CMV Modulation of the Immune System in ANCA-associated Vasculitis (CANVAS)

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

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 Overview

• Status: Unknown
• Conditions: ANCA Associated Vasculitis; CMV Infection
• Intervention / Treatment: Drug: Valaciclovir

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.

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Birmingham, United Kingdom, B15 2TH
    • Wellcome Trust Clinical Research Facility

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Valaciclovir; Active treatment with valaciclovir	Drug: Valaciclovir; 2g q.d.s. orally for 6 months (dose adjusted according to renal function); Other Names: Brand names: Valtrex, Zelitrex
No Intervention: No additional treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with CMV reactivation and time to CMV reactivation	As assessed by measurable viral load on quantitative blood and urine CMV PCR.	Over 12 month period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients experiencing adverse events sufficient to stop treatment	Safety as defined by adverse events sufficient to stop treatment with trial drugs or serious adverse events and suspected unexpected serious adverse reactions (SUSARs).	Over 6 month period (treatment period)
Change in the proportion of the CD4+ CMV specific T cell population from baseline to 6 months	Change in the proportion of CD3+CD4+CD28- T-cells	Baseline to 6 months
Change in markers of inflammation from baseline to 6 months	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).	Baseline to 6 months
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)	Change in proportion of CD3+CD4+CD28- T-cells	6 months to 12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the immune phenotype of the CD4+ and CD8+ T-cell compartment from baseline to 6 months	Change in the proportion of naive and memory CD4+ and CD8+ T-cells	Baseline to 6 months
Change in the immune phenotype of CD4+ CMV-specific T-cells	Change in cytokine production Change in inhibitory receptor expression	Baseline to 6 months

Collaborators and Investigators

• Sponsor: Professor Lorraine Harper
• Collaborators: Wellcome Trust
• Investigators: Principal Investigator: Lorraine Harper, MRCP PhD, University of Birmingham

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: July 1, 2013
• Primary Completion (Actual): February 1, 2016
• Study Completion (Anticipated): September 1, 2017

Study Registration Dates

• First Submitted: June 29, 2012
• First Submitted That Met QC Criteria: July 3, 2012
• First Posted (Estimate): July 4, 2012

Study Record Updates

• Last Update Posted (Estimate): November 30, 2016
• Last Update Submitted That Met QC Criteria: November 29, 2016
• Last Verified: November 1, 2016

More Information

Terms related to this study

• Keywords: ANCA associated vasculitis; CMV; Valaciclovir; CD4+CD28- T-cells
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Virus Diseases; Infections; Immune System Diseases; Autoimmune Diseases; DNA Virus Infections; Herpesviridae Infections; Systemic Vasculitis; Cytomegalovirus Infections; Vasculitis; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Anti-Infective Agents; Antiviral Agents; Valacyclovir
• Other Study ID Numbers: CMV-001; 097962/Z/11/Z (Other Grant/Funding Number: Wellcome Trust); 2012-001970-28 (EudraCT Number)