Clinical trial NCT01633476: CMV Modulation of the Immune System in ANCA-associated Vasculitis
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: ANCA Associated Vasculitis
CMV Infection
Keywords: CMV
ANCA associated vasculitis
CD4+CD28- T-cells
Valaciclovir
Lead sponsor: University of Birmingham
Sponsor class: OTHER
Collaborators: name: Wellcome Trust
First posted: 2012-07-04
Enrollment: 38
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Documented diagnosis of Wegener's granulomatosis (now called Granulomatosis with Polyangiitis), microscopic polyangiitis or renal limited vasculitis according to Chapel Hill Consensus Conference criteria.
* In stable remission (no documented clinical disease activity) for at least 6 months prior to entry.
* On maintenance immunosuppression with prednisolone, mycophenolate mofetil or azathioprine alone or in combination (maximum 2 agents).
* Documented evidence of CMV infection (CMV-specific immunoglobulin G detected in peripheral blood).
* Documentation that female patients of child bearing potential are not pregnant and using an appropriate form of contraception.
* Written informed consent for study participation

Exclusion Criteria:

* Stage 5 chronic kidney disease (eGFR\<15ml/minute/1.73m2).
* Other significant chronic infection (HIV, HBV, HCV, TB).
* B-cell or T-cell depleting therapy within 12 months.
* Treatment with anti-CMV therapies in last month
* Underlying medical conditions, which in the opinion of the Investigator place the patient at unacceptably high risk for participating in the study.
* Inability to fully or appropriately participate in the study.

Primary outcomes:
measure: Proportion of patients with CMV reactivation and time to CMV reactivation
timeFrame: Over 12 month period
Secondary outcomes:
measure: Proportion of patients experiencing adverse events sufficient to stop treatment
timeFrame: Over 6 month period (treatment period)
measure: Change in the proportion of the CD4+ CMV specific T cell population from baseline to 6 months
timeFrame: Baseline to 6 months
measure: Change in markers of inflammation from baseline to 6 months
timeFrame: Baseline to 6 months
measure: 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)
timeFrame: 6 months to 12 months
Other outcomes:
measure: Change in the immune phenotype of the CD4+ and CD8+ T-cell compartment from baseline to 6 months
timeFrame: Baseline to 6 months
measure: Change in the immune phenotype of CD4+ CMV-specific T-cells
timeFrame: Baseline to 6 months
Locations:
city: Birmingham
country: United Kingdom
facility: Wellcome Trust Clinical Research Facility
Study officials:
affiliation: University of Birmingham
name: Lorraine Harper, MRCP PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Morgan MD, Pachnio A, Begum J, Roberts D, Rasmussen N, Neil DA, Bajema I, Savage CO, Moss PA, Harper L. CD4+CD28- T cell expansion in granulomatosis with polyangiitis (Wegener's) is driven by latent cytomegalovirus infection and is associated with an increased risk of infection and mortality. Arthritis Rheum. 2011 Jul;63(7):2127-37. doi: 10.1002/art.30366.
citation: Chanouzas D, Sagmeister M, Faustini S, Nightingale P, Richter A, Ferro CJ, Morgan MD, Moss P, Harper L. Subclinical Reactivation of Cytomegalovirus Drives CD4+CD28null T-Cell Expansion and Impaired Immune Response to Pneumococcal Vaccination in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. J Infect Dis. 2019 Jan 7;219(2):234-244. doi: 10.1093/infdis/jiy493.
citation: Chanouzas D, Dyall L, Nightingale P, Ferro C, Moss P, Morgan MD, Harper L. Valaciclovir to prevent Cytomegalovirus mediated adverse modulation of the immune system in ANCA-associated vasculitis (CANVAS): study protocol for a randomised controlled trial. Trials. 2016 Jul 22;17(1):338. doi: 10.1186/s13063-016-1482-2.
citation: Chanouzas D, Dyall L, Dale J, Moss P, Morgan M, Harper L. CD4+CD28- T-cell expansions in ANCA-associated vasculitis and association with arterial stiffness: baseline data from a randomised controlled trial. Lancet. 2015 Feb 26;385 Suppl 1:S30. doi: 10.1016/S0140-6736(15)60345-2.