Clinical Trial Results:
Anti-viral prophylaxis for prevention of cytomegalovirus (CMV) reactivation in immunocompetent patients in critical care.
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Summary
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EudraCT number |
2010-024646-30 |
Trial protocol |
GB |
Global end of trial date |
19 Jan 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
28 Dec 2019
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First version publication date |
28 Dec 2019
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Other versions |
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Summary report(s) |
Antiviral drugs suppress CMV reactivation in critically ill adults JAMA Int Med 2017 CMV suppression trial statistical report |
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 |
CCCC_CMV_protocol
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01503918 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
University Hospitals Birmingham
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Sponsor organisation address |
Edgbaston, Birmingham, United Kingdom, B15 2TH
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Public contact |
Professor Julian Bion, University of Birmingham, 0044 (0)1213716816, J.F.Bion@bham.ac.uk
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Scientific contact |
Professor Julian Bion, University of Birmingham, 0044 (0)1213716816, J.F.Bion@bham.ac.uk
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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 |
19 Jan 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
31 Jan 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
19 Jan 2017
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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 |
Does the use of antiviral prophylaxis using valganciclovir or valaciclovir effectively and safely suppress cytomegalovirus reactivation in critically ill patients in intensive care?
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Protection of trial subjects |
Patients were critically ill, undergoing mechanical ventilation in an intensive care unit. They received 24/7 1:1 nursing care with a minimum of twice daily consultant review.
During the study we observed an imbalance in hospital mortality rates, with an unexpectedly low mortality rate in the controls, and high in the group assigned to aciclovir. We undertook an independent blinded case record review and could find no explanation for the mortality difference other than severity of illness: all deaths were expected. After discussion with the Data Monitoring Committee we suspended further recruitment to the aciclovir arm, continuing recruitment to the ganciclovir group.
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Background therapy |
All patients received life supporting treatments and drugs as part of their standard care in the ICU. | ||
Evidence for comparator |
Patients were randomly assigned to continue standard intensive care treatments, or to standard treatments with the addition of either aciclovir or ganciclovir. | ||
Actual start date of recruitment |
30 Jan 2012
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Long term follow-up planned |
No
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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 |
United Kingdom: 124
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Worldwide total number of subjects |
124
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EEA total number of subjects |
124
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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) |
80
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From 65 to 84 years |
42
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85 years and over |
2
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Recruitment
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Recruitment details |
Informed consent was obtained from patient representatives using a two-stage procedure, first for sampling to determine CMV status, and then for those who were CMV antibody negative, consent to participate in the trial of antiviral prophylaxis. Accruals started in January 2012 and finished in January 2014. | |||||||||
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Pre-assignment
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Screening details |
Patients were eligible for the study if they were seropositive for CMV, already in the ICU for more than 24 hours, and mechanically ventilated, with the ICU stay and mechanical ventilation anticipated to continue for at least 48 hours. | |||||||||
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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 |
Not blinded | |||||||||
Blinding implementation details |
Not blinded
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Control | |||||||||
Arm description |
Standard care | |||||||||
Arm type |
No intervention | |||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Arm title
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Intervention Goups: Valaciclovir/acyclovir or valganciclovir | |||||||||
Arm description |
Patients randomized to the valacyclovir hydrochloride arm received2g4times a day by the enteral route. Patients unable to receive enteral medication received intravenous aciclovir sodium, 10 mg/kg of ideal body weight, 3 times a day until they were able to receive enteral medication. Patients randomized to the valganciclovir hydrochloride arm received 450mg once a day by the enteral route. Patients in this group who were unable to receive enteral medication received intravenous ganciclovir sodium, 2.5mg/kg ideal body weight, once a day until they were able to receive enteral medication | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Valaciclovir/acyclovir
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Investigational medicinal product code |
n/a
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Other name |
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Pharmaceutical forms |
Tablet, Injection
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Routes of administration |
Intravascular use , Enteral use
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Dosage and administration details |
Patients randomized to the valacyclovir
hydrochloride arm received2g4times a day by the
enteral route. Patients unable to receive enteral medication received
intravenous aciclovir sodium, 10 mg/kg of ideal body
weight, 3 times a day until they were able to receive enteral
medication.
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Investigational medicinal product name |
Valganciclovir hydrochloride
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Investigational medicinal product code |
n/a
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Other name |
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Pharmaceutical forms |
Injection, Tablet
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Routes of administration |
Enteral use , Intravascular use
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Dosage and administration details |
Patients randomized to the valganciclovir hydrochloride arm received 450mg once a day by the enteral route.
Patients in this group who were unable to receive enteral medication received intravenous ganciclovir sodium,
2.5mg/kg ideal body weight, once a day until they were able to receive enteral medication.
