ANCA Associated VasculitisPhase 2CANVASNCT01633476
CMV Modulation of the Immune System in ANCA-associated Vasculitis
A Phase 2 study testing Valaciclovir in people with ANCA Associated Vasculitis and CMV Infection, run by Professor Lorraine Harper at 1 site in United Kingdom.
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… Read more about this study
- Who is it for?
- Ages 16 years and older
- Conditions the study is for
- ANCA Associated Vasculitis, CMV Infection
- What is being tested?
- Valaciclovir
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 38 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- Jul 2013to Sep 2017
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 16 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Wellcome Trust Clinical Research Facility
Birmingham, B15 2TH
About this study
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
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.
Read the 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.
- Conditions
- ANCA Associated Vasculitis, CMV Infection
- Being tested
- Valaciclovir
- Keywords
- CMV, ANCA associated vasculitis, CD4+CD28- T-cells, Valaciclovir
- Medical subject headings
- Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Cytomegalovirus Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ValaciclovirDrug
Also called Brand names: Valtrex, Zelitrex
2g q.d.s. orally for 6 months (dose adjusted according to renal function)
| Study group | Role | What they receive |
|---|---|---|
| Valaciclovir | Active comparator | Active treatment with valaciclovir Receives: Drug: Valaciclovir |
| No additional treatment | No intervention | No additional treatment |
What is being measured
The primary outcome is the main question the study is designed to answer.
Proportion of patients with CMV reactivation and time to CMV reactivation
As assessed by measurable viral load on quantitative blood and urine CMV PCR.
Measured: Over 12 month period
Secondary outcomes (4)
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).
Measured: 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
Measured: 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).
Measured: 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
Measured: 6 months to 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Jul 2012 (estimated)
- Study startJul 2013
- Primary completionFeb 2016
- Study completionSep 2017 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for ANCA Associated VasculitisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 38 participants (actual)
Sponsor and investigators
- Lead sponsor
- Professor Lorraine Harper
- Sponsor type
- University, hospital or other
- Collaborators
- Wellcome Trust
- Responsible party
- Sponsor-investigator, Professor Lorraine Harper, University of Birmingham
- Investigators
- Lorraine Harper, MRCP PhD, Principal investigator, University of Birmingham
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01633476
- Sponsor's protocol ID
- CMV-001
- Other IDs
- 097962/Z/11/Z, 2012-001970-28
- Acronym
- CANVAS
- Status last verified
- Nov 2016
- First submitted
- 29 Jun 2012
- Last updated
- 30 Nov 2016
- Results posted
- No
- Data monitoring committee
- No
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.
PubMed 21437878Chanouzas 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.
PubMed 30102389Chanouzas 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.
PubMed 27450392Chanouzas 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.
PubMed 26312852
Study at a glance
From the registry record, last updated by the sponsor on 30 Nov 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01633476
- Acronym / sponsor ID
- CANVAS / CMV-001
- Conditions
- ANCA Associated Vasculitis, CMV Infection
- Keywords
- CMV, ANCA associated vasculitis, CD4+CD28- T-cells, Valaciclovir
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 38 participants (actual)
- Lead sponsor
- Professor Lorraine HarperUniversity, hospital or other
- Collaborators
- Wellcome Trust
- Study start
- Jul 2013
- Primary completion
- Feb 2016 (actual)
- Study completion
- Sep 2017 (estimated)
- First posted
- 4 Jul 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Valaciclovir | Active comparator | Drug: ValaciclovirActive treatment with valaciclovir |
| No additional treatment | No intervention | –No additional treatment |
Who may qualify
- Ages
- 16 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (6 listed)
- 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.
Key exclusion criteria (6 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ValaciclovirAlso: Brand names: Valtrex, Zelitrex2g q.d.s. orally for 6 months (dose adjusted according to renal function) | Drug | Valaciclovir |
Primary outcome
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.
4 secondary outcomes
Proportion of patients experiencing adverse events sufficient to stop treatment
Time frame: Over 6 month period (treatment period)
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 markers of inflammation from baseline to 6 months
Time frame: 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)
Time frame: 6 months to 12 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Nov 2016.
- Background: PubMed 21437878Morgan 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.
- Derived from this study: PubMed 30102389Chanouzas 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.
- Derived from this study: PubMed 27450392Chanouzas 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.
- Derived from this study: PubMed 26312852Chanouzas 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Lorraine Harper, MRCP PhD principal investigator
University of Birmingham
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Valaciclovir in people with ANCA Associated Vasculitis and CMV Infection, run by Professor Lorraine Harper at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 30 Nov 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Proportion of patients with CMV reactivation and time to CMV reactivation (time frame: Over 12 month period). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01633476, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Nov 2016.