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    Clinical Trial Results:
    A multicenter, open label, single-arm pilot study to evaluate the efficacy and safety of oral apremilast in patients with moderate to severe palmoplantar pustulosis (PPP) (APLANTUS)

    Summary
    EudraCT number
    		 2016-005122-11
    Trial protocol
    		 DE  
    Global end of trial date
    29 Aug 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Jul 2021
    First version publication date
    04 Jul 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    069-008
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Prof. Dr. Kristian Reich
    Sponsor organisation address
    Martinistrasse 52, Hamburg, Germany, 20246
    Public contact
    Prof. Dr. Kristian Reich, Prof. Dr. Kristian Reich, +49 40 7410 59314, k.reich@uke.de
    Scientific contact
    Prof. Dr. Kristian Reich, Prof. Dr. Kristian Reich, +49 40 7410 59314, k.reich@uke.de
    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
    29 Nov 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Aug 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Aug 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate a significant improvement of Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) at week 20 compared with baseline in moderate to severe chronic palmoplantar pustulosis under apremilast therapy.
    Protection of trial subjects
    Patients were free to discontinue their participation in the study at any time. Withdrawal from the study did not affect or prejudice the patient’s further treatment. Patients could be withdrawn from study treatment and assessments at any time, if deemed necessary by the Investigator. Moreover, to mitigate potential gastrointestinal side effects (primarily mild-to-moderate nausea and diarrhoea), dose titration was implemented in this study in accordance with the Summary of Product Characteristics (SmPC).
    Background therapy
    		 Not applicable.
    Evidence for comparator
    		 The wide spectrum of antiinflammatory actions of apremilast might be important in the therapy of PPP. PPP is characterized by a strong inflammation in lesional skin, in which both the innate and adaptive immune systems are represented. While PPP has great similarities in the cytokine profiles compared to plaque-type psoriasis, including overexpression of IL-17 and TNF-α, neutrophils are more prominent both clinically (pustules) and in histopathology in PPP compared to plaque-type psoriasis. Apremilast has already proven to be effective in the treatment of plaque-type psoriasis and psoriatic arthritis, and in a sub-analysis also in palmoplantar involvement of plaque-psoriasis. Given the wide overlap of clinical, immunological and histological features of PPP and plaque-type psoriasis in conjunction with the observation that apremilast also effectively targets the innate immune system (e.g. neutrophils) it might be speculated that apremilast could successfully be used in the treatment of PPP.
    Actual start date of recruitment
    29 Nov 2018
    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
    Germany: 21
    Worldwide total number of subjects
    21
    EEA total number of subjects
    21
    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)
    15
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a national study with all patients being included at 5 German sites. Twenty-four patients signed the ICF and were assessed for eligibility, of whom 3 were screening failures. The remaining 21 patients received apremilast treatment. A patient did not complete 20 weeks of treatment and prematurely discontinued the study due to an AE (nausea)

    Pre-assignment
    Screening details
    		 Adults with chronic PPP (disease history of at least 6 months of diagnosis), who were eligible for treatment with systemic therapy defined as having PPP inadequately controlled by topical treatment and/or phototherapy and/or previous systemic therapy, and with chronic moderate to severe PPP defined as patients with a PPPASI ≥12.

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable. This was an open-label, single-arm study.

    Arms
    Arm title
    		 Full analysis set (FAS)
    Arm description
    		 The full analysis set (FAS) consisted of all patients who received at least one dose of study drug.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Apremilast
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast was taken orally twice daily (except Day 1). Patients received tablets in blister/bottles sufficient for one month. To mitigate potential gastrointestinal side effects (primarily mild-to-moderate nausea and diarrhoea), dose titration was implemented in this study in accordance with the Summary of Product Characteristics (SmPC). A titration pack included tablets of 10, 20 and 30 mg for a period of one month. During the first 5 days, the dosage was up-titrated. The initial dose on day 1 was 10 mg in the morning; this was increased to 10 mg in the morning and evening on day 2. The evening dose was further increased by 10 mg (to 20 mg) on day 3. On day 4, the morning dose was increased to 20 mg, so that 20 mg was taken twice daily, and on day 5 the evening dose was increased to 30 mg. From Day 6 onwards, patients received the 30 mg dose twice a day. Subsequent packs included only tablets of 30 mg strength.

