Idiopathic Pulmonary Fibrosis Clinical Trial
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)
Verified date | September 2022 |
Source | Kadmon Corporation, LLC |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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
Status | Completed |
Enrollment | 76 |
Est. completion date | April 13, 2021 |
Est. primary completion date | April 13, 2021 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years and older |
Eligibility | 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-? 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 |
Country | Name | City | State |
---|---|---|---|
United States | Piedmont Healthcare Pulmonary and Critical Care Research | Austell | Georgia |
United States | Medical University of South Carolina | Charleston | South Carolina |
United States | St. Francis Medical Institute | Clearwater | Florida |
United States | Pulmonix, LLC | Greensboro | North Carolina |
United States | Pulmonary Disease Specialists, PA, d/b/a PDS Research | Kissimmee | Florida |
United States | Central Florida Pulmonary Group, PA | Orlando | Florida |
United States | Pulmonary Associates, PA | Phoenix | Arizona |
United States | University of Pittsburgh Medical Center | Pittsburgh | Pennsylvania |
United States | UC Davis Medical Center, Division of Pulmonary/CC/SM | Sacramento | California |
United States | University of Arizona | Tucson | Arizona |
Lead Sponsor | Collaborator |
---|---|
Kadmon Corporation, LLC |
United States,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | 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 | |
Primary | 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 | |
Primary | 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. | |
Primary | 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. | |
Primary | 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 | |
Primary | 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 | 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 | |
Secondary | 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) | |
Secondary | 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) | |
Secondary | 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 | |
Secondary | 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) | |
Secondary | 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) | |
Secondary | 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) | |
Secondary | 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) | |
Secondary | 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) | |
Secondary | 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) | |
Secondary | 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) | |
Secondary | 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) | |
Secondary | 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) | |
Secondary | 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) | |
Secondary | 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) | |
Secondary | 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) | |
Secondary | 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) | |
Secondary | 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) |
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