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    Clinical Trial Results:
    A randomised, double-blind, placebo-controlled, parallel-group trial of Vitamin D supplementation compared to placebo in people presenting with their First Episode of psychosis (DFEND) Neuroprotection Design

    Summary
    EudraCT number
    2014-002639-32
    Trial protocol
    GB  
    Global end of trial date
    20 Dec 2019

    Results information
    Results version number
    v2(current)
    This version publication date
    11 Jul 2021
    First version publication date
    10 Feb 2021
    Other versions
    v1
    Version creation reason
    • New data added to full data set
    • Correction of full data set
    • Changes to summary attachments
    Results delayed by COVID available to be posted
    Summary report(s)
    Clinical Study report

    Trial information

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    Trial identification
    Sponsor protocol code
    3310
    Additional study identifiers
    ISRCTN number
    ISRCTN12424842
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    King's College London
    Sponsor organisation address
    The Strand, London, United Kingdom, WC2R 2LS
    Public contact
    Dr Fiona Gaughran, Institute of Psychiatry, +44 2032286000, fiona.1.gaughran@kcl.ac.uk
    Scientific contact
    Dr Fiona Gaughran, Institute of Psychiatry, +44 2032286000, fiona.1.gaughran@kcl.ac.uk
    Sponsor organisation name
    South London and Maudsley NHS Foundation Trust
    Sponsor organisation address
    Denmark Hill, London, United Kingdom, SE5 8AZ
    Public contact
    Dr Fiona Gaughran, Institute of Psychiatry, +44 2032286000, fiona.1.gaughran@kcl.ac.uk
    Scientific contact
    Dr Fiona Gaughran, Institute of Psychiatry, +44 2032286000, fiona.1.gaughran@kcl.ac.uk
    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
    20 Dec 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Dec 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Dec 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine whether the addition of 120,000 IU monthly of vitamin D (cholecalciferol) supplement to standard treatments is more effective than placebo in improving outcomes (Positive And Negative Syndrome Scale Total score – PANSS) at six month follow-up in those with First Episode Psychosis.
    Protection of trial subjects
    Patients are free to withdraw consent for study treatment and/or consent to participate in the study at any time and without the prejudice to further treatment. Patients who withdraw from study treatment, but are willing to continue to participate in the follow-up visits, should be followed according to the procedures outlined in the protocol. The role of the trial steering committee for this trial was to provide independent oversight of ethical and safety aspects of the trial
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    19 Jan 2016
    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
    United Kingdom: 149
    Worldwide total number of subjects
    149
    EEA total number of subjects
    149
    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)
    149
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Recruitment took place from 19th Jan 2016 to 14th June 2019 at 5 NHS sites within the English Mental Health Care System. Participants were recruited from two sources within the involved centres: community mental health services and inpatient services.

    Pre-assignment
    Screening details
    All patients within Early Intervention Services and First Episode Psychosis inpatient units who met the eligibility criteria were invited to participate in the study. Members of the research team regularly attended community team bases and wards to talk to staff and potentially interested patients.

    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, Data analyst, Assessor
    Blinding implementation details
    Blinded members of staff included all research team members at site level including chief investigator (CI), principal investigator (PI), researchers conducting participant follow ups and trial statisticians. Throughout the trial, no emergency unblinding occurred.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Vitamin D
    Arm description
    The IMP was given orally as a 6mL dose of liquid, via a syringe. This corresponded to 120,000 IU of vitamin D3. Placebo was administered the same way.
    Arm type
    Experimental

    Investigational medicinal product name
    Cholecalciferol
    Investigational medicinal product code
    Other name
    Vigantol Oil, Vitamin D3
    Pharmaceutical forms
    Oral drops, solution
    Routes of administration
    Oral use
    Dosage and administration details
    Cholecalciferol (vitamin D3), 120,000 IU per month (equivalent to 4,000 IU per day), was given orally as Vigantol® oil (by Merck GmbH) cholecalciferol dispersed in triglyceride oil as vehicle; containing 20,000 IU cholecalciferol per 1ml drop, and administered as 6mL given in a graduated oral syringe by a fully trained member of the research team for 6 months.

