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    Clinical Trial Results:
    Efficacy of oral alitretinoin treatment in patients with palmo-plantar pustulosis (PPP) inadequately responding to standard topical treatment

    Summary
    EudraCT number
    		 2010-022843-39
    Trial protocol
    		 DE   GB   NL  
    Global end of trial date
    16 Apr 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Apr 2016
    First version publication date
    18 Dec 2014
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ATN117221
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01245140
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    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
    16 Apr 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Apr 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Determine the response, based on the palmo-plantar pustulosis psoriasis area and severity index (PPPASI) at the end of treatment (week 24).
    Protection of trial subjects
    Not applicable.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Apr 2011
    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
    Netherlands: 3
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Germany: 20
    Worldwide total number of subjects
    33
    EEA total number of subjects
    33
    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)
    28
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The total study duration was 33 weeks, with a Screening Period of up to 4 weeks, followed by 24 weeks of treatment and a 5-week safety Follow-up Period. Participants who met eligibility criteria were randomized (2:1) to receive 30 milligrams (mg) alitretinoin or matching placebo, given orally as gelatin capsules, once daily (QD) for up to 24 weeks.

    Period 1
    Period 1 title
    Overall Study (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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Matching placebo
    Arm description
    		 Participants received matching placebo orally QD for up to 24 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    daily dosing Formulation: CAPSULE CONTENT - Soya-bean oil (refined), partially hydrogenated soya-bean oil, triglycerides (medium chain), beeswax (yellow), all-rac-α-tocopherol CAPSULE SHELL – gelatin, glycerol, sorbitol (liquid [non-crystallising]), water (purified), iron oxide (E 172)

    Arm title
    		 Alitretinoin 30 mg
    Arm description
    		 Participants received an alitretinoin 30 milligram (mg) capsule orally QD for up to 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alitretinoin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    30 milligrams (mg), daily dosing Formulation: CAPSULE CONTENT - Soya-bean oil (refined), partially hydrogenated soya-bean oil, triglycerides (medium chain), beeswax (yellow), all-rac-α-tocopherol CAPSULE SHELL – gelatin, glycerol, sorbitol (liquid [non-crystallising]), water (purified), iron oxide (E 172)

    Number of subjects in period 1
    		Matching placebo Alitretinoin 30 mg
    Started
    9
    24
    Completed
    6
    14
    Not completed
    3
    10
         'Refused Treatment/Did Not Cooperate '
    -
    1
         Adverse event, non-fatal
    1
    3
         Withdrawal by Subject
    -
    1
         Lack of efficacy
    2
    4
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Matching placebo
    Reporting group description
    		 Participants received matching placebo orally QD for up to 24 weeks.

    Reporting group title
    Alitretinoin 30 mg
    Reporting group description
    		 Participants received an alitretinoin 30 milligram (mg) capsule orally QD for up to 24 weeks.

    Reporting group values
    		 Matching placebo Alitretinoin 30 mg Total
    Number of subjects
    		 9 24 33
    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)
    		 49 ( 16.32 ) 48.83 ( 14.94 ) -
    Gender categorical
    Units: Subjects
        Female
    		 5 14 19
        Male
    		 4 10 14
    Race, Customized
    Units: Subjects
        Caucasian/White
    		 8 22 30
        Oriental
    		 1 0 1
        Black
    		 0 1 1
        North African
    		 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Matching placebo
    Reporting group description
    		 Participants received matching placebo orally QD for up to 24 weeks.

    Reporting group title
    Alitretinoin 30 mg
    Reporting group description
    		 Participants received an alitretinoin 30 milligram (mg) capsule orally QD for up to 24 weeks.

    Primary: Change from Baseline in the palmo-plantar pustulosis psoriasis area and severity index (PPPASI) score at the end of treatment (EOT) (Week 24) or at the last assessment

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    End point title
    		 Change from Baseline in the palmo-plantar pustulosis psoriasis area and severity index (PPPASI) score at the end of treatment (EOT) (Week 24) or at the last assessment
    End point description
    The investigator evaluated the PPPASI score on a 5-point scale. The parameters of erythema, total number of pustules, and desquamation were scored for the right/left palm and the right/left sole. After correcting the scores for area (based on a 7-point scale) and the site involved (palm or sole), the PPPASI score per palm/sole was produced. The final PPPASI score was calculated as the sum of the PPPASI score for the right sole + the PPPASI score for the left sole + the PPPASI score for the right palm + the PPPASI score for the left palm and ranges from 0 (no palmo-plantar pustulosis psoriasis [PPP]) to 72 (most severe PPP). Change from Baseline is defined as value at the EOT minus the Baseline value.
    End point type
    Primary
    End point timeframe
    Baseline and EOT (Week 24) or the last assessment
    End point values
    		 Matching placebo Alitretinoin 30 mg
    Number of subjects analysed
    9 [1]
    22 [2]
    Units: scores on a scale
        arithmetic mean (standard deviation)
    -44.6 ( 45.9 )
    -45.2 ( 32.8 )
    Notes
    [1] - Full Analysis Set: treated participants with >=1 efficacy result after receiving study medication
    [2] - Full Analysis Set: treated participants with >=1 efficacy result after receiving study medication
    Statistical analysis title
    		 Statistical Analysis for Primary Endpoint #1
    Comparison groups
    Matching placebo v Alitretinoin 30 mg
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9705
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.5731
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -30.9738
         upper limit
    		 32.12

    Primary: Number of participants with PPPASI 50 response and PPPASI 75 response

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    End point title
    		 Number of participants with PPPASI 50 response and PPPASI 75 response
    End point description
    The investigator evaluated the PPPASI score on a 5-point scale. The parameters of erythema, total number of pustules, and desquamation were scored for the right/left palm and the right/left sole. After correcting the scores for area (based on a 7-point scale) and the site involved (palm or sole), the PPPASI score per palm/sole was produced. The final PPPASI score was calculated as the sum of the PPPASI score for the right sole + the PPPASI score for the left sole + the PPPASI score for the right palm + the PPPASI score for the left palm and ranges from 0 (no palmo-plantar pustulosis psoriasis [PPP]) to 72 (most severe PPP). Change from Baseline is defined as value at the EOT minus the Baseline value. PPPASI 50 response and PPPASI 75 response are defined as a 50% and 75% decrease, respectively, in the PPPASI score from Baseline.
    End point type
    Primary
    End point timeframe
    From Baseline until EOT (Week 24) or the last assessment
    End point values
    		 Matching placebo Alitretinoin 30 mg
    Number of subjects analysed
    9 [3]
    22 [4]
    Units: participants
        PPPASI 50 response
    6
    11
        PPPASI 75 response
    3
    5
    Notes
    [3] - Full Analysis Set
    [4] - Full Analysis Set
    Statistical analysis title
    		 PPPASI 50 response
    Comparison groups
    Matching placebo v Alitretinoin 30 mg
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4564
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 PPPASI 75 response
    Comparison groups
    Matching placebo v Alitretinoin 30 mg
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6595
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Total pustule count at Baseline; Weeks 4, 8, 12, 16, and 20; and at EOT (Week 24)

