dcSSC: Efficacy and Safety of Belumosudil in Subjects With Diffuse Cutaneous Systemic Sclerosis
Study Details
Study Description
Brief Summary
This is a phase 2, open-label, single-cohort, multicenter trial of belumosudil in subjects with Diffuse Cutaneous Systemic Sclerosis (dcSSc). An estimated total of 12 to 15 subjects will receive belumosudil 200 mg administered orally (PO) twice daily (BID) for 52 weeks. The primary analysis will be at 24 weeks.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Detailed Description
The primary objective of this phase 2, open-label, single-cohort, multicenter trial is 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 will be approximately 14 months (4 weeks for screening, 52 weeks of dosing period, and 4 weeks of Follow-up)
Subjects who have signed an Institutional Review Board/Independent Ethics Committee-(IRB/IEC)-approved informed consent form (ICF) and met all of the inclusion/exclusion criteria will be enrolled. A total of 12 to 15 to subjects at approximately 5 to 6 sites will receive 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 will be analyzed using Week 24 data.
Efficacy will be assessed throughout the 52-week dosing period using:
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Composite Response Index in Systemic Sclerosis (CRISS)
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Modified Rodnan Skin Score (mRSS)
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Pulmonary Function Tests (PFTs)
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Physician Global Assessment
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Patient Global Assessment
Safety will be assessed throughout the study and will include:.
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Physical examinations (PEs)
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Vital sign measurements
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Weight measurements
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Blood sample collection for hematology and chemistry; urinalysis
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Electrocardiograms (ECGs)
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Adverse event (AE) assessments
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Concomitant medication assessments
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Pregnancy testing for females of childbearing potential.
Reasons for discontinuation of treatment because of toxicity will be documented. Careful monitoring of all toxicities will be carried out. Dosing can be reduced 1 dose level. If the dose is not tolerated, then the subject will be discontinued from the study. If there is a interruption of dosing, after 14 days the subject will be discontinued from the study.
Subjects will be given a study drug diary to record the details of each dose of belumosudil 200 mg. Diaries will be dispense/collected on each visit. Compliance with dosing will be confirmed using subject diaries, which will be examined at each visit by site staff to determine if dosing is as instructed per protocol and follow-up.
A 4-Week Safety Follow-up Visit will occur 28 days (± 3 days) after the last dose of study drug.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Belumosudil 200 mg PO BID Subjects will receive open-label belumosudil 200 mg orally twice daily |
Drug: Belumosudil
12 to 15 subjects with dcSSc will receive belumosudil 200 mg PO BID for 52 weeks
Other Names:
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Outcome Measures
Primary Outcome Measures
- Efficacy: CRISS at Week 24 [24 weeks]
The primary efficacy endpoint is the effect of belumosudil 200 mg BID on the Combined Response Index in Diffuse Cutaneous Systemic Sclerosis (CRISS) after 24 weeks of therapy with belumosudil 200 mg PO BID at the end of Week 24 in the Modified Intent-to-Treat (mITT) Population. The CRISS exponential algorithm determines the predicted probability of improvement from baseline, incorporating changes in mRSS, FVC% predicted, SHAQ-DI, and physician and Patient Global Assessments. The outcome is a continuous variable between 0.0 and 1.0 (0-100%). A higher score indicates greater probability of improvement. A CRISS score ≥ 20% is considered a clinically meaningful improvement.
Secondary Outcome Measures
- Efficacy: CRISS at Weeks 8, 16, 36, and 52 [Up to 52 weeks]
The efficacy of belumosudil 200 mg PO BID after 8 weeks, after 16 weeks, after 36 weeks, and after 52 weeks.
- Efficacy: mRSS at Week 24 [24 weeks]
The efficacy of belumosudil 200 mg PO BID as measured by the Modified Rodnan Skin Score after 24 weeks The mRSS is a measure of skin thickness rated with scores ranging from 0 (normal) to 3 (severe skin thickening) across 17 different sites. The total score is the sum of the individual skin scores in the 17 body areas (i.e., face, hands, fingers; proximal area of the arms, distal area of the arms, thorax, abdomen; proximal area of the legs, and distal area of the legs, feet), yielding a range of 0 to 51 units.
- Efficacy: Forced Vital Capacity (FVC) at Week 24 [24 weeks]
The efficacy of belumosudil 200 mg PO BID as measured by the Forced Vital Capacity after 24 weeks of therapy.
- Efficacy: Physician Global Assessment at Week 24 [24 weeks]
The efficacy of belumosudil 200 mg PO BID at Week 24 as measured by the Physician Global Assessment after 24 weeks of therapy. The Physician Global Assessment is based on a single question: "How was your overall health during the last week?" The investigator uses a Visual Analog Scale (VAS) to answer in a range from 0 (extremely poor) to 100 (excellent).
- Efficacy: Patient Global Assessment at Week 24 [24 weeks]
The efficacy of belumosudil 200 mg PO BID at Week 24 as measured by the Patient Global Assessment after 24 weeks of therapy. The Patient Global Assessment is based on a single question: "How was your overall health during the last week?" The patient uses a Visual Analog Scale (VAS) to answer in a range from 0 (extremely poor) to 100 (excellent).
