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    Clinical Trial Results:
    A Phase II, multicentre, randomised, placebo-controlled, double-masked trial of RP101 ophthalmic formulation versus vehicle in post-menopausal women with moderate to severe dry eye syndrome

    Summary
    EudraCT number
    		 2017-005160-18
    Trial protocol
    		 AT   HU   DE  
    Global end of trial date
    18 Nov 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Jun 2022
    First version publication date
    26 Jun 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RP101-200
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03821415
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 CRO code number: CRO-17-132
    Sponsors
    Sponsor organisation name
    Redwood Pharma AB
    Sponsor organisation address
    Ringvägen 100E, 9th Floor, Stockholm, Sweden, SE-118 60
    Public contact
    Redwood Pharma AB, Sponsor representative, Redwood Pharma AB, 0046 (08)55934737, martin.vidaeus@redwoodpharma.com
    Scientific contact
    Redwood Pharma AB, Sponsor representative, Redwood Pharma AB, 0046 (08)55934737, martin.vidaeus@redwoodpharma.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
    24 Jun 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to establish the effective dose/dose regimen of RP101 in post-menopausal women with moderate to severe dry eye syndrome applying RP101 ophthalmic sterile solution or matching placebo (vehicle) once (q.d.) or twice a day (b.i.d.) for 3 months
    Protection of trial subjects
    The indication proposed for RP101 is dry eye syndrome of moderate-to-severe intensity in postmenopausal women. Therefore, the population selected for the present study was composed of postmenopausal women for at least 3 years presenting with symptoms specific for dry eye syndrome of moderate-to-severe intensity. Patients presenting with severe Meibomian gland dysfunction were excluded due to its potential interference, since a Meibomian gland dysfunction of severe intensity would lead to underestimate the RP101 effect. The participants in the study could receive benefit from the study treatment because they could experience a relief of dry eye symptoms during the study. Also the patients randomly allocated to the control arm, who received the vehicle (RP101 without the active substance), could receive some benefit from IntelliGel (placebo; vehicle) which was expected to have lubricant properties due to its rheological behaviour. Safety of the subjects was monitored throughout the study.
    Background therapy
    		 All the previous ocular therapies for moderate/severe dry eye symptom up to screening were discontinued. At study start, all patients used the same topical lubricant for 14 consecutive days (run-in period) in order to start at baseline at homogeneous conditions. During the run-in, all the subjects used the same ocular product (Oculotect®) in order to standardise baseline conditions. After the run-in, the subjects were randomised and started the allocated study treatment. In case of need during the study treatment, the patients could instil Larmabak®, artificial tears, as rescue medication in addition to the study treatment.
    Evidence for comparator
    		 In the present study, 2 strengths of RP101 were investigated: 0.1% and 0.05%. IntelliGel® (RP101 vehicle) was selected as the placebo (vehicle) in this study because of its unique properties and to mask the study.
    Actual start date of recruitment
    18 Jan 2019
    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
    Austria: 8
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Hungary: 89
    Worldwide total number of subjects
    104
    EEA total number of subjects
    104
    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)
    63
    From 65 to 84 years
    41
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited from 18JAN2019 to 28JUN2019 Territories were: Vienna, Austria; München, Germany; Greifswald, Germany; Mainz, Germany; Létavértes, Hungary; Budapest, Hungary; Székesfehérvár Berényi, Hungary

    Pre-assignment
    Screening details
    		 During screening, inclusion and exclusion criteria were checked and only eligible patients enrolled in the study. At study start, all patients used the same topical lubricant for 14 consecutive days (run-in period) in order to start at baseline at homogeneous conditions. All screened patients are listed on the screen log.

    Pre-assignment period milestones
    Number of subjects started
    		 104
    Number of subjects completed
    		 104

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Clinical staff, CRO, CRAs, Sponsor, patients were blinded. Blinding was open by data managers only after DB lock. Breaking of an individual randomisation code by the investigator during the study was allowed only when knowledge of the code was essential for the subject's health.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment group 1
    Arm description
    		 Active investigational product (T1) twice a day
    Arm type
    		 Experimental

    Investigational medicinal product name
    RP101 0.05%, 17-β-oestradiol-3-phosphate ophthalmic sterile solution
    Investigational medicinal product code
    T1
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    One drop (28 µL) according to the treatment group and dose regimen was instilled into each eye twice a day (b.i.d.), approximately every 12 h (08:30 ± 1.5 h and 20:30 ± 1.5 h), for 90±3 consecutive days.

    Arm title
    		 Treatment group 2
    Arm description
    		 Active investigational product (T2) and placebo
    Arm type
    		 Experimental

    Investigational medicinal product name
    RP101 0.1%, 17-β-oestradiol-3-phosphate ophthalmic sterile solution
    Investigational medicinal product code
    T2
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    One drop (28 µL) of T2 was instilled into each eye once a day at approximately 8:30 ± 1.5 h for 90±3 consecutive days.

    Investigational medicinal product name
    RP101 matching placebo, ophthalmic sterile solution
    Investigational medicinal product code
    P
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    One drop (28 µL) of P was instilled into each eye once a day at 20:30 ± 1.5 h for 90±3 consecutive days.

    Arm title
    		 Treatment group 3
    Arm description
    		 Active investigational product twice a day
    Arm type
    		 Experimental

    Investigational medicinal product name
    RP101 0.1%, 17-β-oestradiol-3-phosphate ophthalmic sterile solution
    Investigational medicinal product code
    T2
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    One drop (28 µL) of T2 was instilled into each eye twice a day (b.i.d.), approximately every 12 h (08:30 ± 1.5 h and 20:30 ± 1.5 h), for 90±3 consecutive days.

    Arm title
    		 Treatment group 4
    Arm description
    		 Placebo twice a day
    Arm type
    		 Placebo

    Investigational medicinal product name
    RP101 matching placebo, ophthalmic sterile solution
    Investigational medicinal product code
    P
    Other name
    Pharmaceutical forms
    Eye drops, solution
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    One drop (28 µL) of P was instilled into each eye twice a day (b.i.d.), approximately every 12 h (08:30 ± 1.5 h and 20:30 ± 1.5 h), for 90±3 consecutive days

    Number of subjects in period 1
    		Treatment group 1 Treatment group 2 Treatment group 3 Treatment group 4
    Started
    27
    25
    26
    26
    Completed
    20
    22
    13
    22
    Not completed
    7
    3
    13
    4
         Consent withdrawn by subject
    1
    1
    3
    1
         Adverse event, non-fatal
    6
    2
    10
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 104 104
    Age categorical
    Age range of the women in the study was 39-83 years
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 63 63
        From 65-84 years
    		 41 41
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.9 ± 8.7 -
    Gender categorical
    Only post-menopausal women were included in the study, according to the protocol requirements
    Units: Subjects
        Female
    		 104 104
        Male
    		 0 0
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    aAl randomised subjects who received at least one dose of the investigational product and had at least one post-randomisation assessment of the primary efficacy data. This analysis set was used for the primary efficacy analysis. This analysis set corresponded also to the Intent-To-Treat set.

    Subject analysis set title
    PP set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All randomised subjects who fulfilled the study protocol requirements in terms of investigational product administration and collection of primary efficacy data and with no major deviations that could affect study results. This analysis set was used for the sensitivity analyses;

    Subject analysis set title
    Saftey set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who received at least one dose of investigational product. This analysis set was used for the safety analyses

    Subject analysis set title
    PK set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PK Set (only for the PK sub-study): all randomised subjects who had evaluable PK data readouts. This analysis set was used for the PK analysis;

    Subject analysis sets values
    		 Full Analysis Set PP set Saftey set PK set
    Number of subjects
    104
    67
    104
    71
    Age categorical
    Age range of the women in the study was 39-83 years
    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)
    62.9 ± 8.7
    61.7 ± 8.5
    62.9 ± 8.7
    61.2 ± 8.4
    Gender categorical
    Only post-menopausal women were included in the study, according to the protocol requirements
    Units: Subjects
        Female
    104
    67
    104
    71
        Male
    0
    0
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    Treatment group 1
    Reporting group description
    		 Active investigational product (T1) twice a day

    Reporting group title
    Treatment group 2
    Reporting group description
    		 Active investigational product (T2) and placebo

    Reporting group title
    Treatment group 3
    Reporting group description
    		 Active investigational product twice a day

    Reporting group title
    Treatment group 4
    Reporting group description
    		 Placebo twice a day

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    aAl randomised subjects who received at least one dose of the investigational product and had at least one post-randomisation assessment of the primary efficacy data. This analysis set was used for the primary efficacy analysis. This analysis set corresponded also to the Intent-To-Treat set.

    Subject analysis set title
    PP set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All randomised subjects who fulfilled the study protocol requirements in terms of investigational product administration and collection of primary efficacy data and with no major deviations that could affect study results. This analysis set was used for the sensitivity analyses;

    Subject analysis set title
    Saftey set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who received at least one dose of investigational product. This analysis set was used for the safety analyses

    Subject analysis set title
    PK set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PK Set (only for the PK sub-study): all randomised subjects who had evaluable PK data readouts. This analysis set was used for the PK analysis;