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    End point title
    		 Total pustule count at Baseline; Weeks 4, 8, 12, 16, and 20; and at EOT (Week 24)
    End point description
    The overall number of fresh and older pustules on the left and right palms and soles was assessed at Baseline, at each visit during the treatment period (Weeks 4, 8, 12, 16, and 20), and at the EOT visit. The total pustule count was calculated as the sum of the pustule count for the left/right palm and left/right sole.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 4, 8, 12, 16, and 20; and EOT (Week 24)
    End point values
    		 Matching placebo Alitretinoin 30 mg
    Number of subjects analysed
    9 [5]
    22 [6]
    Units: Pustule count
    arithmetic mean (standard deviation)
        Baseline, n=9, 22
    82.7 ( 59.1 )
    106 ( 128.2 )
        Week 4, n=9, 20
    71.6 ( 66.5 )
    31 ( 43.5 )
        Week 8, n=7, 20
    69.7 ( 30.8 )
    30.4 ( 38.6 )
        Week 12, n=7, 17
    70.4 ( 63.2 )
    21.5 ( 37.8 )
        Week 16, n=6, 16
    26.8 ( 25.5 )
    26 ( 42 )
        Week 20, n=6, 14
    35.8 ( 37.7 )
    30.5 ( 51.2 )
        End of Treatment, n=8, 20
    55.4 ( 104.5 )
    33.6 ( 49.6 )
    Notes
    [5] - Full Analysis Set. Only participants available at the specified time points were analyzed (n=X, X).
    [6] - Full Analysis Set. Only participants available at the specified time points were analyzed (n=X, X).
    No statistical analyses for this end point

    Secondary: Absolute change from Baseline (BL) in total pustule count at Weeks 4, 8, 12, 16, and 20 and at EOT (Week 24)

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    End point title
    		 Absolute change from Baseline (BL) in total pustule count at Weeks 4, 8, 12, 16, and 20 and at EOT (Week 24)
    End point description
    The overall number of fresh and older pustules on the left and right palms and soles was assessed at Baseline, at each visit during the treatment period (Weeks 4, 8, 12, 16, and 20), and at the End of Treatment visit. The total pustule count was calculated as the sum of the pustule count for the left/right palm and left/right sole. Change from Baseline is defined as the value at the post-Baseline visit minus the Baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 4, 8, 12, 16, and 20; and EOT (Week 24)
    End point values
    		 Matching placebo Alitretinoin 30 mg
    Number of subjects analysed
    9 [7]
    22 [8]
    Units: Pustule count
    arithmetic mean (standard deviation)
        Week 4, n=9, 20
    -11.1 ( 58.4 )
    -75.3 ( 113.2 )
        Week 8, n=7, 20
    -7.9 ( 51.5 )
    -75.9 ( 124.4 )
        Week 12, n=7, 17
    -7.1 ( 75.5 )
    -74.2 ( 111.7 )
        Week 16, n=6, 16
    -55.2 ( 56.5 )
    -75.6 ( 113 )
        Week 20, n=6, 14
    -46.2 ( 37.8 )
    -65.1 ( 106.4 )
        End of Treatment, n=8, 20
    -31.3 ( 79.4 )
    -82.1 ( 121.3 )
    Notes
    [7] - Full Analysis Set. Only participants available at the specified time points were analyzed (n=X, X).
    [8] - Full Analysis Set. Only participants available at the specified time points were analyzed (n=X, X).
    Statistical analysis title
    		 Change in Total Pustule Count: BL to Last Visit
    Comparison groups
    Matching placebo v Alitretinoin 30 mg
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.51
    Method
    		 Wilcoxon test: Exact Test
    Confidence interval

    Secondary: Summary of the Modified Psoriasis Area Severity Index (mPASI) score at Baseline; Weeks 4, 8, 12, 16, and 20; and EOT (Week 24)

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    End point title
    		 Summary of the Modified Psoriasis Area Severity Index (mPASI) score at Baseline; Weeks 4, 8, 12, 16, and 20; and EOT (Week 24)
    End point description
    Psoriatic plaques were graded based on three criteria: redness (R), thickness (T), and scaliness (S). Severity was rated for each criterion on a 5-point scale (0=no involvement, up to 4=severe involvement). The fraction of the total surface area affected on the head, upper extremities, trunk, and lower extremities was graded on a 7-point scale (0=no involvement, up to 6=greater than 90% involvement). The four body regions were weighted to reflect their respective proportion of body surface area, and the composite mPASI score for all body regions was calculated based on the redness, thickness, and scaliness scores of plaques (0-4 each) for the head, upper extremities, trunk, and lower extremities and the area of psoriatic involvement score (0-6). The highest possible mPASI score is 72; the lowest is 0. mPASI scores were continuous, with 0.1 increments within these values.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 4, 8, 12, 16, and 20; and EOT (Week 24)
    End point values
    		 Matching placebo Alitretinoin 30 mg
    Number of subjects analysed
    9 [9]
    22 [10]
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Baseline, n=9, 21
    0.2 ( 0.4 )
    0.5 ( 0.9 )
        Week 4, n=9, 20
    0.3 ( 0.6 )
    0.4 ( 0.9 )
        Week 8, n=7, 20
    0 ( 0.1 )
    0.4 ( 0.9 )
        Week 12, n=7, 17
    0 ( 0.1 )
    0.4 ( 0.9 )
        Week 16, n=6, 16
    0 ( 0 )
    0.2 ( 0.5 )
        Week 20, n=6, 14
    0 ( 0.1 )
    0.1 ( 0.3 )
        End of Treatment, n=8, 20
    0.7 ( 1.9 )
    0.3 ( 0.7 )
    Notes
    [9] - Full Analysis Set. Only participants available at the specified time points were analyzed (n=X, X).
    [10] - Full Analysis Set. Only participants available at the specified time points were analyzed (n=X, X).
    Statistical analysis title
    		 Relative change in mPASI score: BL to Last Visit
    Comparison groups
    Matching placebo v Alitretinoin 30 mg
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.12
    Method
    		 Wilcoxon test: Exact Test
    Confidence interval

