment (EOT) Normal FVC: Healthy males 20 to 60 years: 4.75 to 5.25 L; healthy females 20 to 60 years: 3.25 to 3.75 L | Up to 96 weeks (Weeks 24, 48, and 96) | 
| Efficacy: Mean Change in Mean FEV1/FVC Ratio From Baseline at Weeks 24, 48, and 96 and EOT | Change in the mean ratio of Forced Expiratory Volume in 1 Second (FEV1) divided by the Forced Vital Capacity (FVC) at Week 24, Week 48, Week 96, and End-of-Treatment (EOT) Normal FEV1: 80% to 120% FEV1/FVC = Within 5% of predicted ratio | Up to 96 weeks (Weeks 24, 48, and 96) | 
| Efficacy: Mean Changes in FVC% Predicted at Week 24 by GAP Stage and by Use of Pirfenidone or Nintedanib-- | Changes in the mean Forced Vital Capacities (FVC)% Predicted at Week 24 by Gender/Age/Physiology (GAP) Stage and by the previous use of pirfenidone and/or nintedanib prior to the study for Belumosudil-WC compared to BSC-NC. GAP is measured by points as follows: (G) Gender: Female = 0 points; Male = 1 point (A) Age: ≤ 60 years = 0 points; 61-65 years = 1 point; > 65 years = 2 points (P) Physiology: FVC% Predicted: > 75% = 0 points; 50-75% = 1 point; ≤ 50% = 2 points DLCO% (diffusing lung capacity of carbon monoxide by % predicted) Predicted: > 55% = 0 points; 36-55% = 1 point, ≤ 35% = 2 points; cannot perform = 3 points GAP Stage: Stage I = 0 to 3 points Stage II = 4 to 5 points Stage III = 6 to 8 points | 24 weeks | 
| Efficacy: Percentages of Subjects With Decrease ≥ 5% in FVC% Predicted From Baseline at Weeks 24, 48, and 96 | Percentage of subjects exhibiting at least a 5% decrease in Forced Vital Capacity (FVC)% Predicted from baseline at Week 24, at Week 48, and at Week 96 | Up to 96 weeks (Weeks 24, 48, and 96) | 
| Efficacy: Percentage of Subjects With Decrease ≥ 10% in FVC% Predicted at Weeks 24, 48, and 96 | Percentage of subjects who exhibited at least a 10% decrease in Forced Vital Capacity (FVC)% Predicted from baseline at Week 24, at Week 48, and at Week 96 | Up to 96 weeks (Weeks 24, 48, and 96) | 
| Efficacy: Mean Change in 6MWD at Weeks 24, 48, and 96 | The mean change in the 6-mile Walking Distance (6MWD), i.e., the distance a subject can walk in 6 minutes, from baseline to Week 24, to Week 48, and to Week 96. Positive change = improvement; negative change = worsening | Up to 96 weeks (Weeks 24, 48, and 96) | 
| Efficacy: Percentages of Subjects With ≥ 50 Meter Improvement in 6MWD at Weeks 24, 48, and 96 | The percentage of subjects who have at least a 50 meter improvement in the 6-mile Walking Distance (6MWD), i.e., the distance a subject can walk in 6 minutes, from baseline to Week 24, Week 48, and Week 96. | Up to 96 weeks (Weeks 24, 48, and 96) | 
| Efficacy: Mean Changes in DLCO (%) at Weeks 24, 48, and 96 | The diffusing capacity for carbon dioxide (DLCO) is a measure of the conductance of gas transfer from inspired gas to the red blood cells. Normal DLCO is > 75% of predicted up to 140%. Severity is generally rated as: Mild: 60% to lower limit of normal Moderate: 40% to 60% Severe: < 40% | Up to 96 weeks (Weeks 24, 48, and 96) | 
| Efficacy: Percentages of Subjects With Change From Baseline in DLCO (%) ≤ -15% at Weeks 24, 48, and 96 | Percentage of the number of subjects who exhibit less than a -15% decrease in diffusing capacity of carbon monoxide (DLCO), measured as % from baseline at Week 24, Week 48, and Week 96 The diffusing capacity for carbon dioxide (DLCO) is a measure of the conductance of gas transfer from inspired gas to the red blood cells. Normal DLCO is > 75% of predicted up to 140%. Severity is generally rated as: Mild: 60% to lower limit of normal Moderate: 40% to 60% Severe: < 40% | Up to 96 weeks (Weeks 24, 48, and 96) | 
| Efficacy: Mean Changes in Total Lung Fibrosis Score, by HRCT, From Baseline at Weeks 24, 48, and 96 | The change in Total Lung Fibrosis mean score from baseline at Weeks 24, 48, and 96. Measurements using quantitative high-resolution computerized tomography (HRCT) and include (1) extent of fibrotic abnormality; (2) fibrosis score; (3) ground glass opacity; (4) honeycombing score; (5) kurtosis of lung voxel intensity; (6) skewness of lung voxel intensity; (7) standard deviation of voxel; (8) CT total lung volume; (9) normal lung; (10) reticular score; and (11) evaluation of change on sequential scans. The Quantitative Lung Fibrosis (QLF) score measures the extent of reticular patterns with architectural distortion due to fibrosis using a support vector machine classifier. Range: 0 to 100. Higher scores imply greater impairment. | Up to 96 weeks (Weeks 24, 48, and 96) | 
