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    Clinical Trial Results:
    A dual-center prospective phase I/II trial to establish safety, tolerability and to obtain first data on efficacy of losartan in children with recessive dystrophic epidermolysis bullosa (RDEB)

    Summary
    EudraCT number
    		 2015-003670-32
    Trial protocol
    		 DE   AT  
    Global end of trial date
    12 Feb 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Sep 2022
    First version publication date
    03 Sep 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    REFLECT
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 DRKS: DRKS00009269
    Sponsors
    Sponsor organisation name
    Medical Center - University of Freiburg
    Sponsor organisation address
    Breisacher Str. 153, Freiburg, Germany, 79110
    Public contact
    Prof. Dr. Dimitra Kiritsi, Medical Center - University of Freiburg, ++49 761270-67100, dimitra.kiritsi@uniklinik-freiburg.de
    Scientific contact
    Prof. Dr. Dimitra Kiritsi, Medical Center - University of Freiburg, ++49 761270-67100, dimitra.kiritsi@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 Oct 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Feb 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Feb 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Establish tolerability and saftey of losartan in children with moderate to serve RDEB
    Protection of trial subjects
    Risk-based monitoring was done according to ICH-GCP E6 and SOPs to verify that patients’ rights and wellbeing are protected, reported trial data are accurate, complete and verifiable from source documents and that the trial is conducted in compliance with the currently approved protocol/amendment, with ICH-GCP and with the applicable regulatory requirements to ensure safety and integrity of clinical trial data.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Jul 2017
    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: 29
    Worldwide total number of subjects
    29
    EEA total number of subjects
    29
    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)
    24
    Adolescents (12-17 years)
    5
    Adults (18-64 years)
    0
    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
    		 29
    Number of subjects completed
    		 29

    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: prospective, open, single-arm phase I/II clinical trial

    Arms
    Arm title
    		 Losartan
    Arm description
    		 Study medication: Losartan potassium, 2.5 mg/ml, extemporaneous oral liquid suspension.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Losartan HEXAL
    Investigational medicinal product code
    Losartan potassium
    Other name
    Pharmaceutical forms
    Film-coated tablet, Oral liquid, Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Dosage form: Film-coated tablets Strength: 50 mg Maximum daily dose: 1.4 mg/kg

    Number of subjects in period 1
    		Losartan
    Started
    29
    Completed
    29

    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
    		 29 29
    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)
    		 24 24
        Adolescents (12-17 years)
    		 5 5
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 6.44 ± 3.81 -
    Gender categorical
    Units: Subjects
        Female
    		 13 13
        Male
    		 16 16
    Subject analysis sets

    Subject analysis set title
    SAF
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All analyses (safety and efficacy) were performed in the safety population (SAF) which included all patients who fulfilled the inclusion and exclusion criteria, and for whom treatment was started, i.e. 29 patients.

    Subject analysis sets values
    		 SAF
    Number of subjects
    29
    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)
    24
        Adolescents (12-17 years)
    5
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ±
    Gender categorical
    Units: Subjects
        Female
        Male

    End points

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    End points reporting groups
    Reporting group title
    Losartan
    Reporting group description
    		 Study medication: Losartan potassium, 2.5 mg/ml, extemporaneous oral liquid suspension.

    Subject analysis set title
    SAF
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All analyses (safety and efficacy) were performed in the safety population (SAF) which included all patients who fulfilled the inclusion and exclusion criteria, and for whom treatment was started, i.e. 29 patients.

    Primary: Occurrence of a serious safety concern

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    End point title
    		 Occurrence of a serious safety concern [1]
    End point description
    The primary endpoint was defined as the occurrence of a serious safety concern, specified as one of the following side effects of losartan: • clinically relevant severe hypotension • immediate hypersensitivity reactions to the drug • clinical relevant severe hypo- und hyperkalaemia
    End point type
    Primary
    End point timeframe
    During study
    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: Single arm trial.
    End point values
    		 SAF
    Number of subjects analysed
    29
    Units: Number of patients
    0
    No statistical analyses for this end point

    Secondary: Birmingham Epidermolysis Bullosa Severity Score

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    End point title
    		 Birmingham Epidermolysis Bullosa Severity Score
    End point description
    Birmingham Epidermolysis Bullosa Severity Score (BEBS) (0=best, 100=worst)
    End point type
    Secondary
    End point timeframe
    Difference between baseline and month 9
    End point values
    		 Losartan
    Number of subjects analysed
    28
    Units: Severity Score
        arithmetic mean (confidence interval 95%)
    -3.00 (-5.79 to -0.21)
    No statistical analyses for this end point

    Secondary: Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) Total activity score

