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Study of Salvage Therapy to Treat Patients With Granulomatosis With Polyangiitis

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Interventional
Eligible Ages 18 Years and Over
Gender All
More Inclusion & Exclusion 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

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT04871191
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase 2
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

Assistance Publique - Hôpitaux de Paris
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

Benjamin Terrier, MD, PhD
Principal Investigator Affiliation AP-HP - Service médecine interne
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

OtherOther
Overall Status Not yet recruiting
Countries France
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

Granulomatosis With Polyangiitis, Anti-neutrophil Cytoplasmic Antibody-associated Vasculitis
Additional Details

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.

Arms & Interventions

Arms

Active Comparator: Rituximab + cDMARD

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.

Experimental: Tocilizumab

Tocilizumab will be administered subcutaneously every week at a fixed dose of 162 mg per week.

Experimental: Abatacept

Abatacept will be administered subcutaneously every week at a fixed dose of 125 mg per week.

Interventions

Drug: - Rituximab

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.

Drug: - Tocilizumab

Subcutaneous injection of 162 mg per week

Drug: - Abatacept

Subcutaneous injection of 125 mg per week

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

International Sites

Hôpital de la Croix Saint Simon, Paris, France

Status

Address

Hôpital de la Croix Saint Simon

Paris, , 75020

Site Contact

Jonathan London, MD

jlondon@hopital-dcss.org

+ 33 1 44 64 16 02