Clinical trial NCT03919799: KD025 in Subjects With Diffuse Cutaneous Systemic Sclerosis
Official title: A Phase 2, Randomized, Placebo-controlled, Double-blind, Open-label Extension Multicenter Study to Evaluate the Efficacy and Safety of Belumosudil (KD025) in Subjects With Diffuse Cutaneous Systemic Sclerosis
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: System; Sclerosis
Diffuse Cutaneous Systemic Sclerosis
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2019-04-18
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Three groups (1:1:1) to receive orally administered belumosudil 200 mg QD, belumosudil 200 mg BID, or matched placebo for 28 weeks. The study was double-blinded for the first 28 weeks followed by an open-label extension of 24 weeks.

After unblinding, the participants in the belumosudil groups continued on the same belumosudil dose whereas the participants in the placebo group were re-randomized to one of the belumosudil doses (200 mg QD or 200 BID) in 1:1 fashion.
Primary purpose: TREATMENT

Brief summary: This randomized, placebo-controlled phase 2 study was seeking to evaluate the efficacy and safety of belumosudil (KD025) for the treatment of diffuse cutaneous systematic sclerosis. Enrolment was terminated earlier than planned for business reasons unrelated to safety. A total of 36 participants were enrolled and randomized into 3 groups to either receive orally administered belumosudil (200 milligrams \[mg\] once daily \[QD\] and 200 mg twice daily \[BID\]) or matched placebo in 1:1:1 ratio in the double-blind (DB) period of this study. Study drug dosing was for 52 weeks: double-blinded for the first 28 weeks followed by an open-label extension of 24 weeks. After unblinding, the participants on belumosudil continued on the same belumosudil dose whereas the participants in the placebo group were re-randomized to one of the belumosudil doses in a 1:1 ratio.

Detailed description: Systemic sclerosis (SSc) is a chronic autoimmune disease that causes widespread microvascular damage and excessive deposition of collagen in the skin and internal organs. Limited cutaneous systemic sclerosis is primarily cutaneous, affecting the hands, arms, and face. Diffuse cutaneous systemic sclerosis (dcSSc) is a more serious manifestation of the disease and is often rapidly progressive, not only involving the skin, but also involving internal organs including kidney, heart, and lungs.

Eligibility criteria: Inclusion Criteria:

1. 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 criteria.
2. Had disease duration (defined as interval from first non-Raynaud disease manifestation) of less than or equal to (\<=) 5 years.
3. Had mRSS of \>= 15 but \<= 35.
4. Active disease defined as any of the following within the 6 months prior to screening:

   1. Increase in mRSS by \>= 3 units.
   2. Increase in mRSS by \>= 2 units with involvement of 1 new body area.
   3. Involvement of 2 new body areas.
   4. Symptoms indicative of skin activity such as severe cutaneous itching or burning.
5. Participants who had received concomitant immunosuppression must be on a stable dose for at least 3 months prior to screening.
6. Adequate organ and bone marrow functions evaluated during the 28 days prior to enrollment as follows:

   1. Absolute neutrophil count \>= 1.5\*10\^9/L.
   2. Platelet count \>=100\*10\^9/L.
   3. Total bilirubin \<= 1.0\*upper limit of normal (ULN).
   4. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and serum creatinine \<= 1.5\*ULN.
7. 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 have 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.

   1. Women of childbearing potential (i.e., menstruating women) 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.
   2. Sexually active women of childbearing potential enrolled in the study must agree to use 2 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 (1) intrauterine device plus 1 barrier method; (2) on stable doses of hormonal contraception for at least 3 months (e.g., oral, injectable, implant, transdermal) plus 1 barrier method; or (3) two barrier methods. Effective barrier methods were male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm), or a vasectomized partner.
8. 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 7 above during the treatment period and for at least 3 months after the last dose of study drug.
9. Male participants must not donate sperm for 3 months after last dose of study drug.
10. Able to provide written informed consent prior to the performance of any study-specific procedures.

Exclusion Criteria:

1. Participant had corrected QT interval QTcF greater than (\>) 450 milliseconds.
2. Ongoing use or current use of concomitant medication known to have the potential for QTc prolongation.
3. Female participant who was pregnant or breastfeeding.
4. 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).
5. 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.
6. Chronic heart failure with New York Heart Association Class II, III, or IV.
7. Acute or chronic liver disease (e.g., cirrhosis).
8. Positive human immunodeficiency virus (HIV) test.
9. Active hepatitis C virus (HCV), hepatitis B virus (HBV), or positive whole blood tuberculin test.
10. 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.
11. Has had previous exposure to belumosudil or known allergy/sensitivity to belumosudil, or any other ROCK2 inhibitor.
12. Scleroderma renal crisis within 4 months prior to enrollment.
13. FVC \<= 50% Predicted.