    Primary: Schirmer’s test type II (with anaesthesia) result

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    End point title
    		 Schirmer’s test type II (with anaesthesia) result
    End point description
    Schirmer's test was performed to measure basal aqueous tear secretion following the instillation of a preservative-free anaesthetic eye drop. Both eyes could be tested at the same time. Schirmer’s plus® strips were used. This test was conducted in a dimly lit room. While the patient looked upwards, the lower lid was drawn downwards gently and temporally. The rounded bent end of a sterile strip was inserted in the lower conjunctival sac over the temporal one-third of the lower eyelid margin. The test was to be done without touching directly the Schirmer’s test strip with the fingers to avoid contamination of skin oils. The patients were instructed to close their eyes gently. After a 5-min elapse, the Schirmer’s test strip was removed and the length of the tear absorption on the strip measured (as mm/5 min). The wetting distance at 5 min for each eye was recorded in the CRF.
    End point type
    Primary
    End point timeframe
    3 months
    End point values
    		 Treatment group 1 Treatment group 2 Treatment group 3 Treatment group 4
    Number of subjects analysed
    20
    22
    13
    22
    Units: mm/5 min
        arithmetic mean (standard deviation)
    9.6 ± 7.2
    6.8 ± 5.7
    9.6 ± 4.4
    8.6 ± 5.3
    Statistical analysis title
    		 Wilcoxon rank
    Statistical analysis description
    Statistical analysis on changes from baseline between groups and in changes from baseline within groups
    Comparison groups
    Treatment group 1 v Treatment group 2 v Treatment group 3 v Treatment group 4
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon Rank Sum Test
    Confidence interval
    Notes
    [1] - No significant changes among groups. Significant changes at all post-dose times as compared to baseline values
    Statistical analysis title
    		 Chi-square
    Statistical analysis description
    Pairwise comparisons were performed only if the null global hypothesis of equal success proportions in the four treatment groups was rejected and in this case χ2 tests for contingency tables with an alpha level of 0.05 was performed for the following comparisons and according to the following comparison order: 1 Group 3 (RP101 0.1% + RP101 0.1%) vs. Group 4 (Placebo + Placebo); 2 Group 2 (RP101 0.1% + Placebo) vs. Group 4 (Placebo + Placebo); 3 Group 1 (RP101 0.05% + RP101 0.05%) vs. Group
    Comparison groups
    Treatment group 2 v Treatment group 3 v Treatment group 1 v Treatment group 4
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 ≤ 0.05
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [2] - No significant difference in success proportions between groups

    Secondary: Ocular tolerability foreign body sensation

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    End point title
    		 Ocular tolerability foreign body sensation
    End point description
    Assessed by the patients using a 0-100 mm visual analogue scale
    End point type
    Secondary
    End point timeframe
    3 months
    End point values
    		 Treatment group 1 Treatment group 2 Treatment group 3 Treatment group 4
    Number of subjects analysed
    15
    17
    8
    18
    Units: mm
        arithmetic mean (standard deviation)
    15.5 ± 14.9
    12.9 ± 19.2
    19.1 ± 16.6
    23.3 ± 23.0
    Statistical analysis title
    		 Wilcoxon rank
    Statistical analysis description
    Comparison of changes from baseline between groups and comparison at each assessment time-point versus baseline within group
    Comparison groups
    Treatment group 1 v Treatment group 2 v Treatment group 3 v Treatment group 4
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon Rank Test
    Confidence interval

    Secondary: Ocular tolerability - burning/stinging

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    End point title
    		 Ocular tolerability - burning/stinging
    End point description
    Assessed by the patients using a 0-100 mm visual analogue scale
    End point type
    Secondary
    End point timeframe
    3 months
    End point values
    		 Treatment group 1 Treatment group 2 Treatment group 3 Treatment group 4
    Number of subjects analysed
    15
    17
    8
    18
    Units: mm
        arithmetic mean (standard deviation)
    17.9 ± 15.8
    8.8 ± 14.7
    19.6 ± 17.0
    27.2 ± 26.9
    Statistical analysis title
    		 Wilcoxon rank
    Statistical analysis description
    Comparison of changes from baseline between groups and comparison at each assessment time-point versus baseline within group
    Comparison groups
    Treatment group 1 v Treatment group 2 v Treatment group 3 v Treatment group 4
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon Rank Test
    Confidence interval

    Secondary: Ocular tolerability - itching

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    End point title
    		 Ocular tolerability - itching
    End point description
    Assessed by the patients using a 0-100 mm visual analogue scale
    End point type
    Secondary
    End point timeframe
    3 months
    End point values
    		 Treatment group 1 Treatment group 2 Treatment group 3 Treatment group 4
    Number of subjects analysed
    15
    17
    8
    18
    Units: mm
        arithmetic mean (standard deviation)
    15.6 ± 12.8
    9.2 ± 9.4
    14.5 ± 13.9
    18.6 ± 18.0
    Statistical analysis title
    		 Wilcoxon rank
    Statistical analysis description
    Comparison of changes from baseline between groups and comparison at each assessment time-point versus baseline within group
    Comparison groups
    Treatment group 1 v Treatment group 2 v Treatment group 3 v Treatment group 4
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon Rank Test
    Confidence interval

    Secondary: Ocular tolerability - Pain

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    End point title
    		 Ocular tolerability - Pain
    End point description
    Assessed by the patients using a 0-100 mm visual analogue scale
    End point type
    Secondary
    End point timeframe
    3 months
    End point values
    		 Treatment group 1 Treatment group 2 Treatment group 3 Treatment group 4
    Number of subjects analysed
    15
    17
    8
    18
    Units: second
        arithmetic mean (standard deviation)
    9.9 ± 10.5
    4.8 ± 5.0
    14.3 ± 15.1
    13.8 ± 14.8
    Statistical analysis title
    		 Wilcoxon rank
    Statistical analysis description
    Comparison of changes from baseline between groups and comparison at each assessment time-point versus baseline within group
    Comparison groups
    Treatment group 1 v Treatment group 2 v Treatment group 3 v Treatment group 4
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon Rank Test
    Confidence interval