    Secondary: Change from Baseline in the mPASI score at EOT (Week 24) or at the last assessment

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    End point title
    		 Change from Baseline in the mPASI score at EOT (Week 24) or at the last assessment
    End point description
    Psoriatic plaques were graded based on three criteria: redness (R), thickness (T), and scaliness (S). Severity was rated for each criterion on a 5-point scale (0=no involvement, up to 4=severe involvement). The fraction of the total surface area affected on the head, upper extremities, trunk, and lower extremities was graded on a 7-point scale (0=no involvement, up to 6=greater than 90% involvement). The four body regions were weighted to reflect their respective proportion of body surface area, and the composite mPASI score for all body regions was calculated based on the redness, thickness, and scaliness scores of plaques (0-4 each) for the head, upper extremities, trunk, and lower extremities and the area of psoriatic involvement score (0-6). The highest possible mPASI score is 72; the lowest is 0. mPASI scores were continuous, with 0.1 increments within these values. Change from Baseline is defined as the value at EOT minus the Baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline and EOT (Week 24) or the last assessment
    End point values
    		 Matching placebo Alitretinoin 30 mg
    Number of subjects analysed
    9 [11]
    22 [12]
    Units: scores on a scale
        arithmetic mean (standard deviation)
    -95.8 ( 7.2 )
    -51 ( 38.3 )
    Notes
    [11] - Full Analysis Set
    [12] - Full Analysis Set
    Statistical analysis title
    		 Secondary Endpoint
    Comparison groups
    Matching placebo v Alitretinoin 30 mg
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2358
    Method
    		 ANCOVA
    Parameter type
    		 Least squared estimation
    Point estimate
    49.4927
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -49.083
         upper limit
    		 148.07

    Secondary: Number of participants with mPASI 50 response and mPASI 75 response

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    End point title
    		 Number of participants with mPASI 50 response and mPASI 75 response
    End point description
    Psoriatic plaques were graded based on three criteria: redness (R), thickness (T), and scaliness (S). Severity was rated for each criterion on a 5-point scale (0=no involvement, up to 4=severe involvement). The fraction of the total surface area affected on the head, upper extremities, trunk, and lower extremities was graded on a 7-point scale (0=no involvement, up to 6=greater than 90% involvement). The four body regions were weighted to reflect their respective proportion of body surface area, and the composite mPASI score for all body regions was calculated. mPASI 50 response and mPASI 75 response is defined as a 50% and 75% decrease, respectively, in the mPASI score from Baseline. FAS=Full Analysis Set.
    End point type
    Secondary
    End point timeframe
    From Baseline until EOT (Week 24)
    End point values
    		 Matching placebo Alitretinoin 30 mg
    Number of subjects analysed
    3 [13]
    6 [14]
    Units: participants
        mPASI 50 response
    3
    2
        mPASI 75 response
    3
    2
    Notes
    [13] - FAS. Participants with lesions in areas of the body other than the hands and feet were assessed.
    [14] - FAS. Participants with lesions in areas of the body other than the hands and feet were assessed.
    Statistical analysis title
    		 mPASI 50 response
    Comparison groups
    Matching placebo v Alitretinoin 30 mg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1667
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 mPASI 75 response
    Comparison groups
    Matching placebo v Alitretinoin 30 mg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1667
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Summary of the Nail Psoriasis Severity Index (NAPSI) score at Baseline, Week 12, and EOT (Week 24)

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    End point title
    		 Summary of the Nail Psoriasis Severity Index (NAPSI) score at Baseline, Week 12, and EOT (Week 24)
    End point description
    The severity of nail lesions was assessed for all participants with psoriatic nail involvement by obtaining the NAPSI score at Baseline, at Week 12, and at the EOT visit. Scores were taken for fingernails only. No scores were taken for participants with traumatic or fungal changes in nails. The nail was divided into quadrants, each of which was rated with a 0 or 1, based on the absence (0) or presence (1) of pathological signs resulting from involvement of both the nail matrix and the nail bed. Each nail was given a score for nail bed psoriasis (0-4) and nail matrix psoriasis (0-4) depending on the presence of nail psoriasis in that quadrant. Possible scores for matrix and nail bed psoriasis: 0=none, 1=present in 1/4 nail, 2=present in 2/4 nail, 3=present in 3/4 nail, 4=present in 4/4 nail. The NAPSI score ranges from 0 to 8 for one nail and from 0 to 80 for 10 nails.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, and EOT (Week 24)
    End point values
    		 Matching placebo Alitretinoin 30 mg
    Number of subjects analysed
    9 [15]
    22 [16]
    Units: scores on a scale
    arithmetic mean (standard deviation)
        NAPSI-bed, Baseline, n=9, 20
    1.1 ( 2.3 )
    1.2 ( 1.9 )
        NAPSI-bed, Week 12, n=7, 17
    0.4 ( 1.1 )
    1.3 ( 3.3 )
        NAPSI-bed, End of Treatment, n=8, 19
    1.6 ( 2.8 )
    0.9 ( 2 )
        NAPSI-matrix, Baseline, n=9, 20
    3.9 ( 6.2 )
    3.6 ( 6.2 )
        NAPSI-matrix, Week 12, n=7, 17
    2.1 ( 3.7 )
    2.6 ( 6 )
        NAPSI-matrix, End of Treatment, n=8, 19
    4.3 ( 6 )
    2.6 ( 6 )
    Notes
    [15] - Full Analysis Set. Only participants available at the specified time points were analyzed (n=X, X).
    [16] - Full Analysis Set. Only participants available at the specified time points were analyzed (n=X, X).
    No statistical analyses for this end point

    Secondary: Absolute change from Baseline in the NAPSI score at Week 12 and EOT (Week 24)

