Clinical Trial Results:
The effect of vitamin D on all-cause mortality in congestive heart failure patients
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
170782
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01326650 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Herz- und Diabeteszentrum NRW
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Sponsor organisation address |
Georgstraße 11, Bad Oeynhausen, Germany, 32545
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Public contact |
Scientific Team Leader, Herz- und Diabeteszentrum NRW, +49 5731971912, azittermann@hdz-nrw.de
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Scientific contact |
Scientific Team Leader, Herz- und Diabeteszentrum NRW, +49 573197912, azittermann@hdz-nrw.de
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
27 Sep 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
02 Jun 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
31 Dec 2016
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To compare in congestive heart failure patients the effect of a daily vitamin D supplement of 4000 IU versus placebo for three years on all-cause mortality.
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Protection of trial subjects |
Only subjects that met all the study inclusion and none of the exclusion criteria were randomized in the study. Safety lab was performed every six months. An independent data monitoring committee reviewed the data. Appropriate medical equipment was also available on site in case of any adverse reactions.
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Background therapy |
All study participants received evidence-based treatment for heart failure patients. | ||
Evidence for comparator |
Mortality is high in end-stage haert failure patients. There was evidence that poor vitamin D status is associated with poor cardiac function and nonfatal and fatal heart failure events. We therefore investigated whether a daily vitamin D supplement versus placebo for 3 years is able to reduce mortality in end-stage heart failure patients. | ||
Actual start date of recruitment |
18 Nov 2010
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy, Scientific research | ||
Long term follow-up duration |
3 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Germany: 400
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Worldwide total number of subjects |
400
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EEA total number of subjects |
400
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
353
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From 65 to 84 years |
47
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85 years and over |
0
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Recruitment
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Recruitment details |
Patients with heart failure with NYHA class II or higher who attended the heart failure unit of Clinic for Thoracic and Cardiovascular Surgery at the Herz- und Diabeteszerum NRW in Bad Oeynhausen, Germany. | |||||||||
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Pre-assignment
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Screening details |
Of 892 patients who met the inclusion and exclusion criteria and were screened, 400 were randomized to the vitamin D or placebo group. | |||||||||
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Period 1
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Period 1 title |
overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||
Roles blinded |
Subject, Monitor, Data analyst, Investigator | |||||||||
Blinding implementation details |
Participants, their treating physicians, and any individual of the heart failure unit of our clinic were masked to treatment allocation. Likewise, the independent data safety board was blinded to treatment allocation. In addition, data analysis was performed by a blinded external biostatistician.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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vitamin D arm | |||||||||
Arm description |
Patients had to take 4000 IU vitamin D daily (eight drops of an oily vitamin D preparation; Vigantol oil, Merck, Darmstadt, Germany) during a meal. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Vigantol oil, Merck, Darmstadt, Germany
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Oral drops
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Routes of administration |
Oral use
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Dosage and administration details |
Patients had to take 4000 IU vitamin D daily (eight drops of an oily vitamin D preparation) during a meal.
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Arm title
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placebo | |||||||||
Arm description |
Patients had to take eight drops of a vitamin D–free oil daily (Migliol oil; Merck) during a meal. | |||||||||
Arm type |
Placebo | |||||||||
Investigational medicinal product name |
Migliol oil; Merck, Darmstadt, Germany
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Oral drops
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Routes of administration |
Oral use
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Dosage and administration details |
eight drops of a vitamin D–free oil daily during a meal.
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Baseline characteristics reporting groups
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Reporting group title |
vitamin D arm
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Reporting group description |
Patients had to take 4000 IU vitamin D daily (eight drops of an oily vitamin D preparation; Vigantol oil, Merck, Darmstadt, Germany) during a meal. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
placebo
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Reporting group description |
Patients had to take eight drops of a vitamin D–free oil daily (Migliol oil; Merck) during a meal. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
vitamin D arm
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
baseline characteristics
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Subject analysis set title |
placebo arm
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
baseline characteristics
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End points reporting groups
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Reporting group title |
vitamin D arm
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Reporting group description |
Patients had to take 4000 IU vitamin D daily (eight drops of an oily vitamin D preparation; Vigantol oil, Merck, Darmstadt, Germany) during a meal. | ||
Reporting group title |
placebo
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Reporting group description |
Patients had to take eight drops of a vitamin D–free oil daily (Migliol oil; Merck) during a meal. | ||
Subject analysis set title |
vitamin D arm
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
baseline characteristics
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Subject analysis set title |
placebo arm
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
baseline characteristics
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End point title |
overall mortality | |||||||||
End point description |
Primary endpoint was all-cause mortality. We used four sources of information to identify the primary endpoint: repeated contacts with the participants, contacts with family physicians, a regular review of medical records, and consultation of the respective registration office. Causes of death were assessed from the medical records or by contacting the family physicians.
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End point type |
Primary
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End point timeframe |
period of 3 years
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Statistical analysis title |
difference in mortality rates | |||||||||
Statistical analysis description |
differences in mortality rates between the placebo and vitamin D group.