    Number of subjects in period 1
    		Full analysis set (FAS)
    Started
    21
    Completed
    20
    Not completed
    1
         Adverse event, non-fatal
    1

    Baseline characteristics

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

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 21 21
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 15 15
        From 65-84 years
    		 6 6
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.76 ( 9.26 ) -
    Gender categorical
    Units: Subjects
        Female
    		 16 16
        Male
    		 5 5
    Race
    Units: Subjects
        White
    		 20 20
        Other (Sinti)
    		 1 1
    Highest educational status
    Units: Subjects
        University degree
    		 2 2
        Professional School
    		 5 5
        Secondary school leaving certificate
    		 14 14
    Is the Patient a smoker?
    Units: Subjects
        Non-smoker
    		 2 2
        Ex-smoker
    		 4 4
        Current smoker
    		 15 15
    Current Involvement of scalp
    Units: Subjects
        No
    		 20 20
        Yes
    		 1 1
    Current Involvement of nails
    Units: Subjects
        No
    		 11 11
        Yes
    		 9 9
        Unknown
    		 1 1
    Psoriatic arthritis
    Three patients (14.3%) were previously diagnosed with psoriatic arthritis, although one of these diagnoses was not verified by a rheumatologist.
    Units: Subjects
        No
    		 18 18
        Yes
    		 3 3
    Psoriasis erythrodermica
    Units: Subjects
        No
    		 21 21
        Yes
    		 0 0
    Psoriasis inversa
    Units: Subjects
        No
    		 19 19
        Yes
    		 2 2
    Psoriasis pustulosa generalisata
    Units: Subjects
        No
    		 21 21
        Yes
    		 0 0
    Plaque Psoriasis
    Units: Subjects
        No
    		 15 15
        Yes
    		 6 6
    Do you suffer from P. vulgaris?
    Units: Subjects
        No
    		 15 15
        Yes
    		 6 6
    Age at initial diagnosis of PPP
    Units: years
        arithmetic mean (standard deviation)
    		 52.10 ( 13.58 ) -
    Number of involved Fingernails
    Units: nails
        arithmetic mean (full range (min-max))
    		 1.22 (0.0 to 5.0) -
    Number of involved Toenails
    Units: nails
        arithmetic mean (full range (min-max))
    		 3.33 (0.0 to 9.0) -
    Subject analysis sets

    Subject analysis set title
    Per protocol set (PPS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per protocol set (PPS) consisted of all patients who received at least one dose of study drug who completed the study with no major protocol violations

    Subject analysis set title
    Full Analysis Set - LOCF
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set (FAS) consisted of all patients who received at least one dose of study drug. Missing values were imputed by the Last Observation Carried Forward (LOCF) method.

    Subject analysis sets values
    		 Per protocol set (PPS) Full Analysis Set - LOCF
    Number of subjects
    20
    21
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    14
        From 65-84 years
    6
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    60.15 ( 9.33 )
    ( )
    Gender categorical
    Units: Subjects
        Female
    15
        Male
    5
    Race
    Units: Subjects
        White
    19
        Other (Sinti)
    1
    Highest educational status
    Units: Subjects
        University degree
    2
        Professional School
    5
        Secondary school leaving certificate
    13
    Is the Patient a smoker?
    Units: Subjects
        Non-smoker
    2
        Ex-smoker
    4
        Current smoker
    14
    Current Involvement of scalp
    Units: Subjects
        No
        Yes
    Current Involvement of nails
    Units: Subjects
        No
        Yes
        Unknown
    Psoriatic arthritis
    Three patients (14.3%) were previously diagnosed with psoriatic arthritis, although one of these diagnoses was not verified by a rheumatologist.
    Units: Subjects
        No
        Yes
    Psoriasis erythrodermica
    Units: Subjects
        No
        Yes
    Psoriasis inversa
    Units: Subjects
        No
        Yes
    Psoriasis pustulosa generalisata
    Units: Subjects
        No
        Yes
    Plaque Psoriasis
    Units: Subjects
        No
        Yes
    Do you suffer from P. vulgaris?
    Units: Subjects
        No
        Yes
    Age at initial diagnosis of PPP
    Units: years
        arithmetic mean (standard deviation)
    ( )
    ( )
    Number of involved Fingernails
    Units: nails
        arithmetic mean (full range (min-max))
    Number of involved Toenails
    Units: nails
        arithmetic mean (full range (min-max))

    End points

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    End points reporting groups
    Reporting group title
    Full analysis set (FAS)
    Reporting group description
    		 The full analysis set (FAS) consisted of all patients who received at least one dose of study drug.

