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    Clinical Trial Results:
    Efficacy and safety of Passiflora Compose in patients newly diagnosed with adjustment disorder with anxiety, as first-line treatment, compared to Alprazolam Efficacité et tolérance de Passiflora composé dans l’anxiété réactionnelle récente, en première intention, en comparaison de l’Alprazolam

    Summary
    EudraCT number
    		 2017-002263-17
    Trial protocol
    		 FR  
    Global end of trial date
    30 Aug 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Mar 2023
    First version publication date
    31 Mar 2023
    Other versions
    Summary report(s)
    		 2017-002263-17 Synopsis PASSIANCE

    Trial information

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    Trial identification
    Sponsor protocol code
    BRN-C-2017-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 U2017-0022-6317
    Sponsors
    Sponsor organisation name
    Laboratoires BOIRON
    Sponsor organisation address
    2 Avenue de l'Ouest Lyonnais, Messimy, France, 69510
    Public contact
    R&D Affaires scientifiques & médicales - BOIRON, Isabelle Chanel, +33 472164315, isabelle.chanel@boiron.fr
    Scientific contact
    R&D Affaires scientifiques & médicales - BOIRON, Isabelle Chanel, +33 472164315, isabelle.chanel@boiron.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
    27 Jun 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Aug 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study is to demonstrate the non-inferiority of PC in comparison to Alprazolam in anxiety disorders after 4 weeks of treatment (efficacy objective).
    Protection of trial subjects
    The Sponsor submitted the study protocol and all information necessary for a detailed review of the clinical study to the competent authorities. The study was started after written approval by the competent authority was available (ANSM: Ref. 170451A-31 and CPP Sud Méditerranée I - Ref. 17 55). This study was performed in accordance with Good Clinical Practice (GCP), the Declaration of Helsinki, in its revision of Somerset West 1996, and in accordance with applicable legal and regulatory requirements, including archiving of essential documents. Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject. It was the responsibility of the investigator to obtain signed informed consent from the patient prior to the patient’s inclusion in the study. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Jan 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
    France: 104
    Worldwide total number of subjects
    104
    EEA total number of subjects
    104
    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)
    95
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study performed with general practitioners from January 2018 to May 2019. Randomization to one of the 2 treatment groups (PC or APZ) was performed with a 1:1 ratio using a block randomization method and stratification by site.

    Pre-assignment
    Screening details
    		 None study-related procedure was started before ICF was signed and dated by both the patient and the investigator - Checked the eligibility criteria list and perform the exams. 104 subjects were enrolled and randomized, 104 subjects were included in the safety population. 84 subjects were included in PP population.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Data analyst, Carer, Assessor, Subject
    Blinding implementation details
    Study medication was presented as visually indistinguishable doses. Each treatment box contained 90 IMP units which was sufficient medication for 1 patient (28 days – 3 doses daily 1:1:1), IMP and counterpart Placebo.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm PC
    Arm description
    		 Experimental Passiflora Composé (PC) along with Placebo of APZ
    Arm type
    		 Experimental

    Investigational medicinal product name
    Passiflora Composé
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Passiflora Composé ® was provided as globuli. Passiflora Composé ® contained Passiflora incarnata 3DH ; Coffea cruda 5CH ; Ignatia amara 4CH ; Nyckterinia capensis 4CH ; Tellurium metallicum 5CH ; Phosphoricum acidum 7CH ; Palladium metallicum 5CH and Magnesium metallicum 5CH. The granuli excipients were saccharose and lactose. Patients were instructed to take 5 globuli, 3 times a day during 4 weeks.

    Investigational medicinal product name
    Placebo - Alprazolam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo of Alprazolam was provided as tablets. It contained no active component. The tablet excipients consisted of microcrystalline cellulose, lactose monohydrate, magnesium stearate and anhydrous colloidal silica. It was not possible to differentiate it from Alprazolam by its appearance and taste. Patients were instructed to take 1 tablet, 3 times a day during 4 weeks.

    Arm title
    		 Arm APZ
    Arm description
    		 Experimental Comparator - Alprazolam (APZ) along with Placebo of PC
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Alprazolam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Alprazolam was provided as tablets. It contained 0.25 mg of active component (APZ) per tablet. The tablet excipients consisted of microcrystalline cellulose, lactose monohydrate, magnesium stearate and anhydrous colloidal silica. Patients were instructed to take 1 tablet, 3 times a day during 4 weeks.

    Investigational medicinal product name
    Placebo - Passiflora Composé
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo of Passiflora Composé was provided as globuli. It contained no active component. The granuli excipients were Saccharose and lactose. It was not possible to differentiate it from Passiflora Composé® by its appearance and taste. Patients were instructed to take 5 globuli, 3 times a day during 4 weeks.

    Number of subjects in period 1
    		Arm PC Arm APZ
    Started
    52
    52
    Completed
    45
    49
    Not completed
    7
    3
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    2
    1
         Physician decision
    1
    -
         Adverse event, non-fatal
    1
    -
         Lost to follow-up
    1
    1
         Protocol deviation
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm PC
    Reporting group description
    		 Experimental Passiflora Composé (PC) along with Placebo of APZ

    Reporting group title
    Arm APZ
    Reporting group description
    		 Experimental Comparator - Alprazolam (APZ) along with Placebo of PC

    Reporting group values
    		 Arm PC Arm APZ Total
    Number of subjects
    		 52 52 104
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 45.1 ( 12.1 ) 45.0 ( 13.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 34 38 72
        Male
    		 18 14 32
    Subject analysis sets

    Subject analysis set title
    Arm PC - Primary Endpoint
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per protocol (PP) population: defined as all patients randomized and treated without any deviation to protocol preventing primary endpoint analysis.

