CMV Modulation of the Immune System in ANCA-associated Vasculitis

CMV Infection Clinical Trial

— CANVAS  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01633476
• Other study ID #: CMV-001
• Secondary ID: 097962/Z/11/Z201
• Status: Active, not recruiting
• Phase: Phase 2
• First received: June 29, 2012
• Last updated: November 29, 2016
• Start date: July 2013
• Est. completion date: September 2017

Study information

• Verified date: November 2016
• Source: University of Birmingham
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory AgencyUnited Kingdom: Research Ethics Committee
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 38
• Est. completion date: September 2017
• Est. primary completion date: February 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 16 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• ANCA Associated Vasculitis
• Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
• CMV Infection
• Cytomegalovirus Infections
• Vasculitis

Intervention

Drug:
• Valaciclovir
2g q.d.s. orally for 6 months (dose adjusted according to renal function)

Locations

Country	Name	City	State
United Kingdom	Wellcome Trust Clinical Research Facility	Birmingham

Sponsors (2)

Lead Sponsor	Collaborator
Professor Lorraine Harper	Wellcome Trust

Country where clinical trial is conducted

United Kingdom, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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	No
Other	Change in the immune phenotype of CD4+ CMV-specific T-cells	Change in cytokine production Change in inhibitory receptor expression	Baseline to 6 months	No
Primary	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	No
Secondary	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)	Yes
Secondary	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	No
Secondary	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	No
Secondary	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	No