Cytomegalovirus Control in Critical Care (CCCC)

Anti-viral Prophylaxis for Prevention of Cytomegalovirus (CMV) Reactivation in Immunocompetent Patients in Critical Care

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.

Study Overview

• Status: Completed
• Conditions: Critical Illness
• Intervention / Treatment: Drug: Valaciclovir/Aciclovir; Drug: Valganciclovir/Ganciclovir

Detailed Description

Background:

* 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.

Aims:

* 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.

Potential Impact:

* 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.

• Study Type: Interventional
• Enrollment (Actual): 124
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B15 2WB
      • University Hospitals Birmingham NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Total hospital stay of less than 7 days
• CMV seropositive
• Critical care stay of >24 hours
• Mechanically ventilated, anticipated to continue for > 48 hours

Exclusion Criteria:

• Known Pregnancy or breast feeding
• Expected to survive less than 48 hours

• Confirmed immunosuppression

  • Known or suspected Human Immunodeficiency Virus infection
  • Known or suspected underlying immunodeficiency (organ transplantation including stem cell transplantation on immunosuppression, congenital immunodeficiency, in receipt of immunosuppressive medication e.g. azathioprine, methotrexate, tacrolimus, cyclosporine, sirolimus, cyclophosphamide within 30 days)
  • Corticosteroids: Prednisolone chronic administration may be used up to a dose of 10mg/day on average over the preceding 30 days, stress dose hydrocortisone (up to 400mg/day) may be used, topical steroids may be used, short duration of higher dose steroids for exacerbations of chronic obstructive pulmonary disease (COPD) up to 1mg/kg prednisolone or equivalent are permitted for up to 14 days
  • Receipt of chemotherapeutic agent within the last 6 months
• Use of systemic antiviral medication other than oseltamivir within the last 7 days.
• Intubated and mechanically ventilated secondary to brain injury alone.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Valaciclovir/Aciclovir	Drug: Valaciclovir/Aciclovir; 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.
EXPERIMENTAL: Valganciclovir/Ganciclovir	Drug: Valganciclovir/Ganciclovir; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to reactivation of cytomegalovirus (CMV) polymerase chain reaction (PCR) (defined as above the lower limit of sample assay).	In the event of patient discharge from hospital or death, the results will be censored at the most proximate blood CMV PCR sample point.	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	*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.	28 days
Time to >1000 CMV copies in blood, urine, throat swab and NDBL (NDBL whilst intubated)	*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.	28 days
Time to >10000 CMV copies in blood, urine, throat swab and NDBL (NDBL whilst intubated)	*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.	28 days
CMV PCR in blood, urine, throat swab and NDBL (NDBL whilst intubated)	*initial CMV copies, area under the curve,and peak CMV copies on PCR	28 days
Markers of inflammation	*interleukin 6 - change in assay between day 0 day 14 and day 28	28 days
Clinical Outcomes	*28 day mortality	28 days
Clinical Outcomes	Organ Failure Free days (SOFA score <2), moderate organ dysfunction free days (SOFA score <5); SOFA score = sequential organ failure assessment score	28 days
Clinical Outcomes	*Time to intensive care discharge	from randomization to intensive care discharge (up to 3 months)
Clinical Outcomes	*Time to hospital discharge	from randomization to hospital discharge (up to 3 months)
Number of Serious Adverse events		28 days
Time to neutropenia (count <1.0x10-9/L)		28 days
Time to thrombocytopenia (platelet <50x10-9/L)		28 days
Use of G-CSF or termination of study drug	G-CSF = Granulocyte colony stimulating factor, a drug used to stimulate the bone marrow	28 days
Number of platelet transfusions received		28 days
Time to renal insufficiency (CrCl <60ml/min, <30ml/min, need for renal support)	CrCl = Creatinine Clearance, calculated using the Cockcroft-Gault formula	28 days

Collaborators and Investigators

• Sponsor: University Hospital Birmingham NHS Foundation Trust
• Collaborators: National Institute for Health Research, United Kingdom
• Investigators: 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

Publications and helpful links

General Publications

• Cowley NJ, Owen A, Shiels SC, Millar J, Woolley R, Ives N, Osman H, Moss P, Bion JF. Safety and Efficacy of Antiviral Therapy for Prevention of Cytomegalovirus Reactivation in Immunocompetent Critically Ill Patients: A Randomized Clinical Trial. JAMA Intern Med. 2017 Jun 1;177(6):774-783. doi: 10.1001/jamainternmed.2017.0895.

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (ACTUAL): January 1, 2014
• Study Completion (ACTUAL): March 1, 2014

Study Registration Dates

• First Submitted: December 30, 2011
• First Submitted That Met QC Criteria: December 31, 2011
• First Posted (ESTIMATE): January 4, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): January 12, 2015
• Last Update Submitted That Met QC Criteria: January 9, 2015
• Last Verified: January 1, 2015

More Information

Terms related to this study

• Keywords: Critical Illness; Cytomegalovirus; Critical Care; Ganciclovir; Valaciclovir; Valganciclovir; Aciclovir
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Critical Illness; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Valacyclovir; Valganciclovir; Ganciclovir; Ganciclovir triphosphate; Acyclovir
• Other Study ID Numbers: RRK4142; 2010-024646-30 (EUDRACT_NUMBER); PB-PG-1010-23225 (OTHER_GRANT: National Institute for Health Research)