Efficacy and Safety of Belumosudil in Subjects With Diffuse Cutaneous Systemic Sclerosis

Study Overview
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Brief Summary
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This was a phase 2, open-label, single-cohort, multicenter trial of belumosudil in participants with Diffuse Cutaneous Systemic Sclerosis (dcSSc). An estimated total of 12 to 15 participants would receive belumosudil 200 milligrams (mg) administered orally (PO) twice daily (BID) for 52 weeks. The primary analysis was at 24 weeks.

Detailed Description
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The primary objective of this phase 2, open-label, single-cohort, multicenter trial was to evaluate the efficacy of belumosudil 200 mg BID using the Combined Response Index in diffuse cutaneous Systemic Sclerosis (CRISS) after 24 weeks of therapy. The duration of the study was approximately 14 months (4 weeks for screening, 52 weeks of dosing period, and 4 weeks of Follow-up) Participants who had signed an Institutional Review Board/Independent Ethics Committee-(IRB/IEC)-approved informed consent form (ICF) and met all of the inclusion/exclusion criteria were enrolled. A total of 10 participants at 6 sites received belumosudil 200 mg in tablet form administered PO BID for 52 weeks. The total duration of the study is approximately 14 months: a 4-week screening period, a 52-week treatment period, and a 4-week follow-up. The primary endpoint was analyzed using Week 24 data. Efficacy was assessed throughout the 52-week dosing period using: Composite Response Index in Systemic Sclerosis (CRISS) Modified Rodnan Skin Score (mRSS) Pulmonary Function Tests (PFTs) Physician Global Assessment Patient Global Assessment Safety was be assessed throughout the study and will include:. Physical examinations (PEs) Vital sign measurements Weight measurements Blood sample collection for hematology and chemistry; urinalysis Electrocardiograms (ECGs) Adverse event (AE) assessments Concomitant medication assessments Pregnancy testing for females of childbearing potential. Reasons for discontinuation of treatment because of adverse events were documented. Careful monitoring of all adverse events was carried out. Dosing could be reduced 1 dose level. If the dose was not tolerated, then the participant was discontinued from the study. If there is an interruption of dosing, after 14 days the participant was discontinued from the study. Participants were given a study drug diary to record the details of each dose of belumosudil 200 mg. Diaries were dispense/collected on each visit. Compliance with dosing was confirmed using participant diaries, which was examined at each visit by site staff to determine if dosing was as instructed per protocol and follow-up. A 4-Week Safety Follow-up Visit occurred 28 days (± 3 days) after the last dose of study drug.

Official Title
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A Phase 2, Open-label Multicenter Study to Evaluate the Efficacy and Safety of Belumosudil in Subjects With Diffuse Cutaneous Systemic Sclerosis (dcSSc)

Conditions
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Diffuse Cutaneous Systemic Sclerosis

