Study of Salvage Therapy to Treat Patients With Granulomatosis With Polyangiitis

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Brief Title

Study of Salvage Therapy to Treat Patients With Granulomatosis With Polyangiitis

Official Title

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

Brief Summary

      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

      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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Proportion of patients with a response or a remission

Secondary Outcome

 Proportion of patients with a response or a remission at week 26 and 52.

Condition

Granulomatosis With Polyangiitis

Intervention

Rituximab

Study Arms / Comparison Groups

 Rituximab + cDMARD
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

42

Start Date

September 2021

Completion Date

December 2024

Primary Completion Date

September 2024

Eligibility Criteria

        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

               1. Both a combination of glucocorticoids plus cyclophosphamide and a combination of
                  glucocorticoids plus rituximab

               2. Or an inadequate response to a combination of glucocorticoids plus rituximab and
                  a contraindication to cyclophosphamide

          -  An inadequate response to treatment defined as follows:

               1. A progressive disease unresponsive to previous standard of care therapy after 12
                  weeks of treatment

               2. Or a lack of response, defined as < 50% reduction in the disease activity score,
                  after 12 weeks of treatment

               3. 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. Patients with childbearing potential should have
             reliable contraception for the 12 months duration of the study

          -  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

               1. aspartate or alanine aminotransferase (AST/SGOT or ALT/SGPT) > 5 times upper
                  limit of normal

               2. Platelet count <100.000/mm3

               3. White blood cell count <2000/mm3
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Benjamin Terrier, MD, PhD, +33 1 44 64 16 02, [email protected]

Location Countries

France

Location Countries

France

Administrative Informations


NCT ID

NCT04871191

Organization ID

P200026


Responsible Party

Sponsor

Study Sponsor

Assistance Publique - Hôpitaux de Paris

Collaborators

 URC-CIC Paris Descartes Necker Cochin

Study Sponsor

Benjamin Terrier, MD, PhD, Study Director, AP-HP - Service médecine interne


Verification Date

February 2021