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    Clinical Trial Results:
    Effects of F17464 in acute exacerbation of schizophrenia. A randomised, double-blind, placebo-controlled, parallel-group, fixed-dose, multicentre study

    Summary
    EudraCT number
    		 2013-005451-32
    Trial protocol
    		 HU   LV   RO  
    Global end of trial date
    22 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jan 2017
    First version publication date
    06 Jan 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    F17464GE201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02151656
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    PIERRE FABRE MEDICAMENT
    Sponsor organisation address
    45 Place Abel Gance, Boulogne, France, 92100
    Public contact
    Agnès MONTAGNE, Institut de Recherche Pierre Fabre, +33 534 50 63 50, agnes.montagne@pierre-fabre.com
    Scientific contact
    Agnès MONTAGNE, Institut de Recherche Pierre Fabre, +33 534 50 63 50, agnes.montagne@pierre-fabre.com
    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
    23 Nov 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Dec 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the potential efficacy of 40 mg/day of oral F17464 in comparison to placebo over 6 weeks in patients with acute exacerbation of schizophrenia
    Protection of trial subjects
    This study was performed in accordance with the ethical principles stated in the Declaration of Helsinki (1964 and its subsequent amendments). This study was conducted in agreement with International Council on Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines and with applicable national regulations in biomedical research (except in one Romanian centre: see "Recruitment details" caption). The first study protocol version in use (Protocol Version 4, Amendment 3, 02 July 2014), all its amendments, and the patient information sheets, were reviewed by the appropriate independent ethics committees (IECs), including local IECs. This study was placebo-controlled (see rationale in "Evidence for comparator" caption). The placebo group received the same medical care as the F17464 group, according to that which would have been provided if they had not participated in this study. If patients showed any early signs of safety concerns or aggravation of symptoms during the study, they were eligible to receive alternative active therapy at any time.
    Background therapy
    		 There was no systematic concomitant administration of any other product than investigational products. Concomitant administration of the following treatments was used as rescue medication for symptom exacerbation and was permitted for severe anxiety, agitation or insomnia: - Lorazepam up to 8 mg/day (oral route), or 4 mg/day (intramuscular [IM] administration); and/or - Oxazepam up to 60 mg/day
    Evidence for comparator
    		 This study was placebo-controlled as there is still a medical need for alternative treatments for acute episodes in schizophrenia with a better efficacy and safety profile. Therefore, it was necessary to demonstrate the efficacy of F17464. The use of a placebo control was critical to the study to allow discrimination between patient outcomes caused by F17464 and outcomes caused by other factors (e.g. the observer or patient expectations, the natural progression of the disease, the conditions of study participation).
    Actual start date of recruitment
    20 Aug 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
    Romania: 58
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Hungary: 13
    Country: Number of subjects enrolled
    Latvia: 17
    Country: Number of subjects enrolled
    Russian Federation: 45
    Worldwide total number of subjects
    134
    EEA total number of subjects
    89
    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)
    134
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 41 centres located in 5 countries (France, Hungary, Romania, Latvia, Russian Federation) were initiated and 30 recruited patients. 158 patients were screened, 134 were randomised and analysed. An additional 13 screened patients (10 randomised) from the Romanian centre 5404 were excluded from the final database due to GCP violation.

    Pre-assignment
    Screening details
    		 Age 18-64 yrs Primary diagnosis of schizophrenia for ≥1 yr; acute exacerbation with prominent active phase symptoms as described by DSM-IV-TR using MINI 6.0 PANSS total score ≥70 and <120 and no reduction ≥20% over pre-assignment period CGI-S ≥4 ≥2 positive sympt. /delusions, hallucin. behav., concept. disorganisation or suspiciousness rated ≥4

    Pre-assignment period milestones
    Number of subjects started
    		 158 [1]
    Number of subjects completed
    		 134

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Protocol deviation: 21
    Reason: Number of subjects
    		 Consent withdrawn by subject: 3
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 158 patients were screened; 24 were not randomised (21 did not meet all eligibility criteria and 3 withdrew their consent).
    Period 1
    Period 1 title
    6-week treatment period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Double-blinding was ensured by identical: - colour, size and aspect of F17464 and placebo capsules, - packaging, labelling and administration of study treatments. A specific process was applied to maintain the blind in data transfer to the IDMC interim analyst, the only person who had access to a partial randomisation list (71 first randomised patients) during the study. Individual prolactin and F17464 plasma levels were kept blinded to the Sponsor and investigators during the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Patients randomised at Visit 2 to placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration: 4 capsules/day (2 capsules b.i.d.)

    Arm title
    		 F17464
    Arm description
    		 Patients randomised at Visit 2 to F17464
    Arm type
    		 Experimental

    Investigational medicinal product name
    F17464
    Investigational medicinal product code
    F17464
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg (4 capsules) /day (2 capsules b.i.d)

    Number of subjects in period 1
    		Placebo F17464
    Started
    67
    67
    Completed
    37
    44
    Not completed
    30
    23
         Consent withdrawn by subject
    7
    9
         Physician decision
    -
    1
         Adverse event, non-fatal
    7
    11
         Lack of efficacy
    16
    2
    Period 2
    Period 2 title
    1-week Follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    During this 7-day Follow-up period, patients were not to take any study treatment; thus, no blinding was needed.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo Follow-up
    Arm description
    		 Patients in placebo arm during Period 1 (study treatment period) having entered Period 2 (7-day Follow-up period without study treatment). Note: even if patients had not completed Period 1, they could enter Period 2; as this possibility is not accepted by the EudraCT system, the numbers of patients having started and completed Period 2 indicated in this form ("milestones" caption) correspond to the subgroup of patients having completed Period 1 on placebo and having started and completed Period 2. The actual number of patients previously receiving placebo in Period 1 and having started Period 2 is 59; of them, 58 completed Period 2 (1 patient did not complete Period 2 for "other" reason ["could not come to site"]).
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 F17464 Follow-up
    Arm description
    		 Patients in F17464 arm during Period 1 (study treatment period) having entered Period 2 (7-day Follow-up period without study treatment). Note: even if patients had not completed Period 1, they could enter Period 2; as this possibility is not accepted by the EudraCT system, the numbers of patients having started and completed Period 2 indicated in this form ("milestones" caption) correspond to the subgroup of patients having completed Period 1 (on F17464) and having started and completed Period 2. The actual number of patients previously receiving F17464 in Period 1 and having started Period 2 is 56; all of them completed Period 2.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2 [2]
    		Placebo Follow-up F17464 Follow-up
    Started
    36
    44
    Completed
    35
    44
    Not completed
    1
    0
         Patient could not come to site
    1
    -
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 1 patient in the Placebo group completed the Treatment period (Period 1) but did not enter the Follow-up period (Period 2) as a new treatment with antipsychotic was initiated.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients randomised at Visit 2 to placebo

    Reporting group title
    F17464
    Reporting group description
    		 Patients randomised at Visit 2 to F17464

    Reporting group values
    		 Placebo F17464 Total
    Number of subjects
    		 67 67 134
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 67 67 134
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 36.48 ( 11.61 ) 38.09 ( 11.32 ) -
    Gender categorical
    Units: Subjects
        Female
    		 28 27 55
        Male
    		 39 40 79
    PANSS total score
    PANSS is a 30-item score measuring specific symptoms, each item ranging from 1 (absent) to 7 (extreme). The total score is built by adding up the single items and the same applies to sub–scale calculations, i.e. positive symptoms (7 items), negative symptoms (7 items) and a general psychopathology scale (16 items). The total score ranges from 30 to 210.
    Units: points
        arithmetic mean (standard deviation)
    		 90 ( 9.2 ) 87.9 ( 9 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients randomised at Visit 2 to placebo

    Reporting group title
    F17464
    Reporting group description
    		 Patients randomised at Visit 2 to F17464
    Reporting group title
    Placebo Follow-up
    Reporting group description
    		 Patients in placebo arm during Period 1 (study treatment period) having entered Period 2 (7-day Follow-up period without study treatment). Note: even if patients had not completed Period 1, they could enter Period 2; as this possibility is not accepted by the EudraCT system, the numbers of patients having started and completed Period 2 indicated in this form ("milestones" caption) correspond to the subgroup of patients having completed Period 1 on placebo and having started and completed Period 2. The actual number of patients previously receiving placebo in Period 1 and having started Period 2 is 59; of them, 58 completed Period 2 (1 patient did not complete Period 2 for "other" reason ["could not come to site"]).

    Reporting group title
    F17464 Follow-up
    Reporting group description
    		 Patients in F17464 arm during Period 1 (study treatment period) having entered Period 2 (7-day Follow-up period without study treatment). Note: even if patients had not completed Period 1, they could enter Period 2; as this possibility is not accepted by the EudraCT system, the numbers of patients having started and completed Period 2 indicated in this form ("milestones" caption) correspond to the subgroup of patients having completed Period 1 (on F17464) and having started and completed Period 2. The actual number of patients previously receiving F17464 in Period 1 and having started Period 2 is 56; all of them completed Period 2.

    Primary: Change in PANSS from baseline to end of treatment (Day 43-LOCF)

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    End point title
    		 Change in PANSS from baseline to end of treatment (Day 43-LOCF)
    End point description
    End point type
    Primary
    End point timeframe
    Day 43 (V9)
    End point values
    		 Placebo F17464
    Number of subjects analysed
    67
    67
    Units: points
    67
    67
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    PANSS total score change from baseline to D43 was analysed using an ANCOVA model after LOCF imputation of missing values, with treatment group as fixed factor on the full analysis set. Both PANSS total score at baseline and country factor were incorporated in the model as covariates. France (with only 1 randomised patient) was grouped with Romania that included the greatest number of patients. Treatment effect was estimated by the difference between adjusted means; a 95% CI was also provided.
    Comparison groups
    Placebo v F17464
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.0141 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -6.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.08
         upper limit
    		 -1.27
    Variability estimate
    Standard deviation
    Dispersion value
    2.5
    Notes
    [1] - Hypotheses tested: H01: F17464 is not > to placebo versus H11: F17464 is > to placebo; H02: no difference between groups versus H12: F17464 is different from placebo. H01 was tested first. If H01 was not rejected, H02 was not to be tested. Such sequential strategy does not require adjustment for multiplicity of tests. Therefore, the test of H01 is one-sided whereas the test of H02 is two-sided. This procedure permits a statistical conclusion about the superiority of F17464 over placebo.
    [2] - 0.0141 is the p value for the two-sided test (H02); 0.007 is the p value for the 1-sided test (H01)

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Whole study duration from signature of consent (V1) to End of Study Visit (expected to be V10/D50 after 1 week of post-treatment follow-up or V9/D43 the End of Treatment Visit if the patient did not enter the follow-up)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    F17464
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo F17464
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 67 (22.39%)
    10 / 67 (14.93%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    General disorders and administration site conditions
    Drug ineffective
    Additional description: Reported terms: lack of efficacy; lack of response SAE if led to extension of per-protocol hospitalisation period
         subjects affected / exposed
    11 / 67 (16.42%)
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    10 / 11
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Schizophrenia
    Additional description: Reported term: worsening of schizophrenia SAE if led to extension of per-protocol hospitalisation period
         subjects affected / exposed
    4 / 67 (5.97%)
    8 / 67 (11.94%)
         occurrences causally related to treatment / all
    2 / 4
    7 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Placebo F17464
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 67 (50.75%)
    44 / 67 (65.67%)
    Investigations
    Blood triglycerides increased
         subjects affected / exposed
    2 / 67 (2.99%)
    5 / 67 (7.46%)
         occurrences all number
    3
    6
    Blood bilirubin increased
         subjects affected / exposed
    1 / 67 (1.49%)
    2 / 67 (2.99%)
         occurrences all number
    1
    2
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 67 (1.49%)
    2 / 67 (2.99%)
         occurrences all number
    1
    2
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 67 (0.00%)
    2 / 67 (2.99%)
         occurrences all number
    0
    2
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    2 / 67 (2.99%)
    0 / 67 (0.00%)
         occurrences all number
    2
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 67 (4.48%)
    4 / 67 (5.97%)
         occurrences all number
    3
    7
    Akathisia
         subjects affected / exposed
    0 / 67 (0.00%)
    3 / 67 (4.48%)
         occurrences all number
    0
    4
    Dizziness
         subjects affected / exposed
    0 / 67 (0.00%)
    3 / 67 (4.48%)
         occurrences all number
    0
    3
    General disorders and administration site conditions
    Drug ineffective
         subjects affected / exposed
    4 / 67 (5.97%)
    0 / 67 (0.00%)
         occurrences all number
    4
    0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    2 / 67 (2.99%)
    3 / 67 (4.48%)
         occurrences all number
    2
    3
    Nausea
         subjects affected / exposed
    2 / 67 (2.99%)
    2 / 67 (2.99%)
         occurrences all number
    2
    3
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea
         subjects affected / exposed
    0 / 67 (0.00%)
    3 / 67 (4.48%)
         occurrences all number
    0
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    6 / 67 (8.96%)
    13 / 67 (19.40%)
         occurrences all number
    18
    20
    Agitation
         subjects affected / exposed
    4 / 67 (5.97%)
    7 / 67 (10.45%)
         occurrences all number
    22
    10
    Anxiety
         subjects affected / exposed
    8 / 67 (11.94%)
    5 / 67 (7.46%)
         occurrences all number
    11
    6
    Schizophrenia
         subjects affected / exposed
    2 / 67 (2.99%)
    4 / 67 (5.97%)
         occurrences all number
    4
    5
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    2 / 67 (2.99%)
    0 / 67 (0.00%)
         occurrences all number
    2
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 67 (1.49%)
    2 / 67 (2.99%)
         occurrences all number
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Feb 2015
    Change in an eligibility criterion related to schizophrenia history (criterion #5) assessed at Visit 1: - Under the first protocol in use (Protocol Version 4), this eligibility criterion was “Schizophrenia history for a minimum of 1 year and maximum 5 years, well documented diagnosis with the first hospitalisation for acute exacerbation of schizophrenia.” - This inclusion criterion was amended in Protocol Version 5 to the following: "Well-documented diagnosis of schizophrenia for a minimum of 1 year before the screening visit (V1)" Rationale: the characteristics of the pre-screened population showed that a significant proportion of the patients had a duration of schizophrenia >5 years and were not enrolled in the study; the population included might therefore be only partly representative of the target population. Consequently, the upper limit of 5 years was deleted.
    21 Oct 2015
    Genotype determination of D2, 5HT1A, 5HT2A and 5HT2C receptors was added to that of D3 receptor with the objective of better documenting the response to F17464 activity (substantial part of the amendment). An independent external expert for blinded PANSS review (Professor Rabinowitz) was included in order to reinforce the validity of the primary efficacy criterion.

    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/16330718
    http://www.ncbi.nlm.nih.gov/pubmed/17650054
    http://www.ncbi.nlm.nih.gov/pubmed/25413553
    http://www.ncbi.nlm.nih.gov/pubmed/24813414
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