Clinical trial NCT01503918: Cytomegalovirus Control in Critical Care
Official title: Anti-viral Prophylaxis for Prevention of Cytomegalovirus (CMV) Reactivation in Immunocompetent Patients in Critical Care
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Critical Illness
Keywords: Critical Illness
Critical Care
Valganciclovir
Ganciclovir
Aciclovir
Valaciclovir
Cytomegalovirus
Lead sponsor: University Hospital Birmingham NHS Foundation Trust
Sponsor class: OTHER
Collaborators: name: National Institute for Health Research, United Kingdom
First posted: 2012-01-04
Enrollment: 124
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Time to reactivation of cytomegalovirus (CMV) polymerase chain reaction (PCR) (defined as above the lower limit of sample assay).
timeFrame: 28 days
Secondary outcomes:
measure: 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.
timeFrame: 28 days
measure: Time to >1000 CMV copies in blood, urine, throat swab and NDBL (NDBL whilst intubated)
timeFrame: 28 days
measure: Time to >10000 CMV copies in blood, urine, throat swab and NDBL (NDBL whilst intubated)
timeFrame: 28 days
measure: CMV PCR in blood, urine, throat swab and NDBL (NDBL whilst intubated)
timeFrame: 28 days
measure: Markers of inflammation
timeFrame: 28 days
measure: Clinical Outcomes
timeFrame: 28 days
measure: Clinical Outcomes
timeFrame: 28 days
measure: Clinical Outcomes
timeFrame: from randomization to intensive care discharge (up to 3 months)
measure: Clinical Outcomes
timeFrame: from randomization to hospital discharge (up to 3 months)
measure: Number of Serious Adverse events
timeFrame: 28 days
measure: Time to neutropenia (count <1.0x10-9/L)
timeFrame: 28 days
measure: Time to thrombocytopenia (platelet <50x10-9/L)
timeFrame: 28 days
measure: Use of G-CSF or termination of study drug
timeFrame: 28 days
measure: Number of platelet transfusions received
timeFrame: 28 days
measure: Time to renal insufficiency (CrCl <60ml/min, <30ml/min, need for renal support)
timeFrame: 28 days
Other outcomes:
Locations:
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham NHS Foundation Trust
state: West Midlands
Study officials:
affiliation: University Hospital Birmingham NHS Foundation Trust
name: Julian F Bion, MD FRCP FRCA
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital Birmingham NHS Foundation Trust
name: Nicholas J Cowley, MBChB MRCP FRCA
role: STUDY_DIRECTOR
affiliation: University Hospital Birmingham NHS Foundation Trust
name: Paul AH Moss, PhD MRCP MRCPath
role: STUDY_DIRECTOR
References:
citation: 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.