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    End point title
    		 Absolute change from Baseline in the NAPSI score at Week 12 and EOT (Week 24)
    End point description
    The severity of nail lesions was assessed for all participants with psoriatic nail involvement by obtaining the NAPSI score at Baseline, at Week 12, and at the EOT visit. Scores were taken for fingernails only. No scores were taken for participants with traumatic or fungal changes in nails. The nail was divided into quadrants, each of which was rated with a 0 or 1, based on the absence (0) or presence (1) of pathological signs resulting from involvement of both the nail matrix and the nail bed. Each nail was given a score for nail bed psoriasis (0-4) and nail matrix psoriasis (0-4) depending on the presence of nail psoriasis in that quadrant. Possible scores for matrix and nail bed psoriasis: 0=none, 1=present in 1/4 nail, 2=present in 2/4 nail, 3=present in 3/4 nail, 4=present in 4/4 nail. The NAPSI score ranges from 0 to 8 for one nail and from 0 to 80 for 10 nails. Change from Baseline is defined as the value at the post-Baseline visit minus the Baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, and EOT (Week 24)
    End point values
    		 Matching placebo Alitretinoin 30 mg
    Number of subjects analysed
    9 [17]
    22 [18]
    Units: scores on a scale
    arithmetic mean (standard deviation)
        NAPSI-bed, Week 12, n=7, 17
    -0.4 ( 1.1 )
    0.3 ( 2.4 )
        NAPSI-bed, End of Treatment, n=8, 18
    0.4 ( 2.2 )
    -0.3 ( 1.6 )
        NAPSI-matrix, Week 12, n=7, 17
    -1.4 ( 3.8 )
    -0.5 ( 2 )
        NAPSI-matrix, End of Treatment, n=8, 18
    0.8 ( 5.5 )
    -0.1 ( 5 )
    Notes
    [17] - Full Analysis Set. Only participants available at the specified time points were analyzed (n=X, X).
    [18] - Full Analysis Set. Only participants available at the specified time points were analyzed (n=X, X).
    No statistical analyses for this end point

    Secondary: Number of participants with any AE or SAE and an AE/SAE related to study treatment

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    End point title
    		 Number of participants with any AE or SAE and an AE/SAE related to study treatment
    End point description
    An AE was any adverse change from the participant’s Baseline (pre-treatment) clinical condition, including intercurrent illness, which occured during the course of a clinical study after written informed consent had been given, whether considered related to treatment or not. The relationship of AEs to the study treatment was assessed as unrelated, remotely related, possibly related, and probably related. For an AE to be considered serious, it fell into one or more of the following categories: results in death, is life threatening, results in persistent or significant disability/incapacity, results in or prolongs inpatient hospitalization, and is a congenital abnormality or birth defect.
    End point type
    Secondary
    End point timeframe
    From Baseline until safety follow up (Week 29)
    End point values
    		 Matching placebo Alitretinoin 30 mg
    Number of subjects analysed
    9 [19]
    24 [20]
    Units: participants
        Any AE
    8
    18
        Any AE remotely related to study medication
    6
    15
        Any SAE
    0
    1
        Any SAE remotely related to study medication
    0
    1
    Notes
    [19] - Safety Population: all randomized participants who received at least one dose of study medication
    [20] - Safety Population: all randomized participants who received at least one dose of study medication
    No statistical analyses for this end point

    Secondary: Absolute change from Baseline in fasted lipid laboratory test values at Weeks 4, 8, 12, 16, and 20; EOT (Week 24); and at safety follow-up (Week 29)

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    End point title
    		 Absolute change from Baseline in fasted lipid laboratory test values at Weeks 4, 8, 12, 16, and 20; EOT (Week 24); and at safety follow-up (Week 29)
    End point description
    Fasted lipid laboratory parameters included triglycerides, total cholesterol, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. Change from Baseline is defined as the value at the post-Baseline visit minus the Baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 4, 8, 12, 16, and 20; EOT (Week 24); and safety follow-up (Week 29)
    End point values
    		 Matching placebo Alitretinoin 30 mg
    Number of subjects analysed
    9 [21]
    24 [22]
    Units: Millimoles per liter (mmol/L)
    arithmetic mean (standard deviation)
        Triglycerides, Week 4, n=9, 19
    0.6 ( 2.3 )
    2.4 ( 3.7 )
        Triglycerides, Week 8, n=7, 20
    1 ( 1.9 )
    3.8 ( 5.7 )
        Triglycerides, Week 12, n=6, 17
    2.5 ( 3.6 )
    5.8 ( 8.7 )
        Triglycerides, Week 16, n=5, 16
    2.6 ( 1.7 )
    4.2 ( 5.2 )
        Triglycerides, Week 20, n=6, 14
    2.6 ( 4.1 )
    5.6 ( 6.2 )
        Triglycerides, End of Treatment, n=7, 20
    -0.7 ( 2.5 )
    3.3 ( 5.6 )
        Triglycerides, safety follow-up, n=9, 21
    1.2 ( 3.4 )
    2.8 ( 5.8 )
        Total cholesterol, Week 4, n=9, 19
    0 ( 0.5 )
    0.6 ( 0.6 )
        Total cholesterol, Week 8, n=7, 20
    -0.2 ( 0.5 )
    0.7 ( 0.8 )
        Total cholesterol, Week 12, n=6, 17
    0.1 ( 0.3 )
    0.7 ( 0.9 )
        Total cholesterol, Week 16, n=5, 16
    0.1 ( 0.5 )
    0.6 ( 0.8 )
        Total cholesterol, Week 20, n=6, 14
    0.1 ( 0.8 )
    0.7 ( 1.1 )
        Total cholesterol, End of Treatment, n=8, 20
    -0.1 ( 0.5 )
    0.7 ( 0.7 )
        Total cholesterol, safety follow-up, n=9, 22
    0 ( 0.5 )
    0.3 ( 0.8 )
        HDL cholesterol, Week 4, n=8, 19
    -0.1 ( 0.2 )
    -0.1 ( 0.1 )
        HDL cholesterol, Week 8, n=7, 20
    -0.1 ( 0.2 )
    -0.2 ( 0.2 )
        HDL cholesterol, Week 12, n=6, 17
    0 ( 0.2 )
    -0.2 ( 0.2 )
        HDL cholesterol, Week 16, n=5, 16
    -0.1 ( 0.1 )
    -0.2 ( 0.2 )
        HDL cholesterol, Week 20, n=6, 14
    0 ( 0.2 )
    -0.2 ( 0.2 )
        HDL cholesterol, End of Treatment, n=7, 20
    -0.1 ( 0.2 )
    -0.1 ( 0.2 )
        HDL cholesterol, safety follow-up, n=9, 22
    -0.1 ( 0.2 )
    0 ( 0.2 )
        LDL cholesterol, Week 4, n=8, 19
    0.2 ( 0.3 )
    0.6 ( 0.5 )
        LDL cholesterol, Week 8, n=7, 20
    0 ( 0.5 )
    0.5 ( 0.6 )
        LDL cholesterol, Week 12, n=6, 17
    -0.1 ( 0.4 )
    0.6 ( 0.6 )
        LDL cholesterol, Week 16, n=5, 16
    0 ( 0.5 )
    0.4 ( 0.5 )
        LDL cholesterol, Week 20, n=6, 14
    0 ( 0.6 )
    0.6 ( 0.9 )
        LDL cholesterol, End of Treatment, n=7, 20
    0 ( 0.4 )
    0.4 ( 0.6 )
        LDL cholesterol, safety follow-up, n=9, 22
    0 ( 0.3 )
    0.3 ( 0.5 )
    Notes
    [21] - Safety Population. Only participants available at the specified time points were analyzed (n=X, X).
    [22] - Safety Population. Only participants available at the specified time points were analyzed (n=X, X).
    No statistical analyses for this end point

