Tocilizumab in Chronic Inflammatory CPPD Disease

Официальное название

Randomized, Double-blind, Multicentre Trial of Tocilizumab Versus Placebo in Chronic Polyarticular Inflammatory of Calcium Pyrophosphate Deposition Disease Refractory to Standard Treatments

Обзор

The aim of this clinical trial is to determine the efficacy of tocilizumab (an IL-6 inhibitor) in treatment-refractory chronic inflammatory forms of CPPD. The main questions this trial aims to answer are: * Can tocilizumab improve joint pain in patients with chronic inflammatory CPPD disease? * Does tocilizumab improve quality of life in patients with chronic inflammatory CPPD disease? Participants will receive a monthly infusion of tocilizumab or placebo for three months.

Подробное описание

Calcium pyrophosphate deposition (CPPD) disease affects 4 to 7% of the adult population. CPP crystals are responsible for inflammatory flares affecting one or more joints. The inflammation triggered by CPP crystals resembles that associated with sodium urate crystals in gout and depends on inflammatory cytokines such as interleukins (IL-) 1β and -6. The usual treatments are those used in gout flares (colchicine, NSAIDs, corticosteroids, IL-1β inhibitors), and most often control monoarticular involvement. The chronic inflammatory polyarticular form, on the other hand, is more difficult to treat, causing significant pain and disability, as well as joint destruction. In refractory forms, or in cases of intolerance to standard treatments, alternative therapies are required. In this context, the investigators treated 11 patients with refractory chronic inflammatory CPPD with tocilizumab (TCZ), an anti-IL-6 receptor (IL-6R) monoclonal antibody. After 3 monthly infusions, improvement was estimated at over 75% (PMID 2213498). Our hypothesis is that inhibiting IL-6 is an effective therapeutic option in chronic inflammatory CPPD refractory to conventional therapies.

Main objective and primary endpoint:

* To demonstrate the efficacy of IL-6 inhibition in treatment-refractory chronic inflammatory forms of CPPD disease. * Our endpoint will be the change in global pain VAS between initiation and M4, i.e. one month after the 3rd infusion. VAS will be assessed after 24 hours off analgesics.

Secondary objectives and endpoints:

* Efficacy: DAS44, number of swollen, painful joints, overall disease activity VAS, fatigue VAS; overall effect on pain: area under the VAS curve (AUC); proportion of patients responding from M2 to M6 (improvement ≥ 50% of initial pain VAS) and complete response (improvement ≥ 80% of initial pain VAS); relapse rate; improvement in quality of life (SF-36, HAQ, EQ-5D-3L questionnaires) * Tolerance: infusion reactions, infections, neutropenia, hepatic cytolysis, lipid profile

This is a phase III, multicentre, randomized, controlled, double-blind, superiority study, including 2 parallel groups with a 1:1 distribution. This trial will involve adults suffering from the chronic inflammatory polyarticular form of CPPD disease.

This study will involve 80 participants recruited in 12 centres in France.

Вмешательства

• Препарат Tocilizumab
  Tocilizumab, 8 mg/kg/month, IV infusion for 3 months Tocilizumab, an anti-IL-6R monoclonal antibody, was approved in January 2009 for the treatment of rheumatoid arthritis. Its indications have since been extended, particularly for the treatment of giant cell arteritis, juvenile chronic arthritis, and severe cytokine release syndrome induced by chimeric antigen receptor T-cell (CAR-T) therapy.
• Другое Placebo
  Saline placebo, IV infusion / month for 3 months

Первичные конечные точки

• Change in overall pain VAS [Срок оценки: 6 months]

Вторичные конечные точки (12)

• Change in the number of swollen and tender joints [Срок оценки: 6 months]
• Overall effect on pain [Срок оценки: 6 months]
• Response to treatment / relapse [Срок оценки: 6 months]
• Flares (ESR) [Срок оценки: 6 months]
• Flares (CRP) [Срок оценки: 6 months]
• Flares (IL-6) [Срок оценки: 6 months]
• Quality of life's Questionnaires (SF-36) [Срок оценки: 6 months]
• Quality of life's Questionnaires (HAQ) [Срок оценки: 6 months]
• Quality of life's Questionnaires (EQ-5D-3L) [Срок оценки: 6 months]
• Patient Safety - Number of Participants with Adverse Events [Срок оценки: 6 months]
• Patient Safety - Number of patients with abnormal laboratory tests results - Mean Neutrophil Count [Срок оценки: 6 months]
• Patient Safety - Number of patients with abnormal laboratory tests results - Mean Platelet Count [Срок оценки: 6 months]

Критерии участия

Критерии включения

• Adults > 18 years
• Diagnosis of CPPD according to ACR/EULAR 2023 classification criteria
• Persistent inflammatory pain (> 3 months) or ≥ 2 arthritics/month
• Number of painful joints (NAD) > 3
• Overall pain VAS (0\_100) > 40 mm
• Failure, intolerance or impossibility of repeated use of usual treatments: colchicine, NSAIDs, corticosteroids and anakinra
• Use of an effective method of contraception in women of childbearing age until 3 months after the end of the study.
• Informed consent

Критерии исключения

• Presence of anti-CPP antibodies > 50 IU/ml
• Recurrent or chronic infections
• History of severe infection (= requiring hospitalization)
• Active infection
• Vaccination with live or attenuated vaccine within 4 weeks prior to inclusion
• History of intestinal ulceration or diverticulitis Untreated latent tuberculosis
• History of viral hepatitis B ou C
• Symptoms suggestive of demyelinating disease of the central nervous system
• History of cancer, active cancer, or suspected cancer
• Neutropenia < 2000 elements/mm3, thrombocytopenia < 100 000/mm3
• Elevated transaminases > 3 x ULN
• Known hypersensitivity to the active substance or one of the excipients;
• Known severe immune deficiency
• Patients not meeting classification criteria
• Concomitant treatment with biological or targeted therapies, or immunosuppressive therapy (including methotrexate, leflunomide, azathioprine), systemic corticosteroids, anakinra, IL-6 inhibitors in subcutaneous injection, anti-TNF agents, and JAK. If these treatments are used before inclusion, a washout period corresponding to at least five times their respective mean terminal half-life must be respected.
• inhibitors.
• Previous treatment with tocilizumab
• Concomitant treatment with methylprednisolone, dexamethasone, atorvastatin, calcium channel blockers, theophylline, warfarin, phenprocoumon, phenytoin, cyclosporine or benzodiazepines
• Dyslipidemia, hypertension or poorly controlled cardiovascular disease
• Scheduled surgery
• Difficulty to understand French, illiteracy
• Pregnant women, women in labor or nursing mothers
• Persons deprived of their liberty, adults under legal protection or unable to express their consent
• Persons not affiliated to a social security scheme or beneficiaries of such a scheme
• Participation in another interventional study

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Простое слепое

Основная цель

Лечение

Центры проведения

Франция · 12 центров

• Groupe Hospitalier de l'Institut Catholique de Lille — Lomme
• Lariboisière hospital — Paris
• Centre Hospitalier Sud-Francilien — Corbeil-Essonnes
• CHU de Dijon — Dijon
• CHU de Nantes — Nantes
• Hôpital Bichat Claude-Bernard — Paris
• Hôpital de la Croix Saint-Simon — Paris
• Hôpital Tenon — Paris
• … и ещё 4 центра

Идентификаторы

NCT: NCT07254637 · APHP220790

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