    Subject analysis set title
    Arm PC – Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety population: defined as all patients randomized who received at least one study treatment dose.

    Subject analysis set title
    Arm APZ - Primary Endpoint
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per protocol (PP) population: defined as all patients randomized and treated without any deviation to protocol preventing primary endpoint analysis.

    Subject analysis set title
    Arm APZ – Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety population: defined as all patients randomized who received at least one study treatment dose.

    Subject analysis sets values
    		 Arm PC - Primary Endpoint Arm PC – Safety population Arm APZ - Primary Endpoint Arm APZ – Safety Population
    Number of subjects
    41
    52
    45
    52
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    45.0 ( 13.1 )
    ( )
    45.1 ( 12.1 )
    Gender categorical
    Units: Subjects
        Female
    15
    38
    11
    34
        Male
    26
    14
    34
    18

    End points

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    End points reporting groups
    Reporting group title
    Arm PC
    Reporting group description
    		 Experimental Passiflora Composé (PC) along with Placebo of APZ

    Reporting group title
    Arm APZ
    Reporting group description
    		 Experimental Comparator - Alprazolam (APZ) along with Placebo of PC

    Subject analysis set title
    Arm PC - Primary Endpoint
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per protocol (PP) population: defined as all patients randomized and treated without any deviation to protocol preventing primary endpoint analysis.

    Subject analysis set title
    Arm PC – Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety population: defined as all patients randomized who received at least one study treatment dose.

    Subject analysis set title
    Arm APZ - Primary Endpoint
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per protocol (PP) population: defined as all patients randomized and treated without any deviation to protocol preventing primary endpoint analysis.

    Subject analysis set title
    Arm APZ – Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety population: defined as all patients randomized who received at least one study treatment dose.

    Primary: Efficacy Primary Endpoint

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    End point title
    		 Efficacy Primary Endpoint
    End point description
    The evolution of the total HAM-A score is measured by the variation of the score between V0 and V2 on the HAM-A scale which comprises 14 questions rated by a 5-point Likert scale from 0 to 4 points, a high score indicates more severe anxiety. The total HAM-A score is calculated by the sum of the answers to the 14 questions (or items) of the HAM-A scale and it can vary from 0 to 56.
    End point type
    Primary
    End point timeframe
    4 weeks
    End point values
    		 Arm PC - Primary Endpoint Arm APZ - Primary Endpoint
    Number of subjects analysed
    41 [1]
    45 [2]
    Units: Score Value Change
    13
    14
    Notes
    [1] - Score Value Change Arithmetic mean : -12,9 Standard deviation: 8,9
    [2] - Score Value Change Arithmetic mean : -13,9 Standard deviation: 7,9
    Statistical analysis title
    		 Arm APZ vs Arm PC
    Comparison groups
    Arm PC - Primary Endpoint v Arm APZ - Primary Endpoint
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 2.8
    Method
    		 ANCOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose (i.e., Day 1) of study drug to last dose date of study drug (i.e., Day 28)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Arm PC
    Reporting group description
    		 Arm PC – Safety population

    Reporting group title
    Arm APZ
    Reporting group description
    		 Arm APZ – Safety Population

    Serious adverse events
    		 Arm PC Arm APZ
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Injury, poisoning and procedural complications
    Carbon monoxide poisoning
    Additional description: PT10007238
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Arm PC Arm APZ
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 52 (13.46%)
    14 / 52 (26.92%)
    Nervous system disorders
    Sciatica
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    2
    Somnolence
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    2 / 52 (3.85%)
    2 / 52 (3.85%)
         occurrences all number
    2
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    2
    Asthenia
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    1 / 52 (1.92%)
    2 / 52 (3.85%)
         occurrences all number
    1
    2
    Abdominal pain upper
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 52 (3.85%)
         occurrences all number
    0
    2
    Dry mouth
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Allergic respiratory disease
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Cough
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 52 (1.92%)
         occurrences all number
    1
    1
    Pruritus
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 52 (3.85%)
         occurrences all number
    0
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Laryngitis
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    Influenza
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Jan 2018
    MS1 - Amendment 1 (Ethic Committee’s approval); included changes in investigative team’s composition: addition of new investigators.
    12 Jun 2018
    MS2- Amendment 2 (Ethic Committee’s approval and Competent Authority’s notification): Due to low recruitment rate, the sponsor submitted a protocol update allowing an extended inclusion period. Amendment 2.
    12 Sep 2018
    MS3- Amendment 3 (Ethic Committee’s approval); included changes in investigative team’s composition: addition of new investigators.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    28 May 2019
    During the course of this study, the recruitment target was not met within the initial time frame. The sponsor decided to extend the recruitment period (see above Amendment 2). Despite this extension of the recruitment period, 104 patients were included instead of the 282 initially planned. The recruitment period was not extended again.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The main objective was to demonstrate the non-inferiority of PC in comparison to Alprazolam in anxiety disorders. The trial terminated before reaching the targeted analysis population. That constitutes limitations to the results.
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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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