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Comparison groups |
vitamin D arm v placebo arm
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Number of subjects included in analysis |
400
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | |||||||||
P-value |
< 0.05 | |||||||||
Method |
Regression, Cox | |||||||||
Parameter type |
Cox proportional hazard | |||||||||
Point estimate |
1.09
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.69 | |||||||||
upper limit |
1.71 | |||||||||
| Notes [1] - lower mortality in the vitamin D versus placebo group was considered |
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End point title |
hospitalization | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
3 years
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Statistical analysis title |
difference in hospitalization rates | |||||||||
Statistical analysis description |
difference in hospitalization rates in the vitamin D versus placebo group
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Comparison groups |
vitamin D arm v placebo arm
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Number of subjects included in analysis |
400
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Analysis specification |
Pre-specified
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Analysis type |
superiority [2] | |||||||||
P-value |
< 0.05 | |||||||||
Method |
Regression, Cox | |||||||||
Parameter type |
Hazard ratio (HR) | |||||||||
Point estimate |
1.26
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.98 | |||||||||
upper limit |
1.63 | |||||||||
| Notes [2] - lower hospitalization rate in the vitamin D versus placebo group |
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End point title |
mechanical circulators support implantation | |||||||||
End point description |
lower rate of MCS implantation in the vitamin D versus placebo group
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End point type |
Secondary
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End point timeframe |
3 years
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Statistical analysis title |
difference in MCS implantation rates | |||||||||
Comparison groups |
vitamin D arm v placebo arm
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Number of subjects included in analysis |
400
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Analysis specification |
Pre-specified
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Analysis type |
superiority [3] | |||||||||
P-value |
< 0.05 | |||||||||
Method |
Regression, Cox | |||||||||
Parameter type |
Hazard ratio (HR) | |||||||||
Point estimate |
1.96
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
1.04 | |||||||||
upper limit |
3.66 | |||||||||
| Notes [3] - lower MCS implantation rate in the vitamin D versus placebo group |
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End point title |
High urgent listing for heart transplantation | |||||||||
End point description |
difference in high urgent listing for heart transplantation between the vitamin D and placebo group
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End point type |
Secondary
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End point timeframe |
3 years
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Statistical analysis title |
difference in high urgent listing for HTx | |||||||||
Comparison groups |
vitamin D arm v placebo arm
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Number of subjects included in analysis |
400
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Analysis specification |
Pre-specified
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Analysis type |
[4] | |||||||||
P-value |
< 0.05 | |||||||||
Method |
Regression, Cox | |||||||||
Parameter type |
Hazard ratio (HR) | |||||||||
Point estimate |
1.07
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.56 | |||||||||
upper limit |
2.03 | |||||||||
| Notes [4] - lower rate of high urgent listing for heart transplantation in the vitamin D versus placebo group |
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End point title |
heart transplantation | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
3 years
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Statistical analysis title |
difference in heart transplantation | |||||||||
Statistical analysis description |
lower transplantation rate in the vitamin D versus placebo group
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Comparison groups |
vitamin D arm v placebo arm
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Number of subjects included in analysis |
400
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
< 0.05 | |||||||||
Method |
Regression, Cox | |||||||||
Parameter type |
Hazard ratio (HR) | |||||||||
Point estimate |
1.11
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.6 | |||||||||
upper limit |
2.07 | |||||||||
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End point title |
resuscitation | |||||||||
End point description |
difference in resuscitation rate
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End point type |
Secondary
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End point timeframe |
3 years
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Statistical analysis title |
difference in resuscitation | |||||||||
Comparison groups |
vitamin D arm v placebo arm
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Number of subjects included in analysis |
400
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Analysis specification |
Pre-specified
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Analysis type |
superiority [5] | |||||||||
P-value |
< 0.05 | |||||||||
Method |
Regression, Cox | |||||||||
Parameter type |
Hazard ratio (HR) | |||||||||
Point estimate |
0.66
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.11 | |||||||||
upper limit |
4.01 | |||||||||
| Notes [5] - lower resuscitation rate in the vtamin D versus placebo group |
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End point title |
hypercalcemia | |||||||||
End point description |
difference in hypercalcemia rate
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End point type |
Secondary
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End point timeframe |
3 years
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Statistical analysis title |
difference in hypercalcemia rates | |||||||||
Comparison groups |
vitamin D arm v placebo arm
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Number of subjects included in analysis |
400
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Analysis specification |
Pre-specified
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Analysis type |
superiority [6] | |||||||||
P-value |
< 0.05 | |||||||||
Method |
Regression, Cox | |||||||||
Parameter type |
Hazard ratio (HR) | |||||||||
Point estimate |
2.05
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.7 | |||||||||
upper limit |
5.98 | |||||||||
| Notes [6] - lower hypercalcemia risk in the placebo versus vitamin D group |
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Adverse events information
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Timeframe for reporting adverse events |
3 years
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Adverse event reporting additional description |
hypercalcemia and hypervitaminosis D were assessed at each 6-month visit during the entire three years of study duration.
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Assessment type |
Systematic | |||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||
Dictionary version |
10
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Reporting groups
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Reporting group title |
vitamin D group
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Reporting group description |
experimental group | |||||||||||||||||||||
Reporting group title |
placebo group
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Reporting group description |
placebo group | |||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| A major limitation is the aforementioned low-statistical power to detect significant treatment differences in the primary endpoint. A further limitation is that the study is largely restricted to male Caucasian patients. | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/28498942 |
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