| Efficacy: Categorical Changes in Lung Fibrosis as Observed by Sequential Scans of Radiologist Visual Assessment, From Baseline at Weeks 24, 48, and 96 | The categorical changes of lung fibrosis using subjective visual assessments by radiologists from sequential scans at baseline, Week 24, Week 48, and Week 96. Changes were categorized as: (1) much better; (2) slightly better; (3) same; (4) slightly worse; and (5) much worse. This categorization is simplified as Better (Much or Slightly); Same; and Worse (Slightly or Much). | Up to 96 weeks (Weeks 24, 48, and 96) | 
| Efficacy: Changes in Mean DTA Lung Fibrosis Score, by Radiologist Visual Assessment, From Baseline at Weeks 24, 48, and 96 | The change in Data-driven Texture Analysis (DTA) Lung Fibrosis mean score using sequential scans from Radiologist's Visual Reads from baseline to Weeks 24, 48, and 96. The change in DTA Lung Fibrosis mean score was measured using sequential scans from Radiologist's Visual Reads from baseline at Weeks 24, 48, and 96. DTA fibrosis score was computed as the number of Region of Interests (ROIs) classified as fibrotic divided by the total number of ROIs sampled from the lung segmentation volume. The DTA fibrosis score ranged from 0 - 100%, where higher scores indicated worsening of disease. | Up to 96 Weeks (Weeks 24, 48, and 96) | 
| Efficacy: Event-free Probability of Acute Exacerbation of IPF | Acute exacerbation of IPF was defined by the following symptoms within 1 month that could not be explained by other reasons: (1) aggravated dyspnea; (2) newly discovered chest interstitial lung abnormality (by radiograph or HRCT); (3) SpO2 decrease to < 88%. Acute exacerbation was diagnosed if Items #1 and #2 were present or if Items #1 and #3 were present and the following AEs did not occur: (A) any AE with the Preferred Term containing the word infection or cardiac failure; (B) pulmonary embolism; (C) pneumothorax. | Up to 96 weeks (Weeks 24, 48, and 96) | 
| Efficacy: Event-free Probability of Progression of IPF | Progression of IPF exacerbation was defined as the probability of a subject exhibiting IPF time from baseline to any of the following: (1) probability of first respiratory-related hospitalization; (2) probability of respiratory-related death; absolute decline in FVC% Predicted value of ≥ 10% vs. FVC %; probability of predicted value recorded at baseline; and (4) probability of absolute decline in DLCO, adjusted for hemoglobin (Hb), Percent of predicted value of ≥ 15% vs. DLCO at baseline. Subjects randomized to and received BSC were censored on crossover. | Up to 96 weeks (Weeks 24, 48, and 96) | 
| Efficacy: Event-free Probability of First Respiratory-related Hospitalization | Probability of first-related hospitalization defined as any AE where the high-level group term contained the terms respiratory and the AE resulted in a hospitalization. Subjects randomized and received BSC were censored on crossover. Note: The hazard ratios for Belumosudil-R vs. BSC-NC and for Belumosudil-WC vs. BSC-NC were not calculable. | Up to 96 weeks (Weeks 24, 48, and 96) | 
| Efficacy: Event-free Probability of Respiratory-related Death | Probability of respiratory-related death, defined as any AE where the high-level group term contained the term respiratory and the AE resulted in a death. Subjects randomized to and who received BSC were censored on crossover. | Up to 96 weeks (Weeks 24, 48, and 96) | 
| Efficacy: Mean Changes in SGRQ From Baseline at Weeks 24, 48 and 96 | The St. George's Respiratory Questionnaire (SGRQ) is a disease-specific instrument designed to measure impact on overall health, daily life, and perceived well-being in subjects with obstructive airways disease consisting of 2 parts: (1) symptoms component (frequency & severity) with a 3-month recall; and (2) activities that cause or are limited by breathlessness. Impact components (social functioning, psychological disturbances resulting from airways disease) refer to current state as the recall. Changes were assessed from baseline at Week 24, at Week 48, and at Week 96. The SGRQ scores range from 0 to 100, with higher scores indicating greater limitations. Based on empirical data and interviews with subjects, a mean change score of 4 units is associated with slightly efficacious treatment, 8 units for moderately efficacious change, and 12 units for very efficacious treatment | Up to 96 weeks (Weeks 24, 48, and 96) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Pulmonary Fibrosis, Fibrosis, Idiopathic Interstitial Pneumonias, Lung Diseases