    Secondary: Absolute change from Baseline in fasted LDL/HDL ratio at Weeks 4, 8, 12, 16, and 20; EOT (Week 24); and at safety follow-up (Week 29)

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    End point title
    		 Absolute change from Baseline in fasted LDL/HDL ratio at Weeks 4, 8, 12, 16, and 20; EOT (Week 24); and at safety follow-up (Week 29)
    End point description
    Change from Baseline is defined as the value at the safety follow up visit minus baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 4, 8, 12, 16, and 20; EOT (Week 24) and safety follow-up (Week 29)
    End point values
    		 Matching placebo Alitretinoin 30 mg
    Number of subjects analysed
    9 [23]
    24 [24]
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline, n=7, 22
    0 ( 0 )
    0 ( 0 )
        Week 4, n=6, 17
    0.3 ( 0.2 )
    0.7 ( 0.4 )
        Week 8, n=6, 18
    0.2 ( 0.6 )
    0.9 ( 0.6 )
        Week 12, n=5, 16
    0.2 ( 0.4 )
    0.9 ( 9 )
        Week 16, n=5, 15
    0.1 ( 0.5 )
    0.9 ( 0.7 )
        Week 20, n=6, 13
    0 ( 0.5 )
    0.7 ( 1.1 )
        End of Treatment, n=7, 19
    0.1 ( 0.4 )
    0.5 ( 0.8 )
        Safety follow-up, n=7, 20
    0.1 ( 0.4 )
    0.1 ( 0.6 )
    Notes
    [23] - Safety Population. Only participants available at the specified time points were analyzed (n=X, X).
    [24] - Safety Population. Only participants available at the specified time points were analyzed (n=X, X).
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated shift in the indicated laboratory values from Baseline (BL) to EOT (Week 24)

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    End point title
    		 Number of participants with the indicated shift in the indicated laboratory values from Baseline (BL) to EOT (Week 24)
    End point description
    Laboratory parameters included triglycerides, total cholesterol, HDL cholesterol, LDL cholesterol, LDL/HDL ratio, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and amylase and lipase. The central laboratory classified a finding as either abnormal or normal.
    End point type
    Secondary
    End point timeframe
    From Baseline until EOT (Week 24)
    End point values
    		 Matching placebo Alitretinoin 30 mg
    Number of subjects analysed
    9 [25]
    24 [26]
    Units: participants
        Triglycerides, BL normal, shift to abnormal
    0
    2
        Triglycerides, BL abnormal, shift to abnormal
    0
    0
        Total cholesterol BL normal, shift to abnormal
    1
    1
        Total cholesterol BL abnormal, shift to abnormal
    0
    1
        HDL cholesterol BL normal, shift to abnormal
    0
    1
        HDL cholesterol BL abnormal, shift to abnormal
    0
    0
        LDL cholesterol BL normal, shift to abnormal
    0
    0
        LDL cholesterol BL abnormal, shift to abnormal
    0
    1
        LDL/HDL ratio BL normal, shift to abnormal
    0
    0
        LDL/HDL ratio BL abnormal, shift to abnormal
    0
    0
        ALT BL normal, shift to abnormal
    0
    0
        ALT BL abnormal, shift to abnormal
    0
    0
        AST BL normal, shift to abnormal
    0
    0
        AST BL abnormal, shift to abnormal
    0
    0
        Bilirubin BL normal, shift to abnormal
    0
    0
        Bilirubin BL abnormal, shift to abnormal
    0
    0
        Amylase BL normal, shift to abnormal
    0
    0
        Amylase BL abnormal, shift to abnormal
    0
    0
        Lipase BL normal, shift to abnormal
    0
    0
        Lipase BL abnormal, shift to abnormal
    0
    0
    Notes
    [25] - Safety Population
    [26] - Safety Population
    No statistical analyses for this end point

    Secondary: Summary of Center for Epidemiological Studies Depression Scale (CES-D) scores at Screening; Baseline; Weeks 4, 8, 12, 16, and 20; EOT (Week 24); and safety follow-up (Week 29)

