Tapering of Rituximab Based on Interval Prolongation Compared to Disease Activity-guided Dose Reduction in Patients With Rheumatoid Arthritis (RITUXERA)

• ClinicalTrials.gov Identifier: NCT06003283
• Recruitment Status: Not yet recruiting
• First Posted: August 21, 2023
• Last Update Posted: December 28, 2023
• Sponsor: Universitaire Ziekenhuizen KU Leuven
• Collaborator: Fonds voor Wetenschappelijk Reumaonderzoek (FWRO)
• Information provided by (Responsible Party): Universitaire Ziekenhuizen KU Leuven

Study Description

Brief Summary:

The goal of this open label multicenter randomized controlled pragmatic superiority trial is to investigate the optimal treatment/tapering strategy with rituximab for patients with rheumatoid arthritis.

The main questions it aims to answer are:

• What is the optimal treatment/tapering strategy for rituximab in patients with rheumatoid arthritis in terms of reducing patient reported disease impact?
• What is the optimal treatment/tapering strategy for rituximab in patients with rheumatoid arthritis in terms of therapeutic efficacy?

Participants will be randomized to one of two study arms:

• Tapering based on disease-activity guided dose reduction (experimental arm)
• Tapering based on interval prolongation (active comparator arm)

Condition or disease	Intervention/treatment	Phase
Rheumatoid Arthritis	Drug: Rituximab	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 134 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

Intervention Model Description

Open label multicenter pragmatic randomized controlled superiority trial. Patients will be 1:1 randomized to either the experimental arm or the active comparator arm.

Study visits are scheduled every 12 weeks (3 months). Recruitment period: 1 year. Trial duration: 2 years.

• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Tapering of Rituximab Based on Interval Prolongation Compared to Disease Activity-guided Dose Reduction in Patients With Rheumatoid Arthritis: The RITUXERA Trial
• Estimated Study Start Date: December 29, 2023
• Estimated Primary Completion Date: December 29, 2026
• Estimated Study Completion Date: December 29, 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Tapering of rituximab based on disease activity guided dose reduction; Treatment with rituximab every 6 months (24 weeks) with dosing based on disease activity, measured by the DAS28-CRP. DAS28-CRP ≤ 3.2: dose reduction according to the following sequence: 1 x 1000 mg IV (maximum), 1 x 500 mg IV, 1 x 200 mg IV (minimum). DAS28-CRP > 3.2: administration of previously effective dose.	Drug: Rituximab; IV rituximab; Other Names: MabThera; Truxima; Ruxience; Rixathon
Active Comparator: Tapering of rituximab based on interval prolongation; Treatment with fixed dose of rituximab (1 x 1000 mg IV) if DAS28-CRP ≥ 3.2 AND interval of at least 6 months (24 weeks) since previous administration of rituximab.	Drug: Rituximab; IV rituximab; Other Names: MabThera; Truxima; Ruxience; Rixathon

Outcome Measures

Primary Outcome Measures :

1. Comparison of disease impact in both study arms, measured using the Rheumatoid Arthritis Impact of Disease (RAID) questionnaire [ Time Frame: Over 2 years (104 weeks) ]
   RAID questionnaire score range: 0 - 10, with higher scores indicating worse status.

Secondary Outcome Measures :

