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

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ClinicalTrials.gov Identifier: NCT01633476
Recruitment Status : Unknown
Verified November 2016 by Professor Lorraine Harper, University of Birmingham.
Recruitment status was:  Active, not recruiting
First Posted : July 4, 2012
Last Update Posted : November 30, 2016
Wellcome Trust
Information provided by (Responsible Party):
Professor Lorraine Harper, University of Birmingham

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.

Condition or disease Intervention/treatment Phase
ANCA Associated Vasculitis CMV Infection Drug: Valaciclovir Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 38 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (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
Study Start Date : July 2013
Actual Primary Completion Date : February 2016
Estimated Study Completion Date : September 2017

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 Name: Brand names: Valtrex, Zelitrex

No Intervention: No additional treatment
No additional treatment

Primary Outcome Measures :
  1. Proportion of patients with CMV reactivation and time to CMV reactivation [ Time Frame: Over 12 month period ]
    As assessed by measurable viral load on quantitative blood and urine CMV PCR.

Secondary Outcome Measures :
  1. Proportion of patients experiencing adverse events sufficient to stop treatment [ Time Frame: Over 6 month period (treatment period) ]
    Safety as defined by adverse events sufficient to stop treatment with trial drugs or serious adverse events and suspected unexpected serious adverse reactions (SUSARs).

  2. Change in the proportion of the CD4+ CMV specific T cell population from baseline to 6 months [ Time Frame: Baseline to 6 months ]
    Change in the proportion of CD3+CD4+CD28- T-cells

  3. Change in markers of inflammation from baseline to 6 months [ Time Frame: 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).

  4. 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 ]
    Change in proportion of CD3+CD4+CD28- T-cells

Other Outcome Measures:
  1. Change in the immune phenotype of the CD4+ and CD8+ T-cell compartment from baseline to 6 months [ Time Frame: Baseline to 6 months ]
    Change in the proportion of naive and memory CD4+ and CD8+ T-cells

  2. Change in the immune phenotype of CD4+ CMV-specific T-cells [ Time Frame: Baseline to 6 months ]
    Change in cytokine production Change in inhibitory receptor expression

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Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01633476

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United Kingdom
Wellcome Trust Clinical Research Facility
Birmingham, United Kingdom, B15 2TH
Sponsors and Collaborators
Professor Lorraine Harper
Wellcome Trust
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Principal Investigator: Lorraine Harper, MRCP PhD University of Birmingham
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Professor Lorraine Harper, Professor of Nephrology, University of Birmingham
ClinicalTrials.gov Identifier: NCT01633476    
Other Study ID Numbers: CMV-001
097962/Z/11/Z ( Other Grant/Funding Number: Wellcome Trust )
2012-001970-28 ( EudraCT Number )
First Posted: July 4, 2012    Key Record Dates
Last Update Posted: November 30, 2016
Last Verified: November 2016
Keywords provided by Professor Lorraine Harper, University of Birmingham:
ANCA associated vasculitis
CD4+CD28- T-cells
Additional relevant MeSH terms:
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Cytomegalovirus Infections
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Vascular Diseases
Cardiovascular Diseases
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Systemic Vasculitis
Autoimmune Diseases
Immune System Diseases
Antiviral Agents
Anti-Infective Agents