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Baseline characteristics reporting groups
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Reporting group title |
Control
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Reporting group description |
Standard care | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Intervention Goups: Valaciclovir/acyclovir or valganciclovir
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Reporting group description |
Patients randomized to the valacyclovir hydrochloride arm received2g4times a day by the enteral route. Patients unable to receive enteral medication received intravenous aciclovir sodium, 10 mg/kg of ideal body weight, 3 times a day until they were able to receive enteral medication. Patients randomized to the valganciclovir hydrochloride arm received 450mg once a day by the enteral route. Patients in this group who were unable to receive enteral medication received intravenous ganciclovir sodium, 2.5mg/kg ideal body weight, once a day until they were able to receive enteral medication | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Control
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Reporting group description |
Standard care | ||
Reporting group title |
Intervention Goups: Valaciclovir/acyclovir or valganciclovir
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Reporting group description |
Patients randomized to the valacyclovir hydrochloride arm received2g4times a day by the enteral route. Patients unable to receive enteral medication received intravenous aciclovir sodium, 10 mg/kg of ideal body weight, 3 times a day until they were able to receive enteral medication. Patients randomized to the valganciclovir hydrochloride arm received 450mg once a day by the enteral route. Patients in this group who were unable to receive enteral medication received intravenous ganciclovir sodium, 2.5mg/kg ideal body weight, once a day until they were able to receive enteral medication | ||
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End point title |
time to first reactivation ofCMVin blood (defined as above the lower limit of the qPCR assay[20 copies/mL]) | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
28 days or until hospital discharge if earlier
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Statistical analysis title |
Analysis | ||||||||||||
Statistical analysis description |
All analyses were performed on an intention-totreat
principle, whereby patients included in the analysiswere
analyzed according to the treatment group to which theywere
randomized regardless of whether they received this treatment.
As the primary outcome of the study was to measure
the efficacy of antiviral drugs to preventCMVreactivation, patientswere
excluded fromthe analyses ofCMVviral load if viral
reactivation had already taken place before initiation of the
study drug on the day
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Comparison groups |
Control v Intervention Goups: Valaciclovir/acyclovir or valganciclovir
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Number of subjects included in analysis |
124
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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 | ||||||||||||
Confidence interval |
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95% | ||||||||||||
sides |
1-sided
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lower limit |
- | ||||||||||||
upper limit |
- | ||||||||||||
Variability estimate |
Standard deviation
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| Notes [1] - All analyses were performed on an intention-totreat principle, whereby patients included in the analysiswere analyzed according to the treatment group to which theywere randomized regardless of whether they received this treatment. As the primary outcome of the study was to measure the efficacy of antiviral drugs to preventCMVreactivation, patientswere excluded fromthe analyses ofCMVviral load if viral reactivation had already taken place before initiation of the study drug on the day of |
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Adverse events information [1]
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Timeframe for reporting adverse events |
Up to 28 days following recruitment
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Adverse event reporting additional description |
Recruitment into the valacyclovir arm stopped prematurely in September2013, following an interim analysis presented to the independentDataMonitoringCommittee, which advised that this arm be closed because of significantly higher mortality in this group.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
Study-specific | ||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
1
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Reporting groups
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Reporting group title |
Control
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Valaciclovir
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Reporting group description |
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Reporting group title |
Valganciclovir
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||
| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: Please refer to the publication. |
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| Frequency threshold for reporting non-serious adverse events: 1% | |||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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02 Sep 2013 |
Recruitment into the valacyclovir arm stopped prematurely in
September2013, following an interim analysis presentedto the
independentDataMonitoringCommittee, which advised that
this arm be closed because of significantly higher mortality in
this group.At this point, 34 participantshadbeen recruitedinto
the valacyclovir arm, 14 (41.2%;95%CI, 24.6%-57.7%)ofwhom had died by 28 days, comparedwith 5 of 37 participants (13.5%; 95% CI, 2.5%-24.5%) in the control arm and 7 of 34 participants (20.6%; 95%CI, 7.0%-34.2%) in the valganciclovir arm. To investigate potential associations between valacyclovir and cause of death, an independent case record review was performed. Reviewers were intensive care physicians independent of the study team; each set of case notes was examined by 2 reviewers blinded to groupallocation.Thereviewers identified all deaths as expected and attributable to the underlying
disease. By the end of the study, mortality in the control group increased from13.5%to 15.9%(7 of 44 participants) for 28-day mortality and to 20.5% (9 of 44 participants) for inhospital mortality. |
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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. | |||
| This is a pilot proof of principle study undetaken to determine whether it would be appropriate to undertake a large-scale RCT. | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/28437539 |
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