    Subject analysis set title
    Per protocol set (PPS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per protocol set (PPS) consisted of all patients who received at least one dose of study drug who completed the study with no major protocol violations

    Subject analysis set title
    Full Analysis Set - LOCF
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set (FAS) consisted of all patients who received at least one dose of study drug. Missing values were imputed by the Last Observation Carried Forward (LOCF) method.

    Primary: PPPASI at week 20

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    End point title
    		 PPPASI at week 20
    End point description
    PPPASI score range from 0–72, with higher scores indicating more severe disease.
    End point type
    Primary
    End point timeframe
    PPPASI Score at Baseline and Week 20
    End point values
    		 Full analysis set (FAS) Per protocol set (PPS) Full Analysis Set - LOCF
    Number of subjects analysed
    21
    20
    21 [1]
    Units: PPPASI Score
    median (inter-quartile range (Q1-Q3))
        Visit 2 – Baseline
    16.50 (14.00 to 19.50)
    15.85 (13.95 to 19.85)
    16.50 (14.00 to 19.50)
        Visit 5 - End of Study - Week 20
    7.65 (4.45 to 10.6)
    7.65 (4.45 to 10.60)
    8.10 (4.50 to 11.20)
    Notes
    [1] - Missing values were imputed by the Last Observation Carried Forward (LOCF) method
    Statistical analysis title
    		 Wilcoxon Signed-rank test
    Comparison groups
    Full analysis set (FAS) v Per protocol set (PPS)
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon Signed-rank test
    Confidence interval
    Notes
    [2] - At Week 20, there was a significant median percentage reduction from baseline of -57.1% (p<0.0001) in the PPPASI Score

    Secondary: PPPASI 50 response

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    End point title
    		 PPPASI 50 response
    End point description
    Patients achieveving a PPPASI 50 response
    End point type
    Secondary
    End point timeframe
    At Visit 3 (Week 4), Visit 4 (Week 12) and Visit 5 (Week 20).
    End point values
    		 Full analysis set (FAS) Per protocol set (PPS)
    Number of subjects analysed
    21
    20
    Units: Subjects
        Visit 3 - Week 4
    7
    7
        Visit 4 - Week 12
    12
    12
        Visit 5 - End of Study - Week 20
    13
    13
    Attachments
    		 Bar chart PPPASI 50 over time (FAS population)
    No statistical analyses for this end point

    Secondary: PPPASI 75 response

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    End point title
    		 PPPASI 75 response
    End point description
    Patients achieving a PPPASI 75 response.
    End point type
    Secondary
    End point timeframe
    At Visit 3 (Week 4), Visit 4 (Week 12) and Visit 5 (Week 20).
    End point values
    		 Full analysis set (FAS) Per protocol set (PPS)
    Number of subjects analysed
    21
    20
    Units: Subjects
        Visit 3 - Week 4
    2
    2
        Visit 4 - Week 12
    6
    6
        Visit 5 - End of Study - Week 20
    3
    3
    Attachments
    		 Bar chart PPPASI 75 over time (FAS population)
    No statistical analyses for this end point

    Secondary: DLQI bands (Visit 2 - Baseline)

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    End point title
    		 DLQI bands (Visit 2 - Baseline)
    End point description
    The DLQI is a dermatology-specific quality of life instrument designed to assess the impact of a disease on the patient’s daily life which is also validated for PPP (15). It is a 10-item questionnaire and can be used to assess 6 different aspects: symptoms and feelings, leisure, daily activities, work or school performance, personal relationship and treatment. The DLQI was calculated by summing the score of each question resulting in a maximum of 30 and a minimum of 0. The higher the score, the more quality of life was impaired. Meaning of DLQI Scores • 0 to 1 = No effect at all on patient's life • 2 to 5 = Small effect on patient's life • 6 to 10 = Moderate effect on patient's life • 11 to 20 = Very large effect on patient's life • 21 to 30 = Extremely large effect on patient's life
    End point type
    Secondary
    End point timeframe
    At Visit 2 (Baseline).
    End point values
    		 Full analysis set (FAS) Per protocol set (PPS)
    Number of subjects analysed
    20
    19
    Units: Subjects
        0-1 no effect at all patient's life
    2
    2
        2-5 small effect on patient's life
    5
    5
        6-10 moderate effect on patient's life
    4
    4
        11-20 very large effect on patient's life
    8
    7
        21-30 extremely large effect on patient's life
    1
    1
    No statistical analyses for this end point

