KD025 in Subjects With Diffuse Cutaneous Systemic Sclerosis
Condition: System; Sclerosis; Diffuse Cutaneous Systemic Sclerosis
MeSH terms: Scleroderma, Systemic; Scleroderma, Diffuse; Sclerosis
Intervention: Belumosudil (KD025); Placebo
Intervention description: ROCK-2 Inhibitor; Inactive substance
Intervention MeSH terms: Belumosudil
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
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.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: Double-blinded for the first 28 Weeks
Enrollment: 36.0
Sex: All
Minimum age: 18 Years
Maximum age: 100 Years
Healthy volunteers: No

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.
    

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.