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    Clinical Trial Results:
    An open label phase II study of Sirolimus in patients with segmental overgrowth syndrome

    Summary
    EudraCT number
    		 2015-005416-15
    Trial protocol
    		 DE  
    Global end of trial date
    19 Jul 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Feb 2025
    First version publication date
    07 Feb 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SIPA-SOS
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 DRKS: DRKS00010085
    Sponsors
    Sponsor organisation name
    Medical Center - University of Freiburg
    Sponsor organisation address
    Breisacher Str. 153, Freiburg, Germany, 79110
    Public contact
    Coordinating investigator: Dr. med. Friedrich Kapp, Medical Center – University of Freiburg, Center for Pediatrics, +49 761270-43000, friedrich.kapp@uniklinik-freiburg.de
    Scientific contact
    Coordinating investigator: Dr. med. Friedrich Kapp, Medical Center – University of Freiburg, Center for Pediatrics, +49 761270-43000, friedrich.kapp@uniklinik-freiburg.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
    01 Aug 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Jul 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jul 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of sirolimus to reduce the size of defined target lesions in patients with segmental overgrowth syndromes.
    Protection of trial subjects
    Before enrolment in the clinical trial, the patient/legal representative was informed that participation in the clinical trial is voluntary and that he/she may withdraw from the clinical trial at any time without having to give reasons and without penalty or loss of benefits to which the patient is otherwise entitled. The treating physician provided the patient/legal representative with information about the treatment methods and the possible risks involved. At the same time, the nature, significance, implications, expected benefits and potential risks of the clinical trial and alternative treatments were explained to the patient/legal representative. During the informed consent discussion, the patient was also informed about the insurance cover that exists and the insured's obligations. The patient/legal representative was given ample time and opportunity to obtain answers to any open questions. All questions relating to the clinical trial should be answered to the satisfaction of the patient and/or his/her legal representative. In addition, the patient/legal representative was given a patient information sheet that contains all the important information in writing.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Oct 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 18
    Worldwide total number of subjects
    18
    EEA total number of subjects
    18
    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)
    7
    Adolescents (12-17 years)
    5
    Adults (18-64 years)
    6
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 18
    Number of subjects completed
    		 18

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

    Arms
    Arm title
    		 Sirolimus
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sirolimus
    Investigational medicinal product code
    Other name
    Rapamune
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Strength: 0.5 mg, 1 mg, 1 mg/mL; Dose: Recommended starting dose of sirolimus: 1.6 mg/m2 (divided in two doses if patients age < 16 years)

    Number of subjects in period 1
    		Sirolimus
    Started
    18
    Completed
    14
    Not completed
    4
         Switch to other clinical trial, week 39
    1
         Lack of compliance, week 13
    1
         Progressive complaints after Sirolimus cessation
    2

    Baseline characteristics

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

    Reporting group values
    		 Overall Total
    Number of subjects
    		 18 18
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 7 7
        Adolescents (12-17 years)
    		 5 5
        Adults (18-64 years)
    		 6 6
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 15.8 ( 8.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 12 12
        Male
    		 6 6

    End points

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    End points reporting groups
    Reporting group title
    Sirolimus
    Reporting group description
    		 -

    Primary: Best response: Complete Remission (CR) or Partial Remission (PR)

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    End point title
    		 Best response: Complete Remission (CR) or Partial Remission (PR) [1]
    End point description
    End point type
    Primary
    End point timeframe
    until 6 months after baseline (start of study therapy)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: A statistical test of the null hypothesis that the probability of best response CR or PR until 6 months after start of treatment was <=2% was tested at a one-sided sign. level of 5%. This null hypothesis can be rejected, if the number of patients with a best response CR or PR until 6 months after start of treatment is >=2 out of 18 patients. As none of the 18 patients had CR or PR at month 6 after start of treatment, according to this decision rule, sirolimus cannot be considered as effective.
    End point values
    		 Sirolimus
    Number of subjects analysed
    18
    Units: Number of patients
    0
    No statistical analyses for this end point

    Secondary: Morphological changes in disfigurement compared to baseline by using a scale for external validation documented by photography

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    End point title
    		 Morphological changes in disfigurement compared to baseline by using a scale for external validation documented by photography
    End point description
    The response scale for patients without progression ranged from 0 (no response compared to screening) to 100 (complete response compared to screening)
    End point type
    Secondary
    End point timeframe
    At month 3, 6 and 9
    End point values
    		 Sirolimus
    Number of subjects analysed
    18 [2]
    Units: Response scale
    arithmetic mean (standard deviation)
        month 3
    7.4 ( 7.2 )
        month 6
    8.3 ( 13.9 )
        month 9
    7.4 ( 8.3 )
    Notes
    [2] - month 3: n=17 patients, month 6: n=16 patients, month 9: n=12 patients
    No statistical analyses for this end point

    Secondary: Neuropsychological tests, Strengths and Difficulties Questionnaire, SDQ parents

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    End point title
    		 Neuropsychological tests, Strengths and Difficulties Questionnaire, SDQ parents
    End point description
    For each of the two patient groups a total difficulty score exists, each containing the subscales emotional symptoms, conduct problems, hyperactivity/inattention, and peer relationship problems. Each subscale ranged from 0-10 points, summing up to a total of 0-40 points for the total difficulty score, where 0 is "perfect" health and 40 is “worst”. Difference to baseline.
    End point type
    Secondary
    End point timeframe
    At month 3, 6 and 9
    End point values
    		 Sirolimus
    Number of subjects analysed
    18 [3]
    Units: Total difficulty score [0-40 points]
    arithmetic mean (confidence interval 95%)
        Month 3
    -0.9 (-3.1 to 1.3)
        Month 6
    -1.7 (-5.5 to 2.2)
        Month 9
    -2.3 (-5.8 to 1.2)
    Notes
    [3] - Day 0, Month 3, Month 6: n=10; Month 9: n=8
    No statistical analyses for this end point

    Secondary: Pain assessment

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    End point title
    		 Pain assessment
    End point description
    Changes in pain compared to baseline by visual pain scales for adults and children. Two age-adapted pain scales for adults/teenagers (≥ 14 years) and children (3-13 years) were used. Both pain scales ranged from 0 (no pain) to 10 (worst pain you can imagine).
    End point type
    Secondary
    End point timeframe
    At month 3, 6 and 9
    End point values
    		 Sirolimus
    Number of subjects analysed
    18 [4]
    Units: Pain scale [0-10 points]
    arithmetic mean (confidence interval 95%)
        Month 3
    -0.3 (-1.5 to 0.9)
        Month 6
    -0.5 (-1.5 to 0.6)
        Month 9
    0.5 (-0.5 to 1.5)
    Notes
    [4] - Day 0: n=18; Month 3: n=18; Month 6: n=17; Month 9: n=14
    No statistical analyses for this end point

    Secondary: Quality of life, WHOQOL-BREF Questionnaire, Physical health

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    End point title
    		 Quality of life, WHOQOL-BREF Questionnaire, Physical health
    End point description
    Changes in quality of life compared to baseline. The WHOQOL-BREF questionnaire was to be answered only by the 6 patients aged ≥ 18 years at baseline.
    End point type
    Secondary
    End point timeframe
    At month 3, 6 and 9
    End point values
    		 Sirolimus
    Number of subjects analysed
    6 [5]
    Units: Domain score [0-100 points]
    arithmetic mean (confidence interval 95%)
        Month 3
    1.8 (-10.2 to 13.8)
        Month 6
    9.3 (-0.9 to 19.5)
        Month 9
    4.8 (-8.8 to 18.3)
    Notes
    [5] - Month 3: n=6; Month 6: n=5; Month 9: n=3
    No statistical analyses for this end point

    Secondary: Biomarker IGF-1

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    End point title
    		 Biomarker IGF-1
    End point description
    Difference to baseline.
    End point type
    Secondary
    End point timeframe
    At month 3, 6 and 9
    End point values
    		 Sirolimus
    Number of subjects analysed
    18 [6]
    Units: IGF-1 [ng/mL]
    arithmetic mean (confidence interval 95%)
        Month 3
    9.3 (-3.8 to 22.5)
        Month 6
    2.7 (-23.3 to 28.6)
        Month 9
    1.0 (-17.4 to 19.4)
    Notes
    [6] - Day 0, Month 3: n=18; Month 6: n=17; Month 9: n=14
    No statistical analyses for this end point

