Study of Salvage Therapy to Treat Patients with Granulomatosis with Polyangiitis

NCT04871191 | Not Yet Recruiting Phase 3 DMC

• 1 other identifier: P200026
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 1

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 tofacitinib.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• 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.

  week 12

Secondary Outcomes (9)

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

  week 26 and 52

• Physician's and patient's global assessment of disease activity

  week 12 and 52

• Patient-reported outcomes

  week 12, 24 and 52

• Adverse events

  week 26 and 52

• Corticosteroids use

  week 26 and 52

Study Arms (3)

Rituximab + cDMARD

ACTIVE COMPARATOR

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

Tocilizumab

EXPERIMENTAL

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

Drug: Tocilizumab

Tofacitinib

EXPERIMENTAL

Tofacitinib will be administered orally at 5 mg twice daily. Tofacitinib will start at week 0. Treatment will continue until week 52.

Drug: Tofacitinib

Interventions

Rituximab DRUG

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.

Also known as: Mabthera

Rituximab + cDMARD

Tocilizumab DRUG

Subcutaneous injection of 162 mg per week

Also known as: RoActemra

Tocilizumab

Tofacitinib DRUG

\- Tofacitinib, administered orally at a dose of 5 mg twice a day. Tofacitinib will start at week 0. Treatment will be continued until week 52

Tofacitinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 either :
• A combination of glucocorticoids plus cyclophosphamide
• AND /OR a combination of glucocorticoids plus rituximab
• 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)

You may not qualify if:

• 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 tofacitinib, or with tocilizumab
• A contraindication to a combination of rituximab plus a cDMARD, to tofacitinib, 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 tocilizumab or tofacitinib 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
• aspartate or alanine aminotransferase (AST/SGOT or ALT/SGPT) \> 5 times upper limit of normal
• Platelet count \<100.000/mm3

Sponsors & Collaborators

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

Study Sites (1)

Hôpital de la Croix Saint Simon

Paris, 75020, France

Location

Related Publications (8)

• 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, Yalcindag 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.

  PMID: 27338776 BACKGROUND

• 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.

  PMID: 20647199 BACKGROUND

• 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.

  PMID: 22021864 BACKGROUND

• 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. doi: 10.1136/ard.2006.062711. Epub 2006 Dec 14.

  PMID: 17170053 BACKGROUND

• 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.

  PMID: 28733791 BACKGROUND

• 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.

  PMID: 25841802 BACKGROUND

• 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.

  PMID: 31320177 BACKGROUND

• 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.

  PMID: 24323392 BACKGROUND

MeSH Terms

Conditions

Granulomatosis with Polyangiitis; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis

Interventions

Rituximab; tocilizumab; tofacitinib

Condition Hierarchy (Ancestors)

Lung Diseases, Interstitial; Lung Diseases; Respiratory Tract Diseases; Systemic Vasculitis; Vasculitis; Vascular Diseases; Cardiovascular Diseases; Skin Diseases, Vascular; Skin Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Benjamin Terrier, MD, PhD

  AP-HP - Service médecine interne

  STUDY DIRECTOR

Central Study Contacts

Jonathan London, MD

CONTACT

+33 1 44 64 16 02; jlondon@hopital-dcss.org

Alice CAMARA

CONTACT

01 58 41 12 11; alice.camara@aphp.fr

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 26, 2021
• First Posted: May 4, 2021
• Study Start: March 1, 2025
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): January 1, 2029
• Last Updated: February 3, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)