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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2013 by University of Birmingham
Sponsor:
Collaborator:
Wellcome Trust
Information provided by (Responsible Party):
Professor Lorraine Harper, University of Birmingham
ClinicalTrials.gov Identifier:
NCT01633476
First received: June 29, 2012
Last updated: August 12, 2013
Last verified: August 2013
  Purpose

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 Intervention Phase
ANCA Associated Vasculitis
CMV Infection
Drug: Valaciclovir
Phase 2

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by University of Birmingham:

Primary Outcome Measures:
  • Proportion of patients with CMV reactivation and time to CMV reactivation [ Time Frame: Over 12 month period ] [ Designated as safety issue: No ]
    As assessed by measurable viral load on quantitative blood and urine CMV PCR.


Secondary Outcome Measures:
  • Proportion of patients experiencing adverse events sufficient to stop treatment [ Time Frame: Over 6 month period (treatment period) ] [ 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 the proportion of the CD4+ CMV specific T cell population from baseline to 6 months [ Time Frame: Baseline to 6 months ] [ Designated as safety issue: No ]
    Change in the proportion of CD3+CD4+CD28- T-cells

  • Change in markers of inflammation from baseline to 6 months [ Time Frame: Baseline to 6 months ] [ Designated as safety issue: No ]
    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).

  • 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 ] [ Designated as safety issue: No ]
    Change in proportion of CD3+CD4+CD28- T-cells


Other Outcome Measures:
  • Change in the immune phenotype of the CD4+ and CD8+ T-cell compartment from baseline to 6 months [ Time Frame: Baseline to 6 months ] [ Designated as safety issue: No ]
    Change in the proportion of naive and memory CD4+ and CD8+ T-cells

  • Change in the immune phenotype of CD4+ CMV-specific T-cells [ Time Frame: Baseline to 6 months ] [ Designated as safety issue: No ]
    Change in cytokine production Change in inhibitory receptor expression


Estimated Enrollment: 50
Study Start Date: July 2013
Estimated Study Completion Date: August 2015
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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

Ages Eligible for Study:   16 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01633476

Contacts
Contact: Lorraine Harper, MRCP PhD +44 (0)121 371 3238 l.harper@bham.ac.uk
Contact: Dimitrios Chanouzas, MRCP +44 (0)79 71 402309 dgchanouzas@doctors.org.uk

Locations
United Kingdom
Wellcome Trust Clinical Research Facility Recruiting
Birmingham, United Kingdom, B15 2TH
Contact: Joanna Gray, Sister    +44 (0)121 627 5836    Joanna.Gray@uhb.nhs.uk   
Contact: Michelle Grinham, Manager    +44 (0)121 627 2030    michelle.grinham@uhb.nhs.uk   
Sub-Investigator: Paul Moss, PhD FRCPath         
Sub-Investigator: Matthew Morgan, MRCP PhD         
Sub-Investigator: Dimitrios Chanouzas, MRCP MSc         
Principal Investigator: Lorraine Harper, MRCP PhD         
Sponsors and Collaborators
Professor Lorraine Harper
Wellcome Trust
Investigators
Principal Investigator: Lorraine Harper, MRCP PhD University of Birmingham
  More Information

Publications:
Responsible Party: Professor Lorraine Harper, Professor of Nephrology, University of Birmingham
ClinicalTrials.gov Identifier: NCT01633476     History of Changes
Other Study ID Numbers: CMV-001, 097962/Z/11/Z, 2012-001970-28
Study First Received: June 29, 2012
Last Updated: August 12, 2013
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
United Kingdom: Research Ethics Committee

Keywords provided by University of Birmingham:
CMV
ANCA associated vasculitis
CD4+CD28- T-cells
Valaciclovir

Additional relevant MeSH terms:
Vasculitis
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
Valacyclovir
Acyclovir
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 22, 2014