Intervention / Treatment
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* Drug: Belumosudil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female participants greater than or equal to (>=) 18 years old with the diagnosis of dcSSc according to the 2013 American College of Rheumatology and European League Against Rheumatism. Had disease duration (defined as interval from first non Raynaud disease manifestation) of less than or equal to (<=) 6 years. Had mRSS of >=15 but <=40. Had active disease as determined by the Principal Investigator within the 6 months prior to screening. Adequate organ and bone marrow functions evaluated during the 28 days prior to enrollment as follows: Absolute neutrophil count >= 1.5*10^9/L Platelet count >= 100*10^9/L Total bilirubin <= 1.0*upper limit of normal (ULN) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and serum creatinine <= 1.5*ULN. Female participants of childbearing potential had a negative pregnancy test at screening. Females of childbearing potential were defined as sexually mature women without prior hysterectomy or who had any evidence of menses in the past 12 months. However, women who had been amenorrheic for 12 or more months were still considered to be of childbearing potential if the amenorrhea was possibly due to prior chemotherapy, anti-estrogens, or ovarian suppression. Women of childbearing potential (i.e., menstruating women) must had a negative urine pregnancy test (positive urine tests were to be confirmed by serum test) documented within the 24-hour period prior to the first dose of study drug. Sexually active women of childbearing potential enrolled in the study agreed to use two forms of accepted methods of contraception during the course of the study and for 3 months after their last dose of study drug. Effective birth control includes (i) intrauterine device plus 1 barrier method; (ii) on stable doses of hormonal contraception for at least 3 months (e.g., oral, injectable, implant, transdermal) plus 1 barrier method; or (iii) 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm), or a vasectomized partner. For male participants who were sexually active and who were partners of premenopausal women: agreement to use 2 forms of contraception as in criterion number 6b above during the treatment period and for at least 3 months after the last dose of study drug. Male participants must not donate sperm for 3 months after last dose of study drug. Able to provide written informed consent prior to the performance of any study-specific procedures. Exclusion Criteria: Participants had corrected QT interval using Fridericia's formula (QTcF) greater than 450 milliseconds. Ongoing use or current use of concomitant medication known to have the potential for QTc prolongation. Female participant who was pregnant or breastfed. Participated in another study with an investigational drug within 28 days of study entry (for studies involving biologics, within 3 half-lives of the biologic). History or other evidence of severe illness or any other conditions that would make the participant, in the opinion of the Investigator, unsuitable for the study. Chronic heart failure with New York Heart Association Classes II, III, or IV. Acute or chronic liver disease (e.g., cirrhosis). Positive human immunodeficiency virus (HIV) test. Active hepatitis C virus (HCV), hepatitis B virus (HBV), or positive whole blood tuberculin test. Diagnosed with any malignancy within 3 years of enrollment, with the exception of basal cell or completely resected squamous cell carcinoma of the skin, resected in situ cervical malignancy, resected breast ductal carcinoma in situ, or low risk prostate cancer after curative resection. Had previous exposure to belumosudil or known allergy/sensitivity to belumosudil, or any other Rho-associated Protein Kinase-2 (ROCK2) inhibitor. Scleroderma renal crisis within 4 months prior to enrollment. Forced vital capacity <= 50% Predicted.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Belumosudil 200 mg PO BID
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Belumosudil<br>Participants received belumosudil 200 mg tablet orally PO, BID for 52 weeks. | Drug: Belumosudil<br>* 10 participants with dcSSc received belumosudil 200 mg PO BID for 52 weeks<br>* Other names: KD025;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Combined Response Index in Diffuse Cutaneous Systemic Sclerosis (CRISS) Score at Week 24 | CRISS components included the following domains: modified Rodnan skin score (mRSS), forced vital capacity (FVC) percent predicted, physician global assessment, patient global assessment, and scleroderma health assessment questionnaire disability-index (SHAQ-DI). An algorithm determines the predicted probability of improvement from Baseline by incorporating change in the mRSS, FVC percent predicted, physician and patient global assessments, and SHAQ-DI. The outcome is a continuous variable between 0.0 and 1.0 (0 to 100%). A higher score indicated greater probability of improvement. Participants are not considered improved if they develop new onset of renal crisis, new onset or worsening of lung fibrosis, new onset of pulmonary arterial hypertension, new onset of left ventricular failure during the trial. CRISS score greater than 60% is considered the minimally important difference. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Combined Response Index in Diffuse Cutaneous Systemic Sclerosis (CRISS) Score at Weeks 8, 16, 36, and 52 | CRISS components included the following domains: mRSS, FVC percent predicted, physician global assessment, patient global assessment, and SHAQ-DI. An algorithm determines the predicted probability of improvement from Baseline by incorporating change in the mRSS, FVC percent predicted, physician and patient global assessments, and SHAQ-DI. The outcome is a continuous variable between 0.0 and 1.0 (0 to 100%). A higher score indicated greater probability of improvement. Participants are not considered improved if they develop new onset of renal crisis, new onset or worsening of lung fibrosis, new onset of pulmonary arterial hypertension, new onset of left ventricular failure during the trial. CRISS score greater than 60% is considered the minimally important difference. | Week 8, 16, 36 and 52 | 
| Modified Rodnan Skin Score (mRSS) at Week 24 | The mRSS is an accepted clinical measure of the skin thickness. The investigator assessed the thickening of the skin using the modified Rodnan Skin Score through simple palpation on 17 different skin sites in the fingers, hands, forearms, arms, feet, legs, and thighs (bilaterally) and face, chest, and abdomen (singly). Each skin site was rated on a 0 to 3 scale; where 0 = normal skin, 1 = mild thickness, 2 = moderate thickness, and 3 = severe thickness and unable to pinch. Individual skin scores in the 17 body areas were summed and defined as the total mRSS which ranged from 0 (no thickening) to 51 (severe thickening), where higher score indicated more severity of skin thickening/worst outcome. | Week 24 | 