    Secondary: Ocular tolerability - sticky feeling

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    End point title
    		 Ocular tolerability - sticky feeling
    End point description
    Assessed by the patients using a 0-100 mm visual analogue scale
    End point type
    Secondary
    End point timeframe
    3 months
    End point values
    		 Treatment group 1 Treatment group 2 Treatment group 3 Treatment group 4
    Number of subjects analysed
    15
    17
    8
    18
    Units: millimetre(s)
        arithmetic mean (standard deviation)
    19.5 ± 22
    6.5 ± 6.1
    16.1 ± 20.4
    24.0 ± 21.4
    Statistical analysis title
    		 Wilcoxon rank
    Comparison groups
    Treatment group 1 v Treatment group 2 v Treatment group 3 v Treatment group 4
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon Rank Test
    Confidence interval

    Secondary: Ocular tolerability - blurred vision

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    End point title
    		 Ocular tolerability - blurred vision
    End point description
    Assessed by the patients using a 0-100 mm visual analogue scale
    End point type
    Secondary
    End point timeframe
    3 months
    End point values
    		 Treatment group 1 Treatment group 2 Treatment group 3 Treatment group 4
    Number of subjects analysed
    15
    17
    8
    18
    Units: millimetre(s)
        arithmetic mean (standard deviation)
    25.5 ± 23.4
    22.1 ± 22.3
    29.0 ± 20.3
    26.2 ± 22.9
    Statistical analysis title
    		 Wilcoxon rank
    Statistical analysis description
    Comparison of changes from baseline between groups and comparison at each assessment time-point versus baseline within group
    Comparison groups
    Treatment group 1 v Treatment group 2 v Treatment group 3 v Treatment group 4
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon Rank Test
    Confidence interval

    Secondary: Ocular tolerability - redness

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    End point title
    		 Ocular tolerability - redness
    End point description
    Assessed by the patients using a 0-100 mm visual analogue scale
    End point type
    Secondary
    End point timeframe
    3 months
    End point values
    		 Treatment group 1 Treatment group 2 Treatment group 3 Treatment group 4
    Number of subjects analysed
    20
    22
    13
    22
    Units: millimetre(s)
        arithmetic mean (standard deviation)
    20.7 ± 20.7
    9.6 ± 10.1
    13.8 ± 12.9
    16.0 ± 13.7
    Statistical analysis title
    		 Wilcoxon rank
    Statistical analysis description
    Comparison of changes from baseline between groups and comparison at each assessment time-point versus baseline within group
    Comparison groups
    Treatment group 1 v Treatment group 2 v Treatment group 3 v Treatment group 4
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon Rank Test
    Confidence interval

    Secondary: Ocular tolerability - tearing

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    End point title
    		 Ocular tolerability - tearing
    End point description
    Assessed by the patients using a 0-100 mm visual analogue scale
    End point type
    Secondary
    End point timeframe
    3 months
    End point values
    		 Treatment group 1 Treatment group 2 Treatment group 3 Treatment group 4
    Number of subjects analysed
    15
    17
    8
    18
    Units: millimetre(s)
        arithmetic mean (standard deviation)
    17.4 ± 13.7
    12.3 ± 11.7
    17.6 ± 16.9
    21.9 ± 23.8
    Statistical analysis title
    		 Wilcoxon rank
    Statistical analysis description
    Comparison of changes from baseline between groups and comparison at each assessment time-point versus baseline within group
    Comparison groups
    Treatment group 1 v Treatment group 2 v Treatment group 3 v Treatment group 4
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon Rank Test
    Confidence interval

    Secondary: Ocular tolerability - eyelid swelling

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    End point title
    		 Ocular tolerability - eyelid swelling
    End point description
    Assessed by the patients using a 0-100 mm visual analogue scale
    End point type
    Secondary
    End point timeframe
    3 months
    End point values
    		 Treatment group 1 Treatment group 2 Treatment group 3 Treatment group 4
    Number of subjects analysed
    15
    17
    8
    18
    Units: millimetre(s)
        arithmetic mean (standard deviation)
    11.8 ± 11.6
    7.1 ± 8.8
    11.4 ± 9.1
    15.6 ± 18.0
    No statistical analyses for this end point

    Secondary: Ocular tolerability - photophobia

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    End point title
    		 Ocular tolerability - photophobia
    End point description
    Assessed by the patients using a 0-100 mm visual analogue scale
    End point type
    Secondary
    End point timeframe
    3 months
    End point values
    		 Treatment group 1 Treatment group 2 Treatment group 3 Treatment group 4
    Number of subjects analysed
    15
    17
    8
    18
    Units: millimetre(s)
        arithmetic mean (standard deviation)
    16.7 ± 12.7
    15.5 ± 19.9
    19.1 ± 15.9
    29.8 ± 31.3
    Statistical analysis title
    		 Wilcoxon rank
    Statistical analysis description
    Comparison of changes from baseline between groups and comparison at each assessment time-point versus baseline within group
    Comparison groups
    Treatment group 1 v Treatment group 2 v Treatment group 3 v Treatment group 4
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon Rank Test
    Confidence interval

    Secondary: Symptom Assessment in Dry Eye - frequency

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    End point title
    		 Symptom Assessment in Dry Eye - frequency
    End point description
    Assessed by the patients using a 0-100 mm visual analogue scale
    End point type
    Secondary
    End point timeframe
    3 months
    End point values
    		 Treatment group 1 Treatment group 2 Treatment group 3 Treatment group 4
    Number of subjects analysed
    20
    22
    13
    22
    Units: millimetre(s)
        arithmetic mean (standard deviation)
    20.4 ± 13.0
    19.8 ± 18.1
    26.3 ± 23.1
    28.6 ± 15.4
    Statistical analysis title
    		 Wilcoxon rank
    Statistical analysis description
    11.1.3 Symptom Assessment in Dry Eye
    Comparison groups
    Treatment group 1 v Treatment group 2 v Treatment group 3 v Treatment group 4
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon Rank Test
    Confidence interval