1. Comparison of disease activity in both study arms, measured using the Disease Activity Score in 28 joints - C-reactive protein (DAS28-CRP) [ Time Frame: Over 2 years (104 weeks) ]
   Main secondary outcome. DAS28-CRP range: 0 - ..., with higher values indicating higher disease activity.
2. Comparison of disease activity in both study arms, measured using the Simplified Disease Activity Index (SDAI) [ Time Frame: Over 2 years (104 weeks) ]
   SDAI range: 0 - ..., with higher values indicating higher disease activity.
3. Comparison of cumulative dose of rituximab in both study arms [ Time Frame: Over 2 years (104 weeks) ]
4. Comparison of cumulative dose of glucocorticoids in both study arms [ Time Frame: Over 2 years (104 weeks) ]
5. Proportion of patients in both study arms achieving a good or moderate European League Against Rheumatism (EULAR) treatment response after administration of rituximab, over a period of 2 years (104 weeks) [ Time Frame: Over 2 years (104 weeks) ]
   A good EULAR response is defined as a decrease in Disease Activity Score in 28 joints - C-reactive protein (DAS28-CRP) > 1.2 and a present DAS-CRP ≤ 3.2. A moderate EULAR response is defined as a decrease in DAS28-CRP > 0.6 to ≤ 1.2 and a present DAS28-CRP ≤ 5.1, or a decrease in DAS28-CRP > 1.2 and a present DAS28-CRP > 3.2. Treatment responses will be evaluated 12 weeks after every administration of rituximab.
6. Comparison of loss of disease control in both study arms [ Time Frame: Over 2 years (104 weeks) ]
   Loss of disease control is defined as achieving a Disease Activity Score in 28 joints - C-reactive protein (DAS28-CRP) > 3.2 with previous DAS28-CRP ≤ 3.2.
7. Comparison of rituximab drug retention rate in both study arms [ Time Frame: Over 2 years (104 weeks) ]
   Defined as the percentage of patients remaining on treatment with rituximab over time.
8. Proportion of patients tapering rituximab below 1000 mg in the experimental arm [ Time Frame: Over 2 years (104 weeks) ]
9. Mean/median interval between rituximab administrations in the active comparator group [ Time Frame: Over 2 years (104 weeks) ]
10. Comparison of serious adverse events/reactions rates in both study arms. [ Time Frame: Over 2 years (104 weeks) ]
    An adverse event or adverse reaction is considered serious if it leads to inpatient hospitalization or prolongation of existing hospitalization, if it results in persistent or significant disability or incapacity, if it results in a life-threatening experience (meaning that the subject was at risk of death), or if it results in death.
11. Comparison of serious infections rate in both study arms. [ Time Frame: Over 2 years (104 weeks) ]
    An infection is considered serious if it leads to inpatient hospitalization or prolongation of existing hospitalization, if it results in persistent or significant disability or incapacity, if it results in a life-threatening experience (meaning that the subject was at risk of death), or if it results in death.

Other Outcome Measures:

1. Comparison of functional status in both study arms, measured using the Health Assessment Questionnaire - Disability Index (HAQ-DI) [ Time Frame: Over 2 years (104 weeks) ]
   HAQ-DI score range: 0 - 3, with higher scores indicating worse functional status.
2. Self-efficacy in both study arms, measured using the Arthritis Self-Efficacy Scale (ASES) [ Time Frame: Over 2 years (104 weeks) ]
   ASES score range: 11 - 110, with higher scores indicating higher perceived self-efficacy.
3. Pain in both study arms, measured using a Visual Analogue Scale (VAS) completed by the patient [ Time Frame: Over 2 years (104 weeks) ]
   VAS pain range: 0 - 100, with higher values indicating higher pain
4. Fatigue in both study arms, measured using a Visual Analogue Scale (VAS) completed by the patient [ Time Frame: Over 2 years (104 weeks) ]
   VAS fatigue range: 0 - 100, with higher values indicating more fatigue.
5. Patient global assessment (PGA) of disease in both study arms, measured using a Visual Analogue Scale (VAS) completed by the patient [ Time Frame: Over 2 years (104 weeks) ]
   VAS PGA range: 0 - 100, with higher values indicating worse disease.
6. Cluster of Differentiation (CD) 19+ and Memory B cell counts in both study arms [ Time Frame: Over 2 years (104 weeks) ]
   Determined at baseline, before administration of rituximab and at year 2 (104 weeks) in both study arms.
7. Immunoglobulin (Ig) counts (IgG, IgA and IgM) in both study arms [ Time Frame: Over 2 years (104 weeks) ]
   Determined at baseline, before administration of rituximab and at year 2 (104 weeks) in both study arms.
8. Professional and vocational participation in both study arms, calculated using the Work Productivity and Activity Impairment questionnaire: General Health (WPAI:GH) [ Time Frame: Over 2 years (104 weeks) ]
   The WPAI:GH calculates the percent work time missed due to health (range 0-100, higher numbers indicating more missed work time), the percent impairment while working due to health (range 0-100, higher numbers indicating higher impairment), the percent overall work impairment due to health (range 0-100, higher numbers indicating higher impairment), and the percent activity impairment due to health (range 0-100, higher numbers indicating higher impairment).
9. Health utility index in both study arms, calculated using the summary index score of the EuroQol - 5 dimensions (EQ-5D) questionnaire [ Time Frame: Over 2 years (104 weeks) ]
   Summary index score range: less than 0 (health state worse than dead, 0 being the value of a health state equivalent to death) to 1 (full health).

