Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   44335   clinical trials with a EudraCT protocol, of which   7366   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    Vitamin D supplementation in cutaneous malignant melanoma outcome

    Summary
    EudraCT number
    		 2012-002125-30
    Trial protocol
    		 BE   HU  
    Global end of trial date
    25 Jul 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Oct 2024
    First version publication date
    11 Oct 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    2012LRDVDCM
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01748448
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UZLeuven / KULeuven
    Sponsor organisation address
    Herestraat 49, Leuven, Belgium, 3000
    Public contact
    Dermatology clinical trials, Dermatology, 0032 16337950, dermatologie-admin@uzleuven.ac.be
    Scientific contact
    Dermatology clinical trials, Dermatology, 0032 16337950, dermatologie-admin@uzleuven.ac.be
    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
    27 Jun 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Jul 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jul 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess whether vitamin D supplementation, in the follow up period after diagnosis and surgery of the primary tumor, has a protective effect on relapse of cutaneous malignant melanoma and whether this protective effect correlates with VDR immunoreactivity in the primary tumour.
    Protection of trial subjects
    A DSMB Committee has analysed key safety aspects (safety parameters and adverse events) in regular intervals during the ongoing trial to ensure patient safety. The DSMB was unblinded and composed of medical experts not involved in the study: a dermatologist, oncologist and statistician. They assessed the safety of patients based on the safety parameters and adverse events. In particular, at regular intervals an unblinded interim analysis was performed to assess the difference between the intervention arms and to exclude an increase in relapse rate in de vitamin D supplemented arm. No early stopping for efficacy was allowed. Safety aspects: - serum calcium, phosphorus, to detect for vitamin D intoxication (every 3 months) - measurement of total WBC and differential (every 6 months) and a record of infection rate (every 3 months) to check for immunosuppressive effects - Adverse clinical events
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Dec 2012
    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
    Hungary: 4
    Country: Number of subjects enrolled
    Belgium: 432
    Worldwide total number of subjects
    436
    EEA total number of subjects
    436
    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)
    321
    From 65 to 84 years
    115
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 After diagnosis, staging and surgical treatment, and after obtaining written informed consent, patient will undergo screening at the investigational site to ensure that the patient meets all other in- and exclusion criteria. Written informed consent must be obtained from patients prior to any study specific procedure.

    Pre-assignment
    Screening details
    		 Screening phase: Patients are recruited at the Departments of Dermatology, Oncosurgery or Medical Oncology at the University Hospitals Leuven (Belgium), and other European academic sites. If all eligibility criteria are met, patients are then randomized to the treatment or control group. Randomisation is completed via IVRS.

    Period 1
    Period 1 title
    Treatment period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst
    Blinding implementation details
    Vitamin D3 supplementation is given to the patients assigned to the treatment group and placebo to the control group in a double blind manner. The randomization schedule will be kept under closure at the data management centre. All other study staff members, dermatologists, trail nurses, and patients will be blinded to the treatment allocation. The DSMB members may be unblinded to assess the safety of the patients.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 D-Cure® (cholecalciferol)
    Arm description
    		 Name investigational product: D-Cure® (amp. cholecalciferol 100.000 U.I./ml) Content of 1 ml amp.: Cholecalciferol 100.000 U.I./ml -DL α-Tocopherol. acetas – Sorbitol. oleic. polyoxyaethylenat. - Aetherol. aurantii corticis dulcis - olie van olijfolie ad 1 ml Administration route: orally
    Arm type
    		 Active comparator

    Investigational medicinal product name
    D-Cure® (amp. cholecalciferol 100.000 U.I./ml)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    D-Cure® amp. 100.000 U.I/ml D-Cure® (oral ampoules) will be stored at room temperature, below 25 °C. Administration route: orally