    Secondary: Quality of life, WHOQOL-BREF Questionnaire, Scocial relationships

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    End point title
    		 Quality of life, WHOQOL-BREF Questionnaire, Scocial relationships
    End point description
    The WHOQOL-BREF questionnaire was to be answered only by the 6 patients aged ≥ 18 years at baseline. Difference to baseline.
    End point type
    Secondary
    End point timeframe
    At month 3, 6 and 9
    End point values
    		 Sirolimus
    Number of subjects analysed
    9 [7]
    Units: Domain score [0-100 points]
    arithmetic mean (confidence interval 95%)
        Month 3
    -4.2 (-16.2 to 7.9)
        Month 6
    0.0 (-12.7 to 12.7)
        Month 9
    5.6 (-26.1 to 37.2)
    Notes
    [7] - Month 3: n=6; Month 6: n=5; Month 9: n=3
    No statistical analyses for this end point

    Secondary: Quality of life, WHOQOL-BREF Questionnaire, Psychological

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    End point title
    		 Quality of life, WHOQOL-BREF Questionnaire, Psychological
    End point description
    The WHOQOL-BREF questionnaire was to be answered only by the 6 patients aged ≥ 18 years at baseline. Difference to baseline.
    End point type
    Secondary
    End point timeframe
    At month 3, 6 and 9
    End point values
    		 Sirolimus
    Number of subjects analysed
    6 [8]
    Units: Domain score [0-100 points]
    arithmetic mean (confidence interval 95%)
        Month 3
    1.4 (-24.1 to 26.8)
        Month 6
    9.2 (0.7 to 17.7)
        Month 9
    4.2 (-6.2 to 14.5)
    Notes
    [8] - Month 3: n=6; Month 6: n=5; Month 9: n=3
    No statistical analyses for this end point

    Secondary: Quality of life, WHOQOL-BREF Questionnaire, Environment

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    End point title
    		 Quality of life, WHOQOL-BREF Questionnaire, Environment
    End point description
    The WHOQOL-BREF questionnaire was to be answered only by the 6 patients aged ≥ 18 years at baseline. Difference to baseline.
    End point type
    Secondary
    End point timeframe
    At month 3, 6 and 9
    End point values
    		 Sirolimus
    Number of subjects analysed
    6 [9]
    Units: Domain score [0-100 points] Day
    arithmetic mean (confidence interval 95%)
        Month 3
    2.1 (-2.4 to 6.6)
        Month 6
    -0.6 (-9.9 to 8.6)
        Month 9
    3.1 (-17.4 to 23.7)
    Notes
    [9] - Month 3: n=6; Month 6: n=5; Month 9: n=3
    No statistical analyses for this end point

    Secondary: Quality of life, KINDL Questionnaire, KINDL® parents

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    End point title
    		 Quality of life, KINDL Questionnaire, KINDL® parents
    End point description
    The KINDL questionnaire is available in 3 versions and was to be answered by/for patients aged < 18 years at baseline (KINDL® parents), for toddlers aged 3-6 years, and for children and teenager aged 7-17 years. Difference to baseline.
    End point type
    Secondary
    End point timeframe
    At Month 3, 6 and 9
    End point values
    		 Sirolimus
    Number of subjects analysed
    18 [10]
    Units: Total score [0-100 points]
    arithmetic mean (confidence interval 95%)
        Month 3
    -9.0 (-16.4 to -1.7)
        Month 6
    -1.0 (-9.4 to 7.3)
        Month 9
    -0.7 (-7.4 to 6.1)
    Notes
    [10] - Day 0: n=12; Month 3: n=9; Month 6: n=7; Month 9: n=8
    No statistical analyses for this end point

    Secondary: Quality of life, Karnofsky Scale, Performance status

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    End point title
    		 Quality of life, Karnofsky Scale, Performance status
    End point description
    For the assessment of the performance status of the patients the Lansky/Karnofsky scales were used. Both scales run from 100% to 0%, where 100% is "perfect" health and 0% is death, with standard intervals of 10%. Difference to baseline.
    End point type
    Secondary
    End point timeframe
    At month 3, 6 and 9
    End point values
    		 Sirolimus
    Number of subjects analysed
    18 [11]
    Units: Scale [0-100 %]
    arithmetic mean (confidence interval 95%)
        Month 3
    2.2 (-1.2 to 5.6)
        Month 6
    2.5 (-1.4 to 6.4)
        Month 9
    5.0 (-0.7 to 10.7)
    Notes
    [11] - Day 0: n=9; Month 3: n=10; Month 6: n=9; Month 9: n=6
    No statistical analyses for this end point

