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    Clinical Trial Results:
    A Double-Masked, Randomised, Placebo-Controlled, Parallel-Group, 12-Week, Phase 2 Study to Investigate the Safety and Efficacy of Ripasudil (K-321) Eye Drops After Descemetorhexis in Patients with Fuchs Endothelial Corneal Dystrophy

    Summary
    EudraCT number
    		 2019-003280-22
    Trial protocol
    		 DE   DK  
    Global end of trial date
    27 Jun 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Jul 2025
    First version publication date
    12 Jul 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    K-321-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04250207
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Kowa Research Institute, Inc.
    Sponsor organisation address
    430 Davis Drive, Suite 200, Morrisville, United States, 27560
    Public contact
    Shona Pendse, MD, MMSc, Kowa Research Institute, Inc., studyrecruitment@kowaus.com
    Scientific contact
    Shona Pendse, MD, MMSc, Kowa Research Institute, Inc., studyrecruitment@kowaus.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Sep 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jun 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to investigate the effect of K-321 dosed for 12 weeks on central ECD in patients with FECD after descemetorhexis.
    Protection of trial subjects
    The study was conducted in accordance with the World Medical Association Declaration of Helsinki; ICH GCP; General Data Protection Regulation or Directive 2001/20/EC (in the EU); the FDA GCP, as described in 21 CFR Parts 11, 50, 54, 56, and 312 and Health Insurance Portability and Accountability Act (in the US); and the laws and regulations of the country where the study was conducted. Prior to the initiation of any study procedures, each patient signed and dated an approved informed consent form. Each patient was assured of his/her right to withdraw from the study at any time.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Jun 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 8
    Country: Number of subjects enrolled
    United States: 34
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Spain: 15
    Worldwide total number of subjects
    65
    EEA total number of subjects
    23
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    30
    From 65 to 84 years
    35
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 After obtaining informed consent at Visit 1, the patient returned for the descemetorhexis operation and randomly assigned to treatment after 1 to 4 weeks (Visit 2). At Visit 2, each patient’s eligibility for study participation was confirmed, which included the requirement of a successful descemetorhexis operation.

    Period 1
    Period 1 title
    Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 K-321 QID
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    K-321
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution in single-dose container
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    K-321 ophthalmic solution 0.4% dosed QID (K-321 QID)

    Arm title
    		 K-321 BID
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    K-321
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution in single-dose container
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    K-321 ophthalmic solution 0.4% dosed BID (K-321 BID)

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo matching K-321
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, solution in single-dose container
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    K-321 Placebo

    Number of subjects in period 1
    		K-321 QID K-321 BID Placebo
    Started
    21
    22
    22
    Completed
    21
    22
    22
    Period 2
    Period 2 title
    40 Week Follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 K-321 QID
    Arm description
    		 Follow-up
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 K-321 BID
    Arm description
    		 Follow-up
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Placebo
    Arm description
    		 Follow-up
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		K-321 QID K-321 BID Placebo
    Started
    21
    22
    22
    Completed
    21
    21
    20
    Not completed
    0
    1
    2
         Rescue keratoplasty
    -
    -
    1
         Withdrawal by patient
    -
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    K-321 QID
    Reporting group description
    		 -

    Reporting group title
    K-321 BID
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 K-321 QID K-321 BID Placebo Total
    Number of subjects
    		 21 22 22 65
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.7 ( 12.28 ) 65.1 ( 9.68 ) 65.3 ( 9.00 ) -
    Gender categorical
    Units: Subjects
        Female
    		 16 13 20 49
        Male
    		 5 9 2 16
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS consisted of all patients who had a successful descemetorhexis procedure, were randomly assigned to receive double-masked study drug, received at least 1 dose of study drug in the study eye, and had at least 1 assessment of central corneal ECD performed after the descemetorhexis procedure on the study eye. (An assessment of “cannot perform due to corneal oedema” was considered a valid assessment for inclusion in the FAS.)

    Subject analysis set title
    Safety Set (SFS)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The SFS consisted of all patients who received any study drug.

