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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

6 Jun 2025 → ongoing

Decision date (initial)

2024-11-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

AP-HP-Programme Hospitalier de Recherche Clinique (PHRC) nationaux 2019.

External identifiers

EU CT number

2024-516687-28-00

EudraCT number

2021-000679-35

ClinicalTrials.gov

NCT04871191

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

The primary objective of this study is to identify the most promising therapeutic strategy for patients with inadequate response to standard of care therapy in granulomatosis with polyangiitis. 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 (cDMARD) (either methotrexate, azathioprine or mycophenolate mofetil, but preferentially methotrexate); tocilizumab; or tofacitinib.

Secondary objectives 1

1. Secondary objectives: To evaluate the safety profile (adverse events), the corticosteroids dose, the sequelae, the functional disability and quality of life, the patient-reported outcomes (PRO) and the evolution of ANCA titers in each salvage therapy group.

Conditions and MedDRA coding

Patients with GPA and inadequate response to standard of care therapy defined as an inadequate response to either a combination of glucocorticoids plus cyclophosphamide AND/OR a combination of glucocorticoids plus rituximab.

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. (1) Newly diagnosed or relapsing granulomatosis with polyangiitis according to the ACR/EULAR 2022 criteria
2. (2) Aged 18 years or older
3. (3) Active clinical manifestations attributable to GPA
4. (4) An inadequate response to previous standard of care therapy including either: a. A combination of glucocorticoids plus cyclophosphamide b. AND/OR a combination of glucocorticoids plus rituximab
5. (5) An inadequate response to treatment defined as follows: a. A progressive disease unresponsive to previous standard of care therapy after 12 weeks of treatment b. Or a lack of response, defined as 50% reduction in the disease activity, after 12 weeks of treatment c. 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
6. (6) 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
7. (7) 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
8. (8) 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)
9. (9) Patients must have an affiliation with a mode of social security (profit or being entitled)

Exclusion criteria 16

1. (1) An allergy or hypersensitivity to monoclonal antibodies or either of the study drugs (rituximab, prednisone, tofacitinib or tocilizumab) or to their excipients
2. (10) 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
3. (11) 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
4. (12) Patients included in other investigational therapeutic study within the previous 3 months
5. (13) Patients suspected not to be observant to the proposed treatments
6. (14) Laboratory parameter exclusions: a. aspartate or alanine aminotransferase (AST/SGOT or ALT/SGPT) > 5 times upper limit of normal b. Platelet count <100.000/mm3 c. White blood cell count <2000/mm3
7. (15) Hepatic failure
8. (2) A previous treatment with a combination of rituximab plus a cDMARD, with tofacitinib, or with tocilizumab
9. (3) 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
10. (4) 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
11. (5) Patients with vasculitis in remission
12. (6) Patients with symptoms attributable to chronic and non-active GPA
13. (7) Patients with severe cardiac failure defined as class IV in New York Heart Association
14. (8) Patients with acute infections or chronic active infections (including tuberculosis, HIV, HBV or HCV)
15. (9) Patients with active cancer or recent cancer (<5 years), except basocellular carcinoma and prostatic cancer of low activity controlled by hormonal treatment
16. (16) Treatment with avacopan within 4 weeks before enrolment

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint will be the proportion of patients with a response or a remission at 12 weeks as 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

Secondary endpoints 1

1. Secondary endpoints: - The proportion of patients with a response or a remission according to the EULAR recommendations at week 24 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. - The patient-reported outcomes (PRO) including: HAQ, SF-36 and VAA-PRO at week 12, 24 and 52-The number of adverse events, expressed as adverse events according to the CTCAE toxicity grading system pe

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Comparator 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Dr Jonathan LONDON

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Dr Jonathan LONDON

Locations

1 EU/EEA country · 40 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 1 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications