Relationship Between T LYmphocytes Depletion and Clinical Response to RITUXimab in Rheumatoid Arthritis (LYRITUX)

Rheumatoid Arthritis Clinical Trial

— LYRITUX  

Official title:

Relationship Between T LYmphocytes Depletion and Clinical Response to RITUXimab in Rheumatoid Arthritis (LYRITUX)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02304354
• Other study ID #: PHRI13-JM/LYRITUX
• Secondary ID: 2014-000859-9120
• Status: Completed
• Phase: Phase 3
• Start date: March 9, 2015
• Est. completion date: December 18, 2019

Study information

• Verified date: May 2021
• Source: University Hospital, Tours
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Rituximab, an anti CD-20 monoclonal antibody targeting B lymphocytes is prescribed in rheumatoid arthritis (RA) patients refractory to TNF alpha antagonists. According to previous studies, 25 to 50% of patients have an insufficient or absence of response to rituximab at week 24. In a recent retrospective study, a CD4+ T-lymphocytes depletion was observed after a first course of rituximab in RA patients. The absolute CD4+ number at week 12 was 37% (±33) of the baseline value, leading to < 200 cells/µL in 5% of patients. Interestingly the absence of CD4+ T-lymphocytes depletion was observed in clinical non-responders, suggesting the involvement of T-lymphocytes in the mechanism of action of rituximab. So far no prospective study have supported the usefulness of lymphocyte phenotyping, in particular T-lymphocytes, to monitor rituximab-treated RA patients.

Description:

Rituximab, an anti CD-20 monoclonal antibody targeting B lymphocytes is prescribed in rheumatoid arthritis (RA) patients refractory to TNF alpha antagonists. According to previous studies, (Edwards, Szczepanski et al. 2004; Cohen, Emery et al. 2006; Emery, Fleischmann et al. 2006) 25 to 50% of patients have an insufficient or absence of response to rituximab at week 24. In the pathogenesis of RA, B and T lymphocytes are tightly linked through the APC fonction and cytokines production of B lymphocytes. At present, a white blood cells count is recommended in routine every 3 months in patients receiving rituximab, since cases of neutropenia have been observed in approximately 8% of patients with lymphoma after treatment. In RA patients, B lymphocytes count before each rituximab course should be done to prevent opportunistic infections (Pham, Fautrel et al. 2008). In a recent retrospective study, a CD4+ T-lymphocytes depletion was observed after a first course of rituximab in RA patients. The absolute CD4+ number at week 12 was 37% (±33) of the baseline value, leading to < 200 cells/µL in 5% of patients. Interestingly the absence of CD4+ T-lymphocytes depletion was observed in clinical non-responders, suggesting the involvement of T-lymphocytes in the mechanism of action of rituximab (Mélet, Mulleman et al. 2013). Moreover, few case reports of RA patients developing opportunist infections in conjunction with CD4+ T-lymphocyte depletion have been published (Teichmann, Woenckhaus et al. 2008; Clifford, Ances et al. 2011). So far no prospective study have supported the usefulness of lymphocyte phenotyping, in particular T-lymphocytes, to monitor rituximab-treated RA patients.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 70
• Est. completion date: December 18, 2019
• Est. primary completion date: April 9, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• RA according to the American College of Rheumatology (ACR) criteria
• Treatment with adalimumab in accordance to the SPC
• Disease modifying anti rheumatic drugs (DMARDs) stable 4 weeks before enrollment and during 16 weeks.
• Signed consent

Exclusion Criteria:

• No anti TNF-alpha failure or contraindication
• Previous adalimumab treatment
• Contraindication to adalimumab, methylprednisolone or methotrexate (when used in combination with adalimumab)
• methotrexate-naive patient
• Any hematologic disease affecting the lymphocytes (in particular lymphomas)
• Any osteo-articular disease which could interfere with the interpretation of the influence of the rituximab on RA

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Drug:
• Rituximab
For rheumatoid arthritis, MabThera is given as two intravenous infusions of 1000 mg with a two-week interval between them. Patients usually respond to treatment within 16 to 24 weeks of initial treatment. After 24 weeks, treatment can be repeated depending on the patient's response.

Locations

Country	Name	City	State
France	Rhumatologie, CHRU de BREST	Brest
France	Rhumatologie, CHD LA ROCHE SUR YON	La Roche Sur Yon
France	Rhumatologie, CHR du MANS	Le Mans
France	Rhumatologie, CHRU de NANTES	Nantes
France	Rhumatologie / IPROS, CHR d'ORLEANS	Orleans
France	Rhumatologie, CHRU de POITIERS	Poitiers
France	Rhumatologie, CHRU de ROUEN	Rouen
France	Rhumatologie, CHRU de TOURS	Tours

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Tours

Country where clinical trial is conducted

France, 

References & Publications (1)

Mélet J, Mulleman D, Goupille P, Ribourtout B, Watier H, Thibault G. Rituximab-induced T cell depletion in patients with rheumatoid arthritis: association with clinical response. Arthritis Rheum. 2013 Nov;65(11):2783-90. doi: 10.1002/art.38107. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	DAS28	Disease Activity Score on 28 joints (DAS28) is a composite score that comprise tender joints count, swollen joints count, patient's disease activity on visual analog scale and erythrocyte sedimentation rate. DAS28 will be measured at baseline, week 2, week 4, week 16 and at the end of the study (i.e. between week 24 and week 48).	up week 48
Primary	T-lymphocyte count	T-lymphocyte count will be measured at baseline, week 2, week 4, week 16 and at the end of the study (i.e. between week 24 and week 48).	up to week 48
Secondary	C reactive Protein (CRP)	CRP will be measured at baseline, week 2, week 4, week 16 and at the end of the study (i.e. between week 24 and week 48).	Baseline up to 48 weeks
Secondary	Immunoglobulines G	Immunoglobuline G concentrations will be measured at baseline, week 16 and at the end of the study (i.e. between week 24 and week 48).	Baseline up to 48 weeks
Secondary	Cytokine profile	the following cytokines (APRIL, BAFF, TNF, IL-1 alpha, IL-17 and IL-6) will be measured at baseline, week 2, week 4, week 16 and at the end of the study (i.e. between week 24 and week 48).	Baseline up to 48 weeks
Secondary	Occurrence of infections	Number of participants with infectious adverse events	Baseline up to 48 weeks
Secondary	Pharmacokinetics (Systemic Clearance and central volume of distribution)	Rituximab concentrations will be measured at baseline, will be measured at baseline, week 2, week 4, week 16 and at the end of the study (i.e. between week 24 and week 48). Pharmacokinetics will be described using a two-compartment model.	Baseline up to 48 weeks
Secondary	FCGR3A 156 F/V gene polymorphism	FCGR3A 156 F/V gene genotyping. Measurements will be carried out at baseline.	Baseline
Secondary	RNA	Gene expression will be analysed at baseline.	Baseline
Secondary	Metabolomic profil	Urines will be analysed at baseline, week 4 and week 16	Baseline up to 16 weeks