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  • Status : Approved
    • First Submitted Date : 2020/03/08
    • Registered Date : 2020/03/25
    • Last Updated Date : 2020/03/20
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1. Background

Background Information
CRIS
Registration Number
KCT0004859 
Unique Protocol ID SCHUH 2013-11-001-001 
Public/Brief Title A prospective study for connective tissue disease related digital ulcer in Korea 
Scientific Title A prospective study for connective tissue disease related digital ulcer in Korea  
Acronym  
MFDS Regulated Study No
IND/IDE Protocol
Registered
at Other Registry
No
Healthcare Benefit
Approval Status
Submitted approval

2. Institutional Review Board/Ethics Committee

Institutional Review Board Information
Board Approval Status Submitted approval 
Board Approval Number SCHUH 2013-11-001-001 
Approval Date 2014-01-02 
Institutional Review Board  
Name Soonchunhyang university Seoul Hospital Institutional Review Board 
Address 59, Daesagwan-ro, Yongsan-gu, Seoul 
Telephone 02-709-9750 
Data Monitoring Committee  

3. Contact Details

Contact Details Information
Contact Person for Principal Investigator / Scientific Queries  
Name Hyun-Sook Kim 
Title Professor 
Telephone +82-2-710-3214 
Affiliation Soon Chun Hyang University Hospital Seoul 
Address 59 Daesagwan-ro, Yongsan-gu, Seoul 04401, Korea 
Contact Person for Public Queries
Name Hyeyoung Kim 
Title Clinical Research Nu 
Telephone +82-2-709-3060 
Affiliation Soon Chun Hyang University Hospital Seoul 
Address 59 Daesagwan-ro, Yongsan-gu, Seoul 04401, Korea 
Contact Person for Updating Information
Name Wonho Choi 
Title Fellowship 
Telephone +82-2-709-3060 
Affiliation Soon Chun Hyang University Hospital Seoul 
Address 59 Daesagwan-ro, Yongsan-gu, Seoul 04401, Korea 

4. Status

Status Information
Study Site Multi-center (Number of center : 4)
Overall Recruitment Status Completed  
Date of First Enrollment 2014-07-01 , Actual
Target Number of Participant 35
Primary Completion Date 2018-01-06 , Actual
Study Completion Date 2018-02-28 , Actual
Recruitment Status by Participating Study Site 1
Name of Study Site Chosun University Hospital 
Recruitment Status Completed  
Date of First Enrollment 2017-01-07 , Actual
Recruitment Status by Participating Study Site 2
Name of Study Site The Catholic University of Korea, Seoul St. Mary's Hospital 
Recruitment Status Completed  
Date of First Enrollment 2014-08-15 , Actual
Recruitment Status by Participating Study Site 3
Name of Study Site Keimyung University Dongsan Medical Center 
Recruitment Status Completed  
Date of First Enrollment 2015-02-15 , Actual
Recruitment Status by Participating Study Site 4
Name of Study Site Soon Chun Hyang University Hospital Seoul 
Recruitment Status Completed  
Date of First Enrollment 2014-07-01 , Actual

5. Source of Monetary / Material Support

Source of Monetary / Material Support Information
Source of Monetary/Material Support 1   
Organization Name Soon Chun Hyang University 
Organization Type University  
Project ID  

6. Sponsor Organization

Sponsor Organization Information
Sponsor Organization 1   
Organization Name Soon Chun Hyang University Hospital Seoul 
Organization Type Medical Institute  