Primary outcomes:
measure: DB Period: Number of Participants With Combined Response Index in Diffuse Cutaneous Systemic Sclerosis (CRISS) Score Greater Than or Equal to (>=) 60 Percent (%) at Week 24
timeFrame: Week 24
Secondary outcomes:
measure: DB Period: Combined Response Index in Diffuse Cutaneous Systemic Sclerosis Score at Week 24
timeFrame: Week 24
measure: OLE Period: Combined Response Index in Diffuse Cutaneous Systemic Sclerosis Score at Week 52
timeFrame: Week 52
measure: DB Period: Change From Baseline in Modified Rodnan Skin Score (mRSS) at Week 24
timeFrame: Baseline, Week 24
measure: DB Period: Change From Baseline in Percent Predicted Forced Vital Capacity (FVC) at Week 24
timeFrame: Baseline, Week 24
measure: DB Period: Change From Baseline in Physician Global Assessment of Participant's Overall Health Using Visual Analogue Scale Score at Week 24
timeFrame: Baseline, Week 24
measure: DB Period: Change From Baseline in Patient Global Assessment of Participant's Overall Health Using Visual Analogue Scale Score at Week 24
timeFrame: Baseline, Week 24
measure: DB Period: Change From Baseline in Scleroderma Health Assessment Questionnaire-Disability Index (SHAQ-DI) Total Score at Week 24
timeFrame: Baseline, Week 24
measure: DB Period: Percentage Improvement in Modified Rodnan Skin Score at Week 24
timeFrame: Baseline, Week 24
measure: DB Period: Percentage Improvement in Physician Global Assessment of Participant's Overall Health Using Visual Analogue Scale (VAS) Score at Week 24
timeFrame: Baseline, Week 24
measure: DB Period: Percentage Improvement in Patient Global Assessment of Participant's Overall Health Using Visual Analogue Scale Score at Week 24
timeFrame: Baseline, Week 24
measure: DB Period: Percentage Improvement in Scleroderma Health Assessment Questionnaire-Disability Index (SHAQ-DI) Total Score at Week 24
timeFrame: Baseline, Week 24
measure: OLE Period: Change From Baseline in Modified Rodnan Skin Score at Week 52
timeFrame: Baseline, Week 52
measure: OLE Period: Change From Baseline in Percent Predicted Forced Vital Capacity at Week 52
timeFrame: Baseline, Week 52
measure: OLE Period: Change From Baseline in Physician Global Assessment of Participant's Overall Health Using Visual Analogue Scale (VAS) Score at Week 52
timeFrame: Baseline, Week 52
measure: OLE Period: Change From Baseline in Patient Global Assessment of Participant's Overall Health Using Visual Analogue Scale Score at Week 52
timeFrame: Baseline, Week 52
measure: OLE Period: Change From Baseline in Scleroderma Health Assessment Questionnaire-Disability Index Total Score at Week 52
timeFrame: Baseline, Week 52
measure: OLE Period: Percentage Improvement in Modified Rodnan Skin Score at Week 52
timeFrame: Baseline, Week 52
measure: OLE Period: Percentage Improvement Physician Global Assessment of Participant's Overall Health Using Visual Analogue Scale (VAS) Score at Week 52
timeFrame: Baseline, Week 52
measure: OLE Period: Percentage Improvement in Patient Global Assessment of Participant's Overall Health Using Visual Analogue Scale Score at Week 52
timeFrame: Baseline, Week 52
measure: OLE Period: Percentage Improvement in Scleroderma Health Assessment Questionnaire-Disability Index Score at Week 52
timeFrame: Baseline, Week 52
measure: DB Period: Change From Baseline in Percent Predicted Forced Vital Capacity Level at Week 24-ILD Participants
timeFrame: Baseline, Week 24
measure: DB Period: Change From Baseline in Percent Predicted Diffusing Capacity of the Lungs for Carbon Monoxide (DLco) at Week 24-ILD Participants
timeFrame: Baseline, Week 24
measure: DB Period: Change From Baseline in Percent Predicted Forced Expiratory Volume (FEV1) at Week 24-ILD Participants
timeFrame: Baseline, Week 24
measure: DB Period: Change From Baseline in Percent Predicted Residual Volume (RV) at Week 24-ILD Participants
timeFrame: Baseline, Week 24
measure: DB Period: Change From Baseline in Percent Predicted Total Lung Capacity (TLC) at Week 24-ILD Participants
timeFrame: Baseline, Week 24
measure: OLE Period: Change From Baseline in Percent Predicted Forced Vital Capacity at Week 52-ILD Participants
timeFrame: Baseline, Week 52
measure: OLE Period: Change From Baseline in Percent Predicted Diffusing Capacity of the Lungs for Carbon Monoxide at Week 52-ILD Participants
timeFrame: Baseline, Week 52
measure: OLE Period: Change From Baseline in Percent Predicted Forced Expiratory Volume at Week 52-ILD Participants
timeFrame: Baseline, Week 52
