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

• ClinicalTrials.gov Identifier: NCT04871191
• Recruitment Status: Not yet recruiting
• First Posted: May 4, 2021
• Last Update Posted: May 4, 2021
• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborator: URC-CIC Paris Descartes Necker Cochin
• Information provided by (Responsible Party): Assistance Publique - Hôpitaux de Paris

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.

Condition or disease	Intervention/treatment	Phase
Granulomatosis With Polyangiitis; Anti-neutrophil Cytoplasmic Antibody-associated Vasculitis	Drug: Rituximab; Drug: Tocilizumab; Drug: Abatacept	Phase 2

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 (Clinical Trial)
• Estimated 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
• Estimated Study Start Date: September 2021
• Estimated Primary Completion Date: September 2024
• Estimated Study Completion Date: December 2024

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 Name: 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 Name: 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 Name: Orencia

Outcome Measures

Primary Outcome Measures :

1. Proportion of patients with a response or a remission [ Time Frame: 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. [ Time Frame: week 26 and 52 ]
   according to the EULAR recommendations
2. Physician's and patient's global assessment of disease activity [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: week 26 and 52 ]
   The area under the curve for corticosteroids at week 26 and 52
6. Vasculitis Damage Index [ Time Frame: 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) [ Time Frame: week 26 and 52 ]
   ranging from 0 to 3, with higher scores indicating worse functional impairment
8. Short Form 36 (SF-36) Health questionnaire [ Time Frame: 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 [ Time Frame: week 26 and 52 ]
   Evolution of ANCA titers in the treatment groups

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Contacts

Contact: Jonathan London, MD; +33 1 44 64 16 02; jlondon@hopital-dcss.org

Contact: Audrey Beclin-Clabaux; +331 58 41 33 82; audrey.clabaux@aphp.fr

Locations

France

Hôpital de la Croix Saint Simon

Paris, France, 75020

Contact: Jonathan London, MD + 33 1 44 64 16 02 jlondon@hopital-dcss.org

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

More Information

Publications:

Yates M, Watts RA, Bajema IM, Cid MC, Crestani B, Hauser T, Hellmich B, Holle JU, Laudien M, Little MA, Luqmani RA, Mahr A, Merkel PA, Mills J, Mooney J, Segelmark M, Tesar V, Westman K, Vaglio A, Yalçındağ N, Jayne DR, Mukhtyar C. EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Ann Rheum Dis. 2016 Sep;75(9):1583-94. doi: 10.1136/annrheumdis-2016-209133. Epub 2016 Jun 23. Erratum in: Ann Rheum Dis. 2017 Aug;76(8):1480.

Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, Kallenberg CG, St Clair EW, Turkiewicz A, Tchao NK, Webber L, Ding L, Sejismundo LP, Mieras K, Weitzenkamp D, Ikle D, Seyfert-Margolis V, Mueller M, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh KA, Kissin EY, Monach PA, Peikert T, Stegeman C, Ytterberg SR, Specks U; RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010 Jul 15;363(3):221-32. doi: 10.1056/NEJMoa0909905.

Holle JU, Dubrau C, Herlyn K, Heller M, Ambrosch P, Noelle B, Reinhold-Keller E, Gross WL. Rituximab for refractory granulomatosis with polyangiitis (Wegener's granulomatosis): comparison of efficacy in granulomatous versus vasculitic manifestations. Ann Rheum Dis. 2012 Mar;71(3):327-33. doi: 10.1136/ard.2011.153601. Epub 2011 Oct 21.

Hellmich B, Flossmann O, Gross WL, Bacon P, Cohen-Tervaert JW, Guillevin L, Jayne D, Mahr A, Merkel PA, Raspe H, Scott DG, Witter J, Yazici H, Luqmani RA. EULAR recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis: focus on anti-neutrophil cytoplasm antibody-associated vasculitis. Ann Rheum Dis. 2007 May;66(5):605-17. Epub 2006 Dec 14. Review.

Sakai R, Kondo T, Kurasawa T, Nishi E, Okuyama A, Chino K, Shibata A, Okada Y, Takei H, Nagasawa H, Amano K. Current clinical evidence of tocilizumab for the treatment of ANCA-associated vasculitis: a prospective case series for microscopic polyangiitis in a combination with corticosteroids and literature review. Clin Rheumatol. 2017 Oct;36(10):2383-2392. doi: 10.1007/s10067-017-3752-0. Epub 2017 Jul 21. Review.

Berti A, Cavalli G, Campochiaro C, Guglielmi B, Baldissera E, Cappio S, Sabbadini MG, Doglioni C, Dagna L. Interleukin-6 in ANCA-associated vasculitis: Rationale for successful treatment with tocilizumab. Semin Arthritis Rheum. 2015 Aug;45(1):48-54. doi: 10.1016/j.semarthrit.2015.02.002. Epub 2015 Feb 20.

Berti A, Warner R, Johnson K, Cornec D, Schroeder DR, Kabat BF, Langford CA, Kallenberg CGM, Seo P, Spiera RF, St Clair EW, Fervenza FC, Stone JH, Monach PA, Specks U, Merkel PA; RAVE-ITN Research Group. The association of serum interleukin-6 levels with clinical outcomes in antineutrophil cytoplasmic antibody-associated vasculitis. J Autoimmun. 2019 Dec;105:102302. doi: 10.1016/j.jaut.2019.07.001. Epub 2019 Jul 15.

Langford CA, Monach PA, Specks U, Seo P, Cuthbertson D, McAlear CA, Ytterberg SR, Hoffman GS, Krischer JP, Merkel PA; Vasculitis Clinical Research Consortium. An open-label trial of abatacept (CTLA4-IG) in non-severe relapsing granulomatosis with polyangiitis (Wegener's). Ann Rheum Dis. 2014 Jul;73(7):1376-9. doi: 10.1136/annrheumdis-2013-204164. Epub 2013 Dec 9.

• Responsible Party: Assistance Publique - Hôpitaux de Paris
• ClinicalTrials.gov Identifier: NCT04871191
• Other Study ID Numbers: P200026
• First Posted: May 4, 2021
• Last Update Posted: May 4, 2021
• Last Verified: February 2021

Individual Participant Data (IPD) Sharing Statement:

• 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:

Granulomatosis with Polyangiitis; Anti-neutrophil cytoplasmic antibody; Salvage therapy; Standard of care therapy; Inadequate response

Additional relevant MeSH terms:

Granulomatosis with Polyangiitis; Vasculitis; Systemic Vasculitis; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Vascular Diseases; Cardiovascular Diseases; Lung Diseases, Interstitial; Lung Diseases; Respiratory Tract Diseases; Autoimmune Diseases; Immune System Diseases; Rituximab; Abatacept; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents