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    Clinical Trial Results:
    Can Vitamin D supplementation improve Hepatitis C cure rates: A pilot multicentre randomised controlled clinical trial

    Summary
    EudraCT number
    		 2013-003573-10
    Trial protocol
    		 GB  
    Global end of trial date
    22 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 May 2017
    First version publication date
    13 May 2017
    Other versions
    Summary report(s)
    		 Summary results viaduct

    Trial information

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    Trial identification
    Sponsor protocol code
    2012GA03
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02053519
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Sponsor R&D number: 2012GA03
    Sponsors
    Sponsor organisation name
    University of Dundee
    Sponsor organisation address
    Ninewells Hospital, Dundee, United Kingdom, DD1 9SY
    Public contact
    Prof John Dillon, University of Dundee, 44 01382383017, j.f.dillon@dundee.ac.uk
    Scientific contact
    Prof John Dillon, University of Dundee, 44 01382383017, j.f.dillon@dundee.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
    05 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 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
    The primary objective is to test if vitamin D supplementation improves the chances of standard treatment for HCV infection being effective. To test this we will measure if there is an improvement in the virologic response - ie the level of virus in the blood, 12 weeks after completion of treatment.
    Protection of trial subjects
    Trial exclusion criteria were designed to minimize the risk of hypercalcemia or renal stones (know side effects of vitamin D therapy); drug exclusions were designed to minimize the risk of interactions with vitamin D. Adverse events were sought at each clinic visit; the directly observed nature of the vitamin D administration once a month ensured close observation of participants throughout the trial.
    Background therapy
    		 Standard HCV therapy was commenced 1-4 weeks after the first dose of vitamin D or placebo. Standard treatment for HCV is generally for 24 weeks. Some genotype 1 patients who do not respond to therapy at week 4 or 12 will have all anti-viral therapy stopped. Other genotype 1 patients who respond but do not become virus negative by 12 weeks of therapy will continue on a further 24 week course of standard therapy, total duration 48 weeks. Standard therapy for HCV genotype 1 patients changed as the trial commenced and some patients received sofosbuvir in addition to interferon for 12 weeks.
    Evidence for comparator
    		 Placebo was selected (in addition to standard therapy) as the aim of the trial was to test efficacy of vitamin D in addition to standard therapy, rather than instead of standard therapy.
    Actual start date of recruitment
    01 Nov 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
    United Kingdom: 72
    Worldwide total number of subjects
    72
    EEA total number of subjects
    72
    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)
    72
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited from hepatitis C treatment services across multiple Scottish secondary care sites

    Pre-assignment
    Screening details
    		 At the screening visit all participants had their medical history taken and gave written informed consent. Confirmation of HCV diagnosis by viral genotype and viral load by PCR was taken from the last available values in the medical notes.

    Period 1
    Period 1 title
    Randomised treatment (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
    Blinding implementation details
    Matching IMP and placebo (base oil) were prepared by an independent provider (Tayside Pharmaceuticals) who dispensed identical bottles with no external indication of allocation group

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Vitamin D3
    Arm description
    		 Oral vitamin D3 100,000 units once per month
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cholecalciferol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    100,000 units once a month, given as 5mls of 20,000 units/ml product (Vigantol oil)

    Arm title
    		 Placebo
    Arm description
    		 Matching placebo given once a month
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    5mls of matching placebo (Mygliol oil as used as base oil in Vigantol oil preparation) given once a month

    Number of subjects in period 1
    		Vitamin D3 Placebo
    Started
    35
    37
    Completed
    30
    30
    Not completed
    5
    7
         Lost to follow-up
    5
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Vitamin D3
    Reporting group description
    		 Oral vitamin D3 100,000 units once per month

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo given once a month

    Reporting group values
    		 Vitamin D3 Placebo Total
    Number of subjects
    		 35 37 72
    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)
    		 42.5 ( 11.6 ) 41.7 ( 8.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 10 13 23
        Male
    		 25 24 49

    End points

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    End points reporting groups
    Reporting group title
    Vitamin D3
    Reporting group description
    		 Oral vitamin D3 100,000 units once per month

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo given once a month

    Subject analysis set title
    ITT analysis set
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All participants with a value for the primary outcome (SVR12)

    Primary: SVR12 (sustained virologic response at 12 weeks)

