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    Clinical Trial Results:
    Effect of Bevacizumab Nasal Spray on Epistaxis Duration in Hereditary Hemorrhagic Telangectasia (ALEGORI)

    Summary
    EudraCT number
    		 2013-004204-19
    Trial protocol
    		 FR  
    Global end of trial date
    07 Sep 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Jun 2021
    First version publication date
    30 Jun 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2013-827
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02106520
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hospices Civils de Lyon
    Sponsor organisation address
    3 Quais des Célestins, Lyon, France, 69003
    Public contact
    Valérie Plattner, Hospices Civils de Lyon, +33 472406840, valerie.plattner@chu-lyon.fr
    Scientific contact
    Valérie Plattner, Hospices Civils de Lyon, +33 472406840, valerie.plattner@chu-lyon.fr
    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
    30 Mar 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Sep 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of 3 different doses of bevacizumab administered as a nasal spray in a repeated manner for the duration of nosebleeds in patients with HHT.
    Protection of trial subjects
    Regular DSMB meeting, all patients have been informed and have signed a consent form
    Background therapy
    		 hereditary hemorrhagic telangiectasia (HHT)
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Apr 2014
    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
    France: 80
    Worldwide total number of subjects
    80
    EEA total number of subjects
    80
    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)
    48
    From 65 to 84 years
    32
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients will be included in the study at the reference center for HHT in Lyon (principal investigator and coordinator) and at 4 skill centers distributed over French territory

    Pre-assignment
    Screening details
    		 Patients were included after checking inclusion/non-inclusion criteria

    Period 1
    Period 1 title
    Phase II (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bevacizumab 25mg
    Arm description
    		 Three administrations of 25 mg of Bevacizumab spaced of 14 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Nasal use
    Dosage and administration details
    Three administrations of 25 mg of Bevacizumab spaced of 14 days

    Arm title
    		 Bevacizumab 50mg
    Arm description
    		 Three administrations of 50 mg of Bevacizumab spaced of 14 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Nasal use
    Dosage and administration details
    Three administrations of 50 mg of Bevacizumab spaced of 14 days

    Arm title
    		 Bevacizumab 75mg
    Arm description
    		 Three administrations of 75 mg of Bevacizumab spaced of 14 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Nasal use
    Dosage and administration details
    Three administrations of 75 mg of Bevacizumab spaced of 14 days

    Arm title
    		 Placebo
    Arm description
    		 Three administrations of placebo spaced of 14 days
    Arm type
    		 Placebo

    Investigational medicinal product name
    sodium chloride.
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Nasal use
    Dosage and administration details
    Three administrations of placebo spaced of 14 days

    Number of subjects in period 1
    		Bevacizumab 25mg Bevacizumab 50mg Bevacizumab 75mg Placebo
    Started
    20
    20
    19
    21
    Completed
    19
    18
    19
    19
    Not completed
    1
    2
    0
    2
         Lost to follow-up
    1
    -
    -
    2
         Protocol deviation
    -
    2
    -
    -

    Baseline characteristics

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

    Reporting group values
    		 Phase II Total
    Number of subjects
    		 80 80
    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)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 48 48
        From 65-84 years
    		 32 32
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 37 37
        Male
    		 43 43

    End points

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    End points reporting groups
    Reporting group title
    Bevacizumab 25mg
    Reporting group description
    		 Three administrations of 25 mg of Bevacizumab spaced of 14 days

    Reporting group title
    Bevacizumab 50mg
    Reporting group description
    		 Three administrations of 50 mg of Bevacizumab spaced of 14 days

    Reporting group title
    Bevacizumab 75mg
    Reporting group description
    		 Three administrations of 75 mg of Bevacizumab spaced of 14 days

    Reporting group title
    Placebo
    Reporting group description
    		 Three administrations of placebo spaced of 14 days

    Primary: monthly mean epistaxis duration

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    End point title
    		 monthly mean epistaxis duration
    End point description
    End point type
    Primary
    End point timeframe
    Before and after treatment
    End point values
    		 Bevacizumab 25mg Bevacizumab 50mg Bevacizumab 75mg Placebo
    Number of subjects analysed
    20
    20
    19
    21
    Units: minute
    arithmetic mean (standard deviation)
        Before treatment
    285.5 ± 433.4
    229.0 ± 215.9
    272.9 ± 396.6
    262.8 ± 230.4
        After treatment
    259.2 ± 378.4
    244.0 ± 346.6
    215.0 ± 232.8
    200.4 ± 201.4
    Statistical analysis title
    		 Intermediary principal outcome (25mg vs placebo)
    Comparison groups
    Placebo v Bevacizumab 25mg
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.71
    Method
    		 t-test, 2-sided
    Parameter type
    		 Log odds ratio
    Point estimate
    0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.65
         upper limit
    		 1.17
    Variability estimate
    Standard deviation
    Statistical analysis title
    		 Intermediary principal outcome (50mg vs placebo)
    Comparison groups
    Placebo v Bevacizumab 50mg
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.72
    Method
    		 t-test, 2-sided
    Parameter type
    		 Log odds ratio
    Point estimate
    0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.63
         upper limit
    		 1.15
    Variability estimate
    Standard deviation
    Statistical analysis title
    		 Intermediary principal outcome (75mg vs placebo)
    Comparison groups
    Placebo v Bevacizumab 75mg
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.67
    Method
    		 t-test, 2-sided
    Parameter type
    		 Log odds ratio
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 1.1
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    6 months after treatment
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Bevacizumab 25mg
    Reporting group description
    		 -

    Reporting group title
    Bevacizumab 50 mg
    Reporting group description
    		 -

    Reporting group title
    Bevacizumab 75mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Bevacizumab 25mg Bevacizumab 50 mg Bevacizumab 75mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 20 (25.00%)
    4 / 20 (20.00%)
    4 / 19 (21.05%)
    6 / 21 (28.57%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Ulna fracture
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Shock haemorrhagic
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 20 (10.00%)
    1 / 19 (5.26%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Reanl colic
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Post sclerosis varice complication
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Right leg infection
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Bevacizumab 25mg Bevacizumab 50 mg Bevacizumab 75mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 20 (70.00%)
    10 / 20 (50.00%)
    12 / 19 (63.16%)
    16 / 21 (76.19%)
    Investigations
    Weight loss poor
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Surgical and medical procedures
    Dyspnoea exertional
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cardiac disorders
    Extrasystoles
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 20 (15.00%)
    1 / 20 (5.00%)
    1 / 19 (5.26%)
    2 / 21 (9.52%)
         occurrences all number
    4
    1
    1
    2
    Sciatica
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ophthalmic migraine
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    0
    1
    Pain
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ear and labyrinth disorders
    Dizziness
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 20 (10.00%)
    0 / 19 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    2
    1
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    2
    0
    0
    1
    Epigastric discomfort
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Aphthous ulcer
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Nasal injury
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Infections and infestations
    Cystitis
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
    3 / 21 (14.29%)
         occurrences all number
    2
    0
    1
    3
    Urinary tract infection
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    2
    0
    0
    3
    Bronchitis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    3 / 19 (15.79%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    3
    1
    Erysipelas
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    0
    1
    Rectal haemorrhage
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    1
    0
    2
    cardiac pain
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tracheitis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Hypophosphataemia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27599328
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