- Efficacy: Change in FVC at Weeks 8, 16, 36, and 52 from Baseline [Up to 52 weeks]
The differences in FVC from baseline after 8 weeks, after 16 weeks, after 36 weeks, and after 52 weeks of therapy.
- Efficacy: Change in mRSS at Weeks 8, 16, 36, and 52 from Baseline [Up to 52 weeks]
The differences in mRSS score from baseline after 8 weeks, after 16 weeks, after 36 weeks, and after 52 weeks of treatment with belumosudil 200 mg BID.
- Efficacy: Change in Physician Global Assessment at Weeks 8, 16, 36, and 52 from Baseline [Up to 52 weeks]
The differences in Physician Global Assessment score from baseline after 8 weeks, after 16 weeks, after 36 weeks, and after 52 weeks of treatment with belumosudil 200 mg BID.
- Efficacy: Change in Patient Global Assessment at Weeks 8, 16, 36, and 52 from Baseline [Up to 52 weeks]
The differences in Patient Global Assessment score from baseline after 8 weeks, after 16 weeks, after 36 weeks, and after 52 weeks of treatment with belumosudil 200 mg BID.
- Efficacy: Change in SHAQ--DI at Weeks 8, 16, 36, and 52 from Baseline [Up to 52 weeks]
The differences in SHAQ--DI score from baseline after 8 weeks, after 16 weeks, after 36 weeks, and after 52 weeks of treatment with belumosudil 200 mg BID.
- Safety: Percentage of Subjects with TEAEs [Up to 56 weeks: 52 weeks of treatment and 4-week follow-up]
The proportion of subjects who experience a treatment-emergent adverse event (TEAE), including severity and relationship to belumosudil 200 mg PO BID at all visits.
- Safety: Percentage of Subjects with SAEs [Up to 56 weeks: 52 weeks of treatment and 4-week follow-up]
The proportion of subjects who experience a serious adverse event (SAE), including severity and relationship to belumosudil 200 mg PO BID at all visits.
Other Outcome Measures
- Exploratory Pharmacodynamics: Association of DNN-derived Fibrosis Score with Skin Gene Expression [52 weeks]
Measure the correlation between DNN-derived Fibrosis Score and Skin Gene Expression in dcSSc subjects receiving belumosudil 200 mg PO BID after 52 weeks of treatment.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Male and female subjects ≥ 18 years old with the diagnosis of dcSSc according to the 2013 American College of Rheumatology and European League Against Rheumatism
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Must have disease duration (defined as interval from first non Raynaud disease manifestation) of ≤ 6 years
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Must have mRSS of ≥ 15 but ≤ 40
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Must have active disease as determined by the Principal Investigator within the 6 months prior to screening
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Adequate organ and bone marrow functions evaluated during the 28 days prior to enrollment as follows:
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Absolute neutrophil count ≥ 1.5 × 10^9/L
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Platelet count ≥ 100 × 10^9/L
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Total bilirubin ≤ 1.0 × upper limit of normal (ULN)
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Alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and serum creatinine ≤ 1.5 × ULN.
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Female subjects of childbearing potential have a negative pregnancy test at screening. Females of childbearing potential are defined as sexually mature women without prior hysterectomy or who have had any evidence of menses in the past 12 months. However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-estrogens, or ovarian suppression.
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Women of childbearing potential (i.e., menstruating women) must have a negative urine pregnancy test (positive urine tests are to be confirmed by serum test) documented within the 24-hour period prior to the first dose of study drug.
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Sexually active women of childbearing potential enrolled in the study must agree 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.
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For male patients who are sexually active and who are 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.
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Male subjects must not donate sperm for 3 months after last dose of study drug.
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Able to provide written informed consent prior to the performance of any study-specific procedures.
Exclusion Criteria:
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Subject has corrected QT interval using Fridericia's formula (QTcF) > 450 ms
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Ongoing use or current use of concomitant medication known to have the potential for QTc prolongation
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Female subject who is pregnant or breastfeeding.
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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).
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History or other evidence of severe illness or any other conditions that would make the subject, in the opinion of the Investigator, unsuitable for the study.
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Chronic heart failure with New York Heart Association Classes II, III, or IV.
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Acute or chronic liver disease (e.g., cirrhosis)
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Positive human immunodeficiency virus (HIV) test.
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Active hepatitis C virus (HCV), hepatitis B virus (HBV), or positive whole blood tuberculin test.
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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.
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Has had previous exposure to belumosudil or known allergy/sensitivity to belumosudil, or any other Rho-associated Protein Kinase-2 (ROCK2) inhibitor.
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Scleroderma renal crisis within 4 months prior to enrollment.
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FVC ≤ 50% Predicted.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of California, Los Angeles Medical Center_Site number 104 | Los Angeles | California | United States | 90095 |
| 2 | Yale University School of Medicine_Site number 140 | New Haven | Connecticut | United States | 06519 |
| 3 | Northwestern University_Site number 124 | Chicago | Illinois | United States | 60611 |
| 4 | Columbia University Medical Center_Site number 086 | New York | New York | United States | 10032 |
| 5 | Virginia Mason Medical Center_Site number 145 | Seattle | Washington | United States | 98101 |
Sponsors and Collaborators
- Kadmon, a Sanofi Company
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- ACT17634
- KD025-215