Clinical Trial Results:
Feasibility study including a double blind (C)controlled study and an open label (C) controlled study for a larger randomised trial measuring the effect of oral vitamin D (I) on morbidity and mortality (O) in men and women aged 65-84 (P)
|
Summary
|
|
EudraCT number |
2011-003699-34 |
Trial protocol |
GB |
Global end of trial date |
22 Mar 2017
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
24 Oct 2019
|
First version publication date |
24 Oct 2019
|
Other versions |
|
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
QA343
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
ISRCTN46328341 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
Sponsor organisation name |
London School of Hygiene & Tropical Medicine
|
||
Sponsor organisation address |
Keppel Street, London`, United Kingdom, WC1E 7HT
|
||
Public contact |
Christine Rake, London School of Hygine & Tropical Medicine, CHRISTINE.RAKE@LSHTM.AC.UK
|
||
Scientific contact |
Julian Peto, London School of Hygine & Tropical Medicine, JULIAN.PETO@LSHTM.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 |
03 Jul 2018
|
||
Is this the analysis of the primary completion data? |
Yes
|
||
Primary completion date |
22 Mar 2017
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
22 Mar 2017
|
||
Was the trial ended prematurely? |
No
|
||
|
General information about the trial
|
|||
Main objective of the trial |
The primary aim of the feasibility study was to establish the procedures required to conduct the main trial and to determine the time taken to recruit and randomise 1,600 participants aged 65-84. The aims of the cluster randomisation of practices were to:
i) compare response (number randomised/number invited) and attrition (attendance at 2-year final visit) in blinded and open practices,
ii) compare allocated treatment compliance in participants on open label vitamin D and blinded participants, and
iii) compare contamination rates (the proportion taking > 400IU/day of vitamin D), particularly between open untreated controls and blinded participants.
|
||
Protection of trial subjects |
This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. All subjects provided written informed consent before undergoing any study-related procedures. The study was reviewed and approved by a Research Ethics Committee (REC) and the Medicines & Healthcare products Regulatory Agency (MHRA). The principle discomfort of the study arose from giving blood samples; we sought to minimize this by employing GP research nurses who were competent phlebotomists. The principle risk (estimated at less than a 1 in 400 chance) arose from vitamin D−induced hypercalcaemia; we sought to minimize this by excluding those with elevated blood calcium level before randomisation; by excluding patients known to be at potentially increased risk of developing hypercalcaemia after vitamin D supplementation (e.g. those with hyperparathyroidism, sarcoidosis or baseline hypercalcaemia); by giving a dose of vitamin D that was sufficient to correct deficiency, but not sufficient to induce hypervitaminosis D; and by monitoring for hypercalcaemia post−randomisation, with unblinded review by data monitoring committee of accumulating data relating to adverse reactions. The proposed regimen of 100,000 IU vitamin D3 monthly (equivalent to 3300 IU per day) represented a dose that was at extremely low risk of inducing adverse effects, but which was sufficient to promote a clinical benefit.
|
||
Background therapy |
N/A | ||
Evidence for comparator |
There is strong but not conclusive evidence that serum 25-hydroxyvitamin D (25(OH)D) should be at least 75 nmol/L for optimal health. Neither the vitamin D reference nutrient intake (RNI) (400IU/day) nor increased consumption of foods containing vitamin D will raise the majority of the UK population aged over 65 years above this level. Plausible effects of vitamin D deficiency include premature death and increased risks of pneumonia, cardiovascular disease, some cancers, dementia, falls and fractures. We therefore proposed the VIDAL (Vitamin D And Longevity) trial, a large randomised trial of high-dose monthly vitamin D3 for 5 years with all-cause mortality as the primary endpoint (20,000 participants aged 65-84 at entry). The VIDAL feasibility study was conducted to assess the feasibility of that larger main trial. As well as demonstrating an expected increase in circulating 25-hydroxyvitamin D levels, the feasibility study sought to establish the study design and procedures required for the main trial. An important feature of the feasibility study was the comparison of a placebo control group with an open control group with no treatment. Randomized double-blind placebo-controlled trials are considered the gold standard, particularly where the endpoint is subjective, but an open control design may be acceptable where the main endpoint is overall mortality. The primary purpose of the feasibility study was to ascertain recruitment levels, but the study also included a cluster randomized comparison of the effects of placebo versus open control trial design on the reliability of self-reported infections and other adverse effects as well as on recruitment, participant acceptability and treatment compliance. The feasibility study therefore provides evidence on an important methodological issue in the design of pragmatic trials in preventive medicine. | ||
Actual start date of recruitment |
27 Mar 2013
|
||
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: 11376
|
||
Worldwide total number of subjects |
11376
|
||
EEA total number of subjects |
11376
|
||
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) |
0
|
||
From 65 to 84 years |
11376
|
||
85 years and over |
0
|
||
|
|||||||||||||||||||||||||||||||
|
Recruitment
|
|||||||||||||||||||||||||||||||
Recruitment details |
Baseline enrolment visits were conducted between 17/04/2013 and 11/12/2014 in 20 GP practices across England. The first patient was randomised on 09/05/2013, and the last patient was randomised on 15/01/2015. | ||||||||||||||||||||||||||||||
|
Pre-assignment
|
|||||||||||||||||||||||||||||||
Screening details |
The 20 GP practices were cluster randomised to open or double-blind individual randomisation within pairs matched approximately on size, whether urban or rural, ethnic mix and ward multiple deprivation index based on practice postcode. Within each practice, patients were individually randomised to vitamin D or control (no treatment or placebo). | ||||||||||||||||||||||||||||||
|
Pre-assignment period milestones
|
|||||||||||||||||||||||||||||||
Number of subjects started |
11376 | ||||||||||||||||||||||||||||||
Number of subjects completed |
1615 | ||||||||||||||||||||||||||||||
|
Pre-assignment subject non-completion reasons
|
|||||||||||||||||||||||||||||||
Reason: Number of subjects |
Not randomised to the trial: 9761 | ||||||||||||||||||||||||||||||
|
Period 1
|
|||||||||||||||||||||||||||||||
Period 1 title |
Overall trial (overall period)
|
||||||||||||||||||||||||||||||
Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
|
||||||||||||||||||||||||||||||
Blinding used |
Not blinded | ||||||||||||||||||||||||||||||
|
Arms
|
|||||||||||||||||||||||||||||||
Are arms mutually exclusive |
Yes
|
||||||||||||||||||||||||||||||
|
Arm title
|
Vitamin D (Blinded) | ||||||||||||||||||||||||||||||
Arm description |
Study participants enrolled at the blinded GP practices received annual study medication packs each containing 12 monthly doses of study oil labelled as “vitamin D3 oil / placebo oil”. The vitamin D (blinded) arm contained 12 bottles each containing 5.2 ml Vigantol® Oil (oily solution of vitamin D3, concentration 0.5 mg/ml). Bottles of study oil contained 5.2 ml to ensure delivery of 5 ml (2.5 mg of vitamin D3) because ~0.2 ml of the oily solution adheres and remains in the bottle. | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Vigantol® Oil
|
||||||||||||||||||||||||||||||
Investigational medicinal product code |
A1 1 CC05 (cholecalciferol)
|
||||||||||||||||||||||||||||||
Other name |
|||||||||||||||||||||||||||||||
Pharmaceutical forms |
Oral liquid
|
||||||||||||||||||||||||||||||
Routes of administration |
Oral use
|
||||||||||||||||||||||||||||||
Dosage and administration details |
Administered orally: 24 x 5 ml (= 24 x 2.5 mg) over two years.
|
||||||||||||||||||||||||||||||
|
Arm title
|
Placebo | ||||||||||||||||||||||||||||||
Arm description |
Study participants enrolled at the blinded GP practices received annual study medication packs each containing 12 monthly doses of study oil labelled as “vitamin D3 oil / placebo oil”. The placebo arm contained 12 bottles each containing 5.2 ml Miglyol® 812 oil. | ||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Miglyol® 812 Oil
|
||||||||||||||||||||||||||||||
Investigational medicinal product code |
N/A
|
||||||||||||||||||||||||||||||
Other name |
|||||||||||||||||||||||||||||||
Pharmaceutical forms |
Oral liquid
|
||||||||||||||||||||||||||||||
Routes of administration |
Oral use
|
||||||||||||||||||||||||||||||
Dosage and administration details |
Administered orally: 24 x 5 ml over two years
|
||||||||||||||||||||||||||||||
|
Arm title
|
Vitamin D (Open) | ||||||||||||||||||||||||||||||
Arm description |
Study participants enrolled at the open GP practices received annual study medication packs each containing 12 monthly doses of study oil labelled as “vitamin D3 oil”. The vitamin D (open) arm contained 12 bottles each containing 5.2 ml Vigantol® Oil (oily solution of vitamin D3, concentration 0.5 mg/ml). Bottles of study oil contained 5.2 ml to ensure delivery of 5 ml (2.5 mg of vitamin D3) because ~0.2 ml of the oily solution adheres and remains in the bottle. | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Vigantol® Oil
|
||||||||||||||||||||||||||||||
Investigational medicinal product code |
A1 1 CC05 (cholecalciferol)
|
||||||||||||||||||||||||||||||
Other name |
|||||||||||||||||||||||||||||||
Pharmaceutical forms |
Oral liquid
|
||||||||||||||||||||||||||||||
Routes of administration |
Oral use
|
||||||||||||||||||||||||||||||
Dosage and administration details |
Administered orally: 24 x 5 ml (= 24 x 2.5 mg) over two years.
|
||||||||||||||||||||||||||||||
|
Arm title
|
Open Control | ||||||||||||||||||||||||||||||
Arm description |
Participants allocated to open control at randomisation are not sent any study oils, nor contacted during the follow-up period, but are invited back to the GP practice for a final study visit at 2-years. | ||||||||||||||||||||||||||||||
Arm type |
No intervention | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
| Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: The worldwide number of participants was the number of subjects invited to take part in the study, which was required for calculation of the first primary endpoint, "participation rates in blind versus open GP practices". The number of subjects reported to be in the baseline period equates to the number of participants actually randomised to the study, which is required for all other endpoints. |
|||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Overall trial
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
Vitamin D (Blinded)
|
||
Reporting group description |
Study participants enrolled at the blinded GP practices received annual study medication packs each containing 12 monthly doses of study oil labelled as “vitamin D3 oil / placebo oil”. The vitamin D (blinded) arm contained 12 bottles each containing 5.2 ml Vigantol® Oil (oily solution of vitamin D3, concentration 0.5 mg/ml). Bottles of study oil contained 5.2 ml to ensure delivery of 5 ml (2.5 mg of vitamin D3) because ~0.2 ml of the oily solution adheres and remains in the bottle. | ||
Reporting group title |
Placebo
|
||
Reporting group description |
Study participants enrolled at the blinded GP practices received annual study medication packs each containing 12 monthly doses of study oil labelled as “vitamin D3 oil / placebo oil”. The placebo arm contained 12 bottles each containing 5.2 ml Miglyol® 812 oil. | ||
Reporting group title |
Vitamin D (Open)
|
||
Reporting group description |
Study participants enrolled at the open GP practices received annual study medication packs each containing 12 monthly doses of study oil labelled as “vitamin D3 oil”. The vitamin D (open) arm contained 12 bottles each containing 5.2 ml Vigantol® Oil (oily solution of vitamin D3, concentration 0.5 mg/ml). Bottles of study oil contained 5.2 ml to ensure delivery of 5 ml (2.5 mg of vitamin D3) because ~0.2 ml of the oily solution adheres and remains in the bottle. | ||
Reporting group title |
Open Control
|
||
Reporting group description |
Participants allocated to open control at randomisation are not sent any study oils, nor contacted during the follow-up period, but are invited back to the GP practice for a final study visit at 2-years. | ||
Subject analysis set title |
Subjects invited from "open" GP practices
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
All subjects from "open" GP practices who were invited to take part in the trial.
|
||
Subject analysis set title |
Subjects invited from "blind" GP practices
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
All subjects from "open" GP practices who were invited to take part in the trial.
|
||
Subject analysis set title |
Subjects randomised to all "blind" GP practices
|
||
Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
All subjects that were randomised from "blind" GP practices
|
||
Subject analysis set title |
All randomised participants allocated to vitamin D
|
||
Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
All randomised participants allocated to receive vitamin D treatment (including both blind and open treatment groups).
|
||
Subject analysis set title |
All randomised participants allocated to control group
|
||
Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
All randomised participants allocated to control groups (including both open and blind control groups).
|
||
Subject analysis set title |
Randomised participants taking vitamin D supplements
|
||
Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
The number of randomised participants taking vitamin D supplements at baseline
|
||
Subject analysis set title |
Randomised participants taking no vitamin D supplementation
|
||
Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
The number of randomised participants taking no vitamin D supplementation at baseline
|
||
|
|||||||||||||
End point title |
Participation rates in blind versus open GP practices | ||||||||||||
End point description |
Proportion of invited participants who were randomised in each GP practice
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Baseline
|
||||||||||||
|
|||||||||||||
| Notes [1] - 828 participants were randomised out of 5508 subjects invited across all "open" GP practices. [2] - 787 participants were randomised out of 5868 subjects invited across all "blind" GP practices. |
|||||||||||||
Statistical analysis title |
Wilcoxon signed rank test | ||||||||||||
Statistical analysis description |
Wilcoxon signed rank test
|
||||||||||||
Comparison groups |
Subjects invited from "open" GP practices v Subjects invited from "blind" GP practices
|
||||||||||||
Number of subjects included in analysis |
1615
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
equivalence | ||||||||||||
P-value |
= 0.7 | ||||||||||||
Method |
Wilcoxon signed rank test | ||||||||||||
Confidence interval |
|||||||||||||
|
|||||||||||||
End point title |
Number of randomised participants returning for the 2 year visit by treatment group [3] | ||||||||||||
End point description |
Proportion of randomised participants returning for the 2-year visit in open control versus open treatment GP practices.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Attendance at the final 2-year visit.
|
||||||||||||
| Notes [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This is a comparison of the treated versus untreated participants in the "open" GP practices. Those randomised in the "blinded" GP practices are excluded; therefore the endpoint should not report statistics for all of the arms in the baseline period. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Chi-squared test | ||||||||||||
Statistical analysis description |
Chi-squared test
|
||||||||||||
Comparison groups |
Vitamin D (Open) v Open Control
|
||||||||||||
Number of subjects included in analysis |
816
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
equivalence | ||||||||||||
P-value |
= 0.008 | ||||||||||||
Method |
Chi-squared | ||||||||||||
Confidence interval |
|||||||||||||
|
|||||||||||||||||||||||||
End point title |
Compliance of participants allocated to study medication [4] | ||||||||||||||||||||||||
End point description |
Compliance of participants allocated to study medication: number of doses taken by study arm. Those randomised to receive no treatment in open GP practices are excluded.
|
||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||
End point timeframe |
Compliance of participants allocated to study medication over the 2 year trial period.
|
||||||||||||||||||||||||
| Notes [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This is a comparison of open vitamin D versus all "blinded" GP practices. Those randomised to receive no treatment in the "open" GP practices are excluded; therefore the endpoint should not report statistics for all of the arms in the baseline period. |
|||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Statistical analysis title |
Chi-squared test | ||||||||||||||||||||||||
Statistical analysis description |
Chi-squared test
|
||||||||||||||||||||||||
Comparison groups |
Vitamin D (Open) v Subjects randomised to all "blind" GP practices
|
||||||||||||||||||||||||
Number of subjects included in analysis |
1194
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
equivalence | ||||||||||||||||||||||||
P-value |
= 0.3 | ||||||||||||||||||||||||
Method |
Chi-squared | ||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
|
|||||||||||||
End point title |
Contamination rates among open untreated controls versus blinded participants [5] | ||||||||||||
End point description |
Contamination (proportion of participants taking >400IU/day of vitamin D): additional self-administered or GP prescribed daily vitamin D from all supplements being taken at the 2-year visit. Combined data from self-report and GP records.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Final 2-year visit
|
||||||||||||
| Notes [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This is a comparison of open untreated controls versus all "blinded" GP practices. Those randomised to receive vitamin D in the "open" GP practices are excluded; therefore the endpoint should not report statistics for all of the arms in the baseline period. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Chi-squared test | ||||||||||||
Statistical analysis description |
Chi-squared test
|
||||||||||||
Comparison groups |
Open Control v Subjects randomised to all "blind" GP practices
|
||||||||||||
Number of subjects included in analysis |
1140
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
equivalence | ||||||||||||
P-value |
= 0.27 | ||||||||||||
Method |
Chi-squared | ||||||||||||
Confidence interval |
|||||||||||||
|
|||||||||||||
End point title |
Serious Adverse Event (SAE) reporting in blind placebo versus blind treated groups [6] | ||||||||||||
End point description |
Report of one or more Serious Adverse Events during the two year trial period, in blind placebo versus blind vitamin D groups.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Two year trial period
|
||||||||||||
| Notes [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This is a comparison of the placebo versus treatment groups within the "blinded" GP practices. Those randomised in the "open" GP practices are excluded; therefore the endpoint should not report statistics for all of the arms in the baseline period. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Chi-squared test | ||||||||||||
Statistical analysis description |
Chi-squared test
|
||||||||||||
Comparison groups |
Vitamin D (Blinded) v Placebo
|
||||||||||||
Number of subjects included in analysis |
787
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
equivalence | ||||||||||||
P-value |
= 0.9 | ||||||||||||
Method |
Chi-squared | ||||||||||||
Confidence interval |
|||||||||||||
|
|||||||||||||
End point title |
Baseline blood 25(OH)D level in treated versus control groups | ||||||||||||
End point description |
Baseline blood 25(OH)D level in participants allocated to vitamin D versus control groups.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Two-sided t-test | ||||||||||||
Statistical analysis description |
Two-sided t-test
|
||||||||||||
Comparison groups |
All randomised participants allocated to vitamin D v All randomised participants allocated to control group
|
||||||||||||
Number of subjects included in analysis |
1608
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
equivalence | ||||||||||||
P-value |
= 0.7 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Confidence interval |
|||||||||||||
|
|||||||||||||
End point title |
Treatment effects: two-year 25(OH)D level in treated versus control groups | ||||||||||||
End point description |
Two-year blood 25(OH)D level in participants allocated to vitamin D versus control groups.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Two year final visit
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Two-sided t-test | ||||||||||||
Statistical analysis description |
Two-sided t-test
|
||||||||||||
Comparison groups |
All randomised participants allocated to control group v All randomised participants allocated to vitamin D
|
||||||||||||
Number of subjects included in analysis |
1448
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
equivalence | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Confidence interval |
|||||||||||||
|
|||||||||||||
End point title |
Vitamin D supplementation and blood 25(OH)D level | ||||||||||||
End point description |
Effect of vitamin D supplementation on average blood 25(OH)D level among all participants at baseline
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Linear regression | ||||||||||||
Statistical analysis description |
Linear regression
|
||||||||||||
Comparison groups |
Randomised participants taking vitamin D supplements v Randomised participants taking no vitamin D supplementation
|
||||||||||||
Number of subjects included in analysis |
1608
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
equivalence | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Regression, Linear | ||||||||||||
Confidence interval |
|||||||||||||
|
||||||||||||||||||||||||||||
End point title |
Number of infections in 2-year trial period in treated versus control groups | |||||||||||||||||||||||||||
End point description |
Number of infections during the 2-year trial period as reported from GP notes for all study participants, comparing controls (untreated or placebo) against vitamin D (open or blind). All infections included (upper and lower respiratory infections, urinary tract infections, skin/mucosal or soft tissue infections and other infections).
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
Two year trial period
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||
|
|||||||||||||||||||||
End point title |
Number of GP appointments in 2-year trial period by treatment group | ||||||||||||||||||||
End point description |
Number of GP appointments during the 2-year trial period as reported from GP notes for all study participants by treatment group.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Two year trial period
|
||||||||||||||||||||
|
|||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||
|
|||||||||||||
End point title |
Change in systolic blood pressure across 2-year trial period in treated and control groups | ||||||||||||
End point description |
Change in systolic blood pressure from recruitment to 2 years between vitamin D (open label and blind) and control (untreated and placebo) groups.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Two year trial period
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Linear regression | ||||||||||||
Statistical analysis description |
Linear regression
|
||||||||||||
Comparison groups |
All randomised participants allocated to vitamin D v All randomised participants allocated to control group
|
||||||||||||
Number of subjects included in analysis |
1458
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
equivalence | ||||||||||||
P-value |
= 0.2 | ||||||||||||
Method |
Regression, Linear | ||||||||||||
Confidence interval |
|||||||||||||
|
|||||||||||||
End point title |
Change in diastolic blood pressure across 2-year trial period in treated and control groups | ||||||||||||
End point description |
Change in diastolic blood pressure from recruitment to 2 years between vitamin D (open label and blind) and control (untreated and placebo) groups
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Two year trial period
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Linear regression | ||||||||||||
Statistical analysis description |
Linear regression
|
||||||||||||
Comparison groups |
All randomised participants allocated to vitamin D v All randomised participants allocated to control group
|
||||||||||||
Number of subjects included in analysis |
1458
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
equivalence | ||||||||||||
P-value |
= 0.03 | ||||||||||||
Method |
Regression, Linear | ||||||||||||
Confidence interval |
|||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From the first dose of study medication to the end of study.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Serious adverse events and adverse reactions were detected either through routine clinical contact with the participant at the GP practice, participant response to quarterly follow-up communications or final visit questions, or linkage with NHS digital to hospital admissions, cancer diagnoses and mortality data.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Non-systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16.0
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Vitamin D (Blinded)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Study participants enrolled at the blinded GP practices received annual study medication packs each containing 12 monthly doses of study oil labelled as “vitamin D3 oil / placebo oil”. The vitamin D (blinded) arm contained 12 bottles each containing 5.2 ml Vigantol® Oil (oily solution of vitamin D3, concentration 0.5 mg/ml). Bottles of study oil contained 5.2 ml to ensure delivery of 5 ml (2.5 mg of vitamin D3) because ~0.2 ml of the oily solution adheres and remains in the bottle. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Study participants enrolled at the blinded GP practices received annual study medication packs each containing 12 monthly doses of study oil labelled as “vitamin D3 oil / placebo oil”. The placebo arm contained 12 bottles each containing 5.2 ml Miglyol® 812 oil. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Vitamin D (Open)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Study participants enrolled at the open GP practices received annual study medication packs each containing 12 monthly doses of study oil labelled as “vitamin D3 oil”. The vitamin D (open) arm contained 12 bottles each containing 5.2 ml Vigantol® Oil (oily solution of vitamin D3, concentration 0.5 mg/ml). Bottles of study oil contained 5.2 ml to ensure delivery of 5 ml (2.5 mg of vitamin D3) because ~0.2 ml of the oily solution adheres and remains in the bottle. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Open Control
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants allocated to open control at randomisation are not sent any study oils, nor contacted during the follow-up period, but are invited back to the GP practice for a final study visit at 2-years. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
09 Oct 2012 |
Include a reminder on the 3-monthly follow-up for participants to contact their GP if they are experiencing symptoms of hypercalcaemia. Allow CCI to send signed prescriptions directly to pharmacy and GP nurses to send ICF to TCC by any medium. |
||
24 Oct 2012 |
Administrative changes: Amending protocol and supporting document terminology for consistency; paper administration of the baseline visit; modification of the lifestyle questions, invitation letter and quarterly follow-up; amendment of previous errors on the PIS and 2-year appointment letter; asking GP practices (instead of TCC) to check study oil dates on the used medication packs brought in to the final practice visit; modifying the remit of the DMC; modifying the format of the unique VIDAL ID; and modifying the verification procedure for the calcium blood test result. Request by TCC of an anonymised version of the quarterly pre-consent spreadsheet, for the purpose of monitoring response rates and reasons for non-participation by 5-year age-group and sex.
Other changes: Inclusion of blood pressure as an additional outcome. Increasing the volume of blood taken for the calcium blood test (from 3ml to 3.5ml) for logistical reasons. Initial recording of SAEs by the practice nurse as well as PI (subject to review and confirmation by the PI).
|
||
30 May 2013 |
Removal of existing sites/PIs and addition of new sites/PIs. |
||
10 Sep 2013 |
Text on IMP bottle and carton labels altered to confirm study oil should be taken orally once a month; Insert added with instructions in IMP delivery pack; Certificate of Analysis for extended shelf life of vigantol oil. |
||
20 Sep 2013 |
Change of PI at four participating sites. |
||
27 Sep 2013 |
Change of PI at one participating site. |
||
04 Feb 2014 |
Removal of existing sites/PIs and addition of new sites/PIs. |
||
08 May 2014 |
Removal of existing site/PI and addition of new site/PI. |
||
01 Jul 2014 |
Minor edits to the statistical section of the protocol and addition of a contamination communication. |
||
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 | |||