    Secondary: DLQI bands (Visit 4 - Week 12)

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    End point title
    		 DLQI bands (Visit 4 - Week 12)
    End point description
    The DLQI is a dermatology-specific quality of life instrument designed to assess the impact of a disease on the patient’s daily life which is also validated for PPP (15). It is a 10-item questionnaire and can be used to assess 6 different aspects: symptoms and feelings, leisure, daily activities, work or school performance, personal relationship and treatment. The DLQI was calculated by summing the score of each question resulting in a maximum of 30 and a minimum of 0. The higher the score, the more quality of life was impaired. Meaning of DLQI Scores • 0 to 1 = No effect at all on patient's life • 2 to 5 = Small effect on patient's life • 6 to 10 = Moderate effect on patient's life • 11 to 20 = Very large effect on patient's life • 21 to 30 = Extremely large effect on patient's life
    End point type
    Secondary
    End point timeframe
    At Visit 4 (Week 12).
    End point values
    		 Full analysis set (FAS) Per protocol set (PPS)
    Number of subjects analysed
    20
    20
    Units: Subjects
        0-1 no effect at all patient's life
    7
    7
        2-5 small effect on patient's life
    5
    5
        6-10 moderate effect on patient's life
    3
    3
        11-20 very large effect on patient's life
    5
    5
        21-30 extremely large effect on patient's life
    0
    0
    No statistical analyses for this end point

    Secondary: DLQI bands (Visit 5 - End of Study - Week 20)

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    End point title
    		 DLQI bands (Visit 5 - End of Study - Week 20)
    End point description
    The DLQI is a dermatology-specific quality of life instrument designed to assess the impact of a disease on the patient’s daily life which is also validated for PPP (15). It is a 10-item questionnaire and can be used to assess 6 different aspects: symptoms and feelings, leisure, daily activities, work or school performance, personal relationship and treatment. The DLQI was calculated by summing the score of each question resulting in a maximum of 30 and a minimum of 0. The higher the score, the more quality of life was impaired. Meaning of DLQI Scores • 0 to 1 = No effect at all on patient's life • 2 to 5 = Small effect on patient's life • 6 to 10 = Moderate effect on patient's life • 11 to 20 = Very large effect on patient's life • 21 to 30 = Extremely large effect on patient's life
    End point type
    Secondary
    End point timeframe
    At Visit 5 (End of Study - Week 20).
    End point values
    		 Full analysis set (FAS) Per protocol set (PPS)
    Number of subjects analysed
    19
    19
    Units: Subjects
        0-1 no effect at all patient's life
    8
    8
        2-5 small effect on patient's life
    4
    4
        6-10 moderate effect on patient's life
    1
    1
        11-20 very large effect on patient's life
    6
    6
        21-30 extremely large effect on patient's life
    0
    0
    No statistical analyses for this end point

    Secondary: Absolute DLQI

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    End point title
    		 Absolute DLQI
    End point description
    Absolute DLQI score by visit.
    End point type
    Secondary
    End point timeframe
    At Visit 2 (Baseline), Visit 4 (Week 12) and Visit 5 (End of Study-Week 20).
    End point values
    		 Full analysis set (FAS) Per protocol set (PPS)
    Number of subjects analysed
    21 [3]
    20 [4]
    Units: DLQI Score
    median (inter-quartile range (Q1-Q3))
        Visit 2 – Baseline
    8.50 (5.00 to 15.50)
    8.00 (5.00 to 16.00)
        Visit 4 - Week 12
    2.50 (1.00 to 10.50)
    2.50 (1.00 to 10.50)
        Visit 5 - End of Study - Week 20
    2.00 (1.00 to 13.00)
    2.00 (1.00 to 13.00)
    Attachments
    		 Box plot of absolute DLQI values over time (FAS)
    Notes
    [3] - Visit 2 (n=20), Visit 4 (n=20) and Visit 5 (n=19)
    [4] - Visit 2 (n=19), Visit 4 (n=20) and Visit 5 (n=19)
    No statistical analyses for this end point

