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KD025 in Subjects With Diffuse Cutaneous Systemic Sclerosis

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ClinicalTrials.gov Identifier: NCT03919799
Recruitment Status : Recruiting
First Posted : April 18, 2019
Last Update Posted : January 28, 2021
Sponsor:
Information provided by (Responsible Party):
Kadmon Corporation, LLC

Brief Summary:
This randomized, placebo-controlled phase 2 study is seeking to evaluate the efficacy and safety of belumosudil (KD025) for the treatment of diffuse cutaneous systematic sclerosis. Upon eligibility confirmation, a total of 60 adult subjects will be enrolled and randomized into 3 groups (1:1:1) to either receive orally administered belumosudil (200 mg once daily and 200 mg twice daily) or matched placebo for 28 weeks. The study will be double-blinded for the first 28 weeks followed by an open-label extension period of 24 weeks. After unblinding, the subjects on belumosudil will continue on the same belumosudil dose whereas the subjects in the placebo group will be re-randomized to one of the belumosudil doses.

Condition or disease Intervention/treatment Phase
System; Sclerosis Diffuse Cutaneous Systemic Sclerosis Drug: Belumosudil (KD025) Drug: Placebo Phase 2

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.

Subjects who have signed an Institutional Review Board/Independent Ethics Committee-approved informed consent form and met all of the inclusion/exclusion criteria will be enrolled. A total of 60 subjects will be randomized into 3 groups (1:1:1) to receive orally administered belumosudil 200 mg once daily (QD; n = 20 subjects), belumosudil 200 mg twice daily (BID; n = 20 subjects), or matched placebo (n = 20 subjects) for 28 weeks. The study will be double-blinded for the first 28 weeks followed by an open-label extension of 24 weeks. After unblinding, the subjects in Group 1 and 2 will continue on the same belumosudil dose whereas the subjects in the placebo group will be re-randomized to either belumosudil 200 mg QD or belumosudil 200 mg BID in 1:1 fashion.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Three groups (1:1:1) to receive orally administered belumosudil 200 mg QD (n = 20 subjects), belumosudil 200 mg BID (n = 20 subjects), or matched placebo (n = 20 subjects) for 28 weeks. The study will be double-blinded for the first 28 weeks followed by an open-label extension of 24 weeks.

After unblinding, the subjects in Group 1 and Group 2 will continue on the same belumosudil dose whereas the subjects in the placebo group will be 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
Primary Purpose: Treatment
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
Actual Study Start Date : July 9, 2019
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : May 2022


Arm Intervention/treatment
Experimental: Group 1
20 subjects will be randomized to receive orally administered belumosudil 200 mg QD double-blinded for the first 28 weeks. Subjects will then will be unblinded and continue on the same belumosudil dose for the remaining 24 weeks.
Drug: Belumosudil (KD025)
ROCK-2 Inhibitor

Experimental: Group 2
20 subjects will be randomized to receive orally administered belumosudil 200 mg BID double-blinded for the first 28 weeks. Subjects will then will be unblinded, and continue on the same belumosudil dose for the remaining 24 weeks.
Drug: Belumosudil (KD025)
ROCK-2 Inhibitor

Placebo Comparator: Group 3
20 subjects will be randomized to receive orally administered matched placebo double-blinded for the first 28 weeks. Subjects will then will be unblinded and re-randomized to one of the belumosudil doses (200 mg QD or 200 mg BID) in a 1:1 fashion.
Drug: Belumosudil (KD025)
ROCK-2 Inhibitor

Drug: Placebo
Inactive substance




Primary Outcome Measures :
  1. Efficacy: CRISS Response of Belumosudil vs. Placebo at Week 24 [ Time Frame: 24 weeks ]
    To evaluate the Combined Response Index in Diffuse Cutaneous Systemic Sclerosis (CRISS) of belumosudil compared to placebo at Week 24.