    Arm title
    		 Placebo: Oil
    Arm description
    		 Name investigational product: Oil Oil will be used as matching placebo for vitamin D (cholecalciferol) Composition: Tocopherol Acetate, sweet orange peel oil, Polyglyceryl oleate, olive oil refined ad 1ml Administration route: orally
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo: Olive oil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The -Olive oil (oral ampoules) will be stored at room temperature, below 25°C. Administration route: orally

    Number of subjects in period 1
    		D-Cure® (cholecalciferol) Placebo: Oil
    Started
    218
    218
    Completed
    216
    217
    Not completed
    2
    1
         Consent withdrawn by subject
    1
    -
         Adverse event, non-fatal
    1
    -
         personal
    -
    1
    Period 2
    Period 2 title
    Follow-up period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst
    Blinding implementation details
    After the treatment period (in which the patients take study medication) (placebo or D-Cure), there is the follow-up period, no more study medication is taken, the study is still double-blind, and the patients are followed at the clinical department, Dermatology or Oncology, for relapse and/or death.

    Arms
    Arm title
    		 Follow up
    Arm description
    		 After the treatment period (in which the patients take study medication, placebo or D-Cure), there is the follow-up period, no more study-medication is taken, the study is still double-blind, and the patients are followed at the clinical department, Dermatology or Oncology, for relapse and/or death.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Follow up
    Started
    433
    Completed
    433

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    D-Cure® (cholecalciferol)
    Reporting group description
    		 Name investigational product: D-Cure® (amp. cholecalciferol 100.000 U.I./ml) Content of 1 ml amp.: Cholecalciferol 100.000 U.I./ml -DL α-Tocopherol. acetas – Sorbitol. oleic. polyoxyaethylenat. - Aetherol. aurantii corticis dulcis - olie van olijfolie ad 1 ml Administration route: orally

    Reporting group title
    Placebo: Oil
    Reporting group description
    		 Name investigational product: Oil Oil will be used as matching placebo for vitamin D (cholecalciferol) Composition: Tocopherol Acetate, sweet orange peel oil, Polyglyceryl oleate, olive oil refined ad 1ml Administration route: orally