7. Study Summary

Study Summary Information
Lay Summary The pathogenesis of systemic sclerosis (SSc) is characterized by diffuse microangiopathy, visceral and vascular fibrosis, inflammation, and autoimmunity. Digital ulcers (DUs) are one of the visible evidences of microangiopathy 1. Nearly half of patients with SSc have experienced DUs in their lifetime. DUs cause pain and functional disability, and lower the quality of life. Further, DUs are complicated by soft tissue infection, osteomyelitis, gangrene, and auto-amputation 2.
Overexpression of endothelin-1 (ET-1) contributes to microangiopathy and vascular fibrosis in SSc, as it has been shown to induce vasoconstriction leading to obliterative vasculopathy and to activate fibroblasts. Bosentan is an orally administered dual ET-1 receptor (ETA and ETB) antagonist. The Randomized Placebo-controlled Investigation of Digital Ulcers in Scleroderma (RAPIDS)-1 and RAPIDS-2 studies were high-quality randomized controlled trials (RCTs) comparing the effect of bosentan to placebo on healing and preventing DUs for 12 and 24 weeks, respectively. In both RCTs, the number of new DUs was significantly reduced, but there was no significant change in DU healing 3, 4. Therefore, in the updated European League against Rheumatism (EULAR) guidelines for the treatment of SSc, bosentan is recommended to prevent the development of new DUs 5. However, some studies have suggested bosentan as a treatment option for SSc-related DUs. A multicenter, retrospective study performed in Spain showed that the median change in the number of DUs was a decrease of 3.6 and 5.0 at 12 and 24 months of bosentan treatment, respectively 6. A prospective 3-year study also reported that cutaneous ulcers in 65% of patients with SSc healed after a median period of 25 weeks 7.
This study aimed to evaluate the clinical outcomes and tolerability of bosentan in treating DUs secondary to SSc or mixed connective tissue disease (MCTD) in Korean patients. The primary endpoints were treatment response including change in the number of DUs over time and complete healing rate. The secondary endpoints were development of new DUs, changes in the semiquantitative scores of nailfold capillaroscopy (NFC), and causes of discontinuation.  

8. Study Design

Study Design Information
Study Type Observational Study 
Observational Study Model Cohort 
Time Perspective Prospective    
Target Number of Participant 35
Cohort/Group Number
Cohort/
Group 1
Cohort/Group
Label
connective tissue disease related digital ulcer in Korea 
Cohort/Group
Description
SSc or mixed connective tissue disease with active digital ulcers in the last 6 months The numbers of healed and new digital ulcers and the largest diameter of digital ulcers were assessed at baseline and at 4, 8, 16, and 24 weeks after treatment with bosentan. The extent of skin thickening was also evaluated using the modified Rodnan total skin score (mRSS) at baseline and 24 weeks 14. At baseline and after 24 weeks, nailfold capillaroscope was performed using a light microscope (SZ-PT; Olympus, Tokyo, Japan) with 200 magnification. 
Biospecimen
Collection & Archiving
Not collect nor Archive 
Biospecimen Description  

9. Subject Eligibility

Subject Eligibility Information
Study Population Description Adults using the medical center for each regional center  
Sampling Method adult patients with systemic slerosis(SSc) or mixed connective tissue disease(MCTD) with active digital ulcers, with or without pulmonary arterial hypertension (PAH), in the last 6 months, from the rheumatology department of the 4 institutions <br />Non-probability sampling.  
Condition(s)/Problem(s) * Diseases of the musculo-skeletal system and connective tissue
Rare Disease Yes
Inclusion
Criteria
Gender Both 
Age 20 Year ~ No Limit
Description adult patients with systemic slerosis(SSc) or mixed connective tissue disease(MCTD) with active digital ulcers, with or without pulmonary arterial hypertension (PAH), in the last 6 months, from the rheumatology department of the 4 institutions <br />All patients fulfilled the 2013 American College of Rheumatology/EULAR classification criteria or the MCTD criteria according to Sharp et al.  
Exclusion Criteria Patients were excluded if they had taken phosphodiesterase type 5 (PDE-5) inhibitors or other endothelin receptor antagonists within 1 month and had used prostacyclin analogues within the previous 3 months 4. The concurrent use of aspirin, calcium channel blocker (CCB), angiotensin-converting enzyme inhibitor (ACEi), and angiotensin II receptor blocker (ARB) was acceptable at the same dose as the last 4 weeks before study enrollment.  
Healthy Volunteers No

10. Outcome Measure(s)

Outcome Measure(s) Information
Type of Primary Outcome Efficacy 
Primary Outcome(s) 1 
Outcome The numbers of healed and new DUs and the largest diameter of DUs were assessed at baseline and at 4, 8, 16, and 24 weeks after treatment with bosentan 
Timepoint assessed at baseline and at 4, 8, 16, and 24 weeks after treatment with bosentan 
Secondary Outcome(s) 1 
Outcome nailfold capillaroscopy was performed using a light microscope (SZ-PT; Olympus, Tokyo, Japan) with 200x magnification 
Timepoint At baseline and after 24 weeks 

11. Study Results and Publication

Study Results and Publication Information
Result Registered No

12. Sharing of Study Data(Deidentified Individual-Patient Data, IPD)

Sharing of Study Data Information
Sharing Statement Yes 
Time of Sharing 2020.04
Way of Sharing To be made available at a later date
(dnjsghaaa@naver.com)
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