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    End point title
    		 Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) Total activity score
    End point description
    Change in the total activity score (0=best, 276=worst) of the Epidermolysis Bullosa Disease Activity and Scarring Index
    End point type
    Secondary
    End point timeframe
    Difference between baseline and month 9
    End point values
    		 Losartan
    Number of subjects analysed
    28
    Units: Scarring Index
        arithmetic mean (confidence interval 95%)
    -7.36 (-16.13 to 1.41)
    No statistical analyses for this end point

    Secondary: Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) – Total damage score

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    End point title
    		 Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) – Total damage score
    End point description
    EBDASI total damage score (ranging from 0=best to 230=worst)
    End point type
    Secondary
    End point timeframe
    Difference between baseline and month 9
    End point values
    		 SAF
    Number of subjects analysed
    28
    Units: Total damage score
        arithmetic mean (confidence interval 95%)
    -10.50 (-20.81 to -0.19)
    No statistical analyses for this end point

    Secondary: Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) – Overall total score

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    End point title
    		 Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) – Overall total score
    End point description
    End point type
    Secondary
    End point timeframe
    Difference between baseline and month 9
    End point values
    		 SAF
    Number of subjects analysed
    28
    Units: Overall total score
        arithmetic mean (confidence interval 95%)
    -17.86 (-31.11 to -4.61)
    No statistical analyses for this end point

    Secondary: Hand function assessment score of Colville and Terrill

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    End point title
    		 Hand function assessment score of Colville and Terrill
    End point description
    Hand function assessment score of Colville and Terrill, ranging from 0=best to 3=worst. Improvement of at least 1 level.
    End point type
    Secondary
    End point timeframe
    Difference between baseline and month 9
    End point values
    		 SAF
    Number of subjects analysed
    28
    Units: Number of patients
    3
    No statistical analyses for this end point

    Secondary: Mayo Dysphagia Questionnaire-day 30 (MDQ-30)

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    End point title
    		 Mayo Dysphagia Questionnaire-day 30 (MDQ-30)
    End point description
    The Mayo Dysphagia Questionnaire-day 30 (MDQ-30) was used to assess oesophageal involvement. Dysphagia score: 0=best, 100=worst
    End point type
    Secondary
    End point timeframe
    Difference between baseline and month 9
    End point values
    		 SAF
    Number of subjects analysed
    28
    Units: Dysphagia score
        arithmetic mean (confidence interval 95%)
    3.04 (-7.20 to 13.27)
    No statistical analyses for this end point

    Secondary: Itch Assessment Scale

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    End point title
    		 Itch Assessment Scale
    End point description
    Itch assessment scale for the pediatric burn patients, ranging from 0=best to 4=worst. Improvement of at least one level.
    End point type
    Secondary
    End point timeframe
    Difference between baseline and month 9
    End point values
    		 SAF
    Number of subjects analysed
    28
    Units: Number of patients
    12
    No statistical analyses for this end point

    Secondary: Wong-Baker FACES Scale for Pain

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    End point title
    		 Wong-Baker FACES Scale for Pain
    End point description
    Wong-Baker FACES Scale for Pain (ranging from 0=best to 10=worst). Improvement of at least 1 level.
    End point type
    Secondary
    End point timeframe
    Difference between baseline and month 9
    End point values
    		 SAF
    Number of subjects analysed
    28
    Units: Number of patients
    9
    No statistical analyses for this end point

    Secondary: Quality of Life in EB (QOLEB)

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    End point title
    		 Quality of Life in EB (QOLEB)
    End point description
    The change in the total score (0=best, 51=worst) of the Quality of Life in EB (QOLEB) during the study.
    End point type
    Secondary
    End point timeframe
    Difference between baseline and month 9
    End point values
    		 SAF
    Number of subjects analysed
    29
    Units: QoL
        arithmetic mean (confidence interval 95%)
    0.54 (-2.40 to 3.47)
    No statistical analyses for this end point

    Secondary: Children’s Dermatology Life Quality Index (CDLQI) - Total scale

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    End point title
    		 Children’s Dermatology Life Quality Index (CDLQI) - Total scale
    End point description
    Change in the total scale (0=best, 30=worst) of the Children’s Dermatology Life Quality Index (CDLQI) during the study
    End point type
    Secondary
    End point timeframe
    Difference between baseline and month 9
    End point values
    		 SAF
    Number of subjects analysed
    28
    Units: CDLQI
        arithmetic mean (confidence interval 95%)
    -2.64 (-4.35 to -0.94)
    No statistical analyses for this end point