measure: OLE Period: Change From Baseline in Percent Predicted Residual Volume at Week 52-ILD Participants
timeFrame: Baseline, Week 52
measure: OLE Period: Change From Baseline in Percent Predicted Total Lung Capacity at Week 52-ILD Participants
timeFrame: Baseline, Week 52
measure: DB Period: Number of Participants With Lung Fibrosis at Baseline and Week 24-ILD Participants
timeFrame: Baseline, Week 24
measure: OLE Period: Number of Participants With Lung Fibrosis at Baseline and Week 52-ILD Participants
timeFrame: Baseline, Week 52
measure: DB Period: Pharmacokinetics: Plasma Concentration of Belumosudil and Its Metabolite (KD025m2)
timeFrame: Pre-dose and 3 hours post-dose at Week 4 and 8
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
timeFrame: For DB period: From Day 1 (Week 0) up to Week 28; for OLE period: from Week 29 up to 4 weeks post last study drug administration (i.e., up to Week 56)
measure: DB Period: Change From Baseline in Vital Signs: Systolic and Diastolic Blood Pressure at Week 24
timeFrame: Baseline, Week 24
measure: OLE: Change From Baseline in Vital Signs: Systolic and Diastolic Blood Pressure at Week 52
timeFrame: Baseline, Week 52
measure: DB Period: Change From Baseline in Vital Signs: Pulse at Week 24
timeFrame: Baseline, Week 24
measure: OLE Period: Change From Baseline in Vital Signs: Pulse at Week 52
timeFrame: Baseline, Week 52
measure: DB Period: Change From Baseline in Vital Signs: Respiratory Rate at Week 24
timeFrame: Baseline, Week 24
measure: OLE Period: Change From Baseline in Vital Signs: Respiratory Rate at Week 52
timeFrame: Baseline, Week 52
measure: DB Period: Change From Baseline in 12-lead Electrocardiogram (ECG) Values: Heart Rate at Week 24
timeFrame: Baseline, Week 24
measure: OLE Period: Change From Baseline in 12-lead Electrocardiogram Values: Heart Rate at Week 52
timeFrame: Baseline, Week 52
measure: DB Period: Change From Baseline in 12-lead Electrocardiogram Values: PR Interval, RR Interval, QRS Interval, QT Interval and QTcF Interval at Week 24
timeFrame: Baseline, Week 24
measure: OLE Period: Change From Baseline in 12-lead Electrocardiogram Values: PR Interval, RR Interval, QRS Interval, QT Interval and QTcF Interval at Week 52
timeFrame: Baseline, Week 52
measure: DB Period: Change From Baseline in Hematological Parameters: Percentage of Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/Leukocytes and Neutrophils/Leukocytes at Week 24
timeFrame: Baseline, Week 24
measure: OLE Period: Change From Baseline in Hematological Parameters: Percentage of Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/Leukocytes and Neutrophils/Leukocytes at Week 52
timeFrame: Baseline, Week 52
measure: DB Period: Change From Baseline in Hematological Parameter: Hematocrit at Week 24
timeFrame: Baseline, Week 24
measure: OLE Period: Change From Baseline in Hematological Parameter: Hematocrit at Week 52
timeFrame: Baseline, Week 52
measure: DB Period: Change From Baseline in Hematological Parameter: Hemoglobin at Week 24
timeFrame: Baseline, Week 24
measure: OLE Period: Change From Baseline in Hematological Parameter: Hemoglobin at Week 52
timeFrame: Baseline, Week 52
measure: DB Period: Change From Baseline in Hematological Parameter: Erythrocytes Mean Corpuscular Volume at Week 24
timeFrame: Baseline, Week 24
measure: OLE Period: Change From Baseline in Hematological Parameter: Erythrocytes Mean Corpuscular Volume at Week 52
timeFrame: Baseline, Week 52
measure: DB Period: Change From Baseline in Hematological Parameter: Platelets at Week 24
timeFrame: Baseline, Week 24
measure: OLE Period: Change From Baseline in Hematological Parameter: Platelets at Week 52
timeFrame: Baseline, Week 52
measure: DB Period: Change From Baseline in Hematological Parameter: Erythrocytes at Week 24
timeFrame: Baseline, Week 24
measure: OLE Period: Change From Baseline in Hematological Parameter: Erythrocytes at Week 52
timeFrame: Baseline, Week 52
measure: DB Period: Change From Baseline in Hematological Parameter: Leukocytes at Week 24
timeFrame: Baseline, Week 24
measure: OLE Period: Change From Baseline in Hematological Parameter: Leukocytes at Week 52
timeFrame: Baseline, Week 52
measure: DB Period: Change From Baseline in Clinical Chemistry Parameter: Albumin, Globulin and Protein at Week 24
timeFrame: Baseline, Week 24
measure: OLE Period: Change From Baseline in Clinical Chemistry Parameter: Albumin, Globulin and Protein at Week 52
timeFrame: Baseline, Week 52