    Secondary: Quality of life, KINDL Questionnaire, KINDL® toddlers

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    End point title
    		 Quality of life, KINDL Questionnaire, KINDL® toddlers
    End point description
    The KINDL questionnaire is available in 3 versions and was to be answered by/for patients aged < 18 years at baseline (KINDL® parents), for toddlers aged 3-6 years, and for children and teenager aged 7-17 years. Difference to baseline.
    End point type
    Secondary
    End point timeframe
    At month 3, 6 and 9. Only month 3 reported here, because only the result of one participant available at month 6 and 9.
    End point values
    		 Sirolimus
    Number of subjects analysed
    18 [12]
    Units: Total score [0-100 points]
    arithmetic mean (confidence interval 95%)
        Month 3
    5.6 (-26.1 to 37.2)
    Notes
    [12] - month 3: n=3
    No statistical analyses for this end point

    Secondary: Quality of life, KINDL Questionnaire, KINDL® children and teenager

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    End point title
    		 Quality of life, KINDL Questionnaire, KINDL® children and teenager
    End point description
    The KINDL questionnaire is available in 3 versions and was to be answered by/for patients aged < 18 years at baseline (KINDL® parents), for toddlers aged 3-6 years, and for children and teenager aged 7-17 years. Difference to baseline.
    End point type
    Secondary
    End point timeframe
    At Month 3, 6 and 9
    End point values
    		 Sirolimus
    Number of subjects analysed
    18 [13]
    Units: Total score [0-100 points]
    arithmetic mean (confidence interval 95%)
        Month 3
    0.2 (-4.2 to 4.5)
        Month 6
    -1.0 (-7.4 to 5.3)
        Month 9
    1.3 (-2.8 to 5.3)
    Notes
    [13] - Day 0: n=7; Month 3: n=7; Month 6: n=6; Month 9: n=7
    No statistical analyses for this end point

    Secondary: Neuropsychological tests, Strengths and Difficulties Questionnaire, SDQ children (≥ 11 years)

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    End point title
    		 Neuropsychological tests, Strengths and Difficulties Questionnaire, SDQ children (≥ 11 years)
    End point description
    For each of the two patient groups a total difficulty score exists, each containing the subscales emotional symptoms, conduct problems, hyperactivity/inattention, and peer relationship problems. Each subscale ranged from 0-10 points, summing up to a total of 0-40 points for the total difficulty score, where 0 is "perfect" health and 40 is “worst”. Difference to baseline.
    End point type
    Secondary
    End point timeframe
    At month 3, 6 and 9
    End point values
    		 Sirolimus
    Number of subjects analysed
    18 [14]
    Units: Total difficulty score [0-40 points]
    arithmetic mean (confidence interval 95%)
        Month 3
    1.5 (-0.8 to 3.8)
        Month 6
    0.3 (-1.8 to 2.4)
        Month 9
    -1.1 (-3.9 to 1.6)
    Notes
    [14] - Day 0: n=11; Month 3: n=12; Month 6: n=11; Month 9: n=9
    No statistical analyses for this end point

    Secondary: Quality of life, Lansky/Karnofsky scale combined, Performance status

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    End point title
    		 Quality of life, Lansky/Karnofsky scale combined, Performance status
    End point description
    For the assessment of the performance status of the patients the Lansky/Karnofsky scales were used. Both scales run from 100% to 0%, where 100% is "perfect" health and 0% is death, with standard intervals of 10%. Difference to baseline.
    End point type
    Secondary
    End point timeframe
    At month 3, 6 and 9
    End point values
    		 Sirolimus
    Number of subjects analysed
    18 [15]
    Units: Scale [0-100 %]
    arithmetic mean (confidence interval 95%)
        Month 3
    2.8 (0.5 to 5.1)
        Month 6
    3.5 (1.0 to 6.1)
        Month 9
    5.7 (2.7 to 8.7)
    Notes
    [15] - Day 0: n=18; Month 3: n=18; Month 6: n=17; Month 9: n=14
    No statistical analyses for this end point

