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A multicenter, randomized, partial double blind, active control, parallel clinical trial to evaluate the efficacy, safety and usability of cyclosporin ophthalmic nanoemulsion 0.05% compared with cyclosporin ophthalmic emulsion 0.05% and diquafosol ophthalmic solution 3%

Status : Approved
First Submitted Date : 2016/11/23 Registered Date : 2016/12/23 Last Updated Date : 2019/08/20

Background - CRIS Registration Number, Unique Protocol ID, Public/Brief Title, Scientific Title, Acronym, MFDS Regulated Study, IND/IDE Protocol, Registered at Other Registry, Name of Registry/Registration Number
1. Background
CRIS Registration Number	KCT0002180
Unique Protocol ID	KCDSG-CCD-01
Public/Brief Title	Prospective clinical trial to evaluate efficacy, safety and usability of nanoemulsion cyclosporin 0.05%, emulsion cyclosporin 0.05% and diquafosol 3% in dry eye patients
Scientific Title	A multicenter, randomized, partial double blind, active control, parallel clinical trial to evaluate the efficacy, safety and usability of cyclosporin ophthalmic nanoemulsion 0.05% compared with cyclosporin ophthalmic emulsion 0.05% and diquafosol ophthalmic solution 3%
Acronym	CCD study
MFDS Regulated Study	No
IND/IDE Protocol	No
Registered at Other Registry	No
Healthcare Benefit Approval Status	Not applicable

Institutional Review Board Information - Clinical research ethics review consisting of approval status, approval number, approval date, committee information, and data monitoring committee.
2. Institutional Review Board/Ethics Committee
Board Approval Status	Submitted approval
Board Approval Number	XC16MIMV0056S
Approval Date	2016-08-09
Institutional Review Board Name	SCMC IRB (Sungmo Catholic Medical Center Institutional Review Board)
Institutional Review Board Address	10, 63-ro, Yeongdeungpo-gu, Seoul
Institutional Review Board Telephone	02-3779-2011
Data Monitoring Committee	No

Contact Details Information - Contact Details Information consisting of Contact Person for Principal Investigator / Scientific Queries, Contact Person for Public Queries, Name of Contact Person for Updating Information, Title, Email, Telephone, Cellular Phone, Affiliation, Address.
3. Contact Details
Contact Person for Principal Investigator / Scientific Queries
Name	Hyun-Seung Kim
Title	M.D.
Telephone	+82-2-1661-7575
Affiliation	The Catholic University of Korea, Yeouido St. Mary's Hospital
Address	10, 63-ro Yeongdeungpo-gu, Seoul, Korea
Contact Person for Public Queries
Name	Hyun-Seung Kim
Title	M.D.
Telephone	+82-2-3779-1848
Affiliation	The Catholic University of Korea, Yeouido St. Mary's Hospital
Address	10, 63-ro Yeongdeungpo-gu, Seoul, Korea
Contact Person for Updating Information
Name	Hanna Kim
Title	TM
Telephone	+82-2-799-0198
Affiliation	Taejoon Pharm
Address	8, Daesagwan-ro 31-gil, Yongsan-gu, Seoul, Korea

