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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 : September 19, 2019
Sponsor:
Information provided by (Responsible Party):
Kadmon Corporation, LLC

Brief Summary:
Phase II Diffuse Cutaneous Systemic Sclerosis study seeking to evaluate the efficacy and safety of KD025. Upon eligibility confirmation, a total of sixty (60) adult subjects will be enrolled and randomized into three (3) groups (1:1:1) to either receive orally administered KD025 (two doses) 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 un-blinding, the subjects on KD025 will continue on the same KD025 dose whereas the subjects in the placebo group will be re-randomized to one of the KD025 doses.

Condition or disease Intervention/treatment Phase
System; Sclerosis Diffuse Cutaneous Systemic Sclerosis Drug: 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 IRB/IEC-approved informed consent form and met all of the inclusion/exclusion criteria will be enrolled. A total of sixty (60) subjects will be randomized into three (3) groups (1:1:1) to receive orally administered KD025 200 mg once daily (QD; n = 20), KD025 200 mg twice daily (BID; n = 20), or matched placebo (n = 20) 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 KD025 dose whereas the subjects in the placebo group will be re-randomized to one of the KD025 doses (200 mg QD or 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 (3) groups (1:1:1) to receive orally administered KD025 200 mg QD (n = 20), KD025 200 mg BID (n = 20), or matched placebo (n = 20) for twenty-eight (28) weeks. The study will be double-blinded for the first twenty-eight (28) weeks followed by an open-label extension of twenty-four (24) weeks. After unblinding, the subjects in Group 1 and 2 will continue on the same KD025 dose whereas the subjects in the placebo group will be re-randomized to one of the KD025 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 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 KD025 200 mg daily, double-blinded for the first 28 weeks. Subjects will then will be unblinded, and continue on the same KD025 dose for the remaining 24 weeks.
Drug: KD025
ROCK-2 Inhibitor

Drug: Placebo
Inactive substance

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

Drug: Placebo
Inactive substance

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 KD025 doses (200 mg daily or 200 twice a day) in a 1:1 fashion.
Drug: KD025
ROCK-2 Inhibitor

Drug: Placebo
Inactive substance




Primary Outcome Measures :
  1. CRISS Response at Week 24 [ Time Frame: 24 weeks ]
    To evaluate the efficacy of KD025 compared to placebo for the Combined Response Index in Diffuse Cutaneous Systemic Sclerosis (CRISS) at Week 24.


Secondary Outcome Measures :
  1. CRISS Response at Week 52 [ Time Frame: 52 weeks ]
    To assess the Combined Response Index in Diffuse Cutaneous Systemic Sclerosis (CRISS) for each group at Week 52.

  2. Efficacy of KD025 in Comparison to Placebo at Week 24 [ Time Frame: 24 weeks ]
    To evaluate the efficacy of KD025 compared to placebo at Week 24 using the Modified Rodnan Skin Score (mRSS). Modified Rodnan Skin Score 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 modified Rodnan Skin Score ranges from 0 (best possible outcome) to 51 (worst possible outcome)

  3. Efficacy of KD025 in Comparison to Placebo at Week 24 [ Time Frame: 24 weeks ]
    To evaluate the efficacy of KD025 compared to placebo at Week 24 using Forced Vital Capacity (FVC).

  4. Quality of life and functional ability assessed by questionnaire [ Time Frame: 24 weeks ]
    To assess the impact of KD025 on quality of life at Week 24 using the Health Assessment Questionnaire-Disability Index (HAQ-DI). To determine the validity and usefulness of a modified Health Assessment Questionnaire (HAQ) for measurement of disease status and changes in disease status over time in patients with systemic sclerosis (SSc). The HAQ-DI scale consists of 20 questions referring to eight component sets: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. The total score indicates the participant's self-assessed level of disability. There are four possible responses for each component: 0 = without any difficulty; 1 = with some difficulty; 2 = with much difficulty; 3 = unable to do. The HAQ-DI is the sum of the domain scores, divided by the number of domains that have a score (i.e. the average score), with total range of 0 to 3, higher scores showing larger functional limitation.

