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    Clinical Trial Results:
    Simvastatin addition to improve symptoms, cognition and metabolic syndrome in patients with recent-onset schizophrenia.

    Summary
    EudraCT number
    		 2013-000834-36
    Trial protocol
    		 NL  
    Global end of trial date
    19 Dec 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Aug 2022
    First version publication date
    03 Aug 2022
    Other versions
    Summary report(s)
    		 copy of medical journal article

    Trial information

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    Trial identification
    Sponsor protocol code
    43806
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ClinicalTrials.gov: NCT01999309
    Sponsors
    Sponsor organisation name
    University Medical Center Utrecht
    Sponsor organisation address
    Heidelberglaan 100, Utrecht, Netherlands,
    Public contact
    S.S. Gangadin, University Medical Center Utrecht, +88 887556366, S.S.Gangadin@umcutrecht.nl
    Scientific contact
    S.S.Gangadin, University Medical Center Utrecht, +88 887556366, S.S.Gangadin@umcutrecht.nl
    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
    10 Nov 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Dec 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Dec 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial is to investigate the proposed beneficial effect of simvastatin as compared to placebo when given in addition to antipsychotic medication on symptom severity as measured with the Positive and Negative Syndrome Scale (PANSS).
    Protection of trial subjects
    Patiants were thorougly screened, patients with hypercholesterolemia were excluded Assessments were kept to a minimum Blood levels were checked every visit by an independent physician to ensure safety Most common side effects of simvastatin were assessed systematically at every visit
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jun 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
    Netherlands: 119
    Worldwide total number of subjects
    119
    EEA total number of subjects
    119
    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)
    119
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited from Dutch inpatient and outpatient settings

    Pre-assignment
    Screening details
    		 2.3. Inclusion criteria 1. A DSM-IV-R diagnosis of: 295.x (schizophrenia, schizophreniform disorder, or schizoaffective disorder) or 298.9 (psychosis NOS) 2. Onset of first psychosis no longer than 3 years ago 3. Age between 18 and 50 years 4. Written informed consent is obtained. 5. Female patients of childbearing potential nee

    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, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Simvastatin
    Arm description
    		 Simvastatin 40mg daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Simvastatin 40mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40mg, one tablet daily

    Arm title
    		 placebo
    Arm description
    		 placebo pill identical in shape, color and smell
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo Simvastatin 40mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40mg, one tablet daily

    Number of subjects in period 1
    		Simvastatin placebo
    Started
    61
    58
    Completed
    47
    43
    Not completed
    14
    15
         Adverse event, non-fatal
    6
    4
         Practical reasons
    1
    1
         Refusal to continue
    7
    8
         Lost to follow-up
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Simvastatin
    Reporting group description
    		 Simvastatin 40mg daily

    Reporting group title
    placebo
    Reporting group description
    		 placebo pill identical in shape, color and smell

    Reporting group values
    		 Simvastatin placebo Total
    Number of subjects
    		 61 58 119
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 61 58 119
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 26.4 ± 5.8 28.0 ± 7.9 -
    Gender categorical
    Units: Subjects
        Female
    		 14 13 27
        Male
    		 47 45 92
    Metabolic syndrome
    Assessed as defined by the American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLB; [17]), by measuring weight, height, blood pressure, waist circumference, and body mass index (BMI).
    Units: Subjects
        yes
    		 14 16 30
        no
    		 47 42 89
    PANSS total
    assessed with Positive and Negative syndrome scale
    Units: scores
        arithmetic mean (standard deviation)
    		 58.9 ± 13.0 56.8 ± 15.0 -
    BACS total
    cognition assessed with Brief Assessment of Cognition in Schizophrenia
    Units: standardised units
        arithmetic mean (standard deviation)
    		 -0.7 ± 0.8 -0.8 ± 0.7 -

    End points

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    End points reporting groups
    Reporting group title
    Simvastatin
    Reporting group description
    		 Simvastatin 40mg daily

    Reporting group title
    placebo
    Reporting group description
    		 placebo pill identical in shape, color and smell

    Primary: PANSS total score

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    End point title
    		 PANSS total score
    End point description
    Schizophrenia symptom severity was evaluated with the Positive and Negative Syndrome Scale (=PANSS total score). reported values are changes from baseline
    End point type
    Primary
    End point timeframe
    12 months post-baseline
    End point values
    		 Simvastatin placebo
    Number of subjects analysed
    47
    43
    Units: scores
        arithmetic mean (standard error)
    54.7 ± 1.5
    52.9 ± 1.7
    Statistical analysis title
    		 Primary endpoint PANSS
    Statistical analysis description
    Linear mixed models for repeated measurements. To model the effect of simvastatin, we included time point, treatment, sex and study site as fixed factors, age and baseline scores as covariates and subject as random intercept factor. To evaluate whether group differences varied over time, we also assessed the time*treatment interaction effect. When significant, group differences were compared at the individual time points.
    Comparison groups
    placebo v Simvastatin
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Confidence interval