    Subject analysis sets values
    		 Full Analysis Set (FAS) Safety Set (SFS)
    Number of subjects
    65
    65
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    65.0 ( 10.23 )
    65.0 ( 10.23 )
    Gender categorical
    Units: Subjects
        Female
    49
    49
        Male
    16
    16

    End points

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    End points reporting groups
    Reporting group title
    K-321 QID
    Reporting group description
    		 -

    Reporting group title
    K-321 BID
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -
    Reporting group title
    K-321 QID
    Reporting group description
    		 Follow-up

    Reporting group title
    K-321 BID
    Reporting group description
    		 Follow-up

    Reporting group title
    Placebo
    Reporting group description
    		 Follow-up

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS consisted of all patients who had a successful descemetorhexis procedure, were randomly assigned to receive double-masked study drug, received at least 1 dose of study drug in the study eye, and had at least 1 assessment of central corneal ECD performed after the descemetorhexis procedure on the study eye. (An assessment of “cannot perform due to corneal oedema” was considered a valid assessment for inclusion in the FAS.)

    Subject analysis set title
    Safety Set (SFS)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The SFS consisted of all patients who received any study drug.

    Primary: Central Corneal ECD at Week 12

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    End point title
    		 Central Corneal ECD at Week 12
    End point description
    Assessed by Cornea Image Analysis Reading Center (CIARC) and was based on assessments performed by specular microscopy.
    End point type
    Primary
    End point timeframe
    Baseline to Week 12
    End point values
    		 K-321 QID K-321 BID Placebo
    Number of subjects analysed
    21
    22
    22
    Units: cells/square millimeter
        arithmetic mean (standard deviation)
    530.86 ( 312.453 )
    468.02 ( 322.361 )
    228.05 ( 297.860 )
    Statistical analysis title
    		 Central Corneal ECD at Week 12
    Comparison groups
    K-321 BID v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0344
    Method
    		 Wilcoxon rank sum test
    Confidence interval
    Statistical analysis title
    		 Central Corneal ECD at Week 12
    Comparison groups
    K-321 QID v Placebo
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0065
    Method
    		 Wilcoxon rank sum test
    Confidence interval

    Secondary: Time to Return of Corneal Thickness to Less than or Equal to Baseline Corneal Thickness

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    End point title
    		 Time to Return of Corneal Thickness to Less than or Equal to Baseline Corneal Thickness
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    		 K-321 QID K-321 BID Placebo
    Number of subjects analysed
    21
    22
    22
    Units: Days
        median (confidence interval 95%)
    50.0 (35.0 to 110.0)
    50.0 (34.0 to 66.0)
    165.0 (112.0 to 366.0)
    Statistical analysis title
    		 Time to Achieve No Corneal Oedema of Study Eye
    Comparison groups
    Placebo v K-321 QID
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0259
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Time to Achieve No Corneal Oedema of Study Eye
    Comparison groups
    K-321 BID v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0068
    Method
    		 Logrank
    Confidence interval

    Secondary: Time to No Corneal Oedema

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    End point title
    		 Time to No Corneal Oedema
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    		 K-321 QID K-321 BID Placebo
    Number of subjects analysed
    21
    22
    22
    Units: Days
        median (confidence interval 95%)
    35.0 (22.0 to 64.0)
    51.5 (50.0 to 269.0)
    267.0 (141.0 to 365.0)
    Statistical analysis title
    		 Time to Achieve No Corneal Oedema of Study Eye
    Comparison groups
    K-321 QID v Placebo
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0021
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Time to Achieve No Corneal Oedema of Study Eye
    Comparison groups
    K-321 BID v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1696
    Method
    		 Logrank
    Confidence interval

