Use of Tocilizumab Drug Levels to Optimize Treatment in RA

NCT03895879 | Recruiting Phase 4 DMC

• 3 other identifiers: TODORA2018-004605-57NL68462.029.19
• Study Type: interventional
• Target: 98
• Locations: 1 country
• Sites: 1

Brief Summary

Tocilizumab concentrations above 1 mg/L are likely to be sufficient for normalizing C-reactive protein (CRP) production in patients with rheumatoid arthritis (RA). In practice, however, a large variability in the concentrations of tocilizumab is found, and a large proportion of patients treated with tocilizumab subcutaneously (sc) have concentrations far above 1 mg/L. These patients can probably lower their doses without losing clinical response. A 52 weeks non-inferiority, multicenter, randomized controlled study will be performed to investigate whether patients with RA with serum trough concentrations of tocilizumab higher than 15 mg/L can increase their dosing interval to every two weeks without losing clinical response. Patients with relatively high trough concentrations will be randomly assigned to continuation of the standard dose or to increase dosing interval to every two weeks. The main objective is to investigate the difference in mean time weighted Disease Activity Score in 28 joints, including erythrocyte sedimentation rate (DAS28-ESR) between the two groups after 28 weeks. It is expected that patients with relatively high trough concentrations can safely increase their dosing interval without losing response.

Conditions

Rheumatoid Arthritis

Keywords

Rheumatoid Arthritis; Tocilizumab; Therapeutic Drug Monitoring; Drug level; Dose reduction

Outcome Measures

Primary Outcomes (1)

• DAS28-ESR

  The difference in mean time weighted DAS28 after 28 weeks between patients undergoing concentration-guided dose reduction or standard dosing.

  28 weeks

Secondary Outcomes (9)

• DAS28-ESR

  52 weeks

• Clinical Disease Activity Index (CDAI)

  28 and 52 weeks

• Simple Disease Activity Index (SDAI)

  28 and 52 weeks

• Health Assessment Questionnaire (HAQ)

  28 and 52 weeks

• Direct medical costs of TDM

  52 weeks

Study Arms (3)

Intervention

EXPERIMENTAL

Tocilizumab administered every 2 weeks

Drug: Tocilizumab

Control

ACTIVE COMPARATOR

Tocilizumab administered every week

Drug: Tocilizumab

Standard dose (screening < 15 mg/L)

ACTIVE COMPARATOR

Tocilizumab administered every week

Drug: Tocilizumab

Interventions

Tocilizumab DRUG

Tocilizumab sc (162 mg) once every 2 weeks

Intervention

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Rheumatoid arthritis according to the American College of Rheumatology (ACR) 1987 or 2010 criteria;
• Current use of subcutaneous tocilizumab 162 mg weekly, for at least the previous 6 months;
• The treating rheumatologist is convinced of the benefit of tocilizumab continuation;
• Written informed consent.

You may not qualify if:

• A scheduled surgery in the next 52 weeks or other pre-planned reasons for treatment discontinuation;
• Changes in the treatment with glucocorticoids and DMARDs such as methotrexate in the past three months.

Sponsors & Collaborators

• Reade Rheumatology Research Institute: lead
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator

Study Sites (1)

Reade Rheumatology Research Institute

Amsterdam, 1056 AB, Netherlands

RECRUITING

Related Publications (4)

• Kneepkens EL, van den Oever I, Plasencia CH, Pascual-Salcedo D, de Vries A, Hart M, Nurmohamed MT, Balsa A, Rispens T, Wolbink G. Serum tocilizumab trough concentration can be used to monitor systemic IL-6 receptor blockade in patients with rheumatoid arthritis: a prospective observational cohort study. Scand J Rheumatol. 2017 Mar;46(2):87-94. doi: 10.1080/03009742.2016.1183039. Epub 2016 Jul 20.

  PMID: 27440258 BACKGROUND

• l'Ami MJ, Krieckaert CL, Nurmohamed MT, van Vollenhoven RF, Rispens T, Boers M, Wolbink GJ. Successful reduction of overexposure in patients with rheumatoid arthritis with high serum adalimumab concentrations: an open-label, non-inferiority, randomised clinical trial. Ann Rheum Dis. 2018 Apr;77(4):484-487. doi: 10.1136/annrheumdis-2017-211781. Epub 2017 Sep 22.

  PMID: 28939629 BACKGROUND

• Frey N, Grange S, Woodworth T. Population pharmacokinetic analysis of tocilizumab in patients with rheumatoid arthritis. J Clin Pharmacol. 2010 Jul;50(7):754-66. doi: 10.1177/0091270009350623. Epub 2010 Jan 23.

  PMID: 20097931 BACKGROUND

• Bastida C, Ruiz-Esquide V, Pascal M, de Vries Schultink AHM, Yague J, Sanmarti R, Huitema ADR, Soy D. Fixed dosing of intravenous tocilizumab in rheumatoid arthritis. Results from a population pharmacokinetic analysis. Br J Clin Pharmacol. 2018 Apr;84(4):716-725. doi: 10.1111/bcp.13500. Epub 2018 Feb 7.

  PMID: 29314183 BACKGROUND

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

tocilizumab

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• Gertjan Wolbink, MD, PhD

  Reade Rheumatology Research Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Femke Hooijberg, MD

CONTACT

0031 20 2421633; f.hooijberg@reade.nl

Sadaf Atiqi, MD

CONTACT

0031 20 2421641; s.atiqi@reade.nl

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: During every study visit the joints of all patients will be examined for pain and swelling by a blinded nurse or physician. The number of painful and swollen joints will be used to calculate the DAS28 score, the primary outcome of the study.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patients with tocilizumab trough concentrations above 15 mg/L will be randomly assigned to dose reduction by increasing their dosing interval from once every week to once every two weeks, or to continuation of the standard dose. All patients with concentrations below 15 mg/L during the first study visit will not be randomized and all continue standard treatment.

Study Record Dates

• First Submitted: March 26, 2019
• First Posted: March 29, 2019
• Study Start: March 1, 2020
• Primary Completion: December 1, 2024
• Study Completion: December 1, 2024
• Last Updated: April 18, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Six months after the final publication from the study is published the data will be shared.
• Access Criteria: Researchers with demonstrable interest in autoimmunity, biologicals, or TDM can contact the investigators of the trial if they are interested in gaining access to the data. Depending on their research objectives the data will be shared.

Locations

NL (1)