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    End point title
    		 Summary of Center for Epidemiological Studies Depression Scale (CES-D) scores at Screening; Baseline; Weeks 4, 8, 12, 16, and 20; EOT (Week 24); and safety follow-up (Week 29)
    End point description
    The CES-D scale is a short, self-report scale designed to measure depressive symptomatology in the general population. The CES-D consists of 20 questions. Participants were instructed to circle the number for each statement that best described how often they felt or behaved a particular way during the past week. The score was the sum of the weights of the 20 items. Responses range from 0 to 3 for each item (0=rarely or none of the time, 1=some or little of the time, 2=moderately or much of the time, 3=most or almost all the time). The CES-D score ranges from 0 to 60, with higher scores indicating greater depression. Participants with a CES-D score of 20 or higher were re-evaluated within 2 weeks. If a CES-D score of 20 or higher was confirmed on the second occasion, and if the score represents an increase over Baseline of 4 points or more, study treatment was interrupted and the participants were referred for psychiatric evaluation.
    End point type
    Secondary
    End point timeframe
    Screening; Baseline; Weeks 4, 8, 12, 16, and 20; EOT (Week 24); and safety follow-up (Week 29)
    End point values
    		 Matching placebo Alitretinoin 30 mg
    Number of subjects analysed
    9 [27]
    24 [28]
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Screening, n=9, 23
    7.2 ( 6.6 )
    5.7 ( 4.7 )
        Baseline, n=9, 24
    7 ( 5.9 )
    4.5 ( 5.9 )
        Week 4, n=9, 20
    5 ( 4.7 )
    2.9 ( 3.5 )
        Week 8, n=7, 20
    2.7 ( 2.8 )
    3.8 ( 6.7 )
        Week 12, n=7, 17
    4 ( 5.7 )
    4.2 ( 6.6 )
        Week 16, n=6, 16
    3.8 ( 4.8 )
    2.9 ( 5.5 )
        Week 20, n=6, 14
    4 ( 3.6 )
    3.6 ( 5.2 )
        End of Treatment, n=8, 20
    7.4 ( 9 )
    3 ( 5.4 )
        Safety follow up, n=9, 22
    4.4 ( 3.9 )
    4.6 ( 6.7 )
    Notes
    [27] - Safety Population. Only participants available at the specified time points were analyzed (n=X, X).
    [28] - Safety Population. Only participants available at the specified time points were analyzed (n=X, X).
    No statistical analyses for this end point

    Secondary: Absolute change from Baseline (BL) in CES-D scores at Weeks 4, 8, 12, 16, and 20; EOT (Week 24); and safety follow-up (Week 29)

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    End point title
    		 Absolute change from Baseline (BL) in CES-D scores at Weeks 4, 8, 12, 16, and 20; EOT (Week 24); and safety follow-up (Week 29)
    End point description
    The CES-D scale is a short, self-report scale designed to measure depressive symptomatology in the general population. The CES-D consists of 20 questions. Participants were instructed to circle the number for each statement that best described how often they felt or behaved a particular way during the past week. The score was the sum of the weights of the 20 items. Responses range from 0 to 3 for each item (0=rarely or none of the time, 1=some or little of the time, 2=moderately or much of the time, 3=most or almost all the time). The CES-D score ranges from 0 to 60, with higher scores indicating greater depression. Participants with a CES-D score of >=20 were re-evaluated within 2 weeks. If a CES-D score of >=20 was confirmed on the second occasion, and if the score represents an increase over BL of 4 points or more, study treatment was interrupted and the participants were referred for psychiatric evaluation. Change from BL is defined as the post-BL value minus the BL value.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 4, 8, 12, 16, and 20; EOT (Week 24); and safety follow-up (Week 29)
    End point values
    		 Matching placebo Alitretinoin 30 mg
    Number of subjects analysed
    9 [29]
    24 [30]
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Week 4, n=9, 20
    -2 ( 2.5 )
    -0.3 ( 2.4 )
        Week 8, n=7, 20
    -2.3 ( 2.4 )
    0.7 ( 7.5 )
        Week 12, n=7, 17
    -1 ( 2.3 )
    0.6 ( 5.4 )
        Week 16, n=6, 16
    -2 ( 2.1 )
    -0.8 ( 4.7 )
        Week 20, n=6, 14
    -1.8 ( 3.6 )
    0.3 ( 4.7 )
        End of Treatment, n=8, 20
    -0.5 ( 6.6 )
    -0.6 ( 4.7 )
        Safety follow-up, n=9, 22
    -2.6 ( 3.9 )
    0.1 ( 3.4 )
    Notes
    [29] - Safety Population. Only participants available at the specified time points were analyzed (n=X, X).
    [30] - Safety Population. Only participants available at the specified time points were analyzed (n=X, X).
    No statistical analyses for this end point

    Secondary: Summary of Columbia Suicide Severity Rating Scale (CSSRS) scores at Screening; Baseline; Weeks 4, 8, 12, 16, and 20; EOT (Week 24); and safety follow-up (Week 29)

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    End point title
    		 Summary of Columbia Suicide Severity Rating Scale (CSSRS) scores at Screening; Baseline; Weeks 4, 8, 12, 16, and 20; EOT (Week 24); and safety follow-up (Week 29)
    End point description
    The assessment of suicidality was conducted using the CSSRS, a brief questionnaire designed to assess severity and change in suicidality by integrating both behavior and ideation using a semi-structured interview to probe participant responses. The CSSRS was designed to (1) provide definitions of suicidal ideation and behavior and nonsuicidal self-injurious behavior and corresponding probes; (2) quantify the full spectrum of suicidal ideation and suicidal behavior and gauge their severity over specified periods; (3) distinguish suicidal behavior and nonsuicidal self-injurious behavior; and (4) employ a user-friendly format that allows integration of information from multiple sources (e.g., direct participant interview, family and other interviews, and medical records). Participants who scored >3 on the CSSRA were removed from the study and referred for psychiatric evaluation. The CCSRS score ranges from 1 to 5, with a higher score representing increased suicidality.
    End point type
    Secondary
    End point timeframe
    Screening; Baseline; Weeks 4, 8, 12, 16, and 20; EOT (Week 24), and safety follow-up (Week 29)
    End point values
    		 Matching placebo Alitretinoin 30 mg
    Number of subjects analysed
    9 [31]
    24 [32]
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Screening, n=3, 10
    0 ( 0 )
    0 ( 0 )
        Baseline, n=3, 10
    0 ( 0 )
    0 ( 0 )
        Week 4, n=3, 09
    0 ( 0 )
    0 ( 0 )
        Week 8, n=3, 09
    0 ( 0 )
    0 ( 0 )
        Week 12, n=3, 07
    0 ( 0 )
    0 ( 0 )
        Week 16, n=2, 07
    0 ( 0 )
    0 ( 0 )
        Week 20, n=2, 6
    0 ( 0 )
    0 ( 0 )
        End of Treatment, n=2, 7
    0 ( 0 )
    0 ( 0 )
        Safety follow up, n=3, 9
    0 ( 0 )
    0 ( 0 )
    Notes
    [31] - Safety Population. Only participants available at the specified time points were analyzed (n=X, X).
    [32] - Safety Population. Only participants available at the specified time points were analyzed (n=X, X).
    No statistical analyses for this end point

