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    Clinical Trial Results:
    A Randomized, Double-blind, Parallel-group Study to Investigate the Efficacy, Safety, and Tolerability of Cariprazine in Patients with Predominant Negative Symptoms of Schizophrenia

    Summary
    EudraCT number
    		 2012-005485-36
    Trial protocol
    		 HU   CZ   ES   PL   BG  
    Global end of trial date
    17 Nov 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Oct 2021
    First version publication date
    24 Oct 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RGH-188-005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Gedeon Richter Plc
    Sponsor organisation address
    Gyömrői út 19-21, Budapest, Hungary, H-1103
    Public contact
    Dr. Balázs Lázár, Gedeon Richter Plc, +36 1 432 6437, RA.ctaRichter@richter.hu
    Scientific contact
    Medical Information Scientific Service, Gedeon Richter Plc, +36 1 505 7032, medinfo@richter.hu
    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
    29 May 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Nov 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Nov 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy, safety and tolerability of cariprazine for the treatment of patients with schizophrenia having predominant negative symptoms.
    Protection of trial subjects
    This clinical study was designed to comply with the International Conference on Harmonisation (ICH) Guidances on General Considerations for Clinical Trials (ICH-E8; 62 FR 66113,17 December 1997), Nonclinical Safety Studies for the Conduct of Human Clinical Studies for Pharmaceuticals (ICH-M3 [R2]; 62 FR 62922, 25 November 1997), and Good Clinical Practice (GCP) (ICH-E6; 62 FR 25692, 9 May 1997). Before the study began, the study centers required approval from an IEC. Compliance with these requirements also indicated conformity with the ethical principles that have their origins in the Declaration of Helsinki. The clinical study protocol, informed consent form (ICF), and all other appropriate study-related documents were reviewed and approved by local independent ethics committees (IECs) constituted in accordance with national regulations as applicable. The ICF was written in compliance with ICH guidelines and other national regulations as appropriate. The informed consent of the patients participating in the study were obtained in line with the ICH GCP guidelines at screening before participating in any study-related procedures.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 May 2013
    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
    Poland: 30
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Bulgaria: 32
    Country: Number of subjects enrolled
    Czechia: 48
    Country: Number of subjects enrolled
    France: 22
    Country: Number of subjects enrolled
    Hungary: 33
    Country: Number of subjects enrolled
    Croatia: 15
    Country: Number of subjects enrolled
    Romania: 7
    Country: Number of subjects enrolled
    Russian Federation: 108
    Country: Number of subjects enrolled
    Serbia: 46
    Country: Number of subjects enrolled
    Ukraine: 118
    Worldwide total number of subjects
    460
    EEA total number of subjects
    188
    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)
    458
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 533 patients were screened for eligibility; 461 patients were randomized to receive double-blind treatment; 460 subjects received at least 1 dose of double-blind treatment..

    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
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cariprazine
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cariprazine hydrochloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Oral formulation, once daily with doses of 3.0 mg/day, 4.5 mg/day, 6.0 mg/day. Day 0 to 6: 1.5 mg/day, Day 7 to 13: 3.0 mg/day, Day 14 to 182: 4.5 mg/day with the option to decrease to 3.0 mg/day from Day 21, in case of poor tolerability, or to increase to 6.0 mg/day from Day 21, in case of impending psychotic deterioration. Decreasing or increasing the dose of the double-blind study medication from the target dose was allowed only once for each modification.

    Arm title
    		 Risperidone
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Risperidone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Oral formulation, once daily with doses of 3.0 mg/day, 4.0 mg/day, 6.0 mg/day. Day 0 to 6: 2.0 mg/day, Day 7 to 13: 3.0 mg/day, Day 14 to 182: 4.0 mg/day with the option to decrease to 3.0 mg/day from Day 21, in case of poor tolerability, or to increased to 6.0 mg/day from Day 21, in case of impending psychotic deterioration. Decreasing or increasing the dose of the double-blind study medication from the target dose was allowed only once for each modification.

    Number of subjects in period 1
    		Cariprazine Risperidone
    Started
    230
    230
    Completed
    178
    178
    Not completed
    52
    52
         Consent withdrawn by subject
    15
    15
         Adverse event, non-fatal
    22
    25
         Other
    5
    7
         Non compliance
    3
    2
         Lost to follow-up
    2
    1
         Protocol deviation
    3
    -
         Lack of efficacy
    2
    2

    Baseline characteristics

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

    Reporting group title
    Risperidone
    Reporting group description
    		 -

    Reporting group values
    		 Cariprazine Risperidone Total
    Number of subjects
    		 230 230 460
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 228 230 458
        65 years
    		 2 0 2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 40.2 ( 10.5 ) 40.7 ( 11.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 106 90 196
        Male
    		 124 140 264
    Subject analysis sets

    Subject analysis set title
    Cariprazine - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    PANSS= Positive and Negative Syndrome Scale The ITT population consisted of all patients in the safety population who had at least 1 post baseline assessment on the PANSS factor scores for negative symptoms.