    Secondary: Time to Achieve Central Corneal ECD 700 cells/mm2 or more

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    End point title
    		 Time to Achieve Central Corneal ECD 700 cells/mm2 or more
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    		 K-321 QID K-321 BID Placebo
    Number of subjects analysed
    21
    22 [1]
    22 [2]
    Units: Days
        median (confidence interval 95%)
    141.0 (83.0 to 363.0)
    181.0 (113.0 to 9999)
    273.0 (135.0 to 9999)
    Notes
    [1] - 9999 = NA: Median upper limit unestimable as curve < 0.50.
    [2] - 9999 = NA: Median upper limit unestimable as curve < 0.50.
    Statistical analysis title
    		 Time to Achieve Central Corneal ECD 700 cells/mm2
    Comparison groups
    K-321 QID v Placebo
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1209
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Time to Achieve Central Corneal ECD 700 cells/mm2
    Comparison groups
    K-321 BID v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7116
    Method
    		 Logrank
    Confidence interval

    Secondary: Central Corneal ECD at Week 52

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    End point title
    		 Central Corneal ECD at Week 52
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    		 K-321 QID K-321 BID Placebo
    Number of subjects analysed
    21
    22
    22
    Units: cells/square millimeters
        arithmetic mean (standard deviation)
    751.45 ( 407.259 )
    633.05 ( 313.372 )
    431.79 ( 327.488 )
    Statistical analysis title
    		 Central Corneal ECD at Week 52
    Comparison groups
    K-321 QID v Placebo
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0047
    Method
    		 Wilcoxon Rank Sum Test
    Confidence interval
    Statistical analysis title
    		 Central Corneal ECD at Week 52
    Comparison groups
    K-321 BID v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0625
    Method
    		 Wilcoxon Rank Sum Test
    Confidence interval

    Secondary: Proportion of patients who achieve central corneal ECD of 700 cells/mm2 or more at Week 12

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    End point title
    		 Proportion of patients who achieve central corneal ECD of 700 cells/mm2 or more at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 K-321 QID K-321 BID Placebo
    Number of subjects analysed
    21
    21
    16
    Units: Patients
    number (not applicable)
        Number
    6
    4
    2
        Percent
    28.6
    19.0
    12.5
    Statistical analysis title
    		 Proportion of patients who achieve central corneal
    Comparison groups
    K-321 QID v Placebo
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4227
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Proportion of patients who achieve central corneal
    Comparison groups
    K-321 BID v Placebo
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6796
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Proportion of patients who achieve central corneal ECD of 700 cells/mm2 or more at Week 52

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    End point title
    		 Proportion of patients who achieve central corneal ECD of 700 cells/mm2 or more at Week 52
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    		 K-321 QID K-321 BID Placebo
    Number of subjects analysed
    19
    18
    15
    Units: percent
    number (not applicable)
        Number
    15
    8
    5
        Percent
    78.9
    44.4
    33.3
    Statistical analysis title
    		 Central corneal ECD of 700 cells/mm2 or more
    Comparison groups
    K-321 QID v Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0135
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Central corneal ECD of 700 cells/mm2 or more
    Comparison groups
    K-321 BID v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5154
    Method
    		 Pearson Chi-square test
    Confidence interval

    Secondary: Change in Central Corneal Thickness from Baseline at Week 12

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    End point title
    		 Change in Central Corneal Thickness from Baseline at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 K-321 QID K-321 BID Placebo
    Number of subjects analysed
    20
    21
    21
    Units: micrometer
        arithmetic mean (standard deviation)
    0.59 ( 86.332 )
    -22.69 ( 61.127 )
    100.19 ( 137.191 )
    Statistical analysis title
    		 Change from Baseline in Central Corneal Thickness
    Comparison groups
    K-321 QID v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0127
    Method
    		 Wilcoxon rank sum test
    Confidence interval
    Statistical analysis title
    		 Change from Baseline in Central Corneal Thickness
    Comparison groups
    K-321 BID v Placebo
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0014
    Method
    		 Wilcoxon rank sum test
    Confidence interval