    Secondary: Symptom Assessment in Dry Eye - severity

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    End point title
    		 Symptom Assessment in Dry Eye - severity
    End point description
    Assessed by the patients using a 0-100 mm visual analogue scale
    End point type
    Secondary
    End point timeframe
    3 months
    End point values
    		 Treatment group 1 Treatment group 2 Treatment group 3 Treatment group 4
    Number of subjects analysed
    20
    22
    13
    22
    Units: millimetre(s)
        arithmetic mean (standard deviation)
    22.9 ± 15.3
    20.0 ± 19.0
    23.8 ± 17.5
    29.2 ± 14.4
    Statistical analysis title
    		 Wilcoxon rank
    Statistical analysis description
    Comparison of changes from baseline between groups and comparison at each post-dose assessment time versus baseline
    Comparison groups
    Treatment group 1 v Treatment group 2 v Treatment group 3 v Treatment group 4
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon Rank Test
    Confidence interval

    Secondary: Tear film break up time (TFBUT)

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    End point title
    		 Tear film break up time (TFBUT)
    End point description
    TFBUT was measured after instillation of sodium fluorescein solution in the inferior conjunctival cul-de-sac of each eye. The patient was instructed to blink several times to thoroughly mix the fluorescein with the tear film. In order to achieve maximum fluorescence, the examiner waited approximately 30 sec after instillation before evaluating TFBUT. With the aid of a slit lamp, the examiner monitored the integrity of the tear film, noting the time to form lacunae (clear spaces in the tear film) from the time that the eye was open after the last blink. The TFBUT was measured twice during the first minute after fluorescein instillation. If the 2 readings differed by more than 2 sec a third reading was to be taken. The TFBUT value was the average of the 2 or 3 measurements
    End point type
    Secondary
    End point timeframe
    3 months
    End point values
    		 Treatment group 1 Treatment group 2 Treatment group 3 Treatment group 4
    Number of subjects analysed
    20
    22
    13
    22
    Units: second
        arithmetic mean (standard deviation)
    4.6 ± 1.0
    4.7 ± 3.0
    4.1 ± 0.9
    5.9 ± 5.7
    Statistical analysis title
    		 Wilcoxon rank
    Statistical analysis description
    Comparison of changes from baseline between groups and comparison at each post-dose assessment time versus baseline
    Comparison groups
    Treatment group 1 v Treatment group 2 v Treatment group 3 v Treatment group 4
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon Rank Test
    Confidence interval

    Secondary: Visual acuity

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    End point title
    		 Visual acuity
    End point description
    Visual acuity was measured using retroilluminated light box and ETDRS 4 meter distance acuity charts. If 20 or more letters were read at 4 metres, the visual acuity score was recorded as the number of letters correct at 4 metres plus 30. If no letters were correctly read at either 4 metres or 1 metre, then the visual acuity score was to be recorded as “0”.
    End point type
    Secondary
    End point timeframe
    3 months
    End point values
    		 Treatment group 1 Treatment group 2 Treatment group 3 Treatment group 4
    Number of subjects analysed
    20
    22
    13
    22
    Units: millimetre(s)
        arithmetic mean (standard deviation)
    82.4 ± 7.2
    74.9 ± 18.3
    82.0 ± 4.4
    81.8 ± 6.7
    Statistical analysis title
    		 Wilcoxon rank
    Statistical analysis description
    Comparison of changes from baseline between groups and comparison at each post-dose assessment time versus baseline
    Comparison groups
    Treatment group 1 v Treatment group 2 v Treatment group 3 v Treatment group 4
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon Rank Test
    Confidence interval

    Secondary: SLE - Eyelid - Meibomian Glands

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    End point title
    		 SLE - Eyelid - Meibomian Glands
    End point description
    The SLE was performed before the instillation of any dilating or anaesthetic eye drops or fluorescein agent. For the examination, the patient sat at the slit lamp. Grading of the eyelids, conjunctiva, cornea, lens and anterior chamber was done according to the following 0-3 score scale: Eyelid - Meibomian glands (evaluation of the central 10 Meibomian gland openings in the mid-portion of the upper eyelid) with 0 = None (none are plugged); 1 = Mild (1 to 2 glands are plugged); 2 = Moderate (3 to 4 glands are plugged); 3 = Severe (All glands are plugged).
    End point type
    Secondary
    End point timeframe
    3 months
    End point values
    		 Treatment group 1 Treatment group 2 Treatment group 3 Treatment group 4
    Number of subjects analysed
    20
    22
    13
    22
    Units: scores
        arithmetic mean (standard deviation)
    0 ± 0
    0 ± 0
    0 ± 0
    0.1 ± 0.3
    No statistical analyses for this end point