    Secondary: Absolute change from Baseline in the CSSRS score at Weeks 4, 8, 12, 16, and 20; EOT (Week 24); and safety follow-up (Week 29)

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    End point title
    		 Absolute change from Baseline in the CSSRS score at Weeks 4, 8, 12, 16, and 20; EOT (Week 24); and safety follow-up (Week 29)
    End point description
    The assessment of suicidality was conducted using the CSSRS, a brief questionnaire designed to assess severity and change in suicidality by integrating both behavior and ideation using a semi-structured interview to probe participant responses. The CSSRS was designed to (1) provide definitions of suicidal ideation and behavior and nonsuicidal self-injurious behavior and corresponding probes; (2) quantify the full spectrum of suicidal ideation and suicidal behavior and gauge their severity over specified periods; (3) distinguish suicidal behavior and nonsuicidal self-injurious behavior; and (4) employ a user-friendly format that allows integration of information from multiple sources (e.g., direct participant interview, family and other interviews, and medical records). Participants who scored >3 on the CSSRA were removed from the study and referred for psychiatric evaluation. The CCSRS score ranges from 1 to 5, with a higher score representing increased suicidality.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 4, 8, 12, 16, and 20; EOT (Week 24); and safety follow-up (Week 29)
    End point values
    		 Matching placebo Alitretinoin 30 mg
    Number of subjects analysed
    9 [33]
    24 [34]
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Week 4, n=3, 9
    0 ( 0 )
    0 ( 0 )
        Week 8, n=3, 9
    0 ( 0 )
    0 ( 0 )
        Week 12, n=3, 7
    0 ( 0 )
    0 ( 0 )
        Week 16, n=2, 7
    0 ( 0 )
    0 ( 0 )
        Week 20, n=2, 6
    0 ( 0 )
    0 ( 0 )
        End of Treatment, n=2, 7
    0 ( 0 )
    0 ( 0 )
        Safety follow-up, n=3, 9
    0 ( 0 )
    0 ( 0 )
    Notes
    [33] - Safety Population. Only participants available at the specified time points were analyzed (n=X, X).
    [34] - Safety Population. Only participants available at the specified time points were analyzed (n=X, X).
    No statistical analyses for this end point

    Secondary: Summary of systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Screening, Baseline, and EOT (Week 24)

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    End point title
    		 Summary of systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Screening, Baseline, and EOT (Week 24)
    End point description
    SBP and DBP were assessed at Screening, Baseline, and EOT.
    End point type
    Secondary
    End point timeframe
    Screening, Baseline, and EOT (Week 24)
    End point values
    		 Matching placebo Alitretinoin 30 mg
    Number of subjects analysed
    9 [35]
    24 [36]
    Units: millimeters of mercury (mmHg)
    arithmetic mean (standard deviation)
        SBP, Screening, n=9, 23
    130.8 ( 13.7 )
    131.3 ( 16.3 )
        SBP, Baseline, n=9, 24
    122.8 ( 14 )
    126.3 ( 16.1 )
        SBP, EOT, n=8, 20
    122.4 ( 13.7 )
    128.7 ( 21.4 )
        DBP, Screening, n=9, 23
    78 ( 10.7 )
    79.7 ( 9.6 )
        DBP, Baseline, n=9, 24
    77.4 ( 12.2 )
    79.1 ( 7.5 )
        DBP, EOT, n=8, 20
    76 ( 12.2 )
    75.4 ( 10.5 )
    Notes
    [35] - Safety Population. Only participants available at the specified time points were analyzed (n=X, X).
    [36] - Safety Population. Only participants available at the specified time points were analyzed (n=X, X).
    No statistical analyses for this end point

    Secondary: Summary of heart rate (HR) at Baseline, Screening, and EOT (Week 24)

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    End point title
    		 Summary of heart rate (HR) at Baseline, Screening, and EOT (Week 24)
    End point description
    HR is defined as the rate at which the heart beats.
    End point type
    Secondary
    End point timeframe
    Screening, Baseline, and EOT (Week 24)
    End point values
    		 Matching placebo Alitretinoin 30 mg
    Number of subjects analysed
    9 [37]
    24 [38]
    Units: beats per minute (bpm)
    arithmetic mean (standard deviation)
        Screening, n=9, 23
    68.3 ( 6 )
    74 ( 7.3 )
        Baseline, n=9, 24
    72.3 ( 6.2 )
    75.2 ( 8.8 )
        EOT, n=8, 20
    70.1 ( 6.6 )
    74.7 ( 7.8 )
    Notes
    [37] - Safety Population. Only participants available at the specified time points were analyzed (n=X, X).
    [38] - Safety Population. Only participants available at the specified time points were analyzed (n=X, X).
    No statistical analyses for this end point

    Secondary: Summary of body weight at Screening, Baseline ,and EOT (Week 24)

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    End point title
    		 Summary of body weight at Screening, Baseline ,and EOT (Week 24)
    End point description
    Body weight was measured at Screening, Baseline, and EOT.
    End point type
    Secondary
    End point timeframe
    Screening, Baseline, and EOT (Week 24)
    End point values
    		 Matching placebo Alitretinoin 30 mg
    Number of subjects analysed
    9 [39]
    24 [40]
    Units: kilograms (kg)
    arithmetic mean (standard deviation)
        Screening, n=9, 24
    89.3 ( 15.5 )
    72.8 ( 12.6 )
        Baseline, n=8, 24
    89.6 ( 16.6 )
    72.9 ( 12.9 )
        EOT, n=8, 19
    88.9 ( 16.5 )
    73.8 ( 13.4 )
    Notes
    [39] - Safety Population. Only participants available at the specified time points were analyzed (n=X, X).
    [40] - Safety Population. Only participants available at the specified time points were analyzed (n=X, X).
    No statistical analyses for this end point

    Secondary: Change from Baseline in SBP and DBP at EOT (Week 24)