    Secondary: Change in Central Corneal Thickness from Baseline at Week 52

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    End point title
    		 Change in Central Corneal Thickness from Baseline at Week 52
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    		 K-321 QID K-321 BID Placebo
    Number of subjects analysed
    20
    21
    21
    Units: micrometer
        arithmetic mean (standard deviation)
    -6.74 ( 65.888 )
    -25.88 ( 44.360 )
    55.29 ( 155.649 )
    Statistical analysis title
    		 Change in Central Corneal Thickness at Week 52
    Comparison groups
    K-321 QID v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5181
    Method
    		 Wilcoxon rank sum test
    Confidence interval
    Statistical analysis title
    		 Change in Central Corneal Thickness at Week 52
    Comparison groups
    K-321 BID v Placebo
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1898
    Method
    		 Wilcoxon rank sum test
    Confidence interval

    Secondary: Percentage Change from Baseline in Central Corneal Thickness at Week 12

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    End point title
    		 Percentage Change from Baseline in Central Corneal Thickness at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 K-321 QID K-321 BID Placebo
    Number of subjects analysed
    20
    21
    17
    Units: percent
        arithmetic mean (standard deviation)
    0.73 ( 15.895 )
    -3.65 ( 9.467 )
    10.70 ( 17.611 )
    Statistical analysis title
    		 Difference to Placebo
    Comparison groups
    K-321 QID v Placebo
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0608
    Method
    		 Wilcoxon rank sum test
    Confidence interval
    Statistical analysis title
    		 Difference to Placebo
    Comparison groups
    K-321 BID v Placebo
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0071
    Method
    		 Wilcoxon rank sum test
    Confidence interval

    Secondary: Percentage Change from Baseline in Central Corneal Thickness at Week 52

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    End point title
    		 Percentage Change from Baseline in Central Corneal Thickness at Week 52
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    		 K-321 QID K-321 BID Placebo
    Number of subjects analysed
    18
    18
    15
    Units: percent
        arithmetic mean (standard deviation)
    -2.90 ( 8.634 )
    -5.63 ( 5.614 )
    -3.68 ( 11.182 )
    Statistical analysis title
    		 Difference to Placebo
    Comparison groups
    K-321 QID v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.555
    Method
    		 Wilcoxon rank sum test
    Confidence interval
    Statistical analysis title
    		 Compared to Placebo
    Comparison groups
    K-321 BID v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8718
    Method
    		 Wilcoxon rank sum test
    Confidence interval

    Secondary: Proportion of patients who achieve corneal thickness less than or equal to baseline corneal thickness at Week 12

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    End point title
    		 Proportion of patients who achieve corneal thickness less than or equal to baseline corneal thickness at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 K-321 QID K-321 BID Placebo
    Number of subjects analysed
    20
    21
    18
    Units: participants
    number (not applicable)
        Number
    13
    17
    5
        Percent
    65.0
    81.0
    27.8
    Statistical analysis title
    		 Difference to Placebo
    Comparison groups
    K-321 QID v Placebo
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.0218
    Method
    		 Pearson Chi-square test
    Confidence interval
    Statistical analysis title
    		 Difference to Placebo
    Comparison groups
    K-321 BID v Placebo
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0013
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Proportion of patients who achieve corneal thickness less than or equal to baseline corneal thickness at Week 52

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    End point title
    		 Proportion of patients who achieve corneal thickness less than or equal to baseline corneal thickness at Week 52
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    		 K-321 QID K-321 BID Placebo
    Number of subjects analysed
    18
    18
    16
    Units: percent
    number (not applicable)
        Number
    14
    15
    13
        Percent
    77.8
    83.3
    81.3
    Statistical analysis title
    		 Difference to Placebo
    Comparison groups
    K-321 QID v Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.9999
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Difference to Placebo
    Comparison groups
    K-321 BID v Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.9999
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Proportion of patients who achieve no corneal oedema at Week 12

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    End point title
    		 Proportion of patients who achieve no corneal oedema at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 K-321 QID K-321 BID Placebo
    Number of subjects analysed
    21
    22
    22
    Units: participants
    number (not applicable)
        Number
    17
    12
    2
        Percent
    81.0
    54.5
    9.1
    Statistical analysis title
    		 Difference to Placebo
    Comparison groups
    K-321 QID v Placebo
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Difference to Placebo
    Comparison groups
    K-321 BID v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0028
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Proportion of patients who achieve no corneal oedema at Week 52

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    End point title
    		 Proportion of patients who achieve no corneal oedema at Week 52
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    		 K-321 QID K-321 BID Placebo
    Number of subjects analysed
    21
    22
    22
    Units: Participants
    number (not applicable)
        Number
    17
    13
    13
        Percent
    81.0
    59.1
    59.1
    Statistical analysis title
    		 No corneal oedema at Week 52
    Comparison groups
    K-321 QID v Placebo
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1854
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 No corneal oedema at Week 52
    Comparison groups
    K-321 BID v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.9999
    Method
    		 Pearson Chi-square test
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    52 Weeks
    Adverse event reporting additional description
    All AEs were collected starting from the time that the patient gave consent until the date of completion or withdrawal from the study. Adverse events were deemed to be treatment-emergent if the onset date was on or after the date of first treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    K-321 QID
    Reporting group description
    		 -

    Reporting group title
    K-321 BID
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 K-321 QID K-321 BID Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    3 / 22 (13.64%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Alcohol rehabilitation
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Terminal ileitis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 K-321 QID K-321 BID Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 21 (57.14%)
    11 / 22 (50.00%)
    14 / 22 (63.64%)
    Investigations
    Intraocular pressure increased
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    2 / 22 (9.09%)
         occurrences all number
    0
    1
    4
    Injury, poisoning and procedural complications
    Wrist fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    0
    2
    Eye disorders
    Conjunctival hyperaemia
         subjects affected / exposed
    3 / 21 (14.29%)
    3 / 22 (13.64%)
    0 / 22 (0.00%)
         occurrences all number
    3
    3
    0
    Corneal degeneration
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 22 (4.55%)
    1 / 22 (4.55%)
         occurrences all number
    2
    1
    1
    Eye pruritus
         subjects affected / exposed
    1 / 21 (4.76%)
    3 / 22 (13.64%)
    0 / 22 (0.00%)
         occurrences all number
    1
    3
    0
    Photophobia
         subjects affected / exposed
    1 / 21 (4.76%)
    2 / 22 (9.09%)
    2 / 22 (9.09%)
         occurrences all number
    1
    3
    2
    Punctate keratitis
         subjects affected / exposed
    1 / 21 (4.76%)
    2 / 22 (9.09%)
    1 / 22 (4.55%)
         occurrences all number
    1
    2
    1
    Vision blurred
         subjects affected / exposed
    1 / 21 (4.76%)
    2 / 22 (9.09%)
    3 / 22 (13.64%)
         occurrences all number
    1
    2
    4
    Visual acuity reduced
         subjects affected / exposed
    1 / 21 (4.76%)
    3 / 22 (13.64%)
    0 / 22 (0.00%)
         occurrences all number
    1
    4
    0
    Corneal oedema
         subjects affected / exposed
    4 / 21 (19.05%)
    2 / 22 (9.09%)
    7 / 22 (31.82%)
         occurrences all number
    4
    3
    10
    Eye pain
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 22 (9.09%)
    5 / 22 (22.73%)
         occurrences all number
    0
    3
    5
    Corneal disorder
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 22 (9.09%)
    1 / 22 (4.55%)
         occurrences all number
    0
    2
    1
    Foreign body sensation in eyes
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 22 (9.09%)
    1 / 22 (4.55%)
         occurrences all number
    0
    2
    1
    Diplopia
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 22 (9.09%)
    0 / 22 (0.00%)
         occurrences all number
    0
    2
    0
    Eye Allergy (study eye)
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    0
    Eye allergy (non-study eye)
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    0
    Eye irritation
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 22 (9.09%)
    1 / 22 (4.55%)
         occurrences all number
    0
    2
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 21 (4.76%)
    2 / 22 (9.09%)
    0 / 22 (0.00%)
         occurrences all number
    1
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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