    Reporting group values
    		 D-Cure® (cholecalciferol) Placebo: Oil Total
    Number of subjects
    		 218 218 436
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 157 164 321
        From 65-84 years
    		 61 54 115
    Age continuous
    Units: years
        median (standard deviation)
    		 54.9 ( 13.12 ) 55.0 ( 13.27 ) -
    Gender categorical
    Units: Subjects
        Female
    		 112 125 237
        Male
    		 106 93 199
    Current smoking
    Units: Subjects
        No
    		 99 76 175
        Yes
    		 33 37 70
        Never smoked
    		 85 105 190
        unknown
    		 1 0 1
    Education (highest level)
    Units: Subjects
        Primary
    		 9 8 17
        Secondary school
    		 75 68 143
        Vocational training
    		 43 40 83
        Vocational university
    		 62 59 121
        University graduated
    		 27 42 69
        Other
    		 1 1 2
        unknown
    		 1 0 1
    Naevus Phenotype_Number of benign naevi (>2mm)
    Units: Subjects
        <25
    		 93 91 184
        25-49
    		 63 49 112
        50-100
    		 37 44 81
        >100
    		 23 34 57
        unknown
    		 2 0 2
    Naevus Phenotype_Actinic Keratosis
    Units: Subjects
        Yes
    		 23 26 49
        No or unknown
    		 195 192 387
    Naevus Phenotype_Ephilides (freckles) on the face
    Units: Subjects
        yes
    		 45 35 80
        no or unknown
    		 173 183 356
    Naevus Phenotype_Idiopathic guttate hypomelanosis (legs and/or arms)
    Units: Subjects
        yes
    		 30 24 54
        no or unknown
    		 188 194 382
    Laboratory investigations_Serum phosphate
    Units: Subjects
        Not done
    		 1 1 2
        Within normal range
    		 197 196 393
        Outside normal range: not clinically significant
    		 20 21 41
    Pathology_Time of diagnosis
    Units: Subjects
        Newly diagnosed
    		 53 53 106
        Diagnosis <= 6 Months Ago
    		 105 102 207
        Diagnosis 6<-12 Months Ago
    		 60 63 123
    Pathology_Histological subtype
    Units: Subjects
        Nodular melanoma
    		 38 29 67
        Superficial spreading melanoma
    		 115 142 257
        Acrolentigineus melanoma
    		 8 6 14
        Lentigo maligna melanoma
    		 7 5 12
        Unknown
    		 23 21 44
        Other
    		 27 15 42
    Pathology_Clark
    Units: Subjects
        Level II
    		 9 10 19
        Level III
    		 78 72 150
        Level IV
    		 107 114 221
        Level V
    		 15 12 27
        Unknown
    		 9 10 19
    Pathology_Ulceration
    Units: Subjects
        Yes
    		 42 40 82
        No or unknown
    		 176 178 354
    Pathology_Mitoses
    Units: Subjects
        Yes
    		 189 187 376
        No or unknown
    		 29 31 60
    Pathology_VDR immuno-reactivity in the primary tumor
    Units: Subjects
        nul
    		 2 3 5
        1+
    		 62 57 119
        2+
    		 75 73 148
        3+
    		 20 19 39
        Failed
    		 6 11 17
        Not done
    		 53 55 108
    Metastasis and Staging_Sentinel Node Biopsy
    Units: Subjects
        Yes
    		 177 182 359
        No or unknown
    		 41 36 77
    Metastasis and Staging_Metastasis in Lymph Nodes
    Units: Subjects
        Yes
    		 34 33 67
        No or Unknown
    		 184 185 369
    Metastasis and Staging_Staging AJCC 8th edition
    Units: Subjects
        IA
    		 24 26 50
        IB
    		 101 108 209
        IIA
    		 29 30 59
        IIB
    		 18 14 32
        IIC
    		 10 6 16
        IIIA
    		 14 10 24
        IIIB
    		 9 8 17
        IIIC
    		 10 14 24
        IIID
    		 0 1 1
        IV
    		 1 0 1
        Unknown
    		 2 1 3
    Body Mass Index (BMI)
    Units: kg/m²
        arithmetic mean (standard deviation)
    		 27 ( 5 ) 27 ( 4 ) -
    Laboratory investigations_Vitamin-D
    Units: ng/ml
        median (inter-quartile range (Q1-Q3))
    		 24 (18 to 30) 21 (16 to 29) -
    Laboratory investigations_Vitamin-D
    Units: ng/ml
        arithmetic mean (standard deviation)
    		 24 ( 9 ) 23 ( 9 ) -
    Laboratory investigations_Serum calcium
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 9 ( 1 ) 10 ( 1 ) -
    Laboratory investigations_Serum calcium
    Units: mg/dL
        median (inter-quartile range (Q1-Q3))
    		 10 (9 to 10) 10 (9 to 10) -
    Pathology_Breslow
    Units: mm
        arithmetic mean (standard deviation)
    		 2 ( 2 ) 2 ( 2 ) -
    Pathology_Breslow
    Units: mm
        median (inter-quartile range (Q1-Q3))
    		 1 (1 to 2) 1 (1 to 2) -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    D-Cure® (cholecalciferol)
    Reporting group description
    		 Name investigational product: D-Cure® (amp. cholecalciferol 100.000 U.I./ml) Content of 1 ml amp.: Cholecalciferol 100.000 U.I./ml -DL α-Tocopherol. acetas – Sorbitol. oleic. polyoxyaethylenat. - Aetherol. aurantii corticis dulcis - olie van olijfolie ad 1 ml Administration route: orally

    Reporting group title
    Placebo: Oil
    Reporting group description
    		 Name investigational product: Oil Oil will be used as matching placebo for vitamin D (cholecalciferol) Composition: Tocopherol Acetate, sweet orange peel oil, Polyglyceryl oleate, olive oil refined ad 1ml Administration route: orally
    Reporting group title
    Follow up
    Reporting group description
    		 After the treatment period (in which the patients take study medication, placebo or D-Cure), there is the follow-up period, no more study-medication is taken, the study is still double-blind, and the patients are followed at the clinical department, Dermatology or Oncology, for relapse and/or death.

    Primary: Relapse-Free Survival_Death or relapse

    		 Close Top of page
    End point title
    		 Relapse-Free Survival_Death or relapse
    End point description
    The difference in relapse-free survival will be compared between the two treatment groups by means of a Cox proportional hazards model for interval censored data stratified for time since diagnosis (3 strata: 0, 6 or 12 months ago). The model will be fitted using PROC ICPHREG using the EMCIM algorithm and the baseline hazards will be estimated using cubic splines. The best fitting model using 2 to 5 degrees of freedom will be chosen based on Akaike Information Criterion (AIC). The hazard ratio with a 95% confidence interval and corresponding p-value will be reported. It will be verified whether the treatment effect is stratum dependent. This will be done by analysing each stratum separately and performing a Chi-square test to compare the treatment effect between the 3 strata. If found significant, the strata will be reported separately.
    End point type
    Primary
    End point timeframe
    Treatment period and follow up period
    End point values
    		 D-Cure® (cholecalciferol) Placebo: Oil
    Number of subjects analysed
    218
    218
    Units: number
        Death or Relapse
    41
    32
    Statistical analysis title
    		 Primary endpoint: relapse free survival
    Statistical analysis description
    A comparison between the 2 treatment groups was conducted using a COX proportional hazards model stratified by time since diagnosis. Tied survival times were managed usinf Efron's method.
    Comparison groups
    D-Cure® (cholecalciferol) v Placebo: Oil
    Number of subjects included in analysis
    436
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.324
    Method
    		 Fisher exact
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 2.03

    Primary: Relapse-Free Survival_Estimated Event Rates

    		 Close Top of page
    End point title
    		 Relapse-Free Survival_Estimated Event Rates
    End point description
    The difference in relapse-free survival will be compared between the two treatment groups by means of a Cox proportional hazards model for interval censored data stratified for time since diagnosis (3 strata: 0, 6 or 12 months ago). The model will be fitted using PROC ICPHREG using the EMCIM algorithm and the baseline hazards will be estimated using cubic splines. The best fitting model using 2 to 5 degrees of freedom will be chosen based on Akaike Information Criterion (AIC). The hazard ratio with a 95% confidence interval and corresponding p-value will be reported. It will be verified whether the treatment effect is stratum dependent. This will be done by analysing each stratum separately and performing a Chi-square test to compare the treatment effect between the 3 strata. If found significant, the strata will be reported separately.
    End point type
    Primary
    End point timeframe
    Overal period and follow up period
    End point values
    		 D-Cure® (cholecalciferol) Placebo: Oil
    Number of subjects analysed
    218
    218
    Units: Percentage
    number (confidence interval 95%)
        At 12 Months
    4.68 (2.54 to 8.52)
    7.24 (4.42 to 11.72)
        At 24 Months
    12.53 (8.64 to 18.01)
    9.34 (6.06 to 14.27)
        At 36 Months
    14.93 (10.60 to 20.83)
    11.76 (7.95 to 17.21)
        At 72 Months
    26.51 (19.37 to 35.64)
    20.70 (14.26 to 29.52)
    Statistical analysis title
    		 Primary endpoint: relapse free survival
    Statistical analysis description
    A comparison between the 2 treatment groups was conducted using a COX proportional hazards model stratified by time since diagnosis. Tied survival times were managed usinf Efron's method.
    Comparison groups
    D-Cure® (cholecalciferol) v Placebo: Oil
    Number of subjects included in analysis
    436
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.324
    Method
    		 Fisher exact
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 2.03

    Secondary: Melanoma-Related Death_melanoma/non-melanoma related death

    		 Close Top of page
    End point title
    		 Melanoma-Related Death_melanoma/non-melanoma related death
    End point description
    Melanoma related death will be analysed by a Fine and Gray model (Fine and Gray, 1999) stratified for time since diagnosis (3 strata: 0, 6 or 12 months ago) and in which non melanoma-related death is treated as a competing risk. The hazard ratio with a 95% confidence interval and corresponding p-value will be reported. In case the relation to melanoma is unknown, it will be analysed as related. A sensitivity analysis for which the assumption is made that the death is not related will be performed.
    End point type
    Secondary
    End point timeframe
    Treatment period and follow up period
    End point values
    		 D-Cure® (cholecalciferol) Placebo: Oil
    Number of subjects analysed
    218
    218
    Units: number
        Melanoma-Related Death
    10
    11
        Non-Melanoma Related Death
    3
    2
    No statistical analyses for this end point

    Secondary: Melanoma-Related Death_Estimated Event Rates

    		 Close Top of page
    End point title
    		 Melanoma-Related Death_Estimated Event Rates
    End point description
    Melanoma related death will be analysed by a Fine and Gray model (Fine and Gray, 1999) stratified for time since diagnosis (3 strata: 0, 6 or 12 months ago) and in which non melanoma-related death is treated as a competing risk. The hazard ratio with a 95
    End point type
    Secondary
    End point timeframe
    Treatment period and follow-up period
    End point values
    		 D-Cure® (cholecalciferol) Placebo: Oil
    Number of subjects analysed
    218
    218
    Units: percent
    number (confidence interval 95%)
        At 12.0 Months
    0.5 (0.0 to 2.5)
    0.5 (0.0 to 2.5)
        At 24.0 Months
    2.6 (1.0 to 5.6)
    2.1 (0.7 to 4.9)
        At 36.0 Months
    3.7 (1.6 to 7.2)
    3.2 (1.3 to 6.6)
        At 72.0 Months
    7.0 (3.3 to 12.6)
    8.1 (4.0 to 14.1)
    No statistical analyses for this end point

    Secondary: Overall Survival_ All-Cause death

    		 Close Top of page
    End point title
    		 Overall Survival_ All-Cause death
    End point description
    Overall survival will be analysed using a Cox proportional hazards model for right censored data stratified for time since diagnosis (3 strata: 0, 6 or 12 months ago). The hazard ratio with a 95% confidence interval and corresponding p-value will be reported. It will be verified whether the treatment effect is stratum dependent. This will be done by analysing each stratum separately and performing a Chi-square test to compare the treatment effect between the 3 strata. If found significant, the strata will be reported separately.
    End point type
    Secondary
    End point timeframe
    Treatment period and follow-up period
    End point values
    		 D-Cure® (cholecalciferol) Placebo: Oil
    Number of subjects analysed
    218
    218
    Units: number
        All-Cause Death
    13
    13
        All-Cause Death Within 72 Months
    13
    12
    No statistical analyses for this end point

    Secondary: Overall Survival_ Estimated Event Rates

    		 Close Top of page
    End point title
    		 Overall Survival_ Estimated Event Rates
    End point description
    Overall survival will be analysed using a Cox proportional hazards model for right censored data stratified for time since diagnosis (3 strata: 0, 6 or 12 months ago). The hazard ratio with a 95% confidence interval and corresponding p-value will be reported. It will be verified whether the treatment effect is stratum dependent. This will be done by analysing each stratum separately and performing a Chi-square test to compare the treatment effect between the 3 strata. If found significant, the strata will be reported separately.
    End point type
    Secondary
    End point timeframe
    Treatment period and follow-up period
    End point values
    		 D-Cure® (cholecalciferol) Placebo: Oil
    Number of subjects analysed
    218
    218
    Units: percent
    number (confidence interval 95%)
        At 12 Months
    0.48 (0.07 to 3.35)
    0.49 (0.07 to 3.44)
        At 24 Months
    2.59 (1.08 to 6.11)
    2.08 (0.78 to 5.44)
        At 36 Months
    3.74 (1.80 to 7.70)
    3.23 (1.46 to 7.06)
        At 72 Months
    11.83 (6.54 to 20.88)
    9.50 (5.19 to 17.04)
    No statistical analyses for this end point

    Secondary: Evolution of 25(OH)D3_Summary over Time (mean)

    		 Close Top of page
    End point title
    		 Evolution of 25(OH)D3_Summary over Time (mean)
    End point description
    The evolution of 25(OH)D3 serum levels will be described descriptively over time. In addition, the influence of a 10-fold genetic SNP on the baseline Vitamine D level will be investigated by means of an analysis of variance (ANOVA). For those patients randomized to the Vitamin D group, the changes in 25(OH)D3 serum level from baseline to 6 and 12 months will be compared for each genetic snip. A random intercept model with the 6- and 12-months measurement as response and the baseline value, time (6 or 12 months), a genetic snip and the interaction between time and snip as covariate will be fitted to the data. The change from baseline at 6 and 12 months by SNP will be reported with a 95% CI.
    End point type
    Secondary
    End point timeframe
    From baseline untill End of Study = Treatment period
    End point values
    		 D-Cure® (cholecalciferol) Placebo: Oil
    Number of subjects analysed
    218 [1]
    218 [2]
    Units: ng/ml
    arithmetic mean (standard deviation)
        Baseline
    24 ( 9 )
    23 ( 9 )
        Month 3
    40 ( 10 )
    21 ( 6 )
        Month 6
    43 ( 11 )
    23 ( 9 )
        Month 9
    38 ( 12 )
    25 ( 11 )
        Month 12
    44 ( 11 )
    24 ( 9 )
        Month 15
    39 ( 12 )
    21 ( 7 )
        Month 18
    44 ( 11 )
    24 ( 11 )
        Month 21
    40 ( 9 )
    27 ( 8 )
        Month 24
    42 ( 11 )
    24 ( 9 )
        Month 27
    44 ( 9 )
    21 ( 8 )
        Month 30
    44 ( 12 )
    27 ( 8 )
        Month 33
    40 ( 9 )
    29 ( 5 )
        Month 36
    40 ( 12 )
    25 ( 7 )
        Month 39
    38 ( 6 )
    21 ( 8 )
        Study End
    43 ( 12 )
    27 ( 9 )
    Notes
    [1] - Number of subjects is different from each time point.
    [2] - Number of subjects is different from each time point.
    No statistical analyses for this end point

    Secondary: Evolution of 25(OH)D3_Summary over Time (median)

