CMV Modulation of the Immune System in ANCA-associated Vasculitis (CANVAS)
The purpose of this study is to determine whether Cytomegalovirus (CMV) reactivation in ANCA-associated vasculitis (AAV) patients can be effectively and safely reduced using an antiviral agent (valaciclovir) and whether this in turn improves the function of the immune system thereby also improving the body's ability to fight other infections.
The primary hypothesis is that repeated episodes of CMV reactivation in AAV patients drive the expansion and functional impairment of CMV-specific T-cells, with increased susceptibility to infection. Inhibition of CMV replication with valaciclovir will block further stimulation of CMV specific T-cells and increase the functional capacity of the immune system.
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Basic Science
|Official Title:||Does CMV Reactivation Cause Functional Impairment of CMV Specific CD4+ T-cells? The Potential for Valaciclovir to Prevent CMV-mediated Adverse Modulation of the Immune System in Patients With ANCA-associated Vasculitis|
- Proportion of patients with CMV reactivation and time to CMV reactivation [ Time Frame: Over 12 month period ] [ Designated as safety issue: No ]As assessed by measurable viral load on quantitative blood and urine CMV PCR.
- Proportion of patients experiencing adverse events sufficient to stop treatment [ Time Frame: Over 6 month period (treatment period) ] [ Designated as safety issue: Yes ]Safety as defined by adverse events sufficient to stop treatment with trial drugs or serious adverse events and suspected unexpected serious adverse reactions (SUSARs).
- Change in the proportion of the CD4+ CMV specific T cell population from baseline to 6 months [ Time Frame: Baseline to 6 months ] [ Designated as safety issue: No ]Change in the proportion of CD3+CD4+CD28- T-cells
- Change in markers of inflammation from baseline to 6 months [ Time Frame: Baseline to 6 months ] [ Designated as safety issue: No ]Change in markers of inflammation including serum concentrations of pro and anti-inflammatory cytokines (TNF-a, IFN-g, IL-2, IL-6, IL-10, IL-17) and a marker of systemic inflammation (highly sensitive CRP).
- Persistence of valaciclovir effect on proportion of CD4+ CMV-specific T cells at 6 months post treatment (i.e. change from 6 months to 12 months) [ Time Frame: 6 months to 12 months ] [ Designated as safety issue: No ]Change in proportion of CD3+CD4+CD28- T-cells
- Change in the immune phenotype of the CD4+ and CD8+ T-cell compartment from baseline to 6 months [ Time Frame: Baseline to 6 months ] [ Designated as safety issue: No ]Change in the proportion of naive and memory CD4+ and CD8+ T-cells
- Change in the immune phenotype of CD4+ CMV-specific T-cells [ Time Frame: Baseline to 6 months ] [ Designated as safety issue: No ]Change in cytokine production Change in inhibitory receptor expression
|Study Start Date:||July 2013|
|Estimated Study Completion Date:||September 2017|
|Primary Completion Date:||February 2016 (Final data collection date for primary outcome measure)|
Active Comparator: Valaciclovir
Active treatment with valaciclovir
2g q.d.s. orally for 6 months (dose adjusted according to renal function)
Other Name: Brand names: Valtrex, Zelitrex
No Intervention: No additional treatment
No additional treatment
Infection is the commonest cause of death in patients with ANCA-associated vasculitis (AAV). The investigators have shown that the expansion of CD4+CD28- T-cells present in patients with AAV is driven by CMV and this expansion is associated with increased infection risk. It is suggested that these cells are driven by CMV reactivation and express markers of T-cell exhaustion with reduced cytokine production and inhibitory receptor expression. However the phenotype of CMV-specific T cells in those with extreme expansions of CD4+CD28- T-cells has not been explored.
The investigators aim to investigate the phenotype of CMV-specific T-cells comparing those patients with extreme expansions of CD4+CD28- T-cells to those with smaller expansions and relate this to CMV reactivation. The investigators will monitor CMV reactivation in urine and blood monthly by qPCR. This will be correlated with the expansion of CD4+CD28- T-cells and the phenotype of these cells, specifically looking at cytokine production and inhibitory receptor expression. The investigators will identify CMV-specific T-cells by MHC class II tetramers or by stimulating with CMV lysate. The investigators will proceed to undertake a randomised controlled trial with valaciclovir or no treatment to investigate whether the reduction of CMV reactivation improves the phenotype of CD4+CD28- T-cells in these patients.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01633476
|Wellcome Trust Clinical Research Facility|
|Birmingham, United Kingdom, B15 2TH|
|Principal Investigator:||Lorraine Harper, MRCP PhD||University of Birmingham|