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 [ Time Frame: 6 months ] [ Designated as safety issue: No ]As assessed by measurable viral load on quantitative blood or urine CMV PCR.
- Proportion of patients experiencing adverse events sufficient to stop treatment [ Time Frame: 6 months ] [ 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 immune phenotype of the CD4+ CMV specific T cell population at 6 months [ Time Frame: 6 months ] [ Designated as safety issue: No ]Change in surface marker expression of CD4+ CMV specific T cells, Change in cytokine expression of CD4+CD28- CMV specific T cells, Change in inhibitory receptor expression of CD4+CD28- CMV specific T cells.
- Change in markers of inflammation [ Time Frame: 6 months ] [ Designated as safety issue: No ]Change in markers of inflammation including serum concentrations of pro and anti-inflammatory cytokines (TNF, IFN, IL-2, IL-6, IL-10, IL-17), markers of systemic inflammation (highly sensitive CRP, ESR).
- Persistence of valaciclovir effect on immune phenotype of CD4+ T cells at 6 months post treatment [ Time Frame: 12 months from start of study ] [ Designated as safety issue: No ]Change in surface marker expression of CD4+ CMV specific T cells, Change in cytokine expression of CD4+CD28- CMV specific T cells, Change in inhibitory receptor expression of CD4+CD28- CMV specific T cells.
|Study Start Date:||August 2012|
|Estimated Study Completion Date:||August 2015|
|Estimated Primary Completion Date:||May 2015 (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.
|Contact: Lorraine Harper, MRCP PhD||+44 (0)121 371 email@example.com|
|Contact: Dimitrios Chanouzas, MRCP||+44 (0)79 71 firstname.lastname@example.org|
|Wellcome Trust Clinical Research Facility|
|Birmingham, United Kingdom, B15 2TH|
|Principal Investigator:||Lorraine Harper, MRCP PhD||University of Birmingham|