    Subject analysis set title
    Risperidone - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    PANSS= Positive and Negative Syndrome Scale The ITT population consisted of all patients in the safety population who had at least 1 post baseline assessment on the PANSS factor scores for negative symptoms.

    Subject analysis sets values
    		 Cariprazine - ITT Risperidone - ITT
    Number of subjects
    227
    229
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    225
    229
        65 years
    2
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    40.1 ( 10.4 )
    40.8 ( 11.1 )
    Gender categorical
    Units: Subjects
        Female
    105
    90
        Male
    122
    139

    End points

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

    Reporting group title
    Risperidone
    Reporting group description
    		 -

    Subject analysis set title
    Cariprazine - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    PANSS= Positive and Negative Syndrome Scale The ITT population consisted of all patients in the safety population who had at least 1 post baseline assessment on the PANSS factor scores for negative symptoms.

    Subject analysis set title
    Risperidone - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    PANSS= Positive and Negative Syndrome Scale The ITT population consisted of all patients in the safety population who had at least 1 post baseline assessment on the PANSS factor scores for negative symptoms.

    Primary: Change from baseline to endpoint (Week 26 or early termination) in the PANSS factor score for negative symptoms

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    End point title
    		 Change from baseline to endpoint (Week 26 or early termination) in the PANSS factor score for negative symptoms
    End point description
    Change from Baseline = CFB; PANSS=Positive and Negative Symptom Scale; MMRM=mixed-effects model for repeated measures; The primary efficacy parameter was the CFB to endpoint (Week 26/ET) in the PANSS factor score for negative symptoms. The PANSS factor score for negative symptoms ranged from 7 to 49, a lower score was favorable. The primary analysis was performed using a mixed-effects model for repeated measures (MMRM) with treatment group, study center, visit, and treatment group–by-visit interaction as the fixed effects and the baseline value and baseline value–by-visit interaction as the covariates. An unstructured covariance matrix was used to model the covariance of within-patient scores.
    End point type
    Primary
    End point timeframe
    from Baseline to Week 26 (Endpoint)
    End point values
    		 Cariprazine - ITT Risperidone - ITT
    Number of subjects analysed
    227
    229
    Units: Mean change from baseline
    least squares mean (standard error)
        Week 1
    -1.08 ( 0.095 )
    -0.91 ( 0.118 )
        Week 2
    -2.41 ( 0.145 )
    -2.19 ( 0.159 )
        Week 3
    -3.67 ( 0.195 )
    -3.34 ( 0.209 )
        Week 4
    -4.65 ( 0.234 )
    -4.11 ( 0.222 )
        Week 6
    -5.38 ( 0.246 )
    -4.99 ( 0.247 )
        Week 10
    -6.48 ( 0.266 )
    -5.89 ( 0.268 )
        Week 14
    -7.50 ( 0.295 )
    -6.38 ( 0.301 )
        Week 18
    -8.17 ( 0.303 )
    -6.75 ( 0.307 )
        Week 22
    -8.59 ( 0.310 )
    -7.15 ( 0.328 )
        Week 26
    -8.90 ( 0.324 )
    -7.44 ( 0.347 )
    Statistical analysis title
    		 Mean Difference at week 26
    Comparison groups
    Cariprazine - ITT v Risperidone - ITT
    Number of subjects included in analysis
    456
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.002 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.4
         upper limit
    		 -0.5
    Notes
    [1] - Change from Baseline = CFB; LS=Least Square Using this model, there was a statistically significant difference (P = 0.002) in favor of cariprazine over risperidone at Week 26. The LS mean CFB at Week 26 were -8.9 and -7.4 for cariprazine and risperidone, respectively.
    [2] - Cariprazine was statistically significant compared with risperidone, P < 0.01.

    Secondary: Change from baseline to endpoint (Week 26) in the Personal and Social Performance scores

