Study of Salvage Therapy to Treat Patients With Granulomatosis With Polyangiitis

Study Overview
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Brief Summary
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The purpose of this study is to identify the most promising therapeutic strategy for patients with granulomatosis with polyangiitis and inadequate response to standard of care therapy. It will evaluate the efficacy to induce remission of three different salvage strategies including: a combination of rituximab with addition of a conventional disease-modifying antirheumatic drugs (either methotrexate, azathioprine or mycophenolate mofetil, but preferentially methotrexate); tocilizumab; or abatacept.

Detailed Description
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Granulomatosis with polyangiitis (GPA) is an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV). Combination of glucocorticoids and either cyclophosphamide or rituximab is the standard of care for remission-induction of new-onset organ-threatening or life-threatening GPA. Few patients fail to respond to both cyclophosphamide and rituximab, but it is not uncommon for patients to have persistent disease activity resulting in inability to taper glucocorticoids, which is also considered refractory disease. The current recommendations for patients with GPA refractory to remission-induction therapy are to switch from cyclophosphamide to rituximab or from rituximab to cyclophosphamide. However, there are no recommendations for the management of patients with inadequate response after both treatments. Treatment with a biologic disease-modifying antirheumatic drugs (DMARD) or a combination of rituximab and a cDMARD are potential treatments options but have not been properly evaluated in such cases. Among biologic DMARD that have been evaluated in AAV, some have shown promising results, including tocilizumab and abatacept. Identifying the most promising therapeutic strategy for patients with GPA and inadequate response to standard of care therapy may improve management of GPA.

Official Title
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Salvage Therapy for Patients With Inadequate Response to Standard of Care Therapy in Granulomatosis With Polyangiitis

Conditions
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Granulomatosis With Polyangiitis, Anti-neutrophil Cytoplasmic Antibody-associated Vasculitis

Intervention / Treatment
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* Drug: Rituximab
* Drug: Tocilizumab
* Drug: Abatacept


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed or relapsing granulomatosis with polyangiitis according to American College of Rheumatology criteria, EMA classification algorithm and/or the 2012 revised Chapel Hill Consensus Conference definition. Aged 18 years or older Active clinical manifestations attributable to GPA An inadequate response to previous standard of care therapy including Both a combination of glucocorticoids plus cyclophosphamide and a combination of glucocorticoids plus rituximab Or an inadequate response to a combination of glucocorticoids plus rituximab and a contraindication to cyclophosphamide An inadequate response to treatment defined as follows: A progressive disease unresponsive to previous standard of care therapy after 12 weeks of treatment Or a lack of response, defined as < 50% reduction in the disease activity score, after 12 weeks of treatment Or a persistent active disease attributable to either a vasculitic or a granulomatous manifestation of GPA that requires the maintenance of corticosteroids ≥ 7.5 mg/day of equivalent prednisone after ≥ 12 weeks of treatment. A stable dose of oral glucocorticoids of ≥ 7.5 mg/day of equivalent prednisone within the 4 weeks before enrollment. Pulses of methylprednisolone (1 to 3 pulses of 7.5 to 15 mg/kg each; ≤ 1000 mg) are allowed if necessary, according to severity before starting the experimental treatment. A stable dose of conventional disease-modifying anti-rheumatic drugs (cDMARD) within 4 weeks before enrollment if the patient is currently treated with a cDMARD Patients must have the ability to understand the requirements of the study, provide written informed consent prior to participation in the study (including consent for the use and disclosure of research-related health information) and comply with the study protocol procedures (including required study visits) Patients must have an affiliation with a mode of social security (profit or being entitled) Exclusion Criteria: An allergy or hypersensitivity to monoclonal antibodies or either of the study drugs (rituximab, abatacept or tocilizumab) or to their excipients A previous treatment with a combination of rituximab plus a cDMARD, with abatacept, or with tocilizumab A contraindication to a combination of rituximab plus a cDMARD, to abatacept, or to tocilizumab (including an ongoing infection; history of recent cancer <5 years before enrollment, except for cured non-melanoma skin cancer); pregnancy; and breastfeeding. Patients with severe vasculitis manifestations that requires plasma exchange therapy including severe renal failure with a creatinine level ≥350 µmol/L or severe alveolar haemorrhage Patients with vasculitis in remission Patients with symptoms attributable to chronic and non-active GPA Patients with severe cardiac failure defined as class IV in New York Heart Association Patients with acute infections or chronic active infections (including HIV, HBV or HCV) Patients with active cancer or recent cancer (<5 years), except basocellular carcinoma and prostatic cancer of low activity controlled by hormonal treatment Pregnant women and lactation. All women with childbearing potential are required to have a negative serum pregnancy test before treatment and must agree to maintain highly effective contraception from the date of consent through the end of the study, and for women who are taking abatacept through 14 weeks after the last treatment administration, for women who are taking tocilizumab through 3 months after the last treatment administration, for women who are taking rituximab in combination with methotrexate through 6 months after the last treatment administration, for women who are taking rituximab in combination with mycofenolate mofetil or with azathioprine through 3 months after the last treatment administration Patients with other uncontrolled diseases, including drug or alcohol abuse, severe psychiatric diseases, that could interfere with participation in the trial according to the protocol Patients included in other investigational therapeutic study within the previous 3 months Patients suspected not to be observant to the proposed treatments Laboratory parameter exclusions aspartate or alanine aminotransferase (AST/SGOT or ALT/SGPT) > 5 times upper limit of normal Platelet count <100.000/mm3 White blood cell count <2000/mm3

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Rituximab + cDMARD<br>Rituximab will be administered at 375 mg/m²/week for four consecutive weeks. Maintenance rituximab at a fixed dose of 500 mg will be administered at week 24 and at week 52. The choice of the cDMARD will be left to the treating clinician and will include either methotrexate, azathioprine or mycophenolate mofetil, but the choice will be preferably methotrexate. Methotrexate will be administered orally or subcutaneously at 0.3 mg/kg/week, azathioprine orally at 2-3 mg/kg/d and mycophenolate mofetil orally at 2-3 g/d. | Drug: Rituximab<br>* 375 mg/m²/week for four consecutive weeks (Week 0, 1, 2 and 3) Maintenance rituximab at a fixed dose of 500 mg will be administered at week 24 and at week 52.<br>* Other names: Mabthera;|
| Experimental: Tocilizumab<br>Tocilizumab will be administered subcutaneously every week at a fixed dose of 162 mg per week. | Drug: Tocilizumab<br>* Subcutaneous injection of 162 mg per week<br>* Other names: RoActemra;|
| Experimental: Abatacept<br>Abatacept will be administered subcutaneously every week at a fixed dose of 125 mg per week. | Drug: Abatacept<br>* Subcutaneous injection of 125 mg per week<br>* Other names: Orencia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with a response or a remission | defined according to the EULAR recommendations. Remission is defined as the absence of disease activity attributable to active disease qualified by the need for ongoing stable maintenance immunosuppressive therapy. The term ''active disease'' is not restricted to vasculitis only, but also includes other inflammatory features like granulomatous inflammation. Response is defined as a 50% reduction of disease activity score and absence of new manifestations. | week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with a response or a remission at week 26 and 52. | according to the EULAR recommendations | week 26 and 52 | 
| Physician's and patient's global assessment of disease activity | The difference between the physician's and patient's global assessment of disease activity between baseline and week 12 and between baseline and week 52 using a scale ranging from 0 to 100, with higher scores indicating more activity. | week 12 and 52 | 
| Patient-reported outcomes | The patient-reported outcomes (PRO) including the ANCA-associated vasculitis patient-reported outcomes (AAV-PRO) questionnaire, a 29-item profile measure comprising six domains, with higher scores meaning more active disease, at week 12, 24, and 52 after randomization, and during the long-term follow-up. | week 12, 24 and 52 | 
| Adverse events | The number of adverse events, expressed as adverse events according to the CTCAE toxicity grading system per patient-year at week 26 and 52 for the following adverse events combined: death (all causes), grade 2 or higher leukopenia or thrombocytopenia, grade 3 or higher infections, hemorrhagic cystitis, malignancies, venous thromboembolic events, hospitalization resulting either from the disease or from a complication due to the study treatment, infusion reactions (within 24 hours of infusion) that result in the cessation of further infusions | week 26 and 52 | 
| Corticosteroids use | The area under the curve for corticosteroids at week 26 and 52 | week 26 and 52 | 
| Vasculitis Damage Index | The Vasculitis Damage Index (VDI, scoring from 0 to 58, higher scores indicating more damage) at week 26 and 52 | week 26 and 52 | 
| Health Assessment Questionnaire (HAQ) | ranging from 0 to 3, with higher scores indicating worse functional impairment | week 26 and 52 | 
| Short Form 36 (SF-36) Health questionnaire | scores range from 0 to 100 for each component, with lower scores indicating greater impairment of quality of life | week 26 and 52 | 
| ANCA titers | Evolution of ANCA titers in the treatment groups | week 26 and 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Granulomatosis with Polyangiitis, Anti-neutrophil cytoplasmic antibody, Salvage therapy, Standard of care therapy, Inadequate response