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    End point title
    		 SVR12 (sustained virologic response at 12 weeks)
    End point description
    Sustained virologic response 12 weeks after stopping treatment. Response = undetectable Hep C RNA at any point beyond 12 weeks post end of interferon-based treatment. Missing data analysed as treatment failure.
    End point type
    Primary
    End point timeframe
    12 weeks after cessation of standard (interferon based) Hep C treatment
    End point values
    		 Vitamin D3 Placebo ITT analysis set
    Number of subjects analysed
    35
    37
    72
    Units: patients
        Treatment success
    29
    27
    56
        Treatment failure
    6
    10
    16
    Statistical analysis title
    		 Adjusted odds ratio for treatment success
    Comparison groups
    Vitamin D3 v Placebo
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.44
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 6.97

    Secondary: Time to stopping standard treatment (adherence)

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    End point title
    		 Time to stopping standard treatment (adherence)
    End point description
    Time to stopping standard (interferon-based) treatment as a measure of adherence; comparison between vitamin D and placebo groups
    End point type
    Secondary
    End point timeframe
    Baseline to 48 weeks
    End point values
    		 Vitamin D3 Placebo
    Number of subjects analysed
    35
    37
    Units: days
        median (inter-quartile range (Q1-Q3))
    195 (112 to 270)
    224 (119 to 303)
    Statistical analysis title
    		 Hazard ratio-time to stopping standard treatment
    Statistical analysis description
    Cox regression analysis
    Comparison groups
    Placebo v Vitamin D3
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.33
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 2.09

    Secondary: 25-hydroxyvitamin D levels

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    End point title
    		 25-hydroxyvitamin D levels
    End point description
    Change from baseline averaged over follow up period
    End point type
    Secondary
    End point timeframe
    Baseline to 48 weeks
    End point values
    		 Vitamin D3 Placebo
    Number of subjects analysed
    35
    37
    Units: nmol/L
        arithmetic mean (standard deviation)
    16.7 ( 39.5 )
    -7.9 ( 21.8 )
    Statistical analysis title
    		 Between group difference in 25OHD levels
    Comparison groups
    Vitamin D3 v Placebo
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    24.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 12.2
         upper limit
    		 37.2

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Screening visit to 48 weeks (final visit)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    Vitamin D3
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 Vitamin D3 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 37 (5.41%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
    Additional description: Ulcer on leg
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Intentional overdose
    Additional description: Intentional heroin overdose
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Vitamin D3 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 35 (80.00%)
    31 / 37 (83.78%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 35 (2.86%)
    6 / 37 (16.22%)
         occurrences all number
    1
    6
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    6 / 35 (17.14%)
    8 / 37 (21.62%)
         occurrences all number
    6
    9
    Vomiting
         subjects affected / exposed
    3 / 35 (8.57%)
    3 / 37 (8.11%)
         occurrences all number
    3
    4
    Appetite disorder
         subjects affected / exposed
    2 / 35 (5.71%)
    3 / 37 (8.11%)
         occurrences all number
    2
    3
    Throat irritation
         subjects affected / exposed
    3 / 35 (8.57%)
    2 / 37 (5.41%)
         occurrences all number
    3
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 35 (8.57%)
    3 / 37 (8.11%)
         occurrences all number
    3
    3
    Influenza-like illness
         subjects affected / exposed
    2 / 35 (5.71%)
    2 / 37 (5.41%)
         occurrences all number
    2
    2
    Respiratory tract infection
         subjects affected / exposed
    4 / 35 (11.43%)
    1 / 37 (2.70%)
         occurrences all number
    8
    1
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    4 / 35 (11.43%)
    7 / 37 (18.92%)
         occurrences all number
    5
    7
    Pruritis
         subjects affected / exposed
    5 / 35 (14.29%)
    3 / 37 (8.11%)
         occurrences all number
    5
    3
    Rash
         subjects affected / exposed
    4 / 35 (11.43%)
    2 / 37 (5.41%)
         occurrences all number
    5
    2
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    6 / 35 (17.14%)
    6 / 37 (16.22%)
         occurrences all number
    6
    6
    Renal and urinary disorders
    Urinary tract infection
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 37 (0.00%)
         occurrences all number
    4
    0
    Metabolism and nutrition disorders
    Weight decreased
         subjects affected / exposed
    4 / 35 (11.43%)
    0 / 37 (0.00%)
         occurrences all number
    4
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Oct 2013
    Revision of protocol to v2.0 with additional exclusion criteria added

    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.
    Recruited fewer participants than originally powered for. Changes in background therapy for hepatitis C mean results may not now be applicable to current standard of care. High cure rates in placebo group limit ability to detect treatment effect.
    For support, Contact us.
    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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