    		 Close Top of page
    End point title
    		 Evolution of 25(OH)D3_Summary over Time (median)
    End point description
    The evolution of 25(OH)D3 serum levels will be described descriptively over time. In addition, the influence of a 10-fold genetic SNP on the baseline Vitamine D level will be investigated by means of an analysis of variance (ANOVA). For those patients randomized to the Vitamin D group, the changes in 25(OH)D3 serum level from baseline to 6 and 12 months will be compared for each genetic snip. A random intercept model with the 6- and 12-months measurement as response and the baseline value, time (6 or 12 months), a genetic snip and the interaction between time and snip as covariate will be fitted to the data. The change from baseline at 6 and 12 months by SNP will be reported with a 95% CI.
    End point type
    Secondary
    End point timeframe
    From baseline untill End of Study = Treatment period
    End point values
    		 D-Cure® (cholecalciferol) Placebo: Oil
    Number of subjects analysed
    218 [3]
    218 [4]
    Units: ng/ml
    median (inter-quartile range (Q1-Q3))
        Baseline
    24 (18 to 30)
    21 (16 to 29)
        Month 3
    38 (33 to 51)
    20 (18 to 23)
        Month 6
    41 (36 to 49)
    24 (17 to 30)
        Month 9
    37 (27 to 46)
    21 (17 to 34)
        Month 12
    44 (36 to 51)
    22 (18 to 28)
        Month 15
    38 (31 to 42)
    21 (16 to 26)
        Month 18
    44 (36 to 50)
    23 (18 to 30)
        Month 21
    38 (32 to 47)
    25 (23 to 26)
        Month 24
    42 (35 to 50)
    24 (18 to 29)
        Month 27
    40 (38 to 51)
    18 (17 to 30)
        Month 30
    46 (34 to 53)
    26 (20 to 32)
        Month 33
    39 (34 to 44)
    29 (26 to 32)
        Month 36
    39 (31 to 48)
    24 (20 to 29)
        Month 39
    36 (34 to 41)
    21 (15 to 26)
        Study End
    42 (34 to 50)
    27 (20 to 33)
    Notes
    [3] - Number of subjects is different in all timepoints
    [4] - Number of subjects is different in all timepoints
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    In this study, the collection period for adverse events starts at randomisation and ends when the patient completes the study or at premature termination. (untill end of overall period)
    Adverse event reporting additional description
    The investigator will use the following terms to assess the severity of the adverse event: mild, moderate, severe The investigator will use the following causality terms to assess the relationship of the adverse event or clinical efficacy event to the use of the investigational medicinal product: Reasonable causal relationship or not.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26
    Reporting groups
    Reporting group title
    Adverse events_Control group
    Reporting group description
    		 An adverse event (AE) is defined as any untoward medical occurrence in a patient administered an investigational medicinal product and which does not necessarily have a causal relationship with this treatment.

    Reporting group title
    Adverse events_Vit-D group
    Reporting group description
    		 An adverse event (AE) is defined as any untoward medical occurrence in a patient administered an investigational medicinal product and which does not necessarily have a causal relationship with this treatment.

