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    Clinical Trial Results:
    Vitamin D supplementation to palliative cancer patients - A double blind, randomised controlled trial

    Summary
    EudraCT number
    		 2017-000268-14
    Trial protocol
    		 SE  
    Global end of trial date
    21 May 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Nov 2021
    First version publication date
    14 Nov 2021
    Other versions
    Summary report(s)
    		 Clinical Study Report for Palliative D

    Trial information

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    Trial identification
    Sponsor protocol code
    170113
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Stockholms Läns Landsting
    Sponsor organisation address
    Bergtallsvägen 12, Stockholm, Sweden, 12559
    Public contact
    Linda Björkhem-Bergman, ASIH Stockholm Södra, Långbro Park, linda.bjorkhem-bergman@ki.se
    Scientific contact
    Linda Björkhem-Bergman, ASIH Stockholm Södra, Långbro Park, linda.bjorkhem-bergman@ki.se
    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
    21 May 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 May 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    21 May 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to test the hypothesis vitamin D supplementation for 12 weeks reduces opioid consumption.
    Protection of trial subjects
    All collected data was coded with study numbers
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Aug 2017
    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
    Sweden: 244
    Worldwide total number of subjects
    244
    EEA total number of subjects
    244
    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)
    87
    From 65 to 84 years
    143
    85 years and over
    14

    Subject disposition

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    Recruitment
    Recruitment details
    		 ‘Palliative-D’ was a multicenter, double-blind parallel group, 1:1, randomized, placebo-controlled trial performed at three palliative care facilities in Stockholm, Sweden; ASIH Stockholm Södra, ASIH Stockholm Norr and ASIH Stockholms Sjukhem.

    Pre-assignment
    Screening details
    		 Included patients were admitted to one of the three recruiting palliative care facilities, ≥18 years old, had advanced and/or metastatic cancer in palliative phase (any type of cancer), a life expectancy of at least three months as assessed by one of the three study physician and 25-OHD ≤50 nmol/L. Ongoing oncological treatment was allowed.

    Period 1
    Period 1 title
    Nov 2017 - June 2020 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer
    Blinding implementation details
    Trial masking for patients, trial staff and care providers continued until data had been analysed.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Vitamin D
    Arm description
    		 Patients were randomly assigned 1:1 to vitamin D3 oil drops (colour and taste matched) 4000 IU/day or placebo (oil drops) for 12 weeks, dispensed in identical, sequentially numbered bottles. Randomization was performed using a computer-generated randomization list to generate a permutated block randomization with a block size of four. Randomization was not stratified. Trial masking for patients, trial staff and care providers continued until data had been analysed. Detremin 20 000 IU/ml (cholecalciferol solved in Miglyol oil) and placebo (Miglyol oil) were prepared according to Good Manufacturing Practice by Nextpharma. Eurofins LC2, a centralized randomization unit, was responsible for labelling, blinding, and randomization. Detremin was provided from Renapharma Sweden, and placebo was from Nextpharma, France.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Detremin
    Investigational medicinal product code
    Other name
    cholecalciferol solved in Miglyol oil
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were randomly assigned 1:1 to vitamin D3 oil drops (colour and taste matched) 4000 IU/day or placebo (oil drops) for 12 weeks, dispensed in identical, sequentially numbered bottles. Detremin 20 000 IU/ml (cholecalciferol solved in Miglyol oil) and placebo (Miglyol oil) were prepared according to Good Manufacturing Practice by Nextpharma. Eurofins LC2, a centralized randomization unit, was responsible for labelling, blinding, and randomization. Detremin was provided from Renapharma Sweden, and placebo was from Nextpharma, France.

    Arm title
    		 Placebo
    Arm description
    		 Patients were randomly assigned 1:1 to vitamin D3 oil drops (colour and taste matched) 4000 IU/day or placebo (oil drops) for 12 weeks, dispensed in identical, sequentially numbered bottles. Randomization was performed using a computer-generated randomization list to generate a permutated block randomization with a block size of four. Randomization was not stratified. Trial masking for patients, trial staff and care providers continued until data had been analysed. Detremin 20 000 IU/ml (cholecalciferol solved in Miglyol oil) and placebo (Miglyol oil) were prepared according to Good Manufacturing Practice by Nextpharma. Eurofins LC2, a centralized randomization unit, was responsible for labelling, blinding, and randomization. Detremin was provided from Renapharma Sweden, and placebo was from Nextpharma, France.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Detremin
    Investigational medicinal product code
    Other name
    cholecalciferol solved in Miglyol oil
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were randomly assigned 1:1 to vitamin D3 oil drops (colour and taste matched) 4000 IU/day or placebo (oil drops) for 12 weeks, dispensed in identical, sequentially numbered bottles. Detremin 20 000 IU/ml (cholecalciferol solved in Miglyol oil) and placebo (Miglyol oil) were prepared according to Good Manufacturing Practice by Nextpharma. Eurofins LC2, a centralized randomization unit, was responsible for labelling, blinding, and randomization. Detremin was provided from Renapharma Sweden, and placebo was from Nextpharma, France.

    Investigational medicinal product name
    Detremin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were randomly assigned 1:1 to vitamin D3 oil drops (colour and taste matched) 4000 IU/day or placebo (oil drops) for 12 weeks, dispensed in identical, sequentially numbered bottles. Randomization was performed using a computer-generated randomization list to generate a permutated block randomization with a block size of four. Randomization was not stratified. Trial masking for patients, trial staff and care providers continued until data had been analysed. Detremin 20 000 IU/ml (cholecalciferol solved in Miglyol oil) and placebo (Miglyol oil) were prepared according to Good Manufacturing Practice by Nextpharma. Eurofins LC2, a centralized randomization unit, was responsible for labelling, blinding, and randomization. Detremin was provided from Renapharma Sweden, and placebo was from Nextpharma, France.

    Number of subjects in period 1
    		Vitamin D Placebo
    Started
    121
    123
    Completed
    67
    83
    Not completed
    54
    40
         Death due to cancer
    36
    24
         Consent withdrawn by subject
    9
    8
         Adverse event, non-fatal
    2
    4
         Protocol deviation
    7
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nov 2017 - June 2020
    Reporting group description
    		 -

    Reporting group values
    		 Nov 2017 - June 2020 Total
    Number of subjects
    		 244 244
    Age categorical
    ITT-population, median age and IQR: 68 (61-75)
    Units: Subjects
        Above 18 years
    		 244 244
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 68 (61 to 75) -
    Gender categorical
    49% male
    Units: Subjects
        Female
    		 124 124
        Male
    		 120 120
    Subject analysis sets

    Subject analysis set title
    Primary outcome ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    244 patients were included in the ITT-analysis, which was based on 769 observations and 4 time-points over 12 weeks. Groups were well balanced at baseline (Table 1). The ITT-analysis did not show a significant difference between the slopes: beta -0.60 (95%CI -1.21; 0.02; p=0.06) and in the adjusted analysis: beta -0.59 (95%CI -1.20 to 0.03; p=0.06)

    Subject analysis set title
    Primary outcome PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    In the PP-analysis (n=150), based on 450 observations, the vitamin D-group had significantly less increase of opioid doses during the study period compared to the placebo-group; beta -0.56 (95%CI -1.07; -0.05; p=0.03) in both the unadjusted and adjusted analysis, i.e. 0.56 µg less fentanyl/h and week with vitamin D treatment and corresponding to 6.72 ug/h after 12 weeks.

    Subject analysis sets values
    		 Primary outcome ITT Primary outcome PP
    Number of subjects
    244
    150
    Age categorical
    ITT-population, median age and IQR: 68 (61-75)
    Units: Subjects
        Above 18 years
    244
    150
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    68 (61 to 75)
    68 (61 to 75)
    Gender categorical
    49% male
    Units: Subjects
        Female
    124
    76
        Male
    120
    74

    End points

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    End points reporting groups
    Reporting group title
    Vitamin D
    Reporting group description
    		 Patients were randomly assigned 1:1 to vitamin D3 oil drops (colour and taste matched) 4000 IU/day or placebo (oil drops) for 12 weeks, dispensed in identical, sequentially numbered bottles. Randomization was performed using a computer-generated randomization list to generate a permutated block randomization with a block size of four. Randomization was not stratified. Trial masking for patients, trial staff and care providers continued until data had been analysed. Detremin 20 000 IU/ml (cholecalciferol solved in Miglyol oil) and placebo (Miglyol oil) were prepared according to Good Manufacturing Practice by Nextpharma. Eurofins LC2, a centralized randomization unit, was responsible for labelling, blinding, and randomization. Detremin was provided from Renapharma Sweden, and placebo was from Nextpharma, France.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients were randomly assigned 1:1 to vitamin D3 oil drops (colour and taste matched) 4000 IU/day or placebo (oil drops) for 12 weeks, dispensed in identical, sequentially numbered bottles. Randomization was performed using a computer-generated randomization list to generate a permutated block randomization with a block size of four. Randomization was not stratified. Trial masking for patients, trial staff and care providers continued until data had been analysed. Detremin 20 000 IU/ml (cholecalciferol solved in Miglyol oil) and placebo (Miglyol oil) were prepared according to Good Manufacturing Practice by Nextpharma. Eurofins LC2, a centralized randomization unit, was responsible for labelling, blinding, and randomization. Detremin was provided from Renapharma Sweden, and placebo was from Nextpharma, France.

    Subject analysis set title
    Primary outcome ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    244 patients were included in the ITT-analysis, which was based on 769 observations and 4 time-points over 12 weeks. Groups were well balanced at baseline (Table 1). The ITT-analysis did not show a significant difference between the slopes: beta -0.60 (95%CI -1.21; 0.02; p=0.06) and in the adjusted analysis: beta -0.59 (95%CI -1.20 to 0.03; p=0.06)

    Subject analysis set title
    Primary outcome PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    In the PP-analysis (n=150), based on 450 observations, the vitamin D-group had significantly less increase of opioid doses during the study period compared to the placebo-group; beta -0.56 (95%CI -1.07; -0.05; p=0.03) in both the unadjusted and adjusted analysis, i.e. 0.56 µg less fentanyl/h and week with vitamin D treatment and corresponding to 6.72 ug/h after 12 weeks.

    Primary: Decline in opioid doses

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    End point title
    		 Decline in opioid doses
    End point description
    Mean difference in change in long-acting opioid dose between the treatment arms, measured as fentanyl ug/hour during 12 weeks, based on 4 time-points: 0, 4, 8 and 12 weeks, and adjusted for baseline opioid-values. Values are presented as beta coefficinet and 95%CI.
    End point type
    Primary
    End point timeframe
    12 weeks
    End point values
    		 Vitamin D Placebo Primary outcome ITT
    Number of subjects analysed
    67 [1]
    83 [2]
    67 [3]
    Units: ug/h
        number (confidence interval 95%)
    -0.56 (-1.07 to -0.05)
    0 (0 to 0)
    -0.60 (-1.21 to 0.02)
    Notes
    [1] - PP analysis, beta coeffienct on the differance between the two treatment arms
    [2] - PP
    [3] - PP analysis, beta coefficent bewteen the two treatment arms
    Statistical analysis title
    		 Linear mixed effect regression
    Statistical analysis description
    Primary analysis was done using linear mixed effect regression using information from three time points: 4, 8 and 12 weeks, adjusting for the baseline value.
    Comparison groups
    Vitamin D v Primary outcome ITT
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.07
         upper limit
    		 -0.05

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Nov 2017 to June 2020
    Adverse event reporting additional description
    According to the study protocol, only GI-symptoms, increase in creatinine levels, hypercalcemia and renal failure needed to be recorded as adverse events. Data on this was collected at baseline and after 4, 8 and 12 weeks.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    1.0
    Reporting groups
    Reporting group title
    Vitamin D
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Vitamin D Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 123 (0.81%)
         number of deaths (all causes)
    26
    24
         number of deaths resulting from adverse events
    0
    0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 123 (0.81%)
         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: 1%
    Non-serious adverse events
    		 Vitamin D Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 121 (4.13%)
    4 / 123 (3.25%)
    Gastrointestinal disorders
    diarrhoea, nausea
         subjects affected / exposed
    2 / 121 (1.65%)
    1 / 123 (0.81%)
         occurrences all number
    5
    4
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 123 (0.81%)
         occurrences all number
    5
    4
    Renal and urinary disorders
    hypercalcemia or increase in creatinine
         subjects affected / exposed
    3 / 121 (2.48%)
    2 / 123 (1.63%)
         occurrences all number
    5
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Jan 2019
    The exclusion criteria were changed from exclusion of patients on any type of vitamin D treatment or supplementation to allowing recruitment of patients on daily doses of vitamin D up to 400 IE/day. The change was made since large number of patients met this exclusion criterion and since this dose was not considered to affect the endpoints. 2) We added eGFR < 30 ml/h as an exclusion criterion for safety reasons.

    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/32936046
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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