    Arm title
    Placebo
    Arm description
    The comparator drug of Vigantol® oil will be achieved by using an organoleptically matched triglyceride oil (Miglyol® 812 oil) for the placebo.
    Arm type
    Placebo

    Investigational medicinal product name
    Miglyol® 812 oil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops, solution
    Routes of administration
    Oral use
    Dosage and administration details
    Active and placebo treatment will be administered orally as 6mL given in a graduated oral syringe by a trained researcher once a month for 6 months.

    Number of subjects in period 1
    Vitamin D Placebo
    Started
    74
    75
    Completed
    50
    54
    Not completed
    24
    21
         Consent withdrawn by subject
    7
    11
         Physician decision
    4
    1
         Lost to follow-up
    10
    6
         moved out of area
    3
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Vitamin D
    Reporting group description
    The IMP was given orally as a 6mL dose of liquid, via a syringe. This corresponded to 120,000 IU of vitamin D3. Placebo was administered the same way.

    Reporting group title
    Placebo
    Reporting group description
    The comparator drug of Vigantol® oil will be achieved by using an organoleptically matched triglyceride oil (Miglyol® 812 oil) for the placebo.

    Reporting group values
    Vitamin D Placebo Total
    Number of subjects
    74 75 149
    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 of the study population
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    27.76 ± 8.74 28.39 ± 8.39 -
    Gender categorical
    Units: Subjects
        Female
    23 37 60
        Male
    51 38 89
    Baseline CDS score
    Calgary Depression Scale (CDS) is a nine-item scale that assesses the level of depression, higher scores being worse. Scores are attributed by the researcher following an interview with the participant. There was one missing value in each of the trial arms.
    Units: score
        arithmetic mean (standard deviation)
    5.37 ± 5.26 5.95 ± 5.24 -
    Baseline GAF Disability score
    The GAF (Global Assessment of Functioning) has two scores (Disability and Symptoms) rated by a study researcher on a patient’s functioning, scores range from 100 to 1 with lower scores being worse. There were no missing values for the baseline GAF scores.
    Units: score
        arithmetic mean (standard deviation)
    62.28 ± 14.52 62.59 ± 16.87 -
    Baseline GAF Symptom score
    Units: score
        arithmetic mean (standard deviation)
    61.51 ± 14.51 62.77 ± 16.27 -
    Baseline PANSS total score
    The Positive and Negative Syndrome Scale (PANSS) measures symptom severity of psychosis, with subscales measuring positive symptoms, negative symptoms and generally psychopathology. Lower scores indicate less severe symptoms, and better clinical outcome. There were no missing values for the baseline PANSS total score or subscores.
    Units: score
        arithmetic mean (standard deviation)
    56.5 ± 12.38 57.28 ± 14.27 -

    End points

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    End points reporting groups
    Reporting group title
    Vitamin D
    Reporting group description
    The IMP was given orally as a 6mL dose of liquid, via a syringe. This corresponded to 120,000 IU of vitamin D3. Placebo was administered the same way.

    Reporting group title
    Placebo
    Reporting group description
    The comparator drug of Vigantol® oil will be achieved by using an organoleptically matched triglyceride oil (Miglyol® 812 oil) for the placebo.

    Primary: Month 6 PANSS total score

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    End point title
    Month 6 PANSS total score
    End point description
    End point type
    Primary
    End point timeframe
    The Positive and Negative Syndrome Scale (PANSS) measures symptom severity of psychosis, with subscales measuring positive symptoms, negative symptoms and generally psychopathology. Lower scores indicate less severe symptoms, and better clinical outcome.
    End point values
    Vitamin D Placebo
    Number of subjects analysed
    50
    53
    Units: score
        arithmetic mean (standard deviation)
    55.88 ± 17.46
    53.04 ± 14.16
    Statistical analysis title
    Mean Difference (VitD – placebo)
    Comparison groups
    Vitamin D v Placebo
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.293
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.981
         upper limit
    2.125
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.294

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    IMP allocation to 28 days post last dose
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Vitamin D
    Reporting group description
    The IMP was given orally as a 6mL dose of liquid, via a syringe. This corresponded to 120,000 IU of vitamin D3. Placebo was administered the same way.