  5. Efficacy of KD025 in Comparison to Placebo at Week 24 [ Time Frame: 24 weeks ]
    To evaluate the efficacy of KD025 compared to placebo at Week 24 for physicians global assessment using visual analog scale to assess overall health between 0-10. A 0 score being extremely poor and 10 being excellent.

  6. Efficacy of KD025 in Comparison to Placebo at Week 24 [ Time Frame: 24 weeks ]
    To evaluate the efficacy of KD025 compared to placebo at Week 24 for patients global assessment using visual analog scale to assess overall health between 0-10. A 0 score being extremely poor and 10 being excellent.

  7. Efficacy of KD025 in Comparison to Placebo at Week 24 [ Time Frame: 24 weeks ]
    To evaluate the efficacy of KD025 compared to placebo at Week 24 for Scleroderma Health Assessment Questionnaire- Disability Index (SHAQ-DI). SHAQ-DI assesses five scleroderma-specific visual analogue scale (VAS) items to explore the impact of participant's disease. These items are developed to measure the effect of scleroderma on five elements of disease that could have a great impact on a participant's daily activities. 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.

  8. Efficacy of KD025 in Comparison to Placebo at Week 52 [ Time Frame: 52 weeks ]
    To evaluate the efficacy of KD025 at Week 52 compared to baseline for subjects randomized to KD025 for Modified Rodnan Skin Score (mRSS). Modified Rodnan Skin Score 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 modified Rodnan Skin Score ranges from 0 (best possible outcome) to 51 (worst possible outcome)

  9. Efficacy of KD025 in Comparison to Placebo at Week 52 [ Time Frame: 52 weeks ]
    To evaluate the efficacy of KD025 at Week 52 compared to baseline for subjects randomized to KD025 for Forced Vital Capacity (FVC).

  10. Efficacy of KD025 in Comparison to Placebo at Week 52 [ Time Frame: 52 weeks ]
    To evaluate the efficacy of KD025 at Week 52 compared to baseline for subjects randomized to KD025 for Health Assessment Questionnaire-Disability Index (HAQ-DI). To determine the validity and usefulness of a modified Health Assessment Questionnaire (HAQ) for measurement of disease status and changes in disease status over time in patients with systemic sclerosis (SSc). The HAQ-DI scale consists of 20 questions referring to eight component sets: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. The total score indicates the participant's self-assessed level of disability. There are four possible responses for each component: 0 = without any difficulty; 1 = with some difficulty; 2 = with much difficulty; 3 = unable to do. The HAQ-DI is the sum of the domain scores, divided by the number of domains that have a score (i.e. the average score), with total range of 0 to 3, higher scores showing larger functional limitation.

  11. Efficacy of KD025 in Comparison to Placebo at Week 52 [ Time Frame: 52 weeks ]
    To evaluate the efficacy of KD025 at Week 52 compared to baseline for subjects randomized to KD025 for physicians global assessment.

  12. Efficacy of KD025 in Comparison to Placebo at Week 52 [ Time Frame: 52 weeks ]
    To evaluate the efficacy of KD025 at Week 52 compared to baseline for subjects randomized to KD025 for patient global assessment.

  13. Efficacy of KD025 in Comparison to Placebo at Week 52 [ Time Frame: 52 weeks ]
    To evaluate the efficacy of KD025 at Week 52 compared to baseline for subjects randomized to KD025 for Scleroderma Health Assessment Questionnaire-Disability Index (SHAQ-DI). SHAQ-DI assesses five scleroderma-specific visual analogue scale (VAS) items to explore the impact of participant's disease. These items are developed to measure the effect of scleroderma on five elements of disease that could have a great impact on a participant's daily activities. 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.

  14. Lung Fibrosis Change Assessment via HRCT [ Time Frame: Baseline, Week 24, and Week 52 ]
    To assess changes in lung fibrosis, via high resolution computerized tomography (HRCT), performed at baseline, Weeks 24 and Week 52 only in subjects with Interstitial lung disease (ILD) at screening.