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    End point title
    		 Change from Baseline in SBP and DBP at EOT (Week 24)
    End point description
    Change from Baseline is defined as the value at EOT minus the Baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline and EOT (Week 24)
    End point values
    		 Matching placebo Alitretinoin 30 mg
    Number of subjects analysed
    8 [41]
    20 [42]
    Units: mmHg
    arithmetic mean (standard deviation)
        SBP
    0.5 ( 12.5 )
    0.7 ( 19.1 )
        DBP
    -0.5 ( 9.8 )
    -4.2 ( 9.8 )
    Notes
    [41] - Safety Population. Only those participants available at the specified time points were analyzed.
    [42] - Safety Population. Only those participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Secondary: Change from Baseline in heart rate at EOT (Week 24)

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    End point title
    		 Change from Baseline in heart rate at EOT (Week 24)
    End point description
    HR is defined as the rate at which the heart beats. Change from Baseline is defined as the value at EOT minus the Baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline and EOT (Week 24)
    End point values
    		 Matching placebo Alitretinoin 30 mg
    Number of subjects analysed
    8 [43]
    20 [44]
    Units: bpm
        arithmetic mean (standard deviation)
    -3.1 ( 10.4 )
    -0.2 ( 10.2 )
    Notes
    [43] - Safety Population. Only those participants available at the specified time points were analyzed.
    [44] - Safety Population. Only those participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Secondary: Change from Baseline in weight at EOT (Week 24)

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    End point title
    		 Change from Baseline in weight at EOT (Week 24)
    End point description
    Change from Bseline is defined as the value at EOT minus the value at Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline and EOT (Week 24)
    End point values
    		 Matching placebo Alitretinoin 30 mg
    Number of subjects analysed
    7 [45]
    19 [46]
    Units: kg
        arithmetic mean (standard deviation)
    -0.8 ( 3.2 )
    -0.5 ( 1.4 )
    Notes
    [45] - Safety Population. Only those participants available at the specified time points were analyzed.
    [46] - Safety Population. Only those participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Secondary: Number of participants with normal/abnormal physical status at Baseline with a worst post-Baseline finding of normal/abnormal

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    End point title
    		 Number of participants with normal/abnormal physical status at Baseline with a worst post-Baseline finding of normal/abnormal
    End point description
    A physical examination for each participant was performed at Baseline and at EOT (Week 24). The primary investigator classified physical status as either normal or abnormal.
    End point type
    Secondary
    End point timeframe
    Baseline and EOT (Week 24)
    End point values
    		 Matching placebo Alitretinoin 30 mg
    Number of subjects analysed
    9 [47]
    24 [48]
    Units: participants
        Baseline normal, worst post-Baseline normal
    6
    18
        Baseline normal, worst post-Baseline abnormal
    1
    0
        Baseline abnormal, worst post-Baseline normal
    1
    1
        Baseline abnormal, worst post-Baseline abnormal
    0
    0
    Notes
    [47] - Safety Population
    [48] - Safety Population
    No statistical analyses for this end point

    Secondary: Number of participants with a negative serum pregnancy test at Screening; Baseline; Weeks 4, 8, 12, 16, and 20; EOT (Week 24); and safety follow-up (Week 29)

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    End point title
    		 Number of participants with a negative serum pregnancy test at Screening; Baseline; Weeks 4, 8, 12, 16, and 20; EOT (Week 24); and safety follow-up (Week 29)
    End point description
    Serum pregnancy tests were performed at each visit for females of childbearing potential.
    End point type
    Secondary
    End point timeframe
    Screening; Baseline; Weeks 4, 8, 12, 16, and 20; EOT (Week 24); safety follow-up (Week 29)
    End point values
    		 Matching placebo Alitretinoin 30 mg
    Number of subjects analysed
    9 [49]
    24 [50]
    Units: participants
        Screening
    4
    7
        Baseline
    4
    7
        Week 4
    4
    4
        Week 8
    3
    4
        Week 12
    3
    3
        Week 16
    3
    2
        Week 20
    2
    2
        EOT
    4
    4
        Safety follow-up
    4
    5
    Notes
    [49] - Safety Population
    [50] - Safety Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    A treatment-emergent adverse event (AE) is defined as any adverse change that occured after treatment commenced and up to 7 days post-treatment.
    Adverse event reporting additional description
    Serious adverse events (SAEs) and non-serious AEs were reported for members of the Safety Population, comprised of all randomized participants who received at least one dose of study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    Matching placebo
    Reporting group description
    		 Participants received matching placebo orally QD for up to 24 weeks.

    Reporting group title
    Alitretinoin 30 mg
    Reporting group description
    		 Participants received an alitretinoin 30 mg capsule orally QD for up to 24 weeks.

    Serious adverse events
    		 Matching placebo Alitretinoin 30 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Matching placebo Alitretinoin 30 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 9 (88.89%)
    16 / 24 (66.67%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Hot flush
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Discomfort
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Allergy to arthropod bite
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Suicidal ideation
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Blood triglycerides increased
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Low-density lipoprotein/high-density lipoprotein ratio increased
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Low-density lipoprotein increased
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Blood potassium increased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Blood pressure increased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 9 (22.22%)
    8 / 24 (33.33%)
         occurrences all number
    3
    11
    Gastrointestinal disorders
    Cheilitis
         subjects affected / exposed
    1 / 9 (11.11%)
    3 / 24 (12.50%)
         occurrences all number
    1
    3
    Nausea
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 24 (8.33%)
         occurrences all number
    1
    4
    Diarrhoea
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Hepatic fibrosis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Granuloma annulare
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Pigmentation disorder
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Skin lesion
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 24 (4.17%)
         occurrences all number
    3
    2
    Pain in extremity
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Joint swelling
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 9 (11.11%)
    7 / 24 (29.17%)
         occurrences all number
    1
    10
    Bronchitis
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 24 (12.50%)
         occurrences all number
    0
    4
    Gout
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Jan 2011
    Change in exclusion criteria: patient safety, clarity Study assessment: Revision laboratory safety test
    20 Nov 2011
    CES-D Questionnaire: To provide more specific guidance on psychiatric referral Change in exclusion criteria: To remove ambiguity and improve clarity and uniform understanding across study centers
    06 Feb 2013
    Change of sponsor, change in inclusion/exclusion criteria: scientific evidence, patient safety

    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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    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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