    Other pre-specified: Hand and Feet Physician Global Assessment (H&F PGA)

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    End point title
    		 Hand and Feet Physician Global Assessment (H&F PGA)
    End point description
    The H&F PGA describes the severity of psoriasis on the hands and/or feet using five categories ranging from 0 (clear) to 4 (severe).
    End point type
    Other pre-specified
    End point timeframe
    At Visit 2 (Baseline), Visit 3 (Week 4) , Visit 4 (Week 12) and Visit 5 (Week 20)
    End point values
    		 Full analysis set (FAS) Per protocol set (PPS)
    Number of subjects analysed
    20 [5]
    20
    Units: Subjects
        Visit 2 - 0 clear
    0
    0
        Visit 2 - 1 almost clear
    0
    0
        Visit 2 - 2 mild
    2
    2
        Visit 2 - 3 moderate
    19
    18
        Visit 2 - 4 severe
    0
    0
        Visit 3 - 0 clear
    0
    0
        Visit 3 - 1 almost clear
    1
    1
        Visit 3 - 2 mild
    10
    10
        Visit 3 - 3 moderate
    9
    9
        Visit 3 - 4 severe
    0
    0
        Visit 4 - 0 clear
    0
    0
        Visit 4 - 1 almost clear
    3
    3
        Visit 4 - 2 mild
    9
    9
        Visit 4 - 3 moderate
    8
    8
        Visit 4 - 4 severe
    0
    0
        Visit 5 - 0 clear
    1
    1
        Visit 5 - 1 almost clear
    1
    1
        Visit 5 - 2 mild
    10
    10
        Visit 5 - 3 moderate
    8
    8
        Visit 5 - 4 severe
    0
    0
    Attachments
    		 H&F PGA at all assessment times (n=20)
    Notes
    [5] - Except at Visit 2 (n=21)
    No statistical analyses for this end point

    Other pre-specified: Pustules count percent change from baseline

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    End point title
    		 Pustules count percent change from baseline
    End point description
    Percentage change from baseline in Pustules count after 20 weeks of treatment with Apremilast
    End point type
    Other pre-specified
    End point timeframe
    At Visit 2 (Baseline) and Visit 5 (End of Study - Week 20)
    End point values
    		 Per protocol set (PPS) Full Analysis Set - LOCF
    Number of subjects analysed
    20
    21 [6]
    Units: percent
        median (inter-quartile range (Q1-Q3))
    -79.82 (-100 to -57.33)
    -76.3 (-100 to -53.4)
    Attachments
    		 Box plot of Pustules count on each visit
    Notes
    [6] - Missing values were imputed by the Last Observation Carried Forward (LOCF) method
    Statistical analysis title
    		 Wilcoxon Signed-rank test
    Statistical analysis description
    Statistical comparison between treatment and baseline values was done based on the Wilcoxon signed-rank test with two-sided p-values <0.05 indicating significance.
    Comparison groups
    Full Analysis Set - LOCF v Per protocol set (PPS)
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 < 0.001
    Method
    		 Wilcoxon Signed-rank test
    Confidence interval
    Notes
    [7] - At Week 20, there was a significant median percentage reduction (Q1, Q3) from baseline in the FAS Population (LOCF) of 76.3% (53.4%, 100%; p<0.001) in the pustules count.

    Other pre-specified: Pustules count 50 and 75 response

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    End point title
    		 Pustules count 50 and 75 response
    End point description
    Patients experiencing a 50% and 75% decrease in Pustules count from baseline
    End point type
    Other pre-specified
    End point timeframe
    At Visit 3 (Week 4), Visit 4 (Week 12) and Visit 5 (End of Study-Week 20).
    End point values
    		 Full analysis set (FAS) Per protocol set (PPS)
    Number of subjects analysed
    21
    20
    Units: Subjects
        Pustules count 50: Visit 3 - Week 4
    13
    14
        Pustules count 50: Visit 4 - Week 12
    18
    17
        Pustules count 50: Visit 5-End of Study-Week 20
    16
    16
        Pustules count 75: Visit 3 - Week 4
    8
    9
        Pustules count 75: Visit 4 - Week 12
    14
    14
        Pustules count 75: Visit 5-End of Study-Week 20
    12
    12
    Attachments
    		 Pustules count reaching 50 and 75 response
    No statistical analyses for this end point

    Other pre-specified: VAS discomfort/pain

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    End point title
    		 VAS discomfort/pain
    End point description
    Visual Analogue Scale (VAS) was used to assess discomfort/pain. The patient was asked to place a vertical stroke on a 100 mm VAS on which the left-hand boundary represented no discomfort/pain, and the right-hand boundary represented discomfort/pain as severe as can be imagined. The distance from the mark to the left-hand boundary was recorded.
    End point type
    Other pre-specified
    End point timeframe
    At Visit 2 (Baseline), Visit 3 (Week 4), Visit 4 (Week 12) and Visit 5 (End of Study - Week 20).
    End point values
    		 Full analysis set (FAS) Per protocol set (PPS)
    Number of subjects analysed
    21
    20
    Units: VAS discomfort/pain
    median (inter-quartile range (Q1-Q3))
        Visit 2 – Baseline
    44.0 (11.0 to 67.0)
    37.5 (9.0 to 61.0)
        Visit 3 - Week 4
    4.0 (0.0 to 19)
    3.0 (0.0 to 19.0)
        Visit 4 - Week 12
    2.0 (0.0 to 27.0)
    1.5 (0.0 to 21.0)
        Visit 5 - End of Study - Week 20
    9.0 (3.0 to 61.0)
    7.5 (2.5 to 29.5)
    Attachments
    		 Mean change of pain measured with VAS Scale (PPS)
    No statistical analyses for this end point

    Other pre-specified: VAS pruritus/itch

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    End point title
    		 VAS pruritus/itch
    End point description
    Visual Analogue Scale (VAS) was used to assess pruritus/itch. The patient was asked to place a vertical stroke on a 100 mm VAS on which the left-hand boundary represented no pruritus/itch, and the right-hand boundary represented pruritus/itch as severe as can be imagined. The distance from the mark to the left-hand boundary was recorded.
    End point type
    Other pre-specified
    End point timeframe
    At Visit 2 (Baseline), Visit 3 (Week 4), Visit 4 (Week 12) and Visit 5 (End of Study - Week 20).
    End point values
    		 Full analysis set (FAS) Per protocol set (PPS)
    Number of subjects analysed
    21
    20
    Units: VAS pruritus/itch
    median (inter-quartile range (Q1-Q3))
        Visit 2 - Baseline
    31.0 (16.0 to 55.0)
    29.5 (12.5 to 49.0)
        Visit 3 - Week 4
    2.0 (2.0 to 48.0)
    11.0 (2.0 to 39.75)
        Visit 4 - Week 12
    25.0 (4.0 to 44.0)
    24.0 (3.5 to 37.25)
        Visit 5 - End of Study - Week 20
    12.0 (6.0 to 49.0)
    11.5 (5.25 to 30.25)
    Attachments
    		 Mean change of pruritus/itch measured with VAS
    No statistical analyses for this end point

    Other pre-specified: Psoriasis Area and Severity Index (PASI)

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    End point title
    		 Psoriasis Area and Severity Index (PASI)
    End point description
    PASI score at all assessment times for 6 patients included in the PPS population. The PASI is a measure of psoriatic disease severity taking into account qualitative lesion characteristics (erythema, thickness, and scaling) and degree of skin surface area involvement on defined anatomical regions. PASI scores range from 0 to 72, with higher scores reflecting greater disease severity. Erythema, thickness, and scaling are scored on a scale of 0 (none) to 4 (very severe) on 4 anatomic regions of the body: head, trunk, upper limbs, and lower limbs. Degree of involvement on each of the 4 anatomic regions is scored on a scale of 0 (no involvement) to 6 (90% to 100% involvement). The total qualitative score (sum of erythema, thickness, and scaling scores) is multiplied by the degree of involvement for each anatomic region and then multiplied by a constant. These values for each anatomic region are summed to yield the PASI score.
    End point type
    Other pre-specified
    End point timeframe
    At Visit 2 (Baseline), Visit 3 (Week 4), Visit 4 (Week 12) and Visit 5 (End of Study - Week 20).
    End point values
    		 Per protocol set (PPS)
    Number of subjects analysed
    6
    Units: PASI Score
    median (inter-quartile range (Q1-Q3))
        Visit 2 - Baseline
    3.85 (1.93 to 5.18)
        Visit 3 - Week 4
    2.27 (0.3 to 3.65)
        Visit 4 - Week 12
    0.5 (0.0 to 2.35)
        Visit 5-End of Study-Week 20
    0.95 (0.0 to 2.28)
    No statistical analyses for this end point

    Other pre-specified: Dynamic H&F PGA

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    End point title
    		 Dynamic H&F PGA
    End point description
    The dynamic H&F PGA describes the global improvement compared with baseline. It relies on the physician’s memory of the baseline severity to evaluate the level of alteration. The categories vary between 0 (cleared) and 6 (worse).
    End point type
    Other pre-specified
    End point timeframe
    At Visit 3 (Week 4), Visit 4 (Week 12) and Visit 5 (End of Study - Week 20).
    End point values
    		 Per protocol set (PPS)
    Number of subjects analysed
    20
    Units: Subjects
        Visit 3 - 0 cleared
    0
        Visit 3 - 1 excellent
    2
        Visit 3 - 2 good
    4
        Visit 3 - 3 slight
    3
        Visit 3 - 4 unchanged
    4
        Visit 3 - 5 fair
    7
        Visit 3 - 6 worse
    0
        Visit 4 - 0 cleared
    0
        Visit 4 - 1 excellent
    5
        Visit 4 - 2 good
    5
        Visit 4 - 3 slight
    2
        Visit 4 - 4 unchanged
    2
        Visit 4 - 5 fair
    6
        Visit 4 - 6 worse
    0
        Visit 5 - 0 cleared
    0
        Visit 5 - 1 excellent
    5
        Visit 5 - 2 good
    7
        Visit 5 - 3 slight
    2
        Visit 5 - 4 unchanged
    2
        Visit 5 - 5 fair
    4
        Visit 5 - 6 worse
    0
    Attachments
    		 Dynamic H&F PGA per visit
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs from baseline (V2) until the patient’s last study visit and all SAEs upon ICF signature (V1) until 30 days after the patient had stopped study participation as well as those SAEs suspected of being related to the IMP at any time thereafter.
    Adverse event reporting additional description
    The date of onset, intensity, relationship of the AE to study drug, action(s) taken, seriousness, time course, duration and outcome were recorded.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    FAS population
    Reporting group description
    		 Since the FAS consisted of all patients who received at least one dose of study drug, the FAS additionally served as safety analysis set and was used for analysis of safety endpoints.

    Serious adverse events
    		 FAS population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 21 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 FAS population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 21 (90.48%)
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    3
    Post procedural swelling
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Ligament sprain
    Additional description: No treatment-emergent
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Surgical and medical procedures
    Artificial crown procedure
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Endodontic procedure
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 21 (23.81%)
         occurrences all number
    7
    Nerve compression
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Tension headache
    Additional description: No treatment-emergent
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    6 / 21 (28.57%)
         occurrences all number
    6
    Diarrhoea
         subjects affected / exposed
    5 / 21 (23.81%)
         occurrences all number
    6
    Abdominal pain
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    2
    Abdominal pain upper
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    2
    Epulis
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Flatulence
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Gastritis
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Toothache
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Nasal dryness
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Dermatitis
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Eczema
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Hyperkeratosis
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Psychiatric disorders
    Anxiety disorder
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Exostosis
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Intervertebral disc disorder
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Limb discomfort
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Tendonitis
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Infections and infestations
    Nasopharyngitis
    Additional description: One event of nasopharyngitis was no treatment-emergent
         subjects affected / exposed
    5 / 21 (23.81%)
         occurrences all number
    6
    Cystitis
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Gastrointestinal infection
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Influenza
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Respiratory tract infection
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Sinusitis
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1
    Urinary tract infection
    Additional description: No treatment-emergent
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Jun 2018
    Protocol Final 3.0 (07-Jun-2018) was authorized after the following changes were made: • Change of the sponsor`s address – Prof. Dr. Reich remained being the sponsor as private person although his office address changed • New data manager • New statistician • Correction of the packaging of the study drug (30 mg) • The ICF was updated according to the new General Data Protection Regulation (GDPR). There were no changes in the planned statistical analyses once the Statistical Analysis Plan was finalized and the database was locked.

    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.
    The interpretation of APLANTUS study is limited by the short-term 20-week treatment period and the size of the population.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34077577
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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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