  15. Plasma Concentration Analysis [ Time Frame: Pre-dose and 3 hours post-dose at Week 4, and Week 8 ]
    To measure plasma concentration of KD025 on Weeks 4 and 8 immediately prior to KD025 dosing and 3 hours post-dose.

  16. Adverse Event Review [ Time Frame: Through study completion, an average of 52 weeks ]
    To assess the safety of KD025 compared to placebo in subjects with Diffuse Cutaneous Systemic Sclerosis by examining the percentage of subjects with treatment-emergent adverse events (CTCAE v5.0) in subjects with diffuse cutaneous systemic sclerosis


Other Outcome Measures:
  1. 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. Histology on skin biopsy samples [ Time Frame: Baseline, Week 24, and Week 52 ]
    Hematoxylin and eosin (H&E) stain on skin biopsy samples taken from subjects at baseline, Week 24 and optionally at Week 52.

  3. Gene Expression on 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 (ACR) and European League Against Rheumatism (EULAR) 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 ≤ 45
  4. Increase in mRSS by ≥ 2 units at screening within the previous 6 months
  5. Must be receiving a stable dose of mycophenolate mofetil (≤ 3 gm/day) or methotrexate (≤ 25 mg/week) for at least 4 weeks
  6. Adequate organ and bone marrow functions evaluated during the fourteen (14) days prior to enrollment as follows:

    1. Absolute neutrophil count ≥ 1.5 × 109/L
    2. Platelet count ≥ 100 × 109/L
    3. Total bilirubin ≤ 1.0 × upper limit of normal (ULN);
    4. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN; 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 twelve (12) months. However, women who have been amenorrheic for twelve (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 two forms of accepted methods of contraception during the course of the study and for three (3) months after their last dose of study drug. Effective birth control includes (i) IUD plus one barrier method; (ii) on stable doses of hormonal contraception for at least 3 months (e.g., oral, injectable, implant, transdermal) plus one barrier method; or (iii) 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 two (2) forms of contraception as in criterion number 7 above during the treatment period and for at least three (3) months after the last dose of study drug.
  9. 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 twenty-eight (28) days of study entry;
  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 III/IV;
  6. Known history of human immunodeficiency virus (HIV) or active hepatitis C virus (HCV) or hepatitis B virus (HBV);
  7. Diagnosed with any malignancy within three (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;
  8. Has had previous exposure to KD025 or known allergy/sensitivity to KD025, or any other ROCK2 inhibitor;
  9. Scleroderma renal crisis within four (4) months prior to enrollment;
  10. 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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United States, Arizona
Viable Research Management/Titan Clinical Solutions Recruiting
Phoenix, Arizona, United States, 85004
Contact: Shauna Harrell    602-770-8030    sharrell@viableresearch.org   
United States, California
Pacific Arthrirtis Care Center Recruiting
Los Angeles, California, United States, 90045
Contact: Emma Hasan    310-297-6812    elove1945@gmail.com   
United States, Florida
St. Francis Medical Institute Withdrawn
Clearwater, Florida, United States, 33765
Omega Research DeBary Recruiting
DeBary, Florida, United States, 32713
Contact: Kwabena Ayesu    386-668-4202    kayesu@omegarcllc.com   
United States, Maryland
Johns Hopkins University Recruiting
Baltimore, Maryland, United States, 21224
Contact: Gwen Leatherman    410-550-8582    gleathe@jhmi.edu   
United States, Washington
Premier Clinical Research Recruiting
Spokane, Washington, United States, 99202
Contact: Amy Bardwell    509-343-3710 ext 1159    ABardwell@premierclinicalresearch.com   
Sponsors and Collaborators
Kadmon Corporation, LLC

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Responsible Party: Kadmon Corporation, LLC
ClinicalTrials.gov Identifier: NCT03919799     History of Changes
Other Study ID Numbers: KD025-209
First Posted: April 18, 2019    Key Record Dates
Last Update Posted: September 19, 2019
Last Verified: September 2019

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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