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Able and willing to give written informed consent and participate in the study before any study procedure.
• Age ≥ 18 years.
• Understanding and able to write in Dutch or French.
• Diagnosis of rheumatoid arthritis according to the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Classification Criteria for rheumatoid arthritis.
• Previous response to rituximab, defined as a minimum of one successful rituximab cycle (= a moderate/good EULAR response 16 weeks after the first administration of rituximab).
• Current treatment with rituximab.
• Need for a subsequent rituximab cycle according to the Belgian reimbursement criteria for the use of rituximab in rheumatoid arthritis (DAS28 score ≥3.2).
• Stable dose of methotrexate or other conventional synthetic disease-modifying antirheumatic drugs (DMARDs) 4 weeks prior to baseline.

Exclusion Criteria:

• Current treatment with another biological DMARD than rituximab.
• Current treatment with a targeted synthetic DMARD.
• Pregnancy or pregnancy wish.
• Presence of an absolute contraindication to treatment with rituximab, according to the label of rituximab and according to medical judgement.

Contacts and Locations

Contacts

Contact: Patrick Verschueren, MD, PhD; 016342541 ext +32; patrick.verschueren@uzleuven.be

Contact: Johan Joly, MSc; 016340258 ext +32; johan.joly@uzleuven.be

Locations

Belgium

ZNA Jan Palfijn

Merksem, Antwerpen, Belgium, 2170

Contact: Alla Ishchenko, MD

Reumacentrum Genk

Genk, Limburg, Belgium, 3600

Contact: Philip Remans, MD, PhD

ReumaClinic Genk

Genk, Limburg, Belgium, 3600

Contact: Johan Vanhoof, MD

OLV Aalst

Aalst, Oost-Vlaanderen, Belgium, 9300

Contact: Tom Zwaenepoel, MD

RZ Heilig Hart

Leuven, Vlaams-Brabant, Belgium, 3000

Contact: Veerle Taelman, MD

University Hospitals Leuven (UZ Leuven)

Leuven, Vlaams-Brabant, Belgium, 3000

Contact: Patrick Verschueren, MD, PhD

Contact: Johan Joly, MSc

Sub-Investigator: Elias De Meyst, MD

Cliniques Universitaires Saint-Luc Bruxelles

Brussel, Belgium, 1000

Sponsors and Collaborators

Universitaire Ziekenhuizen KU Leuven

Fonds voor Wetenschappelijk Reumaonderzoek (FWRO)

Investigators

• Principal Investigator: Patrick Verschueren, MD, PhD; University Hospitals Leuven/KU Leuven

More Information

• Responsible Party: Universitaire Ziekenhuizen KU Leuven
• ClinicalTrials.gov Identifier: NCT06003283
• Other Study ID Numbers: S67309
• First Posted: August 21, 2023
• Last Update Posted: December 28, 2023
• Last Verified: July 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by Universitaire Ziekenhuizen KU Leuven:

Rheumatoid arthritis; Rituximab; Tapering; Disease impact

Additional relevant MeSH terms:

Arthritis; Arthritis, Rheumatoid; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Rituximab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents