Clinical Trial Results:
Can Vitamin D supplementation improve Hepatitis C cure rates: A pilot multicentre randomised controlled clinical trial
Summary
|
|
EudraCT number |
2013-003573-10 |
Trial protocol |
GB |
Global end of trial date |
22 Dec 2015
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
13 May 2017
|
First version publication date |
13 May 2017
|
Other versions |
|
Summary report(s) |
Summary results viaduct |
Trial Information
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 |
2012GA03
|
||
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT02053519 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
Sponsor R&D number: 2012GA03 | ||
Sponsors
|
|||
Sponsor organisation name |
University of Dundee
|
||
Sponsor organisation address |
Ninewells Hospital, Dundee, United Kingdom, DD1 9SY
|
||
Public contact |
Prof John Dillon, University of Dundee, 44 01382383017, j.f.dillon@dundee.ac.uk
|
||
Scientific contact |
Prof John Dillon, University of Dundee, 44 01382383017, j.f.dillon@dundee.ac.uk
|
||
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
05 Dec 2016
|
||
Is this the analysis of the primary completion data? |
Yes
|
||
Primary completion date |
22 Dec 2015
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
22 Dec 2015
|
||
Was the trial ended prematurely? |
No
|
||
General information about the trial
|
|||
Main objective of the trial |
The primary objective is to test if vitamin D supplementation improves the chances of standard treatment for HCV infection being effective. To test this we will measure if there is an improvement in the virologic response - ie the level of virus in the blood, 12 weeks after completion of treatment.
|
||
Protection of trial subjects |
Trial exclusion criteria were designed to minimize the risk of hypercalcemia or renal stones (know side effects of vitamin D therapy); drug exclusions were designed to minimize the risk of interactions with vitamin D.
Adverse events were sought at each clinic visit; the directly observed nature of the vitamin D administration once a month ensured close observation of participants throughout the trial.
|
||
Background therapy |
Standard HCV therapy was commenced 1-4 weeks after the first dose of vitamin D or placebo. Standard treatment for HCV is generally for 24 weeks. Some genotype 1 patients who do not respond to therapy at week 4 or 12 will have all anti-viral therapy stopped. Other genotype 1 patients who respond but do not become virus negative by 12 weeks of therapy will continue on a further 24 week course of standard therapy, total duration 48 weeks. Standard therapy for HCV genotype 1 patients changed as the trial commenced and some patients received sofosbuvir in addition to interferon for 12 weeks. | ||
Evidence for comparator |
Placebo was selected (in addition to standard therapy) as the aim of the trial was to test efficacy of vitamin D in addition to standard therapy, rather than instead of standard therapy. | ||
Actual start date of recruitment |
01 Nov 2013
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
No
|
||
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
United Kingdom: 72
|
||
Worldwide total number of subjects |
72
|
||
EEA total number of subjects |
72
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
0
|
||
Adolescents (12-17 years) |
0
|
||
Adults (18-64 years) |
72
|
||
From 65 to 84 years |
0
|
||
85 years and over |
0
|
|
||||||||||||||||
Recruitment
|
||||||||||||||||
Recruitment details |
Participants were recruited from hepatitis C treatment services across multiple Scottish secondary care sites | |||||||||||||||
Pre-assignment
|
||||||||||||||||
Screening details |
At the screening visit all participants had their medical history taken and gave written informed consent. Confirmation of HCV diagnosis by viral genotype and viral load by PCR was taken from the last available values in the medical notes. | |||||||||||||||
Period 1
|
||||||||||||||||
Period 1 title |
Randomised treatment (overall period)
|
|||||||||||||||
Is this the baseline period? |
Yes | |||||||||||||||
Allocation method |
Randomised - controlled
|
|||||||||||||||
Blinding used |
Double blind | |||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | |||||||||||||||
Blinding implementation details |
Matching IMP and placebo (base oil) were prepared by an independent provider (Tayside Pharmaceuticals) who dispensed identical bottles with no external indication of allocation group
|
|||||||||||||||
Arms
|
||||||||||||||||
Are arms mutually exclusive |
Yes
|
|||||||||||||||
Arm title
|
Vitamin D3 | |||||||||||||||
Arm description |
Oral vitamin D3 100,000 units once per month | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Cholecalciferol
|
|||||||||||||||
Investigational medicinal product code |