    Secondary: Quality of life, Lansky scale, Performance status

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    End point title
    		 Quality of life, Lansky scale, Performance status
    End point description
    For the assessment of the performance status of the patients the Lansky/Karnofsky scales were used. Both scales run from 100% to 0%, where 100% is "perfect" health and 0% is death, with standard intervals of 10%. Difference to baseline.
    End point type
    Secondary
    End point timeframe
    At month 3, 6 and 9
    End point values
    		 Sirolimus
    Number of subjects analysed
    18 [16]
    Units: Scale [0-100 %]
    arithmetic mean (confidence interval 95%)
        Month 3
    3.8 (-0.6 to 8.1)
        Month 6
    5.0 (0.5 to 9.5)
        Month 9
    6.3 (1.9 to 10.6)
    Notes
    [16] - Day 0: n=9; Month 3: n=8; Month 6: n=8; Month 9: n=8
    No statistical analyses for this end point

    Secondary: Biomarker IGFBP-3

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    End point title
    		 Biomarker IGFBP-3
    End point description
    Difference to baseline.
    End point type
    Secondary
    End point timeframe
    At month 3, 6 and 9
    End point values
    		 Sirolimus
    Number of subjects analysed
    18 [17]
    Units: IGFBP-3 [μg/mL]
    arithmetic mean (confidence interval 95%)
        Month 3
    0.5 (0.2 to 0.8)
        Month 6
    0.3 (-0.1 to 0.8)
        Month 9
    0.2 (-0.2 to 0.7)
    Notes
    [17] - Day 0, Month 3: n=18; Month 6: n=17; Month 9: n=14
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Complete study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    Sirolimus
    Reporting group description
    		 1,6 mg/m² sirolimus daily over 6 months

    Serious adverse events
    		 Sirolimus
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 18 (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
    		 Sirolimus
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 18 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Chest pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    4
    Feeling abnormal
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Malaise
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Pain
         subjects affected / exposed
    3 / 18 (16.67%)
         occurrences all number
    5
    Peripheral swelling
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    4 / 18 (22.22%)
         occurrences all number
    7
    Vaccination site reaction
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 18 (16.67%)
         occurrences all number
    3
    Dyspnoea
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Epistaxis
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Oropharyngeal pain
         subjects affected / exposed
    3 / 18 (16.67%)
         occurrences all number
    4
    Vocal cord inflammation
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Productive cough
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Mood altered
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Arthropod sting
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Muscle rupture
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Sunburn
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Extrasystoles
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Tachycardia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 18 (55.56%)
         occurrences all number
    19
    Peroneal nerve palsy
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Presyncope
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Vertigo
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Eye disorders
    Dyschromatopsia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Eye inflammation
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 18 (16.67%)
         occurrences all number
    5
    Diarrhoea
         subjects affected / exposed
    4 / 18 (22.22%)
         occurrences all number
    5
    Aphthous ulcer
         subjects affected / exposed
    9 / 18 (50.00%)
         occurrences all number
    17
    Abdominal pain upper
         subjects affected / exposed
    4 / 18 (22.22%)
         occurrences all number
    4
    Faeces soft
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Haematochezia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Lip dry
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    4 / 18 (22.22%)
         occurrences all number
    7
    Swollen tongue
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Toothache
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    3 / 18 (16.67%)
         occurrences all number
    3
    Alopecia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Photosensitivity reaction
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Skin disorder
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Back pain
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Joint swelling
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Muscle spasms
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Pain in extremity
         subjects affected / exposed
    6 / 18 (33.33%)
         occurrences all number
    6
    Infections and infestations
    COVID-19
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Conjunctivitis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Cystitis
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    3
    Hordeolum
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Infection
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    9 / 18 (50.00%)
         occurrences all number
    12
    Pharyngitis
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Respiratory tract infection
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Rhinitis
         subjects affected / exposed
    5 / 18 (27.78%)
         occurrences all number
    8
    Scarlet fever
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Subcutaneous abscess
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Viral sinusitis
         subjects affected / exposed
    1 / 18 (5.56%)
         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
    11 Nov 2020
    CTP version V5.0: The main changes of the substantial amendment applied to the following items: • Primary purpose was a better definition of inclusion/exclusion criteria, objectives and endpoints • Most importantly, stable disease (SD) has been removed as successful treatment outcome, obviating the need for the observation period before therapy start • There were administrative modifications (including change of the coordinating investigator and project manager, redistribution of responsibilities for the conduct of the study, update of addresses, introduction of data monitoring committee (DMC), some wording specifications, and use of the CTCAE version 5.0 instead off 4.0

    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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