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| Name | Class |
|---|---|
| Fresenius AG | INDUSTRY |
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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:
Participants will receive a monthly infusion of tocilizumab or placebo for three months.
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:
Secondary objectives and endpoints:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Tocilizumab | Experimental |
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| Placebo | Placebo Comparator |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tocilizumab | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in overall pain VAS | 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. | 6 months |
| Measure | Description | Time Frame |
|---|---|---|
| Change in the number of swollen and tender joints | Disease Activity Score (DAS44), number of swollen and painful joints, Patient assessment of overall disease activity by a visual analogue scale (VAS) ranging from 0 (no activity) to 100 mm (maximal activity). Those outcomes will be assessed at inclusion, before each infusion at months M1, M2, M3, then at M4 (primary outcome) and M6 | 6 months |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Augustin Latourte, Associate Professor | Contact | +33 1 49 95 62 90 | augustin.latourte@aphp.fr |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Groupe Hospitalier de l'Institut Catholique de Lille | Lomme | Lille | 59462 | France |
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| ID | Term |
|---|---|
| D002805 | Chondrocalcinosis |
| ID | Term |
|---|---|
| D001168 | Arthritis |
| D007592 | Joint Diseases |
| D009140 | Musculoskeletal Diseases |
| D000070657 | Crystal Arthropathies |
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| ID | Term |
|---|---|
| C502936 | tocilizumab |
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TociCCAre is a phase II, randomised, double-blind, placebo-controlled comparative study. The study aims to demonstrate the efficacy of tocilizumab in treating chronic polyarticular inflammation associated with CPP crystals.
It is a superiority study with 1:1 randomisation into two parallel groups.
This multicentre study has 12 participating centres, including centres specialising in microcrystalline diseases and a reference centre for Gitelman syndrome (one of whose complications is extensive PPC crystal deposition), located at the HEGP hospital in Paris.
Patients will be enrolled during consultations and hospitalisations by the principal investigator or their co-investigators.
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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.
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| Placebo | Other | Saline placebo, IV infusion / month for 3 months |
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| Overall effect on pain | Area under the curve (AUC) of the overall pain visual analogue scale (VAS) ranging from 0 (no pain) to 100 mm (worst pain ever experienced) based on assessments at baseline, before each infusion at months M1, M2, M3 and at M4 and M6 (end of the study). Overall pain VAS will be collected after a 24-hour washout of analgesics. | 6 months |
| Response to treatment / relapse | Response to treatment will be defined as an improvement ≥ 50% of initial pain visual analogue scale (VAS) ranging from 0 (no pain) to 100 mm (worst pain ever experienced) Complete response will be defined as an improvement ≥ 80% of initial pain VAS This outcome will be assessed from M2 to M6. Relapse will be assessed in responders at 6 months, and the time from response to relapse will be determined. | 6 months |
| Flares (ESR) | Outcome Measures - Inflammatory Biomarkers Erythrocyte Sedimentation Rate (ESR) Unit: millimeters (mm) Frequency: measured at each visit No aggregation of this measure is planned to produce a composite value. If aggregation is considered (e.g., to generate an overall inflammation score), a validated statistical method will be specified. | 6 months |
| Flares (CRP) | Outcome Measures - Inflammatory Biomarkers C-reactive Protein (CRP) Unit: milligrams per liter (mg/L) Frequency: measured at each visit No aggregation of this measure is planned to produce a composite value. If aggregation is considered (e.g., to generate an overall inflammation score), a validated statistical method will be specified. | 6 months |
| Flares (IL-6) | Outcome Measures - Inflammatory Biomarkers Interleukin-6 (IL-6) Unit: picograms per milliliter (pg/mL) Frequency: measured at each visit No aggregation of this measure is planned to produce a composite value. If aggregation is considered (e.g., to generate an overall inflammation score), a validated statistical method will be specified. | 6 months |
| Quality of life's Questionnaires (SF-36) | Full Title: Short Form 36 Health Survey (SF-36) Scale Range: 0 to 100 per subscale Interpretation: Higher scores indicate better health status or quality of life Time Points: Baseline, prior to each infusion, and at Months 4 and 6 (M4 and M6) Unit: Score This questionnaire will be analyzed and reported as a distinct outcome measure, in accordance with its specific scoring system. | 6 months |
| Quality of life's Questionnaires (HAQ) | Full Title: Health Assessment Questionnaire (HAQ) Scale Range: 0 to 3 Interpretation: Higher scores indicate worse functional ability (i.e., more disability) Time Points: Baseline, prior to each infusion, and at Months 4 and 6 (M4 and M6) Unit: Score This questionnaire will be analyzed and reported as a distinct outcome measure, in accordance with its specific scoring system. | 6 months |
| Quality of life's Questionnaires (EQ-5D-3L) | Full Title: EuroQol Five Dimensions Three Levels (EQ-5D-3L) Scale Range: 0 to 100 Interpretation: Higher scores indicate better health-related quality of life Time Points: Baseline, prior to each infusion, and at Months 4 and 6 (M4 and M6) Unit: Index value This questionnaire will be analyzed and reported as a distinct outcome measure, in accordance with its specific scoring system. | 6 months |
| Patient Safety - Number of Participants with Adverse Events | Outcome Measure - Number of Participants with Adverse Events Description: Number of participants experiencing any of the following safety-related events at each visit:
Unit of Measure: Count (participants) Time Points: Each visit Note: Each event type will be recorded and analyzed separately but reported under a unified outcome measure to reflect overall safety. | 6 months |
| Patient Safety - Number of patients with abnormal laboratory tests results - Mean Neutrophil Count | Description: Mean neutrophil count measured from blood samples collected at each visit. Unit of Measure: normal: 2500-8000/μL; AE: <1500/μL | 6 months |
| Patient Safety - Number of patients with abnormal laboratory tests results - Mean Platelet Count | Description: Mean platelet count measured from blood samples collected at each visit. Unit of Measure: normal: 150,000-400,000/μL; AE: <75,000/μL | 6 months |
| Patient Safety - Number of patients with abnormal laboratory tests results - Mean Transaminase Levels | Description: Mean levels of transaminases (e.g., ALT, AST) measured to assess hepatic cytolysis. Unit of Measure: ALT/AST normal: <40 U/L; AE: >3×ULN | 6 months |
| Patient Safety - Number of patients with abnormal laboratory tests results - Mean Lipid Profile Values | Description: Mean values of lipid profile components (e.g., total cholesterol, LDL, HDL, triglycerides) measured at each visit. Unit of Measure: normal: TC <200, LDL <130, HDL >45/55, TG <150 mg/dL | 6 months |
| Lariboisière hospital | Paris | Paris Paris | 75010 | France |
| Centre Hospitalier Sud-Francilien | Corbeil-Essonnes | Paris | 91100 | France |
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| CHU de Dijon | Dijon | 21000 | France |
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| CHU de Nantes | Nantes | 44000 | France |
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| Hôpital Bichat Claude-Bernard | Paris | 75018 | France |
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| Hôpital de la Croix Saint-Simon | Paris | 75020 | France |
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| Hôpital Tenon | Paris | 75020 | France |
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| Groupe Hospitalier Intercommunal Le Raincy-Montfermeil | Paris | 93370 | France |
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| Hôpital Le Kremlin Bicêtre | Paris | 94270 | France |
| CHU de Rennes | Rennes | 35200 | France |
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| CHU de Saint-Étienne | Saint-Etienne | 42100 | France |
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