    Secondary: Morphometric Scoring Instrument of Pseudosyndactyly Progression

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    End point title
    		 Morphometric Scoring Instrument of Pseudosyndactyly Progression
    End point description
    Maximal distance of thumb and index finger – Mean of left and right
    End point type
    Secondary
    End point timeframe
    Difference between baseline and month 9
    End point values
    		 SAF
    Number of subjects analysed
    28
    Units: Maximal distance
        arithmetic mean (confidence interval 95%)
    6.92 (3.48 to 10.37)
    No statistical analyses for this end point

    Secondary: Adverse event

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    End point title
    		 Adverse event
    End point description
    Number of patient with at least one adverse event
    End point type
    Secondary
    End point timeframe
    During the whole study period
    End point values
    		 SAF
    Number of subjects analysed
    29
    Units: Number of patients
    25
    No statistical analyses for this end point

    Secondary: Adverse event of severe intensity

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    End point title
    		 Adverse event of severe intensity
    End point description
    Number of patients with at least one AE of severe intensity
    End point type
    Secondary
    End point timeframe
    During study
    End point values
    		 SAF
    Number of subjects analysed
    29
    Units: Number of patients
    2
    No statistical analyses for this end point

    Secondary: Adverse event possibly related to study medication

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    End point title
    		 Adverse event possibly related to study medication
    End point description
    Number of patients with at least one AE possibly related to study medication
    End point type
    Secondary
    End point timeframe
    During study
    End point values
    		 SAF
    Number of subjects analysed
    29
    Units: Number of patients
    1
    No statistical analyses for this end point

    Secondary: Severe adverse event possibly related to study medication

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    End point title
    		 Severe adverse event possibly related to study medication
    End point description
    Number of patients with at least one severe adverse event possibly related to study medication
    End point type
    Secondary
    End point timeframe
    During study
    End point values
    		 SAF
    Number of subjects analysed
    29
    Units: Number of patients
    0
    No statistical analyses for this end point

    Secondary: Serious adverse event

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    End point title
    		 Serious adverse event
    End point description
    Number of patients with at least one serious adverse event
    End point type
    Secondary
    End point timeframe
    During study
    End point values
    		 SAF
    Number of subjects analysed
    29
    Units: Number of patients
    4
    No statistical analyses for this end point

    Secondary: Serious adverse event possibly related to study medication

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    End point title
    		 Serious adverse event possibly related to study medication
    End point description
    Number of patients with at least one SAE possibly related to study medication
    End point type
    Secondary
    End point timeframe
    During study
    End point values
    		 SAF
    Number of subjects analysed
    29
    Units: Number of patients
    0
    No statistical analyses for this end point

    Secondary: Serious adverse event leading to death

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    End point title
    		 Serious adverse event leading to death
    End point description
    Number of patients with at least one SAE leading to death
    End point type
    Secondary
    End point timeframe
    During study
    End point values
    		 SAF
    Number of subjects analysed
    29
    Units: Number of patients
    0
    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
    Losartan
    Reporting group description
    		 Losartan

    Serious adverse events
    		 Losartan
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 29 (13.79%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin bacterial infection
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound infection bacterial
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Product issues
    Device failure
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Losartan
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 29 (79.31%)
    Investigations
    Body temperature increased
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Pain threshold decreased
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Eye injury
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Limb injury
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Surgical and medical procedures
    Artificial crown procedure
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Parasitic infection prophylaxis
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 29 (10.34%)
         occurrences all number
    6
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Impaired healing
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Temperature intolerance
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Eye disorders
    Eye pain
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    2
    Constipation
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    2
    Diarrhoea
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Dysphagia
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Gastritis
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    3 / 29 (10.34%)
         occurrences all number
    4
    Odynophagia
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Tooth disorder
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Epistaxis
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    3 / 29 (10.34%)
         occurrences all number
    3
    Vitiligo
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Groin pain
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Croup infectious
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Gastrointestinal viral infection
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Hand-foot-and-mouth disease
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Medical device site infection
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    2
    Nasopharyngitis
         subjects affected / exposed
    5 / 29 (17.24%)
         occurrences all number
    6
    Oral herpes
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Oral infection
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Otitis media
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Pseudomonas infection
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Tinea infection
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Urinary tract infection
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Viral infection
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences all number
    1
    Wound infection
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 May 2019
    Administrative changes, update of the responsibility list: • change of coordinating investigator • departure of one of the project manager from the CTU Formal specification of the inclusion criterion 3: OLD: Male or female patients from 2 to 16 years (age of >25 months); NEW: Male or female patients from 2 to 16 years (starting from the 25th month of life).
    18 Feb 2020
    Administrative changes, update of the responsibility list: • change of coordinating investigator Synopsis and chapter 3.4 Trial timetable: • Updates regarding timelines

    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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