SATELITE: Study of Salvage Therapy to Treat Patients With Granulomatosis With Polyangiitis

Sponsor
Assistance Publique - Hôpitaux de Paris (Other)
Overall Status
Not yet recruiting
CT.gov ID
NCT04871191
Collaborator
URC-CIC Paris Descartes Necker Cochin (Other)
42
1
3
45
0.9

Study Details

Study Description

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 Design

Study Type:
Interventional
Anticipated Enrollment :
42 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Single (Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
Salvage Therapy for Patients With Inadequate Response to Standard of Care Therapy in Granulomatosis With Polyangiitis
Anticipated Study Start Date :
Sep 1, 2022
Anticipated Primary Completion Date :
Feb 1, 2026
Anticipated Study Completion Date :
Jun 1, 2026

Arms and Interventions

Arm Intervention/Treatment
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.

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.
Other Names:
  • Mabthera
  • Experimental: Tocilizumab

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

    Drug: Tocilizumab
    Subcutaneous injection of 162 mg per week
    Other Names:
  • RoActemra
  • Experimental: Abatacept

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

    Drug: Abatacept
    Subcutaneous injection of 125 mg per week
    Other Names:
  • Orencia
  • Outcome Measures

    Primary Outcome Measures

    1. Proportion of patients with a response or a remission [week 12]

      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.

    Secondary Outcome Measures

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

      according to the EULAR recommendations

    2. Physician's and patient's global assessment of disease activity [week 12 and 52]

      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.

    3. Patient-reported outcomes [week 12, 24 and 52]

      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.

    4. Adverse events [week 26 and 52]

      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

    5. Corticosteroids use [week 26 and 52]

      The area under the curve for corticosteroids at week 26 and 52

    6. Vasculitis Damage Index [week 26 and 52]

      The Vasculitis Damage Index (VDI, scoring from 0 to 58, higher scores indicating more damage) at week 26 and 52

    7. Health Assessment Questionnaire (HAQ) [week 26 and 52]

      ranging from 0 to 3, with higher scores indicating worse functional impairment

    8. Short Form 36 (SF-36) Health questionnaire [week 26 and 52]

      scores range from 0 to 100 for each component, with lower scores indicating greater impairment of quality of life

    9. ANCA titers [week 26 and 52]

      Evolution of ANCA titers in the treatment groups

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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. 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

    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Hôpital de la Croix Saint Simon Paris France 75020

    Sponsors and Collaborators

    • Assistance Publique - Hôpitaux de Paris
    • URC-CIC Paris Descartes Necker Cochin

    Investigators

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

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Assistance Publique - Hôpitaux de Paris
    ClinicalTrials.gov Identifier:
    NCT04871191
    Other Study ID Numbers:
    • P200026
    First Posted:
    May 4, 2021
    Last Update Posted:
    Jun 8, 2022
    Last Verified:
    Jun 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Assistance Publique - Hôpitaux de Paris
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Jun 8, 2022