Randomized, Double-blind, Multicentre Trial of Tocilizumab Versus Placebo in Chronic Polyarticular Inflammatory of Calcium Pyrophosphate Deposition Disease Refractory to Standard Treatments
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 80
- 试验地点
- 12
- 主要终点
- Change in overall pain VAS
研究概览
简要总结
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.
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Participant)
盲法说明
Pharmacy Process: Upon email notification, the pharmacy prepares and dispenses the tocilizumab or placebo. If unable to reconstitute it, they provide a nominative patient kit for external reconstitution.
Non-protocol Handlers: Specially trained nurses reconstitute treatment bags discreetly. Each center has a designated trainer to build a team of these off-protocol handlers.
Pharmacy Oversight: The hospital pharmacist ensures proper management of investigational products. Compliance is checked by a CRA during monitoring.
Blinding Strategy:
A blind CRA monitors clinical activities. An open CRA manages pharmacy stock and is aware of treatment allocation. The trial is double-blind to prevent bias for both patients and investigators.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Tocilizumab
干预措施: Tocilizumab (Drug)
Placebo
干预措施: Placebo (Other)
结局指标
主要结局
Change in overall pain VAS
时间窗: 6 months
Overall pain will be assessed, after 24 hours of discontinuation of analgesics, using a visual analogue scale (VAS) ranging from 0 (no pain) to 100 mm (worst pain ever experienced), at inclusion, before each infusion at months M1, M2, M3, then at M4 (primary outcome) and M6.
次要结局
- Flares (ESR)(6 months)
- Change in the number of swollen and tender joints(6 months)
- Overall effect on pain(6 months)
- Response to treatment / relapse(6 months)
- Flares (CRP)(6 months)
- Flares (IL-6)(6 months)
- Quality of life's Questionnaires (SF-36)(6 months)
- Quality of life's Questionnaires (HAQ)(6 months)
- Quality of life's Questionnaires (EQ-5D-3L)(6 months)
- Patient Safety - Number of Participants with Adverse Events(6 months)
- Patient Safety - Number of patients with abnormal laboratory tests results - Mean Neutrophil Count(6 months)
- Patient Safety - Number of patients with abnormal laboratory tests results - Mean Platelet Count(6 months)
- Patient Safety - Number of patients with abnormal laboratory tests results - Mean Transaminase Levels(6 months)
- Patient Safety - Number of patients with abnormal laboratory tests results - Mean Lipid Profile Values(6 months)