Tocilizumab in Chronic Inflammatory CPPD Disease (TociCCAre)

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Calcium Pyrophosphate Deposition Disease
• Intervention / Treatment: Other: Placebo; Drug: Tocilizumab

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Augustin Latourte, Associate Professor; Phone Number: +33 1 49 95 62 90; Email: augustin.latourte@aphp.fr

Study Locations

• France
  • Dijon, France, 21000
    • CHU de Dijon
    • Contact: RAMON André, Dr; Phone Number: 0380293745; Email: andre.ramon@chu-dijon.fr
  • Nantes, France, 44000
    • CHU de Nantes
    • Contact: LE GOFF Benoit, Dr; Phone Number: 0240083333; Email: benoit.legoff@chu-nantes.fr
  • Paris, France, 75020
    • Hopital Tenon
    • Contact: LETAVERNIER Emmanuel, Pr; Phone Number: 0156016773; Email: emmanuel.letavernier@aphp.fr
  • Paris, France, 75018
    • Hopital Bichat Claude-Bernard
    • Contact: OTTAVIANI Sébastien; Phone Number: 0140258739; Email: sebastien.ottaviani@aphp.fr
  • Paris, France, 75020
    • Hopital de la Croix Saint-Simon
    • Contact: CHAZERAIN Pascal, Dr; Phone Number: 0144641782; Email: PChazerain@hopital-dcss.org
  • Paris, France, 93370
    • Groupe Hospitalier Intercommunal Le Raincy-Montfermeil
    • Contact: DELLAL Azzedine, Dr; Phone Number: 0141708766; Email: azeddine.dellal@ght-gpne.fr
  • Paris, France, 94270
    • Hôpital Le Kremlin Bicêtre
  • Rennes, France, 35200
    • CHU de Rennes
    • Contact: CHOTARD Emilie, Dr; Phone Number: 0299267140; Email: Emilie.CHOTARD@chu-rennes.fr
  • Saint-Etienne, France, 42100
    • CHU de Saint-Etienne
    • Contact: MAROTTE Hubert, Pr; Phone Number: 0477127643; Email: hubert.marotte@chu-st-etienne.fr
  • Lille
    • Lomme, Lille, France, 59462
      • Groupe Hospitalier de l'Institut Catholique de Lille
      • Contact: PASCART Tristan, Dr; Phone Number: 0320225059; Email: pascart.tristan@ghicl.net
  • Paris
    • Corbeil-Essonnes, Paris, France, 91100
      • Centre Hospitalier Sud-Francilien
      • Contact: HILLIQUIN Pascal, Dr; Phone Number: 0161693128; Email: pascal.hilliquin@chsf.fr
  • Paris Paris
    • Paris, Paris Paris, France, 75010
      • Lariboisiere Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Other: Placebo; Saline placebo, IV infusion / month for 3 months
Experimental: Tocilizumab	Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	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
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: Infusion reactions; Neutropenia; Thrombocytopenia; Hepatic cytolysis; Severe infections; Treatment-related adverse events; Abnormal changes in lipid profile 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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Fresenius AG

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): November 1, 2029

Study Registration Dates

• First Submitted: August 14, 2025
• First Submitted That Met QC Criteria: November 19, 2025
• First Posted (Estimated): November 28, 2025

Study Record Updates

• Last Update Posted (Actual): January 14, 2026
• Last Update Submitted That Met QC Criteria: January 13, 2026
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Crystal Arthropathies; Musculoskeletal Diseases; Arthritis; Joint Diseases; Chondrocalcinosis; tocilizumab
• Other Study ID Numbers: APHP220790

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No