Cytomegalovirus Control in Critical Care (CCCC)
The purpose of this study is to determine whether reactivation of latent cytomegalovirus infection in critically ill patients looked after in the intensive care unit can be successfully and safely prevented using antiviral agents. Comparison is made between standard care, and treatment with one of two different antiviral regimens: valaciclovir/aciclovir, which has a favourable side effect profile but requires high dosage to be effective, and valganciclovir/ganciclovir, which has more side effects, but has been demonstrated to be effective in low dosage.
The primary hypothesis is that cytomegalovirus reactivation can be effectively suppressed with antiviral prophylaxis.
|Critical Illness||Drug: Valaciclovir/Aciclovir Drug: Valganciclovir/Ganciclovir||Phase 2|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
|Official Title:||Anti-viral Prophylaxis for Prevention of Cytomegalovirus (CMV) Reactivation in Immunocompetent Patients in Critical Care|
- Time to reactivation of cytomegalovirus (CMV) polymerase chain reaction (PCR) (defined as above the lower limit of sample assay). [ Time Frame: 28 days ]In the event of patient discharge from hospital or death, the results will be censored at the most proximate blood CMV PCR sample point.
- Time to reactivation above the lower limit of assay detection of CMV PCR in urine, throat swab and non-directed bronchiolar lavage (NDBL). NDBL whilst trachea is intubated only. [ Time Frame: 28 days ]*In the event of patient discharge from hospital, death, (or tracheal extubation for NDBL) the results will be censored at the most proximate CMV PCR sample point.
- Time to >1000 CMV copies in blood, urine, throat swab and NDBL (NDBL whilst intubated) [ Time Frame: 28 days ]*In the event of patient discharge from hospital, death, (or tracheal extubation for NDBL) the results will be censored at the most proximate CMV PCR sample point.
- Time to >10000 CMV copies in blood, urine, throat swab and NDBL (NDBL whilst intubated) [ Time Frame: 28 days ]*In the event of patient discharge from hospital, death, (or tracheal extubation for NDBL) the results will be censored at the most proximate CMV PCR sample point.
- CMV PCR in blood, urine, throat swab and NDBL (NDBL whilst intubated) [ Time Frame: 28 days ]*initial CMV copies, area under the curve,and peak CMV copies on PCR
- Markers of inflammation [ Time Frame: 28 days ]*interleukin 6 - change in assay between day 0 day 14 and day 28
- Clinical Outcomes [ Time Frame: 28 days ]*28 day mortality
- Clinical Outcomes [ Time Frame: 28 days ]
- Organ Failure Free days (SOFA score <2), moderate organ dysfunction free days (SOFA score <5)
- SOFA score = sequential organ failure assessment score
- Clinical Outcomes [ Time Frame: from randomization to intensive care discharge (up to 3 months) ]*Time to intensive care discharge
- Clinical Outcomes [ Time Frame: from randomization to hospital discharge (up to 3 months) ]*Time to hospital discharge
- Number of Serious Adverse events [ Time Frame: 28 days ]
- Time to neutropenia (count <1.0x10-9/L) [ Time Frame: 28 days ]
- Time to thrombocytopenia (platelet <50x10-9/L) [ Time Frame: 28 days ]
- Use of G-CSF or termination of study drug [ Time Frame: 28 days ]G-CSF = Granulocyte colony stimulating factor, a drug used to stimulate the bone marrow
- Number of platelet transfusions received [ Time Frame: 28 days ]
- Time to renal insufficiency (CrCl <60ml/min, <30ml/min, need for renal support) [ Time Frame: 28 days ]CrCl = Creatinine Clearance, calculated using the Cockcroft-Gault formula
|Study Start Date:||January 2012|
|Study Completion Date:||March 2014|
|Primary Completion Date:||January 2014 (Final data collection date for primary outcome measure)|
2g valaciclovir, four times a day, enterally for 28 days, or until discharge from the critical care unit, but for a minimum of 14 days unless discharged from hospital. Those unable to receive enteral drugs will receive intravenous aciclovir 10mg/kg three times a day. Dosing modified in the presence of renal dysfunction.
450mg valganciclovir, once a day, by enteral route. Treatment will continue for 28 days, or until discharge from the critical care unit, but for a minimum of 14 days unless discharged from hospital. Intravenous ganciclovir 2.5mg/kg once a day will be used if drugs cannot be given enterally. Treatment dosing will be modified for renal dysfunction
|No Intervention: control|
* Cytomegalovirus (CMV) is a common virus which infects around half the UK population. Infection is usually mild, but after infection the virus is never completely eradicated, and may reactivate in ill health. Reactivation is most commonly seen in those with compromised immune systems, such as people with advanced HIV infection, or whilst on immunosuppression following organ transplantation. CMV reactivation in these patients can be life threatening. There is evidence to support the use of antiviral medication in these groups of immunosuppressed patients to prevent CMV reactivation, and their use is part of standard therapy. There is increasing evidence demonstrating that a third of critically ill patients will reactivate CMV, and these patients have as much as a doubled mortality.
* This study is a proof of concept study designed to assess whether antiviral prophylaxis can effectively and safely suppress CMV reactivation in CMV seropositive high risk critically ill patients. Antiviral prophylaxis is currently not standard practice in critical care units, and no previous trials of prophylaxis have been undertaken in this setting. All commonly used antiviral agents have side effects, and it is important to demonstrate their efficacy and safety in the critical care setting before undertaking a large multicentre trial powered to identify mortality or morbidity differences with prophylaxis. Intravenous ganciclovir, and its oral prodrug valganciclovir have been effectively used as prophylaxis at low doses in immunosuppressed patients. Intravenous aciclovir and its oral prodrug valaciclovir in high dosage have also been demonstrated to be effective as prophylaxis in immunosuppressed patients. This study sets out to determine whether their use in critically ill patients are both effective and safe.
Plan of Investigation:
* This is a prospective, randomised, open-label single centre study. Patients admitted to the Queen Elizabeth Hospital Birmingham critical care unit, and identified by study criteria to be at high risk of CMV reactivation will be assessed for inclusion into the study. Blood will be analysed for CMV antibodies to establish eligibility. Recruited patients will be randomised to receive high dose aciclovir/valaciclovir, or low dose ganciclovir/valganciclovir for the duration of their critical care stay, for a maximum of 28 days, or to enter the control group receiving standard care. CMV viral load by polymerase chain reaction (PCR) will be measured in blood, throat swab, urine, and sputum via non-directed bronchiolar lavage (NDBL) twice weekly.
* Latent CMV infection is common, affecting around half of all adults in the UK. Evidence demonstrates that a third of these patients will reactivate leading to CMV viraemia when critically ill. Epidemiological data from multiple independent groups have identified a doubling in mortality in this group, although a causal link between CMV reactivation and mortality without a trial of antiviral drugs can not be assumed. From these figures, it is estimated that 16.5% of critically ill patients (current mortality rates of around 40%) may benefit from antiviral prophylaxis. Almost no patients are receiving prophylaxis or screening for reactivation worldwide in this group. Demonstration of mortality or morbidity improvements could potentially change worldwide intensive care practice.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01503918
|University Hospitals Birmingham NHS Foundation Trust|
|Birmingham, West Midlands, United Kingdom, B15 2WB|
|Principal Investigator:||Julian F Bion, MD FRCP FRCA||University Hospital Birmingham NHS Foundation Trust|
|Study Director:||Nicholas J Cowley, MBChB MRCP FRCA||University Hospital Birmingham NHS Foundation Trust|
|Study Director:||Paul AH Moss, PhD MRCP MRCPath||University Hospital Birmingham NHS Foundation Trust|