measure: DB Period: Change From Baseline in Clinical Chemistry Parameter: Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, Creatine Kinase, Gamma Glutamyl Transferase, and Lactate Dehydrogenase at Week 24
timeFrame: Baseline, Week 24
measure: OLE Period: Change From Baseline in Clinical Chemistry Parameter: Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, Creatine Kinase, Gamma Glutamyl Transferase, and Lactate Dehydrogenase at Week 52
timeFrame: Baseline, Week 52
measure: DB Period: Change From Baseline in Clinical Chemistry Parameter: Bicarbonate, Blood Urea Nitrogen, Calcium, Chloride, Glucose, Potassium, Magnesium, Phosphate and Sodium at Week 24
timeFrame: Baseline, Week 24
measure: OLE Period: Change From Baseline in Clinical Chemistry Parameter: Bicarbonate, Blood Urea Nitrogen, Calcium, Chloride, Glucose, Potassium, Magnesium, Phosphate and Sodium at Week 52
timeFrame: Baseline, Week 52
measure: DB Period: Change From Baseline in Clinical Chemistry Parameter: Direct Bilirubin, Bilirubin, Creatinine and Urate at Week 24
timeFrame: Baseline, Week 24
measure: OLE Period: Change From Baseline in Clinical Chemistry Parameter: Direct Bilirubin, Bilirubin, Creatinine and Urate at Week 52
timeFrame: Baseline, Week 52
measure: DB Period: Change From Baseline in Clinical Chemistry Parameter: Calcium Corrected at Week 24
timeFrame: Baseline, Week 24
measure: OLE Period: Change From Baseline in Clinical Chemistry Parameter: Calcium Corrected at Week 52
timeFrame: Baseline, Week 52
measure: DB Period: Change From Baseline in Clinical Chemistry Parameter: Glomerular Filtration Rate at Week 24
timeFrame: Baseline, Week 24
measure: OLE Period: Change From Baseline in Clinical Chemistry Parameter: Glomerular Filtration Rate at Week 52
timeFrame: Baseline, Week 52
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Viable Research Management_Site number 131
state: Arizona
city: Scottsdale
country: United States
facility: Mayo Clinic - Scottsdale_Site number 150
state: Arizona
city: La Jolla
country: United States
facility: University of California, SD_Site number 008
state: California
city: Los Angeles
country: United States
facility: Pacific Arthrirtis Care Center_Site number 136
state: California
city: Los Angeles
country: United States
facility: University of California - Los Angeles_Site number 104
state: California
city: Palo Alto
country: United States
facility: Stanford University Medical Center_Site number 143
state: California
city: Farmington
country: United States
facility: University of Connecticut_Site number 147
state: Connecticut
city: New Haven
country: United States
facility: Yale University School of Medicine_Site number 140
state: Connecticut
city: Washington
country: United States
facility: Georgetown University_Site number 035
state: District of Columbia
city: Clearwater
country: United States
facility: St. Francis Medical_Site number 085
state: Florida
city: DeBary
country: United States
facility: Omega Research Consultants_Site number 133
state: Florida
city: Chicago
country: United States
facility: Northwestern Medicine_Site number 124
state: Illinois
city: New Orleans
country: United States
facility: DelRicht Research_Site number 159
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins University School of Medicine_Site number 134
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital_Site number 002
state: Massachusetts
city: Boston
country: United States
facility: Boston University_Site number 137
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota_Site number 051
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic_Site number 146
state: Minnesota
city: New York
country: United States
facility: Hospital For Special Surgery_Site number 138
state: New York
city: New York
country: United States
facility: Columbia University Medical Center_Site number 086
state: New York
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital_Site number 096
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center_Site number 149
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina_Site number 054
state: South Carolina
city: Seattle
country: United States
facility: Virginia Mason Medical Center_Site number 145
state: Washington
city: Spokane
country: United States
facility: Premier Clinical Research_Site number 130
state: Washington
city: Milwaukee
country: United States
facility: Froedtert Hospital and the Medical College of Wisconsin_Site number 012
state: Wisconsin
Study officials:
References: