Tocilizumab vid Kronisk Inflammatorisk CPPD-sjukdom (TociCCAre)
Randomiserad, dubbelblind, multimetrisk studie av Tocilizumab jämfört med placebo vid kronisk polyartikulär inflammation vid kalciumpyrofosfatdepositionssjukdom refraktär mot standardbehandlingar
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.
Studieöversikt
Status
Betingelser
Intervention / Behandling
Detaljerad beskrivning
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: DAS28-CRP, 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 II, 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 13 centres in France.
Studietyp
Inskrivning (Beräknad)
Fas
- Fas 2
Kontakter och platser
Studiekontakt
- Namn: Augustin Latourte, Associate Professor
- Telefonnummer: +33 1 49 95 62 90
- E-post: augustin.latourte@aphp.fr
Studieorter
-
-
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Dijon, Frankrike, 21000
- CHU de Dijon
-
Kontakt:
- RAMON André, Dr
- Telefonnummer: 0380293745
- E-post: andre.ramon@chu-dijon.fr
-
Nantes, Frankrike, 44000
- CHU de Nantes
-
Kontakt:
- LE GOFF Benoit, Dr
- Telefonnummer: 0240083333
- E-post: benoit.legoff@chu-nantes.fr
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Paris, Frankrike, 75020
- Hôpital Tenon
-
Kontakt:
- LETAVERNIER Emmanuel, Pr
- Telefonnummer: 0156016773
- E-post: emmanuel.letavernier@aphp.fr
-
Paris, Frankrike, 75020
- Hôpital de la Croix Saint-Simon
-
Kontakt:
- CHAZERAIN Pascal, Dr
- Telefonnummer: 0144641782
- E-post: PChazerain@hopital-dcss.org
-
Paris, Frankrike, 93370
- Groupe Hospitalier Intercommunal Le Raincy-Montfermeil
-
Kontakt:
- DELLAL Azzedine, Dr
- Telefonnummer: 0141708766
- E-post: azeddine.dellal@ght-gpne.fr
-
Paris, Frankrike, 94270
- Hôpital Le Kremlin Bicêtre
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Paris, Frankrike, 75018
- Hôpital Bichat Claude-Bernard
-
Kontakt:
- OTTAVIANI Sébastien
- Telefonnummer: 0140258739
- E-post: sebastien.ottaviani@aphp.fr
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Pontoise, Frankrike, 95300
- Hôpital NOVO
-
Kontakt:
- Omar AL TABAA, Docteur
- Telefonnummer: 01 30 75 40 40
- E-post: omar.altabaa@ght-novo.fr
-
Rennes, Frankrike, 35200
- CHU de Rennes
-
Kontakt:
- CHOTARD Emilie, Dr
- Telefonnummer: 0299267140
- E-post: Emilie.CHOTARD@chu-rennes.fr
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Saint-Etienne, Frankrike, 42100
- CHU de Saint-Étienne
-
Kontakt:
- MAROTTE Hubert, Pr
- Telefonnummer: 0477127643
- E-post: hubert.marotte@chu-st-etienne.fr
-
-
Lille
-
Lomme, Lille, Frankrike, 59462
- Groupe Hospitalier de l'Institut Catholique de Lille
-
Kontakt:
- PASCART Tristan, Dr
- Telefonnummer: 0320225059
- E-post: pascart.tristan@ghicl.net
-
-
Paris
-
Corbeil-Essonnes, Paris, Frankrike, 91100
- Centre Hospitalier Sud-Francilien
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Kontakt:
- HILLIQUIN Pascal, Dr
- Telefonnummer: 0161693128
- E-post: pascal.hilliquin@chsf.fr
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Paris Paris
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Paris, Paris Paris, Frankrike, 75010
- Lariboisière hospital
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-
Deltagandekriterier
Urvalskriterier
Åldrar som är berättigade till studier
Tar emot friska volontärer
Kön som är behöriga för studier
Beskrivning
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
Studieplan
Hur är studien utformad?
Designdetaljer
- Primärt syfte: Behandling
- Tilldelning: Randomiserad
- Interventionsmodell: Parallellt uppdrag
- Maskning: Enda
Vapen och interventioner
Deltagargrupp / Arm |
Intervention / Behandling |
|---|---|
|
Placebo-jämförare: Placebo
|
Saline placebo, IV infusion / month for 3 months |
|
Experimentell: 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. |
Vad mäter studien?
Primära resultatmått
Resultatmått |
Åtgärdsbeskrivning |
Tidsram |
|---|---|---|
|
Change in overall pain VAS
Tidsram: 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. |
6 months
|
Sekundära resultatmått
Resultatmått |
Åtgärdsbeskrivning |
Tidsram |
|---|---|---|
|
Change in the number of swollen and tender joints
Tidsram: 6 months
|
Disease Activity Score (DAS28-CRP), 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
Tidsram: 6 months
|
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
Tidsram: 6 months
|
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)
Tidsram: 6 months
|
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)
Tidsram: 6 months
|
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)
Tidsram: 6 months
|
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)
Tidsram: 6 months
|
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)
Tidsram: 6 months
|
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)
Tidsram: 6 months
|
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
Tidsram: 6 months
|
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
Tidsram: 6 months
|
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
Tidsram: 6 months
|
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
Tidsram: 6 months
|
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
Tidsram: 6 months
|
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
|
Samarbetspartners och utredare
Samarbetspartners
Studieavstämningsdatum
Studera stora datum
Studiestart (Beräknad)
Primärt slutförande (Beräknad)
Avslutad studie (Beräknad)
Studieregistreringsdatum
Först inskickad
Först inskickad som uppfyllde QC-kriterierna
Första postat (Faktisk)
Uppdateringar av studier
Senaste uppdatering publicerad (Faktisk)
Senaste inskickade uppdateringen som uppfyllde QC-kriterierna
Senast verifierad
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- APHP220790
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