    Primary: BACS total score

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    End point title
    		 BACS total score
    End point description
    Neurocognitive functioning will be assessed with the Brief Assessment of Cognition in Schizophrenia (BACS; [22]), including the following tests: 1.Verbal memory: List Learning 2.Working memory: Digit Sequencing Task 3.Motor speed: Token Motor Task 4.Verbal fluency: Category Instances 5.Verbal fluency: Controlled Oral Word Association Test 6.Attention and speed of information processing: Symbol Coding 7.Executive functions: Tower of London
    End point type
    Primary
    End point timeframe
    12 months post-baseline
    End point values
    		 Simvastatin placebo
    Number of subjects analysed
    48
    43
    Units: standardized units
        arithmetic mean (standard error)
    -0.6 ± 0.4
    -0.6 ± 0.5
    Statistical analysis title
    		 Primary endpoint BACS
    Statistical analysis description
    Analysis of covariance (ANCOVA) was applied for group differences in cognitive performance at 6 and 12 months of treatment, including baseline score as a covariate. BACS total composite score was calculated by converting raw test scores of the subtasks into z-scores and averaging these standardized scores.
    Comparison groups
    Simvastatin v placebo
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.55
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    28-11-2013 - 19-12-2019 (treatment period only)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Simvastatin
    Reporting group description
    		 Simvastatin 40mg daily

    Reporting group title
    placebo
    Reporting group description
    		 placebo pill identical in shape, color and smell

    Serious adverse events
    		 Simvastatin placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 61 (6.56%)
    12 / 58 (20.69%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Psychiatric disorders
    Hospital admission for psychotic relapse
         subjects affected / exposed
    2 / 61 (3.28%)
    2 / 58 (3.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hospital admission for other psychiatric conditions
    Additional description: admissions for: anxiety, depression, substance abuse, suicidal behaviour, agression
         subjects affected / exposed
    4 / 61 (6.56%)
    11 / 58 (18.97%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Simvastatin placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    57 / 61 (93.44%)
    50 / 58 (86.21%)
    Vascular disorders
    Dizziness
         subjects affected / exposed
    2 / 61 (3.28%)
    7 / 58 (12.07%)
         occurrences all number
    3
    7
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 61 (13.11%)
    6 / 58 (10.34%)
         occurrences all number
    8
    6
    Sleep deficit
    Additional description: Sleep disturbance
         subjects affected / exposed
    5 / 61 (8.20%)
    7 / 58 (12.07%)
         occurrences all number
    5
    7
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    11 / 61 (18.03%)
    10 / 58 (17.24%)
         occurrences all number
    25
    15
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 61 (3.28%)
    4 / 58 (6.90%)
         occurrences all number
    2
    5
    Dyspepsia
         subjects affected / exposed
    5 / 61 (8.20%)
    3 / 58 (5.17%)
         occurrences all number
    6
    3
    Nausea
         subjects affected / exposed
    4 / 61 (6.56%)
    9 / 58 (15.52%)
         occurrences all number
    6
    12
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 61 (3.28%)
    5 / 58 (8.62%)
         occurrences all number
    2
    5
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    4 / 61 (6.56%)
    7 / 58 (12.07%)
         occurrences all number
    4
    7
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    10 / 61 (16.39%)
    3 / 58 (5.17%)
         occurrences all number
    13
    4
    Myalgia
         subjects affected / exposed
    13 / 61 (21.31%)
    13 / 58 (22.41%)
         occurrences all number
    13
    13
    Infections and infestations
    Influenza
         subjects affected / exposed
    12 / 61 (19.67%)
    12 / 58 (20.69%)
         occurrences all number
    14
    13

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jun 2014
    Amendment 1, June 2014 - Specification of exclusion due to elevated levels of creatine-kinase (i.e. elevated levels had to co-occur with previously experienced muscle toxicity or familial risk of muscular disorders). - Changes in patient information and informed consent o Addition of an instructional movie clip explaining the involvement of the immune system in psychosis o Storage of blood samples in the UMC Utrecht Biobank - Addition of outcome measures o Magnetic Resonance Imaging scans o Childhood Trauma Questionnaire o Blood samples o Movement disorders (SHRS and BARS) - Additions of study procedures o Urinary pregnancy test at screening
    01 Oct 2014
    Amendment 2, October 2014 - Addition of the University Medical Center Groningen as a study site
    01 Nov 2014
    Amendment 3, November 2014 - Change in study medication o Qualitative composition of the pills was not different from previous batch. The following batches will have a longer shelf life and a slightly different appearance. Placebo appearance was adjusted accordingly.
    01 Apr 2015
    Amendment 4, April 2015 - Changes in recruitment process o Via Utrecht Pharmacy Practice Network for Education Research o Via several mental health care organisations (i.e. GGZ-NHN, GGZ Ingeest, Altrecht GGZ, and Arkin/AMC).
    01 Apr 2017
    Amendment 5, April 2017 - Change in total number of subjects (new target: 150). o Change was made as a result of interim analyses and adjusted power calculations - Changes in patient information and informed consent o Voluntary option for sharing data with other research groups within the UMC Utrecht o Voluntary option for sharing data and material with other research groups outside the UMC Utrecht, specifically abroad. - Changes in recruitment process o Via several mental health care organisations (i.e. Reinier van Arkel, GGZ Centraal).

    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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