Secondary Outcome Measures :
  1. Efficacy: CRISS Response of Belumosudil vs. Placebo at Week 52 [ Time Frame: 52 weeks ]
    To evaluate the Combined Response Index in Diffuse Cutaneous Systemic Sclerosis (CRISS) of belumosudil compared to placebo at Week 52

  2. Efficacy: mRSS of Belumosudil vs. Placebo at Week 24 [ Time Frame: 24 weeks ]
    To evaluate the Modified Rodnan Skin Score (mRSS) of belumosudil compared to placebo at Week 24. The mRSS measures skin thickness and is the sum of scores from 17 surface anatomic areas rated on a 0-3 scale (0 = normal skin; 1 = mild thickness; 2 = moderate thickness; 3 = severe thickness with inability to pinch the skin into a fold). Total mRSS ranges from 0 (best possible outcome) to 51 (worst possible outcome)

  3. Efficacy: FVC of Belumosudil vs. Placebo at Week 24 [ Time Frame: 24 weeks ]
    To evaluate the Forced Vital Capacity (FVC) of belumosudil compared to placebo at Week 24.

  4. Efficacy: Physician Global Assessment of Belumosudil vs. Placebo at Week 24 [ Time Frame: 24 weeks ]
    To evaluate the Physician Global Assessment of belumosudil compared to placebo at Week 24. The Physician Global Assessment uses the using Visual Analog Scale (VAS) to assess overall health between 0-10. A score of 0 represents extremely poor and a score of 10 represents excellent.

  5. Efficacy: Patient Global Assessment of Belumosudil vs. Placebo at Week 24 [ Time Frame: 24 weeks ]
    To evaluate the Patient Global Assessment of belumosudil compared to placebo at Week 24. The Patient Global Assessment uses VAS to assess overall health between 0-10. A score of 0 represents extremely poor and a score of 10 represents excellent.

  6. Efficacy: SHAQ-DI of Belumosudil vs. Placebo at Week 24 [ Time Frame: 24 weeks ]
    To evaluate the Scleroderma Health Assessment Questionnaire- Disability Index (SHAQ-DI) of belumousudil compared to placebo at Week 24. The SHAQ-DI assesses 5 scleroderma-specific VAS items to explore the impact of a subject's disease. Each VAS item is rated separately (0-100 millimeters [mm]), with higher scores indicating more severe disease. The five items are: (1) intestinal disease, (2) breathing problem, (3) Raynaud syndrome,(4) finger ulcers, and (5) overall disease.

  7. Efficacy: mRSS of Belumosudil at Week 52 Compared to Baseline [ Time Frame: 52 weeks ]
    To evaluate the Modified Rodnan Skin Score (mRSS) of belumosudil at Week 52 compared to baseline. The mRSS measures skin thickness and is the sum of scores from 17 surface anatomic areas rated on a 0-3 scale (0 = normal skin; 1 = mild thickness; 2 = moderate thickness; 3 = severe thickness with inability to pinch the skin into a fold). Total mRSS ranges from 0 (best possible outcome) to 51 (worst possible outcome).

  8. Efficacy: FVC of Belumosudil at Week 52 Compared to Baseline [ Time Frame: 52 weeks ]
    To evaluate the Forced Vital Capacity (FVC) of belumosudil at Week 52 compared to baseline for subjects randomized to belumosudil

  9. Efficacy: Physician Global Assessment of Belumosudil Compared to Baseline [ Time Frame: 52 weeks ]
    To evaluate the Physician Global Assessment of belumosudil at Week 52 compared to baseline. The Physician Global Assessment uses VAS to assess overall health between 0-10. A score of 0 represents extremely poor and a score of 10 represents excellent.

  10. Efficacy: Patient Global Assessment of Belumosudil at Week 52 Compared to Baseline [ Time Frame: 52 weeks ]
    To evaluate the Patient Global Assessment of belumosudil at Week 52 compared to baseline. The Patient Global Assessment uses VAS to assess overall health between 0-10. A score of 0 represents extremely poor and a score of 10 represents excellent.

  11. Efficacy: SHAQ-DI of Belumosudil at Week 52 Compared to Baseline [ Time Frame: 52 weeks ]
    To evaluate the Scleroderma Health Assessment Questionnaire-Disability Index (SHAQ-DI) efficacy of belumosudil at Week 52 compared to baseline. These items are developed to measure the effect of scleroderma on 5 elements of disease that could have a great impact on the subject's daily activities. Each VAS item is rated separately (0-100 millimeters [mm]), with higher scores indicating more severe disease. The 5 items are: (1) intestinal disease, (2) breathing problem, (3) Raynaud syndrome, (4) finger ulcers, and (5) overall disease.

  12. Efficacy: Lung Fibrosis Change Assessment for Subjects with ILD with Belumosudil [ Time Frame: 52 weeks ]
    To assess changes in lung fibrosis in subjects with interstitial lung disease (ILD) at screening via high resolution computerized tomography (HRCT), performed at baseline, Week 24, and Week 52 only in subjects with Interstitial lung disease (ILD) at screening.

  13. Pharmacokinetic (PK): Plasma Concentration of Belumosudil [ Time Frame: Up to 8 weeks ]
    To measure plasma concentration of belumosudil at Week 4 and Week 8 immediately prior to belumosudil dosing and 3 hours after dosing

  14. Safety: AEs [ Time Frame: Up to 52 weeks ]
    The incidence of adverse events (AEs), severity, relationship to study drug, and leading to discontinuation from the study for the 3 treatment groups.

  15. Safety: SAEs of Belumosudil [ Time Frame: Up to 52 weeks ]
    The incidence of serious adverse events (SAEs) and relationship to study drug for the 3 treatment groups

  16. Safety: Laboratory Assessments [ Time Frame: Up to 52 weeks ]
    The incidence and shift from baseline in hematologic and clinical chemistry values for the 3 treatment groups

  17. Safety: ECGs [ Time Frame: Up to 52 weeks ]
    Measurement of 12-lead electrocardiogram (ECG) parameters: PR interval; QRS interval; and QTc interval


Other Outcome Measures:
  1. Pharmacodynamic (PD): Biomarker Analysis [ Time Frame: Baseline, Week 24, and Week 52 ]
    To evaluate changes in concentration of collagen biomarkers in serum indicative of extracellular matrix turnover from baseline to Week 24 and Week 52.

  2. PD: Histology of Skin Biopsy Samples [ Time Frame: Up to Week 52 ]
    Hematoxylin and eosin stain on skin biopsy samples taken from subjects at baseline, Week 24, and optionally at Week 52.

  3. PD: Gene Expression of Skin Biopsy Samples [ Time Frame: Baseline, Week 24, and Week 52 ]
    To assess differential gene expression of markers associated with inflammation and fibrosis from skin biopsies taken from subjects at baseline, Week 24, and optionally at Week 52.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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 criteria
  2. Must have disease duration (defined as interval from first non-Raynaud disease manifestation) of ≤ 5 years
  3. Must have 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. Subjects receiving concomitant immunosuppression must be on a stable dose for at least 6 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) and aspartate aminotransferase (AST) within normal limits; and
    5. Serum creatinine ≤ 1.5 × ULN.
  7. 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.

    1. 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.
    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 are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm), or a vasectomized partner
  8. 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 7 above during the treatment period and for at least 3 months after the last dose of study drug
  9. Male subjects 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. Subject has QTcF > 450 ms
  2. Female subject who is pregnant or breastfeeding
  3. 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)
  4. 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
  5. Chronic heart failure with New York Heart Association Class II, III, or IV
  6. Positive human immunodeficiency virus (HIV) test
  7. Active hepatitis C virus (HCV), hepatitis B virus (HBV), or positive whole blood tuberculin test
  8. 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
  9. Has had previous exposure to belumosudil or known allergy/sensitivity to belumosudil, or any other ROCK2 inhibitor
  10. Scleroderma renal crisis within 4 months prior to enrollment
  11. FVC ≤ 50% Predicted.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03919799


Contacts
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Contact: Nicholas Messier 724-778-6150 nicholas.messier@kadmon.com

Locations
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Sponsors and Collaborators
Kadmon Corporation, LLC
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Responsible Party: Kadmon Corporation, LLC
ClinicalTrials.gov Identifier: NCT03919799    
Other Study ID Numbers: KD025-209
First Posted: April 18, 2019    Key Record Dates
Last Update Posted: January 28, 2021
Last Verified: January 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Scleroderma, Systemic
Scleroderma, Diffuse
Sclerosis
Pathologic Processes
Connective Tissue Diseases
Skin Diseases