||||||||||||||||
Other name |
||||||||||||||||
Pharmaceutical forms |
Oral solution
|
|||||||||||||||
Routes of administration |
Oral use
|
|||||||||||||||
Dosage and administration details |
100,000 units once a month, given as 5mls of 20,000 units/ml product (Vigantol oil)
|
|||||||||||||||
Arm title
|
Placebo | |||||||||||||||
Arm description |
Matching placebo given once a month | |||||||||||||||
Arm type |
Placebo | |||||||||||||||
Investigational medicinal product name |
Placebo
|
|||||||||||||||
Investigational medicinal product code |
||||||||||||||||
Other name |
||||||||||||||||
Pharmaceutical forms |
Oral solution
|
|||||||||||||||
Routes of administration |
Oral use
|
|||||||||||||||
Dosage and administration details |
5mls of matching placebo (Mygliol oil as used as base oil in Vigantol oil preparation) given once a month
|
|||||||||||||||
|
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Vitamin D3
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Oral vitamin D3 100,000 units once per month | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Matching placebo given once a month | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
End points reporting groups
|
|||
Reporting group title |
Vitamin D3
|
||
Reporting group description |
Oral vitamin D3 100,000 units once per month | ||
Reporting group title |
Placebo
|
||
Reporting group description |
Matching placebo given once a month | ||
Subject analysis set title |
ITT analysis set
|
||
Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
All participants with a value for the primary outcome (SVR12)
|
|
|||||||||||||||||||||
End point title |
SVR12 (sustained virologic response at 12 weeks) | ||||||||||||||||||||
End point description |
Sustained virologic response 12 weeks after stopping treatment. Response = undetectable Hep C RNA at any point beyond 12 weeks post end of interferon-based treatment. Missing data analysed as treatment failure.
|
||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||
End point timeframe |
12 weeks after cessation of standard (interferon based) Hep C treatment
|
||||||||||||||||||||
|
|||||||||||||||||||||
Statistical analysis title |
Adjusted odds ratio for treatment success | ||||||||||||||||||||
Comparison groups |
Vitamin D3 v Placebo
|
||||||||||||||||||||
Number of subjects included in analysis |
72
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.44 | ||||||||||||||||||||
Method |
Regression, Logistic | ||||||||||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||||||||||
Point estimate |
1.74
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
0.43 | ||||||||||||||||||||
upper limit |
6.97 |
|
|||||||||||||
End point title |
Time to stopping standard treatment (adherence) | ||||||||||||
End point description |
Time to stopping standard (interferon-based) treatment as a measure of adherence; comparison between vitamin D and placebo groups
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to 48 weeks
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Hazard ratio-time to stopping standard treatment | ||||||||||||
Statistical analysis description |
Cox regression analysis
|
||||||||||||
Comparison groups |
Placebo v Vitamin D3
|
||||||||||||
Number of subjects included in analysis |
72
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.33 | ||||||||||||
Method |
Regression, Cox | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
1.28
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.78 | ||||||||||||
upper limit |
2.09 |
|
|||||||||||||
End point title |
25-hydroxyvitamin D levels | ||||||||||||
End point description |
Change from baseline averaged over follow up period
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to 48 weeks
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Between group difference in 25OHD levels | ||||||||||||
Comparison groups |
Vitamin D3 v Placebo
|
||||||||||||
Number of subjects included in analysis |
72
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
24.7
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
12.2 | ||||||||||||
upper limit |
37.2 |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Screening visit to 48 weeks (final visit)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Vitamin D3
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Placebo | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 |
||
31 Oct 2013 |
Revision of protocol to v2.0 with additional exclusion criteria added |
||
Interruptions (globally) |
|||
Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
Recruited fewer participants than originally powered for. Changes in background therapy for hepatitis C mean results may not now be applicable to current standard of care. High cure rates in placebo group limit ability to detect treatment effect. |