    Secondary: SLE - Eyelid - erythema

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    End point title
    		 SLE - Eyelid - erythema
    End point description
    The SLE was performed before the instillation of any dilating or anaesthetic eye drops or fluorescein agent. For the examination, the patient sat at the slit lamp. Grading of the eyelids, conjunctiva, cornea, lens and anterior chamber was done according to the following 0-4 score scale: Eyelid - Erythema, with 0 = None (normal); 1 = Mild (redness localised to a small region of the lid(s) margin OR skin); 2 = Moderate (redness of most or all lid margin OR skin); 3 = Severe (redness of most or all lid margin AND skin); 4 = Very severe (marked diffuse redness of both lid margin AND skin).
    End point type
    Secondary
    End point timeframe
    3 months
    End point values
    		 Treatment group 1 Treatment group 2 Treatment group 3 Treatment group 4
    Number of subjects analysed
    20
    22
    13
    22
    Units: scores
        arithmetic mean (standard deviation)
    0 ± 0
    0 ± 0
    0 ± 0
    0.2 ± 0.5
    No statistical analyses for this end point

    Secondary: SLE - Eyelid - Oedema

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    End point title
    		 SLE - Eyelid - Oedema
    End point description
    The SLE was performed before the instillation of any dilating or anaesthetic eye drops or fluorescein agent. For the examination, the patient sat at the slit lamp. Grading of the eyelids, conjunctiva, cornea, lens and anterior chamber was done according to the following 0-4 score scale: Eyelid - Oedema with 0 = None (normal); 1 = Mild (localised to a small region of the lid); 2 = Moderate (diffuse, most or all lid but not prominent/protruding); 3 = Severe (diffuse, most or all lid AND prominent/protruding); 4 = Very severe (diffuse AND prominent/protruding AND reversion of the lid).
    End point type
    Secondary
    End point timeframe
    3 months
    End point values
    		 Treatment group 1 Treatment group 2 Treatment group 3 Treatment group 4
    Number of subjects analysed
    20
    22
    13
    22
    Units: scores
        arithmetic mean (standard deviation)
    0.1 ± 0.2
    0 ± 0
    0 ± 0
    0.1 ± 0.3
    No statistical analyses for this end point

    Secondary: SLE - conjunctiva - erythema

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    End point title
    		 SLE - conjunctiva - erythema
    End point description
    The SLE was performed before the instillation of any dilating or anaesthetic eye drops or fluorescein agent. For the examination, the patient sat at the slit lamp. Grading of the eyelids, conjunctiva, cornea, lens and anterior chamber was done according to the following 0-3 score scale: Conjunctiva - Erythema with 0 = None (normal); 1 = Mild (a flush reddish colour predominantly confined to the palpebral or bulbar conjunctiva); 2 = Moderate (more prominent red colour of the palpebral or bulbar conjunctiva); 3 = Severe (definite redness of palpebral or bulbar conjunctiva).
    End point type
    Secondary
    End point timeframe
    3 months
    End point values
    		 Treatment group 1 Treatment group 2 Treatment group 3 Treatment group 4
    Number of subjects analysed
    20
    22
    13
    22
    Units: scores
        arithmetic mean (standard deviation)
    0.4 ± 0.6
    0.4 ± 0.5
    0.5 ± 0.7
    0.5 ± 0.7
    No statistical analyses for this end point

    Secondary: SLE - Conjunctiva - oedema

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    End point title
    		 SLE - Conjunctiva - oedema
    End point description
    The SLE was performed before the instillation of any dilating or anaesthetic eye drops or fluorescein agent. For the examination, the patient sat at the slit lamp. Grading of the eyelids, conjunctiva, cornea, lens and anterior chamber was done according to the following 0-4 score scale: Conjunctiva - Oedema with 0 = None (normal); 1 = Mild (slight localised swelling); 2 = Moderate (moderate/medium localised swelling or mild diffuse swelling); 3 = Severe (severe diffuse swelling); 4 = Very severe (very prominent/protruding diffuse swelling).
    End point type
    Secondary
    End point timeframe
    3 months
    End point values
    		 Treatment group 1 Treatment group 2 Treatment group 3 Treatment group 4
    Number of subjects analysed
    20
    22
    13
    22
    Units: scores
        arithmetic mean (standard deviation)
    0.1 ± 0.3
    0.2 ± 0.4
    0.1 ± 0.3
    0.2 ± 0.5
    No statistical analyses for this end point

    Secondary: SLE - Lens

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    End point title
    		 SLE - Lens
    End point description
    The SLE was performed before the instillation of any dilating or anaesthetic eye drops or fluorescein agent. For the examination, the patient sat at the slit lamp. Grading of the eyelids, conjunctiva, cornea, lens and anterior chamber was done according to the following 0-3 score scale: Lens with 0 = No opacification (normal lens); 1 = Mild lens opacification; 2 = Moderate lens opacification; 3 = Severe lens opacification; N/A = Patient with artificial lens
    End point type
    Secondary
    End point timeframe
    3 months
    End point values
    		 Treatment group 1 Treatment group 2 Treatment group 3 Treatment group 4
    Number of subjects analysed
    20
    22
    13
    22
    Units: scores
        arithmetic mean (standard deviation)
    0.1 ± 0.3
    0.3 ± 0.7
    0 ± 0
    0.2 ± 0.5
    No statistical analyses for this end point

    Secondary: SLE - Anterior Chamber Inflammation

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    End point title
    		 SLE - Anterior Chamber Inflammation
    End point description
    The SLE was performed before the instillation of any dilating or anaesthetic eye drops or fluorescein agent. For the examination, the patient sat at the slit lamp. Grading of the eyelids, conjunctiva, cornea, lens and anterior chamber was done according to the following 0-3 score scale: Anterior Chamber Inflammation (Slit beam = 0.3 mm wide, 1.0 mm long) with 0 = None (no Tyndall effect); 1 = Mild (Tyndall effect barely discernible); 2 = Moderate (Tyndall beam in the anterior chamber is moderately intense); 3 = Severe (Tyndall beam in the anterior chamber is severely intense).
    End point type
    Secondary
    End point timeframe
    3 months
    End point values
    		 Treatment group 1 Treatment group 2 Treatment group 3 Treatment group 4
    Number of subjects analysed
    20
    22
    13
    22
    Units: scores
        arithmetic mean (standard deviation)
    0.0 ± 0.0
    0.0 ± 0.0
    0.0 ± 0.0
    0.0 ± 0.0
    No statistical analyses for this end point

    Secondary: Corneal fluorescein staining

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    End point title
    		 Corneal fluorescein staining
    End point description
    Corneal fluorescein staining was graded using the Oxford scheme to evaluate cornea and conjunctiva epithelium damage. The examination was performed after instillation of sodium fluorescein in the inferior conjunctival cul-de-sac of each eye with the aid of a slit lamp. As grading scale of the corneal damage, the NEI/Industry Workshop guideline was used. The cornea was divided into five sectors (central, superior, inferior, nasal and temporal), each of which was scored on a scale of 0–3, with a maximal global score of 15 (total score, here reported).
    End point type
    Secondary
    End point timeframe
    3 months
    End point values
    		 Treatment group 1 Treatment group 2 Treatment group 3 Treatment group 4
    Number of subjects analysed
    20
    22
    13
    22
    Units: Total score
        arithmetic mean (standard deviation)
    2.9 ± 1.7
    3.3 ± 2.0
    3.4 ± 1.9
    2.8 ± 1.9
    Statistical analysis title
    		 Wilcoxon rank
    Statistical analysis description
    Comparison of changes from baseline between groups and comparison at each post-dose assessment time versus baseline within groups
    Comparison groups
    Treatment group 1 v Treatment group 2 v Treatment group 3 v Treatment group 4
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon Rank Test
    Confidence interval

    Secondary: Fundus ophthalmoscopy - Vitreous

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    End point title
    		 Fundus ophthalmoscopy - Vitreous
    End point description
    The fundus examination included ophthalmoscopic assessments of vitreous, macula, retina and optic nerve head. Vitreous examination results were scored according to the following grading criteria: Vitreous: The examiner judged the appearance of the vitreous in the visual axis as Normal (score 0): Absence of any opacity or Abnormal (score 1): Presence of opacity in the vitreous.
    End point type
    Secondary
    End point timeframe
    3 months
    End point values
    		 Treatment group 1 Treatment group 2 Treatment group 3 Treatment group 4
    Number of subjects analysed
    20
    22
    13
    22
    Units: scores
        arithmetic mean (standard deviation)
    0 ± 0
    0 ± 0.2
    0 ± 0
    0 ± 0
    No statistical analyses for this end point

    Secondary: Fundus ophthalmoscopy - Macula, retina, optic nerve head

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    End point title
    		 Fundus ophthalmoscopy - Macula, retina, optic nerve head
    End point description
    The fundus examination included ophthalmoscopic assessments of vitreous, macula, retina and optic nerve head. Macula, retina and optic nerve head examination results were scored according to the following grading criteria: Macula, (Peripheral) Retina and Optic Nerve Head: The examiner provided a separate assessment of the macular, choroid and peripheral retina as Normal (score 0): Absence of any structural or vascular change, inflammation, oedema or haemorrhage or Abnormal (score 1): Evidence of any ongoing or previous structural or vascular change, inflammation, oedema or haemorrhage.
    End point type
    Secondary
    End point timeframe
    3 months
    End point values
    		 Treatment group 1 Treatment group 2 Treatment group 3 Treatment group 4
    Number of subjects analysed
    20
    22
    13
    22
    Units: scores
        arithmetic mean (standard deviation)
    0.3 ± 0.5
    0.5 ± 0.5
    0.5 ± 0.5
    0.5 ± 0.5
    No statistical analyses for this end point

    Other pre-specified: Corneal pachimetry

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    End point title
    		 Corneal pachimetry
    End point description
    Sub-study on 36 of the enrolled patients
    End point type
    Other pre-specified
    End point timeframe
    3 months
    End point values
    		 Treatment group 1 Treatment group 2 Treatment group 3 Treatment group 4
    Number of subjects analysed
    6
    5
    2
    8
    Units: micrometre(s)
        arithmetic mean (standard deviation)
    563 ± 35.6
    574.8 ± 17.4
    597 ± 22.6
    560.1 ± 25.5
    No statistical analyses for this end point