    Serious adverse events
    		 Adverse events_Control group Adverse events_Vit-D group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    33 / 218 (15.14%)
    28 / 218 (12.84%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified
         subjects affected / exposed
    5 / 218 (2.29%)
    6 / 218 (2.75%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 218 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Surgical and medical procedures
         subjects affected / exposed
    6 / 218 (2.75%)
    6 / 218 (2.75%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General disorders and administration site conditions
         subjects affected / exposed
    3 / 218 (1.38%)
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Reproductive system and breast disorders
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 218 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychiatric disorders
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 218 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    2 / 218 (0.92%)
    4 / 218 (1.83%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Nervous system disorders
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Ear and labyrinth disorders
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Eye disorders
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    5 / 218 (2.29%)
    3 / 218 (1.38%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatobiliary disorders
         subjects affected / exposed
    1 / 218 (0.46%)
    2 / 218 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
         subjects affected / exposed
    2 / 218 (0.92%)
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    2 / 218 (0.92%)
    3 / 218 (1.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Endocrine disorders
         subjects affected / exposed
    0 / 218 (0.00%)
    2 / 218 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    4 / 218 (1.83%)
    4 / 218 (1.83%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    1 / 218 (0.46%)
    3 / 218 (1.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Adverse events_Control group Adverse events_Vit-D group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    178 / 218 (81.65%)
    180 / 218 (82.57%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
         subjects affected / exposed
    11 / 218 (5.05%)
    18 / 218 (8.26%)
         occurrences all number
    13
    24
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    1 / 218 (0.46%)
    2 / 218 (0.92%)
         occurrences all number
    1
    2
    Surgical and medical procedures
    Surgical and medical procedures
         subjects affected / exposed
    16 / 218 (7.34%)
    14 / 218 (6.42%)
         occurrences all number
    17
    16
    Pregnancy, puerperium and perinatal conditions
    Pregnancy, puerperium and perinatal conditions
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 218 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    General disorders and administration site conditions
         subjects affected / exposed
    32 / 218 (14.68%)
    36 / 218 (16.51%)
         occurrences all number
    44
    47
    Reproductive system and breast disorders
    Reproductive system and breast disorders
         subjects affected / exposed
    6 / 218 (2.75%)
    6 / 218 (2.75%)
         occurrences all number
    6
    6
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    46 / 218 (21.10%)
    29 / 218 (13.30%)
         occurrences all number
    63
    42
    Psychiatric disorders
    Psychiatric disorders
         subjects affected / exposed
    2 / 218 (0.92%)
    1 / 218 (0.46%)
         occurrences all number
    2
    1
    Product issues
    Product issues
         subjects affected / exposed
    1 / 218 (0.46%)
    42 / 218 (19.27%)
         occurrences all number
    1
    44
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    7 / 218 (3.21%)
    9 / 218 (4.13%)
         occurrences all number
    7
    13
    Nervous system disorders
    Nervous system disorders
         subjects affected / exposed
    7 / 218 (3.21%)
    15 / 218 (6.88%)
         occurrences all number
    7
    16
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
         subjects affected / exposed
    3 / 218 (1.38%)
    8 / 218 (3.67%)
         occurrences all number
    3
    10
    Ear and labyrinth disorders
    Ear and labyrinth disorders
         subjects affected / exposed
    4 / 218 (1.83%)
    7 / 218 (3.21%)
         occurrences all number
    5
    7
    Eye disorders
    Eye disorders
         subjects affected / exposed
    5 / 218 (2.29%)
    9 / 218 (4.13%)
         occurrences all number
    5
    9
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    29 / 218 (13.30%)
    33 / 218 (15.14%)
         occurrences all number
    38
    36
    Hepatobiliary disorders
    Hepatobiliary disorders
         subjects affected / exposed
    2 / 218 (0.92%)
    5 / 218 (2.29%)
         occurrences all number
    2
    6
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
         subjects affected / exposed
    22 / 218 (10.09%)
    35 / 218 (16.06%)
         occurrences all number
    36
    57
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    13 / 218 (5.96%)
    17 / 218 (7.80%)
         occurrences all number
    19
    20
    Endocrine disorders
    Endocrine disorders
         subjects affected / exposed
    99 / 218 (45.41%)
    44 / 218 (20.18%)
         occurrences all number
    132
    50
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    37 / 218 (16.97%)
    39 / 218 (17.89%)
         occurrences all number
    51
    67
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    55 / 218 (25.23%)
    57 / 218 (26.15%)
         occurrences all number
    82
    72
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders
         subjects affected / exposed
    1 / 218 (0.46%)
    2 / 218 (0.92%)
         occurrences all number
    1
    2

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Apr 2013
    Protocol, version 2, 22-03-2013: Adjust in/exclusion criteria
    13 Sep 2013
    Protocol, version 3, 20-08-2013: Addition of new centers
    23 Dec 2015
    Protocol, version 4, 25-11-2015: Change of in-and exclusion criteria, reporting certain abnormal lab values as an adverse event
    19 Oct 2017
    Protocol, version 5, 27-09-2017: Medication change: from 4 oral syringes of 25000 units to 1 ampoule of 100000 units
    26 Mar 2018
    Protocol, version 6, 20-02-2018: Adjustment of Adverse events
    25 Apr 2019
    Protocol, version 7, 19-03-2019: Change of address and addition of additional financing
    17 May 2021
    Protocol, version 8, 05-01-2021: Information about SNPs analysis in lab of VIB

    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/38913652
    http://www.ncbi.nlm.nih.gov/pubmed/28835228
    http://www.ncbi.nlm.nih.gov/pubmed/35312026
    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.

    European Medicines Agency © 1995-Sat May 10 01:08:05 CEST 2025 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA