Salvage treatment options for granulomatosis with polyangiitis

Salvage Therapy for Patients With Inadequate Response to Standard of Care Therapy in Granulomatosis With Polyangiitis

This trial will test three salvage treatments—rituximab plus a conventional DMARD (preferably methotrexate), tocilizumab, or tofacitinib—to try to induce remission in adults with granulomatosis with polyangiitis who have not responded adequately to standard care.

Quick facts

• Phase: Phase 3
• Study type: Interventional
• Enrollment: 42 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Assistance Publique - Hôpitaux de Paris (Academic / other)
• Drugs / interventions: rituximab, tocilizumab, tofacitinib, methotrexate, cyclophosphamide, prednisone
• Locations: 1 site (Paris)
• Trial ID: NCT04871191 on ClinicalTrials.gov

What this trial studies

This Phase 3 interventional trial enrolls adults with active granulomatosis with polyangiitis who had an inadequate response to standard remission‑induction therapy (glucocorticoids plus cyclophosphamide and/or rituximab). Participants are assigned to one of three salvage strategies: rituximab combined with a conventional DMARD (methotrexate preferred), tocilizumab, or tofacitinib. The primary goal is to determine which strategy is most effective at inducing remission and allowing reduction of corticosteroids. Efficacy and safety outcomes will be monitored over the treatment period to guide management of refractory disease.

Who should consider this trial

Good fit: Adults (18+) with active GPA who show inadequate response to prior standard-of-care remission induction with glucocorticoids plus cyclophosphamide and/or rituximab are ideal candidates.

Not a fit: Patients whose disease is controlled by standard therapy or who are unable to attend the study center in Paris are unlikely to benefit from participation.

Why it matters

Potential benefit: If successful, the trial could identify a more effective salvage option that increases remission rates and reduces long-term steroid use for patients who failed standard therapies.

How similar studies have performed: Some biologic DMARDs such as tocilizumab and tofacitinib have shown promising results in prior ANCA‑associated vasculitis studies, while rituximab plus a cDMARD in this refractory setting is less well studied.

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 either :

  1. A combination of glucocorticoids plus cyclophosphamide
  2. AND /OR a combination of glucocorticoids plus rituximab
* 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 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
* 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

Where this trial is running

Paris

• Hôpital de la Croix Saint Simon — Paris, France (Recruiting)

Study contacts

• Study coordinator: Jonathan London, MD

Conditions Granulomatosis With Polyangiitis; Anti-neutrophil Cytoplasmic Antibody-associated Vasculitis; Granulomatosis with Polyangiitis; Anti-neutrophil cytoplasmic antibody; Salvage therapy; Standard of care therapy; Inadequate response