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Study of Salvage Therapy to Treat Patients With Granulomatosis With Polyangiitis (SATELITE)

Primary Purpose

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

Status
Not yet recruiting
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Rituximab
Tocilizumab
Abatacept
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Granulomatosis With Polyangiitis focused on measuring Granulomatosis with Polyangiitis, Anti-neutrophil cytoplasmic antibody, Salvage therapy, Standard of care therapy, Inadequate response

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Hôpital de la Croix Saint Simon

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Experimental

Experimental

Arm Label

Rituximab + cDMARD

Tocilizumab

Abatacept

Arm 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.

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

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Proportion of patients with a response or a remission at week 26 and 52.
according to the EULAR recommendations
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.
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.
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
Corticosteroids use
The area under the curve for corticosteroids at 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
Health Assessment Questionnaire (HAQ)
ranging from 0 to 3, with higher scores indicating worse functional impairment
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
ANCA titers
Evolution of ANCA titers in the treatment groups

Full Information

First Posted
February 26, 2021
Last Updated
February 6, 2023
Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
URC-CIC Paris Descartes Necker Cochin
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1. Study Identification

Unique Protocol Identification Number
NCT04871191
Brief Title
Study of Salvage Therapy to Treat Patients With Granulomatosis With Polyangiitis
Acronym
SATELITE
Official Title
Salvage Therapy for Patients With Inadequate Response to Standard of Care Therapy in Granulomatosis With Polyangiitis
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
March 2023 (Anticipated)
Primary Completion Date
September 2026 (Anticipated)
Study Completion Date
January 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
URC-CIC Paris Descartes Necker Cochin

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Granulomatosis With Polyangiitis, Anti-neutrophil Cytoplasmic Antibody-associated Vasculitis
Keywords
Granulomatosis with Polyangiitis, Anti-neutrophil cytoplasmic antibody, Salvage therapy, Standard of care therapy, Inadequate response

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
42 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Rituximab + cDMARD
Arm Type
Active Comparator
Arm 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.
Arm Title
Tocilizumab
Arm Type
Experimental
Arm Description
Tocilizumab will be administered subcutaneously every week at a fixed dose of 162 mg per week.
Arm Title
Abatacept
Arm Type
Experimental
Arm Description
Abatacept will be administered subcutaneously every week at a fixed dose of 125 mg per week.
Intervention Type
Drug
Intervention Name(s)
Rituximab
Other Intervention Name(s)
Mabthera
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Tocilizumab
Other Intervention Name(s)
RoActemra
Intervention Description
Subcutaneous injection of 162 mg per week
Intervention Type
Drug
Intervention Name(s)
Abatacept
Other Intervention Name(s)
Orencia
Intervention Description
Subcutaneous injection of 125 mg per week
Primary Outcome Measure Information:
Title
Proportion of patients with a response or a remission
Description
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.
Time Frame
week 12
Secondary Outcome Measure Information:
Title
Proportion of patients with a response or a remission at week 26 and 52.
Description
according to the EULAR recommendations
Time Frame
week 26 and 52
Title
Physician's and patient's global assessment of disease activity
Description
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.
Time Frame
week 12 and 52
Title
Patient-reported outcomes
Description
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.
Time Frame
week 12, 24 and 52
Title
Adverse events
Description
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
Time Frame
week 26 and 52
Title
Corticosteroids use
Description
The area under the curve for corticosteroids at week 26 and 52
Time Frame
week 26 and 52
Title
Vasculitis Damage Index
Description
The Vasculitis Damage Index (VDI, scoring from 0 to 58, higher scores indicating more damage) at week 26 and 52
Time Frame
week 26 and 52
Title
Health Assessment Questionnaire (HAQ)
Description
ranging from 0 to 3, with higher scores indicating worse functional impairment
Time Frame
week 26 and 52
Title
Short Form 36 (SF-36) Health questionnaire
Description
scores range from 0 to 100 for each component, with lower scores indicating greater impairment of quality of life
Time Frame
week 26 and 52
Title
ANCA titers
Description
Evolution of ANCA titers in the treatment groups
Time Frame
week 26 and 52

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jonathan London, MD
Phone
+33 1 44 64 16 02
Email
jlondon@hopital-dcss.org
First Name & Middle Initial & Last Name or Official Title & Degree
Audrey Beclin-Clabaux
Phone
+331 58 41 33 82
Email
audrey.clabaux@aphp.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Benjamin Terrier, MD, PhD
Organizational Affiliation
AP-HP - Service médecine interne
Official's Role
Study Director
Facility Information:
Facility Name
Hôpital de la Croix Saint Simon
City
Paris
ZIP/Postal Code
75020
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jonathan London, MD
Phone
+ 33 1 44 64 16 02
Email
jlondon@hopital-dcss.org

12. IPD Sharing Statement

Plan to Share IPD
No
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Results Reference
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Study of Salvage Therapy to Treat Patients With Granulomatosis With Polyangiitis

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