KD025 in Subjects With Diffuse Cutaneous Systemic Sclerosis

Kadmon

Status and phase: Terminated; Phase 2

Conditions: Diffuse Cutaneous Systemic Sclerosis; System; Sclerosis

Treatments: Drug: Belumosudil (KD025); Drug: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT03919799

EFC17665

KD025-209

Details and patient eligibility

About

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.

Full 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.

Enrollment: 36 patients

Sex: All

Ages: 18 to 100 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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36 participants in 5 patient groups, including a placebo group

Belumosudil QD/Belumosudil QD

Experimental group

Description:

Participants received belumosudil 200 mg tablet, QD orally for 28 weeks during the DB period. After completion of DB period, participants entered open-label extension (OLE) period and continued to receive belumosudil 200 mg tablet QD orally for 24 weeks in OLE period (i.e., up to Week 52).

Treatment:

Drug: Belumosudil (KD025)

Belumosudil BID/Belumosudil BID

Experimental group

Description:

Participants received belumosudil 200 mg tablet BID orally, for 28 weeks during the DB period. After completion of DB period, participants entered OLE period and continued to receive belumosudil 200 mg tablet BID orally for 24 weeks in OLE period (i.e., up to Week 52).

Treatment:

Drug: Belumosudil (KD025)

DB Period: Placebo

Placebo Comparator group

Description:

Participants received placebo (matched to belumosudil) tablet, orally for 28 weeks during the DB period.

Treatment:

Drug: Placebo

OLE Period: Placebo/Belumosudil QD

Experimental group

Description:

Participants who had received placebo in the DB period were entered and re-randomized into OLE period and received belumosudil 200 mg tablet QD orally for 24 weeks (i.e., up to Week 52) in the OLE period.

Treatment:

Drug: Belumosudil (KD025)

OLE Period: Placebo/Belumosudil BID

Experimental group

Description:

Participants who had received placebo in the DB period were entered and re-randomized into OLE period and received belumosudil 200 mg tablet BID orally for 24 weeks (i.e., up to Week 52) in the OLE period.

Treatment:

Drug: Belumosudil (KD025)