| Forced Vital Capacity (FVC) Level at Week 24 | FVC was the total amount of air (in liters) exhaled from the lungs during the lung function test measured by spirometer which assessed the change in lung function related to the disease status of an underlying interstitial lung disease. | Week 24 | 
| Physician Global Assessment of Participant's Overall Health Using Visual Analogue Scale (VAS) Score at Week 24 | The Physician Global Assessment (reported by the physician) quantified the participant's overall health during the last week based on a VAS which ranged from 0 (extremely poor) to 100 (excellent). Higher score indicated better outcome. | Week 24 | 
| Patient Global Assessment of Participant's Overall Health Using Visual Analogue Scale (VAS) Score at Week 24 | The Patient Global Assessment (reported by participant) quantified the participant's overall health during the last week based on a VAS which ranged from 0 (extremely poor) to 100 (excellent). Higher score indicated better outcome. | Week 24 | 
| Scleroderma Health Assessment Questionnaire-Disability Index (SHAQ-DI) Total Score at Week 24 | SHAQ-DI included the general health assessment questionnaire-disability index (HAD-DI) assessment and 6 scleroderma-specific VAS items to explore the impact of participant's disease. The general HAD-DI assessment included 8 domains addressing scleroderma related manifestations that contribute to disability. It is a quality of life measure. For each question, level of difficulty was scored from 0 to 3, where 0=no difficulty, 1=some difficulty, 2=much difficulty, 3=unable to do. Some domains in the SHAQ are visual analog scales that are measured first and then changed to a 0-3 scale. SHAQ-DI total score was computed as the sum of domain scores divided by the number of domains answered and it ranged from 0 (no difficulty) to 3 (maximum difficulty), where higher score indicated greater disability/worse functionality. | Week 24 | 
| Change From Baseline in Modified Rodnan Skin Thickness Score (mRSS) at Weeks 8, 16, 36, and 52 | The mRSS is an accepted clinical measure of the skin thickness. The investigator assessed the thickening of the skin using the modified Rodnan Skin Score through simple palpation on 17 different skin sites in the fingers, hands, forearms, arms, feet, legs, and thighs (bilaterally) and face, chest, and abdomen (singly). Each skin site was rated on a 0 to 3 scale; where 0 = normal skin, 1 = mild thickness, 2 = moderate thickness, and 3 = severe thickness and unable to pinch. Individual skin scores in the 17 body areas were summed and defined as the total mRSS which ranged from 0 (no thickening) to 51 (severe thickening), where higher score indicated more severity of skin thickening/worst outcome. A negative change from baseline demonstrates improvement. | Baseline, Week 8, 16, 36 and 52 | 
| Change From Baseline in Forced Vital Capacity (FVC) Level at Weeks 8, 16, 36, and 52 | FVC was the total amount of air (in liters) exhaled from the lungs during the lung function test measured by spirometer which assessed the change in lung function related to the disease status of an underlying interstitial lung disease. Change from Baseline was calculated by subtracting Baseline value from specified values at each reported week (Week 8, 16, 36 and 52). | Baseline, Week 8, 16, 36 and 52 | 
| Change From Baseline in Physician Global Assessment (Reported by the Physician) Quantified of Participant's Overall Health Using Visual Analogue Scale (VAS) Score at Weeks 8, 16, 36, and 52 | The Physician Global Assessment (reported by the physician) quantified the participant's overall health during the last week based on a VAS which ranged from 0 (extremely poor) to 100 (excellent). Higher score indicated better outcome. A positive change from Baseline demonstrated improvement. | Baseline, Week 8, 16, 36 and 52 | 
| Change From Baseline in Patient Global Assessment of Participant's Overall Health Using Visual Analogue Scale (VAS) Score at Weeks 8, 16, 36, and 52 | The Patient Global Assessment (reported by participant) quantified the participant's overall health during the last week based on a VAS which ranged from 0 (extremely poor) to 100 (excellent). Higher score indicated better outcome. A positive change from Baseline demonstrated improvement. | Baseline, Week 8, 16, 36 and 52 | 
| Change From Baseline in Scleroderma Health Assessment Questionnaire-Disability Index (SHAQ-DI) Total Score at Weeks 8, 16, 36, and 52 | SHAQ-DI VAS included the general HAD-DI assessment and 6 scleroderma-specific VAS items to explore the impact of participant's disease. The general HAD-DI assessment included 8 domains addressing scleroderma related manifestations that contribute to disability. It is a quality of life measure. Each activity category consisted of 2 to 3 items. For each question, level of difficulty was scored from 0 to 3, where 0=no difficulty, 1=some difficulty, 2=much difficulty, 3=unable to do. Some domains in the SHAQ are visual analog scales that are measured first and then changed to a 0-3 scale. SHAQ-DI total score was computed as the sum of domain scores divided by the number of domains answered and it ranged from 0 (no difficulty) to 3 (maximum difficulty), where higher score indicated greater disability/worse functionality. | Baseline, Week 8, 16, 36 and 52 | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Adverse event (AE): any untoward medical occurrence in a participant who received investigational medicinal product (IMP) without regard to possibility of causal relationship with the treatment. TEAEs: AEs that developed/worsened or became serious during treatment-emergent period (time of first dose administration of study medication up to 28 days after last dose). Serious AE (SAE): any untoward medical occurrence resulted in any of following outcomes: death, life-threatening, required initial/prolonged in-patient hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. | From first dose administration (i.e., Day 1) of study medication up to 28 days after last dose (i.e., up to 57.5 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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skin diseases, systemic sclerosis, phase 2, Scleroderma Health Assessment Questionnaire Disability Index, Modified Rodnan Skin Score, Combined Response Index in dcSSc (CRISS), diffuse cutaneous systemic sclerosis