    Reporting group title
    Placebo
    Reporting group description
    The comparator drug of Vigantol® oil will be achieved by using an organoleptically matched triglyceride oil (Miglyol® 812 oil) for the placebo.

    Serious adverse events
    Vitamin D Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 74 (8.11%)
    12 / 75 (16.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    0 / 74 (0.00%)
    2 / 75 (2.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    acid reflux
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychotic behaviour
    Additional description: psychotic exacerbation
         subjects affected / exposed
    2 / 74 (2.70%)
    8 / 75 (10.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    deterioration in mental health
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Persecutory delusion
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressive symptom
    Additional description: DEPRESSIVE EPISODE WITH FEATURES OF PSYCHOSIS
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination, visual
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination, olfactory
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 75 (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: 1%
    Non-serious adverse events
    Vitamin D Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    29 / 74 (39.19%)
    37 / 75 (49.33%)
    General disorders and administration site conditions
    Fall
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 75 (0.00%)
         occurrences all number
    2
    0
    lack of motivation
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    restless legs
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Immune system disorders
    Immunology test abnormal
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Respiratory disorder
         subjects affected / exposed
    13 / 74 (17.57%)
    4 / 75 (5.33%)
         occurrences all number
    13
    4
    Psychiatric disorders
    Psychological disorder
         subjects affected / exposed
    13 / 74 (17.57%)
    21 / 75 (28.00%)
         occurrences all number
    13
    21
    Investigations
    raised ALT & Albumin
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    high cholesterol
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 75 (1.33%)
         occurrences all number
    1
    1
    high triglycerides
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Blood neutrophil count decreased
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Cardiac disorders
    Cardiovascular disorder
         subjects affected / exposed
    2 / 74 (2.70%)
    2 / 75 (2.67%)
         occurrences all number
    2
    2
    Nervous system disorders
    Neurological examination abnormal
         subjects affected / exposed
    1 / 74 (1.35%)
    3 / 75 (4.00%)
         occurrences all number
    1
    3
    Blood and lymphatic system disorders
    Haematology test abnormal
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Ear infection
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    0 / 74 (0.00%)
    2 / 75 (2.67%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Gastrointestinal disorder
         subjects affected / exposed
    14 / 74 (18.92%)
    11 / 75 (14.67%)
         occurrences all number
    14
    11
    Hepatobiliary disorders
    Hepatic disorder
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatologic examination abnormal
         subjects affected / exposed
    1 / 74 (1.35%)
    12 / 75 (16.00%)
         occurrences all number
    1
    1
    Renal and urinary disorders
    Urinary tract disorder
         subjects affected / exposed
    1 / 74 (1.35%)
    3 / 75 (4.00%)
         occurrences all number
    1
    3
    Endocrine disorders
    Endocrine disorder
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 75 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal disorder
         subjects affected / exposed
    3 / 74 (4.05%)
    5 / 75 (6.67%)
         occurrences all number
    3
    5
    Infections and infestations
    Sinusitis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    0
    Wisdom teeth removal
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    Toothache
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jan 2017
    Definition of First Episode Psychosis (FEP) changed from “within 6 months of presenting to services” to “within 3 years of presenting to services”. Impact to inclusion criteria.
    27 Jun 2017
    Vitamin D supplement of 400 IU/day was allowed in both treatment arms.
    07 Sep 2017
    Inclusion age increased from 45 to 65 years. Removal of concomitant anticonvulsant therapy from exclusion criteria. Study length reduced from 12 months to 6 months. Change in SAE reporting so that hospitalisations for worsening of mental health symptoms would be recorded as SAEs but not reportable to Sponsor. Blood HCG sample was permitting for pregnancy testing if urine sample could not be provided. Definition of visit window was defined as -2/+2 weeks and 21 days in between doses.
    10 Jul 2018
    Time between doses increased to 24 days. Clarification of window for collection of final assessment -4/+6 weeks from Month 6 anchor date. Pregnancy test not required if medically sterile or post-menopause. Vitamin D levels will be sent to GP at the end of the study.
    07 Jun 2019
    Clarification that AEs were collected until 28-days after the last dose of IMP (if no dose at last visit then no follow-up is needed)

    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/31907006
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