Status Information - Status Information consisting of Study Site, Overall Recruitment Status, Date of First Enrollment, Status of First Enrollment, Target Number of Participant, Primary Completion Date, Recruitment Status by Participating Study Site, Name of Study Site, Recruitment Status, Date of First Enrollment, Status of First Enrollemnt.
4. Status
Study Site	Multi-center Number of center : 12
Overall Recruitment Status	Completed
Date of First Enrollment	2016-10-21 Actual
Target Number of Participant	227
Primary Completion Date	2017-05-30 , Actual
Study Completion Date	2017-07-03 , Actual
Recruitment Status by Participating Study Site 1
Name of Study	Samsung Medical Center
Recruitment Status	Completed
Date of First Enrollment	2016-12-13 ,
Recruitment Status by Participating Study Site 2
Name of Study	Yonsei University Health System, Gangnam Severance Hospital
Recruitment Status	Completed
Date of First Enrollment	2016-11-21 ,
Recruitment Status by Participating Study Site 3
Name of Study	Koera University Guro Hospital
Recruitment Status	Completed
Date of First Enrollment	2016-11-29 ,
Recruitment Status by Participating Study Site 4
Name of Study	The Catholic University of Korea, Yeouido St. Mary's Hospital
Recruitment Status	Completed
Date of First Enrollment	2016-11-09 ,
Recruitment Status by Participating Study Site 5
Name of Study	Kangbuk Samsung Medical Center
Recruitment Status	Completed
Date of First Enrollment	2016-10-25 ,
Recruitment Status by Participating Study Site 6
Name of Study	Chonnam National University Hospital
Recruitment Status	Completed
Date of First Enrollment	2016-11-08 ,
Recruitment Status by Participating Study Site 7
Name of Study	Inje University Ilsan Paik Hospital
Recruitment Status	Completed
Date of First Enrollment	2017-01-11 ,
Recruitment Status by Participating Study Site 8
Name of Study	Kyungpook National University Hospital
Recruitment Status	Completed
Date of First Enrollment	2016-10-21 ,
Recruitment Status by Participating Study Site 9
Name of Study	Seoul National University Hospital
Recruitment Status	Completed
Date of First Enrollment	2016-10-31 ,
Recruitment Status by Participating Study Site 10
Name of Study	Yonsei University Health System, Severance Hospital
Recruitment Status	Completed
Date of First Enrollment	2016-12-08 ,
Recruitment Status by Participating Study Site 11
Name of Study	Asan Medical Center
Recruitment Status	Completed
Date of First Enrollment	2016-10-31 ,
Recruitment Status by Participating Study Site 12
Name of Study	The Catholic University of Korea, Bucheon St. Mary's Hospital
Recruitment Status	Completed
Date of First Enrollment	2016-11-18 ,

Source of Monetary / Material Support Information - Source of Monetary / Material Support Information consisting of Organization Name, Organization Type, Project ID.
5. Source of Monetary / Material Support
1. Source of Monetary/Material Support
Organization Name	Taejoon Pharm
Organization Type	Pharmaceutical Company
Project ID	KCDSG-CCD-01

Sponsor Organization Information - Sponsor Organization Information consisting of Organization Name, Organization Type.
6. Sponsor Organization
1. Sponsor Organization
Organization Name	The Catholic University of Korea, Yeouido St. Mary's Hospital
Organization Type	Medical Institute

Study Summary Information
7. Study Summary
Lay Summary	Dry eye syndrome(DES) is a multifactorial disease easily encountered clinically with 14~30% of reported prevalence but not easily treated properly in practice leaving more way to go. Clinically for DES, conservative therapy focusing to reserve tear amount by supplying artificial tears and/or blocking lacrimal duct flow surgically has been used widely. And, along with DEWS(international Dry Eye Workshop) 2007 guidance, anti-inflammatory therapy using cyclosporin etc has been the choice. More recently, secretagogues like diquafosol has introduced with novel approach to promote water and mucin secretion from goblet cells/conjunctival epithelial cells. As cyclosporin product, an emulsion formulation has been used for the last over 10 years with some complains and/or inconveniences like mandated re-mixing before use, burning sensation or blurred vision after instillation into the eye. To overcome these, nano-technology has introduced and several nano-emulsion type cyclosprin ophthalmic products were approved for market. On the other hand, two popular active ingredients, cyclosporin and diquafosol, seems to share common acting point of goblet cell, but, with limited reports on. On these background, this muticenter study is designed for two goals, to compare cyclosporin and diquafosol and to compare two different cyclosporin products with different particle size. As, nano-emulsion cyclosporin ophthalmic product, CYPORIN®N 0.05% is selected expecting additional advantage containing artificial tear(CMC) and mucoadhesive polymer, Xanthan gum.

Study Summary Information

7. Study Summary

Lay Summary

Dry eye syndrome(DES) is a multifactorial disease easily encountered clinically with 14~30% of reported prevalence but not easily treated properly in practice leaving more way to go.
Clinically for DES, conservative therapy focusing to reserve tear amount by supplying artificial tears and/or blocking lacrimal duct flow surgically has been used widely. And, along with DEWS(international Dry Eye Workshop) 2007 guidance, anti-inflammatory therapy using cyclosporin etc has been the choice. More recently, secretagogues like diquafosol has introduced with novel approach to promote water and mucin secretion from goblet cells/conjunctival epithelial cells.
As cyclosporin product, an emulsion formulation has been used for the last over 10 years with some complains and/or inconveniences like mandated re-mixing before use, burning sensation or blurred vision after instillation into the eye. To overcome these, nano-technology has introduced and several nano-emulsion type cyclosprin ophthalmic products were approved for market.
On the other hand, two popular active ingredients, cyclosporin and diquafosol, seems to share common acting point of goblet cell, but, with limited reports on.
On these background, this muticenter study is designed for two goals, to compare cyclosporin and diquafosol and to compare two different cyclosporin products with different particle size.
As, nano-emulsion cyclosporin ophthalmic product, CYPORIN®N 0.05% is selected expecting additional advantage containing artificial tear(CMC) and mucoadhesive polymer, Xanthan gum.

Study Design Information - Study Design Information consisting of Study Type, Study Purpose, Phase, Intervention Model, Blinding/Masking, Blinded Subject, Allocation, Intervention Type, Intervention Description, Number of Arms, Arm Label, Target Number of Participant, Arm Type, Arm Description.
8. Study Design
Study Type		Interventional Study
Study Purpose		Treatment
Phase		Phase4
Intervention Model		Parallel
Blinding/Masking		Double
Blinded Subject		Subject, Investigator
Allocation		RCT
Intervention Type		Drug
Intervention Description		3 arms (1st arm) Nanoemulsion cyclosporine 0.05% ophthalmic soln. treatment arm: CYPORIN®N 0.05%, 1 drop/time, 2 times/day, 12 weeks, ophthalmic (2nd arm) Emulsion cyclosporine 0.05% ophthalmic soln. treatment arm: RESTASIS® 0.05%, 1 drop/time, 2 times/day, 12 weeks, ophthalmic (3rd arm) Diquafosol tetrasodium ophthalmic soln. treatment arm: Diquas® 3%, 1 drop/time, 6 times/day, 12 weeks, ophthalmic
Number of Arms		3
Arm 1	Arm Label	Nanoemulsion cyclosporine 0.05% ophthalmic soln. treatment Arm
	Target Number of Participant	80
	Arm Type	Experimental
	Arm Description	1 drop/time, 2 times/day, 12 weeks (artificial tear 1 drop/time as available co-medication with recommendation of at least 4 times/day)
Arm 2	Arm Label	Emulsion cyclosporine 0.05% ophthalmic soln. treatment Arm
	Target Number of Participant	80
	Arm Type	Active comparator
	Arm Description	1 drop/time, 2 times/day, 12 weeks (artificial tear 1 drop/time as available co-medication with recommendation of at least 4times/day)
Arm 3	Arm Label	Diquafosol tetrasodium 3% ophthalmic soln. treatment Arm
	Target Number of Participant	80
	Arm Type	Active comparator
	Arm Description	1 drop/time, 6 times/day, 12 weeks (artificial tear 1 drop/time as available co-medication)

Subject Eligibility Information
9. Subject Eligibility
Condition(s)/Problem(s)		* (H00-H59)Diseases of the eye and adnexa (H04.11)Dry eye syndrome Dry eye symdrome
Rare Disease		No
Inclusion Criteria	Gender	Both
	Age	19Year~No Limit
	Description	1) ≥19 years of age 2) moderate to severe Dry eye syndrome (Corneal BFS score(NEI scale) ≥ 4 and ≤ 10 sec on TBUT) 3) volentary agreement with signed informed consent
Exclusion Criteria		1. cyclosporine or diquafosol use in any form(systemic, topical) within 4 weeks 2. medical condition or history within 4 weeks to be treated with topical agents besides artifical tears(glaucoma, ocular allergy, ocular inflammation/infectious disease, etc) 3. new start or medication change within 4 weeks for systemic drugs with probable effect on dry eye codition 4. sjogren syndrome 5. plan to wear contact lens during the study period 6. current or history of ocular disorders possibly affecting the study results(ocular surgery, trauma, diseases) 1) entropion, blepharelosis, blepharoplegia 2) ocular surgery history within 4 weeks or plan during the study period like punctal plug, punctal closure etc 3) herpetics keratopathy, conjunctival scarring by cicatricial keratoconjunctivitis, pterygium, congenital lacrimal gland shortage, neurogenic keratitis, keratoconus, corneal transplantation 7. known hypersensitivity to study medications 8, pregnancy or lactation 9. investigator's judge of inappropiation
Healthy Volunteers		No

Outcome Measure(s) Information - Outcome Measure(s) Information consisting of Type of Primary Outcome, Primary Outcome, Outcome, Timepoint, Secondary Outcome, Outcome, Timepoint.
10. Outcome Measure(s)
Type of Primary Outcome	Efficacy
Primary Outcome(s) 1
Outcome	Changes in corneal conjunctival staining score
Timepoint	12 week
Secondary Outcome(s) 1
Outcome	Changes in corneal conjunctival staining score
Timepoint	4 week
Secondary Outcome(s) 2
Outcome	Changes in corneal staining score
Timepoint	4 week, 12 week
Secondary Outcome(s) 3
Outcome	Changes in conjunctival staining score
Timepoint	4 week, 12 week
Secondary Outcome(s) 4
Outcome	Changes in TBUT (tear break-up time)
Timepoint	4 week, 12 week
Secondary Outcome(s) 5
Outcome	Changes in schirmer I test score
Timepoint	4 week, 12 week
Secondary Outcome(s) 6
Outcome	Changes in OSDI(ocular surface disease index)
Timepoint	4 week, 8 week, 12 week
Secondary Outcome(s) 7
Outcome	Patient global evalution
Timepoint	4 week, 8 week, 12 week
Secondary Outcome(s) 8
Outcome	tear mucin level change [exploratory endpoint]
Timepoint	4 week
Secondary Outcome(s) 9
Outcome	tear cytokine level change [exploratory endpoint]
Timepoint	4 week

Study Results and Publication Information - Study Results and Publication Information consisting of Result Registered, Final Enrollment Number, Number of Publication, Publications, Results Upload, Date of Posting Results, Protocol URL or File Upload, Brief Summary.
11. Study Results and Publication
Result Registered	Yes Published
Final Enrollment Number	227
Number of Publication	2
Publications 1	Chang Hyun Park, Hyung Keun Lee, Mee Kum Kim, Eun Chul Kim, Jae Yong Kim, Tae-im Kim, Hong Kyun Kim, Jong Suk Song, Kyung Chul Yoon, Do Hyung Lee, Tae-Young Chung, Chul Young Choi, Hyun Seung Kim. Comparison of 0.05% cyclosporine and 3% diquafosol solution for dry eye patients: a randomized, blinded, multicenter clinical trial. BMC Ophthalmology. SCI. 2019-06-17 , VOL : 0 page : 0 ~ 0 https://doi.org/10.1186/s12886-019-1136-8
Publications 2	Chang Hyun Park, Mee Kum Kim, Eun Chul Kim, Jae Yong Kim, Tae-Im Kim, Hong Kyun Kim, Jong Suk Song, Kyung-Chul Yoon, Do Hyung Lee, Hyung Keun Lee, Tae-Young Chung, Chul Young Choi, Hyun Seung Kim . Efficacy of Topical Cyclosporine Nanoemulsion 0.05% Compared with Topical Cyclosporine Emulsion 0.05% and Diquafosol 3% in Dry Eye. Korean Journal Ophthalmology. Non SCI. 2019-08-05 , VOL : 33 page : 343 ~ 352 https://doi.org/10.3341/kjo.2018.0116
Results Upload
Date of Posting Results
Protocol URL or File Upload
Brief Summary	Primary endpoints showed statistically significant improvements in all groups. Primary endpoints were -6.60 for the CN group, -5.28 for the CE group, and -6.63 for the DQ group (National Eye Institute scale from 0 to 33), verifying the non-inferiority of CN compared to CE (95% confidence interval, -0.15 to 2.80, Δ>-2.88). In intergroup comparison between CN and CE groups, the CN group had significantly more decreased conjunctival staining score at week 12. Intergroup comparison between CN and DQ groups showed consistent statistically significant improvements in TBUT and Schirmer test in the CN group. In the DQ group, TBUT showed late statistically significant improvement at week 12 and Schirmer test showed relatively short-term statistically significant improvement at week 4. Conclusions: Cyclosporine nanoemulsion 0.05% was equivalently efficient compared to cyclosporine emulsion 0.05% and diquafosol sodium 3%. In addition, CN showed significant improvements in several parameters for treatment of dry eyes.

Sharing of Study Data Information - Sharing of Study Data Information consisting of Sharing Statement, Time of Sharing, Way of Sharing.
12. Sharing of Study Data(Deidentified Individual-Patient Data, IPD)
Sharing Statement	No

1. Background
2. Institutional Review
Board / Ethics Committee
3. Contact Details
4. Status
5. Source of Monetary
/ Material Support
6. Sponsor Organization
7. Study Summary
8. Study Design
9. Subject Eligibility
10. Outcome Measure(s)
11. Study Results
and Publication
12. Sharing of Study Data