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    End point title
    		 Change from baseline to endpoint (Week 26) in the Personal and Social Performance scores
    End point description
    Change from Baseline = CFB; PSP= Personal and Social Performance scale; MMRM=mixed-effects model for repeated measures; LS=Least Squares The CFB in PSP total score was analyzed using an MMRM similar to the one used for the principal analysis of the primary efficacy parameter. The PSP score ranged from 1 to 100, a higher score was favorable.The analysis was only to be formally assessed in case the result of the primary efficacy parameter was determined to be statistically significant.
    End point type
    Secondary
    End point timeframe
    from Baseline to Endpoint (Week 26 or Early Termination)
    End point values
    		 Cariprazine - ITT Risperidone - ITT
    Number of subjects analysed
    227
    229
    Units: Mean change from baseline
    least squares mean (standard deviation)
        Week 6
    6.3 ( 0.5 )
    4.9 ( 0.5 )
        Week 10
    8.6 ( 0.5 )
    6.4 ( 0.6 )
        Week 14
    10.5 ( 0.6 )
    8.0 ( 0.7 )
        Week 18
    11.8 ( 0.6 )
    8.5 ( 0.7 )
        Week 22
    13.2 ( 0.7 )
    8.9 ( 0.7 )
        Week 26
    14.3 ( 0.6 )
    9.7 ( 0.8 )
    Statistical analysis title
    		 Mean Difference at week 26
    Comparison groups
    Cariprazine - ITT v Risperidone - ITT
    Number of subjects included in analysis
    456
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.001 [4]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.7
         upper limit
    		 6.6
    Notes
    [3] - Change from Baseline = CFB; PSP= Personal and Social Performance scale; LS=Least Square Using this model, there was a statistically significant difference (P < 0.001) in CFB in the PSP score in favor of cariprazine over risperidone at Week 26. The LS mean CFB in the PSP scores at Week 26 were 14.3 and 9.7 for cariprazine and risperidone, respectively. The pairwise difference was 4.6 (95% CI: 2.7, 6.6). The CFB in the PSP total score always favored
    [4] - Cariprazine was statistically significant compared with risperidone, P < 0.001.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During the Double-Blind Period
    Adverse event reporting additional description
    Adverse event summaries contain reported adverse events during the double-blind treatment period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Cariprazine Safety population - DB treatment period
    Reporting group description
    		 DB= double blind All patients in the randomized population who took at least 1 dose of Cariprazine. For this safety population, adverse event summaries contain reported adverse events during the double-blind treatment period.

    Reporting group title
    Risperidone Safety population - DB treatment period
    Reporting group description
    		 DB= double blind All patients in the randomized population who took at least 1 dose of Cariprazine. For this safety population, adverse event summaries contain reported adverse events during the double-blind treatment period.

    Serious adverse events
    		 Cariprazine Safety population - DB treatment period Risperidone Safety population - DB treatment period
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 230 (3.04%)
    7 / 230 (3.04%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to the mediastinum
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain neoplasm
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Carcinoid tumour pulmonary
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    Intentional overdose
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness postural
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 230 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 230 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Schizophrenia
         subjects affected / exposed
    4 / 230 (1.74%)
    4 / 230 (1.74%)
         occurrences causally related to treatment / all
    0 / 4
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Persecutory delusion
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 230 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Cariprazine Safety population - DB treatment period Risperidone Safety population - DB treatment period
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    83 / 230 (36.09%)
    92 / 230 (40.00%)
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    19 / 230 (8.26%)
    12 / 230 (5.22%)
         occurrences all number
    20
    12
    Cogwheel rigidity
         subjects affected / exposed
    4 / 230 (1.74%)
    8 / 230 (3.48%)
         occurrences all number
    4
    8
    Dizziness
         subjects affected / exposed
    4 / 230 (1.74%)
    11 / 230 (4.78%)
         occurrences all number
    4
    13
    Headache
         subjects affected / exposed
    13 / 230 (5.65%)
    24 / 230 (10.43%)
         occurrences all number
    20
    30
    Somnolence
         subjects affected / exposed
    9 / 230 (3.91%)
    13 / 230 (5.65%)
         occurrences all number
    10
    13
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 230 (2.17%)
    10 / 230 (4.35%)
         occurrences all number
    5
    10
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    9 / 230 (3.91%)
    6 / 230 (2.61%)
         occurrences all number
    9
    8
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    13 / 230 (5.65%)
    11 / 230 (4.78%)
         occurrences all number
    14
    11
    Insomnia
         subjects affected / exposed
    21 / 230 (9.13%)
    23 / 230 (10.00%)
         occurrences all number
    22
    27
    Schizophrenia
         subjects affected / exposed
    15 / 230 (6.52%)
    10 / 230 (4.35%)
         occurrences all number
    16
    11
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 230 (1.30%)
    7 / 230 (3.04%)
         occurrences all number
    3
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Feb 2013
    Changes included, but were not limited to clarifications on inclusion/exclusion criteria; harmonization on blinding/unblinding procedures; prechilled vacutainers and flash-freezing were removed from the protocol; summarize details of the laboratory methods for urine microscopy testing; addition of IOP measurement to the summary list of assessments; summarize details of opthalmic examination.
    04 Jun 2013
    Changes included, but were not limited to the following: increase number of study centers; changes in the responsabilities for review EAF and issue of the MMAF; the schedule of procedures was edited; chilling of blood samples in an ice bath was removed; Text was added to clarify the fluctuating nature and disease course of schizophrenia; a reference was updated for the most current SmPC for Risperidone.

    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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    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
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