    Other pre-specified: Serum estradiol concentrations

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    End point title
    		 Serum estradiol concentrations
    End point description
    Blood samples for estardiol concentrations measurements were collected at baseline and at day 90 (study end). Serum samples were prepared and the concentration of estradiol in serum was determined at a specified analytical laboratory, using a fully validated LC-MS/MS method, with a lower quantification limit (LQL) of 5.00 pg/mL.
    End point type
    Other pre-specified
    End point timeframe
    3 months
    End point values
    		 Treatment group 1 Treatment group 2 Treatment group 3 Treatment group 4
    Number of subjects analysed
    14
    14
    8
    12
    Units: picograms/milliliters
        arithmetic mean (standard deviation)
    14.53 ± 14.77
    27.12 ± 22.40
    33.92 ± 15.95
    0 ± 5.7
    No statistical analyses for this end point

    Other pre-specified: Intraocular pressure

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    End point title
    		 Intraocular pressure
    End point description
    Safety endpoint IOP was measured as a safety variable using an applanation tonometry after the instillation of a topical anaesthetic. IOP was measured after completion of all other examinations to avoid potential interference . The patient’s head was firmly positioned on the chin rest and against the forehead rest without leaning forward or straining.
    End point type
    Other pre-specified
    End point timeframe
    3 months
    End point values
    		 Treatment group 1 Treatment group 2 Treatment group 3 Treatment group 4
    Number of subjects analysed
    20
    22
    13
    22
    Units: mmHg
        arithmetic mean (standard deviation)
    15.75 ± 1.65
    14.82 ± 1.71
    15.77 ± 1.36
    15.05 ± 1.70
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the signature of the informed consent until the last follow-up
    Adverse event reporting additional description
    Adverse events (AEs) were coded by System Organ Class (SOC) and Preferred Term (PT), using the MedDRA 22.1. AEs were classified as pre-treatment AEs (PTAEs) and treatment-emergent AEs (TEAEs), according to the period of occurrence.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Group 1
    Reporting group description
    		 Group 1: RP101 0.05% + RP101 0.05%

    Reporting group title
    Group 2
    Reporting group description
    		 Group 2: RP101 0.1% + Placebo

    Reporting group title
    Group 3
    Reporting group description
    		 Group 3: RP101 0.1% + RP101 0.1%

    Reporting group title
    Group 4
    Reporting group description
    		 Group 4: Placebo + Placebo

    Serious adverse events
    		 Group 1 Group 2 Group 3 Group 4
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Group 1 Group 2 Group 3 Group 4
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 27 (70.37%)
    18 / 25 (72.00%)
    18 / 26 (69.23%)
    16 / 26 (61.54%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    0
    0
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 27 (3.70%)
    2 / 25 (8.00%)
    3 / 26 (11.54%)
    1 / 26 (3.85%)
         occurrences all number
    1
    5
    5
    1
    Eye disorders
    Vision blurred
         subjects affected / exposed
    14 / 27 (51.85%)
    13 / 25 (52.00%)
    11 / 26 (42.31%)
    9 / 26 (34.62%)
         occurrences all number
    23
    26
    18
    12
    Eye pain
         subjects affected / exposed
    10 / 27 (37.04%)
    9 / 25 (36.00%)
    6 / 26 (23.08%)
    4 / 26 (15.38%)
         occurrences all number
    14
    17
    8
    6
    Eye irritation
         subjects affected / exposed
    4 / 27 (14.81%)
    4 / 25 (16.00%)
    4 / 26 (15.38%)
    5 / 26 (19.23%)
         occurrences all number
    5
    8
    4
    5
    Ocular hyperaemia
         subjects affected / exposed
    7 / 27 (25.93%)
    4 / 25 (16.00%)
    3 / 26 (11.54%)
    2 / 26 (7.69%)
         occurrences all number
    8
    7
    4
    6
    Swelling of eyelid
         subjects affected / exposed
    2 / 27 (7.41%)
    2 / 25 (8.00%)
    2 / 26 (7.69%)
    3 / 26 (11.54%)
         occurrences all number
    4
    2
    2
    3
    Foreign body sensation in eyes
         subjects affected / exposed
    1 / 27 (3.70%)
    2 / 25 (8.00%)
    3 / 26 (11.54%)
    1 / 26 (3.85%)
         occurrences all number
    1
    4
    4
    1
    Photophobia
         subjects affected / exposed
    2 / 27 (7.41%)
    2 / 25 (8.00%)
    1 / 26 (3.85%)
    2 / 26 (7.69%)
         occurrences all number
    2
    5
    1
    3
    Eye pruritus
         subjects affected / exposed
    1 / 27 (3.70%)
    2 / 25 (8.00%)
    1 / 26 (3.85%)
    2 / 26 (7.69%)
         occurrences all number
    1
    2
    1
    3
    Lacrimation increased
         subjects affected / exposed
    0 / 27 (0.00%)
    3 / 25 (12.00%)
    2 / 26 (7.69%)
    1 / 26 (3.85%)
         occurrences all number
    0
    3
    3
    3
    Abnormal sensation in eye
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 25 (0.00%)
    1 / 26 (3.85%)
    3 / 26 (11.54%)
         occurrences all number
    0
    0
    1
    3
    Eye oedema
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Eye swelling
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 25 (4.00%)
    2 / 26 (7.69%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 25 (0.00%)
    2 / 26 (7.69%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    3
    1

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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