Granulomatosis With Polyangiitis, Microscopic Polyangiitis (MPA)
Conditions
Keywords
ANCA-associated vasculitis, cyclophosphamide, glucoccorticoid, rituximab, vasculitis, granulomatosis with polyangiitis, microscopic polyangiitis, GPA, MPA
Brief summary
The purpose of this study is to determine the safety and efficacy of a therapeutic regimen consisting of 4 weeks of glucocorticoids given with a combination of the usual induction agents for ANCA-associated vasculitis. The trial will compare this regimen to the current standard of care treatment and glucocorticoid dosing for ANCA-associated vasculitis with severe kidney involvement. This trial will begin as a pilot to assess feasibility of recruitment and of adherence to the intervention.
Detailed description
ANCA-associated vasculitis (AAV) is an auto-immune disease which often involves the kidneys. It is a serious condition as it can lead to severe kidney impairment, often kidney failure, and may even be life-threatening. Current treatments, typically cyclophosphamide (CYC) or rituximab (RTX) with a tapering course of glucocorticoids (GC), allow most patients to achieve control of their disease (remission). Glucocorticoids are most often used initially at high doses, and then gradually decreased to low doses over at least 6 months. This leads to major treatment toxicities, notably infections and GC-related adverse events, major contributors to patient morbidity and mortality. Recent research has focused on finding ways to reduce treatment-related toxicities without compromising efficacy for controlling disease manifestations. This includes a reduced-dose GC taper for severe AAV from the Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis (PEXIVAS) trial, an even more reduced-dose GC taper in patients with moderate severity AAV from the Effect of Reduced-Dose vs High-Dose Glucocorticoids Added to Rituximab on Remission Induction in ANCA-Associated Vasculitis (LOVAS) trial, and a novel GC-sparing agent examined in the Avacopan for the Treatment of ANCA-Associated Vasculitis (ADVOCATE) trial. Despite these advances, patients still experience high rates of infections, one of the major causes of death in the first year after diagnosis, particularly in patients with most severe forms of disease. Also, novel GC-sparing drugs are costly and have limited availability throughout the world; patients who cannot access this get exposed to significant amounts of GC and must suffer their dreaded side effects. This study addresses the unresolved issues of unacceptably high infection risk and of providing a widely available means of reducing GC exposure to minimise treatment side effects. The investigators will examine an induction treatment regimen for severe AAV consisting of 2 doses of IV CYC in combination with 4 weeks of GC and standard RTX. The control arm will be the current standard of care treatment for severe AAV. Non-controlled studies suggest the use of short duration CYC with RTX allows for minimisation of up-front GC use, as little as 1-2 weeks, but this needs to be tested in a prospective, controlled manner. The investigators hypothesize that the combination of CYC with standard RTX will allow less GC to be used for AAV. This study will begin as a pilot to examine the feasibility of the conducting the study, adherence to the intervention regimen, and of recruiting patients. If feasibility is demonstrated, the study will be extended to a full-scale trial.
Interventions
DRUGCyclophosphamide
IV Cyclophosphamide 15mg/kg/dose (age and eGFR adjusted), 2 doses 2 weeks apart
DRUGStandard of Care (SOC)
Participants will receive standard of care induction agent and glucocorticoid taper, at investigator discretion
DRUGPrednisone
4 weeks prednisone taper
DRUGRituximab (R)
Rituximab infusions, dosing and schedule at clinician/investigator discretion
Sponsors
Ottawa Hospital Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open-label, randomised controlled trial
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* New diagnosis of, or relapse of, granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA), consistent with Chapel-Hill consensus definitions * Positive ELISA test for anti-meyloperoxidase (MPO) or anti-proteinase 3 (PR3) * Severe kidney involvement from active AAV, characterised by both of the following: * eGFR \< 40ml/min/1.73m2 (Patients known to have a stable eGFR \<40 ml/min/1.73m2 for \>3 months prior to enrollment are NOT eligible) * Biopsy proven at least focal necrotizing/crescentic glomerulonephritis OR active urinary sediment by microscopy (greater than or equal to 10 red blood cells \[RBC\]/high power field with erythrocyte casts or greater than or equal to 20% dysmorphic RBCs or greater than or equal to 5% acanthocytes without an alternative cause.
Exclusion criteria
(any of the following) * A diagnosis of vasculitis other than GPA or MPA (including eosinophilic granulomatosis with polyangiitis, IgA vasculitis, cryoglobulinemic vasculitis, rheumatoid vasculitis) * Positive anti-glomerular basement membrane antibody test or renal biopsy demonstrating linear glomerular immunoglobulin deposition * A diagnosis of systemic lupus erythematosus or Sjögren's syndrome * Receipt of dialysis for \>21 days immediately prior to randomization or prior renal transplant * Age \<18 * Pregnant at time of screening * Treatment with \>1 IV dose of CYC and/or \>14 days PO CYC and/or \>14 days of prednisone/prednisone (less than or equal to 30mg/day) and/or \>1 dose of RTX within the 28 days immediately prior to randomization * Chronic viral infection: HIV. HBV or HCV * Untreated latent mycobacterium tuberculosis infection * Active infection at time of presentation * A comorbidity or condition that, in the opinion of the investigator, precludes the use of GC, CYC or RTX
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pilot trial: percent adherence to intervention regimen | 12 weeks | Pilot trial: percent adherence in the intervention arm (non-adherence will be defined as the use of more than 25% of the total expected oral prednisone in the intervention arm at 12 weeks) |
| Full-scale trial: Rate of serious infection | 26 weeks | Full-scale trial: rate of serious infection (Infection occurring after randomisation requiring IV antibiotics, or leading to hospitalisation or death) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pilot trial: recruitment rate | 52 weeks | Pilot trial: recruitment rate measured as incidence rate based on randomised participants/centre-month |
| Full-scale trial: Remission rate | 26 weeks | Full-scale trial: Remission defined as absence of manifestations due to active AAV. Remission status will be determined at study visits based on clinician judgement. If a participant is not in remission at an assessment point, the affected organ system (based on Birmingham Vasculitis Activity Score \[BVAS\]) will be captured. If a participant is transitioned to or being planned for maintenance therapy at their study visit, then they will also be considered to have achieved remission. |
Countries
Canada
Contacts
CONTACTDavid Massicotte-Azarniouch, MD, MSc
PRINCIPAL_INVESTIGATORDavid Massicotte-Azarniouch, MD, MSc
The Ottawa Hospital
Outcome results
None listed