Using Adalimumab Serum Concentration to Choose a Subsequent Biological DMARD in Rheumatoid Arthritis Patients Failing Adalimumab Treatment

NCT04251741 | Unknown Phase 4 DMC

• 1 other identifier: ADDORA-switch
• Study Type: interventional
• Target: 86
• Locations: 1 country
• Sites: 2

Brief Summary

A potential application of therapeutic drug monitoring is to predict efficacy after switch to another biological in the case of inefficacy of the previous TNF-inhibitor (TNFi) in rheumatoid arthritis (RA) patients. It has been shown that when antidrug antibodies against adalimumab are detected (resulting in lower drug serum concentrations) in patients failing adalimumab, a normal response to a next TNF blocker can be anticipated. However, when clinical response is unsatisfactory and no antidrug antibodies against the first TNFi are detected (generally drug levels are adequate in this case), this predicts a lower response to a next TNFi. This means drug resistant failure in the former, compared to class resistant failure in latter category of patients. The current RA treatment strategy after failure of the first TNF-inhibitor is to start either a second TNFi or a non-TNFi. However, by channelling patients with sufficient adalimumab concentration to a non-TNFi will provide higher chance of disease control. Patients with very low or undetectable drug levels have an equal or potential higher chance of disease control with a drug of the same class (i.e. another TNFi).

Conditions

Rheumatoid Arthritis

Keywords

Adalimumab; Rheumatoid arthritis; Therapeutic Drug Monitoring; Drug level; Switching; Failure; Non-response; Subsequent biological

Outcome Measures

Primary Outcomes (1)

• mean time weighted DAS28-CRP

  difference in mean time weighted DAS28-CRP between the two groups

  24 weeks

Secondary Outcomes (9)

• Good or moderate response according the EULAR response criteria

  12 en 24 weeks

• Minimal disease activity (DAS28-CRP<2.9)

  24 weeks

• Non-responders

  24 weeks

• Number of adverse events

  24 weeks

• Severity of adverse events

  24 weeks

Study Arms (2)

Usual care group

ACTIVE COMPARATOR

Based on a secondary randomization schedule patients are treated with etanercept or a non-TNFi (abatacept, rituximab, tocilizumab, or sarilumab)

Other: Usual care

'Drug concentration guided' group

EXPERIMENTAL

Patients with a concentration \<1.0 mg/L switch to etanercept and patients with a concentration ≥ 1.0 start a non-TNFi (abatacept, rituximab, tocilizumab, or sarilumab)

Diagnostic Test: Adalimumab trough concentration

Interventions

Adalimumab trough concentration DIAGNOSTIC_TEST

In the 'drug concentration guided' group, switching to subsequent biological is based on adalimumab trough concentration

'Drug concentration guided' group

Usual care OTHER

In the usual care group, switch to subsequent biological is based on secondary randomisation

Usual care group

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• rheumatoid arthritis patient, according to American College of Rheumatology (ACR) 1987 and/or EULAR/ACR 2010 criteria;
• recently failed treatment with adalimumab (defined as DAS28-CRP \>2.9) and not treated with a subsequent bDMARD or target synthetic DMARD (tsDMARD)
• Received adalimumab for at least 10 weeks in standard dosing (40mg subcutaneously every other week, either in monotherapy or combined with methotrexate or leflunomide)
• Stop adalimumab due to inefficacy, either alone or combined with side effects
• who has agreed to participate (written informed consent);
• age 16 years or older.

You may not qualify if:

• Treatment with another TNF-inhibitor prior to adalimumab
• Treatment with all non-TNFi options (abatacept, rituximab, sarilumab and tocilizumab) prior to adalimumab
• scheduled surgery during the follow-up of the study or other pre-planned reasons for treatment discontinuation
• life expectancy shorter than follow-up period of the study;
• no possibility to safely receive an TNF-inhibitor or a non TNF-inhibitor

Sponsors & Collaborators

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

Study Sites (2)

Sint Maartenskliniek

Ubbergen, Gelderland, 6574NA, Netherlands

Location

Reade Rheumatology Research Institute

Amsterdam, North Holland, 1056AB, Netherlands

Location

Related Publications (4)

• Cantini F, Niccoli L, Nannini C, Cassara E, Kaloudi O, Giulio Favalli E, Becciolini A, Benucci M, Gobbi FL, Guiducci S, Foti R, Mosca M, Goletti D. Second-line biologic therapy optimization in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Semin Arthritis Rheum. 2017 Oct;47(2):183-192. doi: 10.1016/j.semarthrit.2017.03.008. Epub 2017 Mar 22.

  PMID: 28413099 BACKGROUND

• Hyrich KL, Lunt M, Watson KD, Symmons DP, Silman AJ; British Society for Rheumatology Biologics Register. Outcomes after switching from one anti-tumor necrosis factor alpha agent to a second anti-tumor necrosis factor alpha agent in patients with rheumatoid arthritis: results from a large UK national cohort study. Arthritis Rheum. 2007 Jan;56(1):13-20. doi: 10.1002/art.22331.

  PMID: 17195186 BACKGROUND

• Jamnitski A, Bartelds GM, Nurmohamed MT, van Schouwenburg PA, van Schaardenburg D, Stapel SO, Dijkmans BA, Aarden L, Wolbink GJ. The presence or absence of antibodies to infliximab or adalimumab determines the outcome of switching to etanercept. Ann Rheum Dis. 2011 Feb;70(2):284-8. doi: 10.1136/ard.2010.135111. Epub 2010 Nov 10.

  PMID: 21068090 BACKGROUND

• L' Ami MJ, Ruwaard J, Krieckaert C, Nurmohamed MT, van Vollenhoven RF, Rispens T, Wolbink GJ. Serum drug concentrations to optimize switching from adalimumab to etanercept in rheumatoid arthritis. Scand J Rheumatol. 2019 Jul;48(4):266-270. doi: 10.1080/03009742.2019.1577915. Epub 2019 Apr 23.

  PMID: 31012365 BACKGROUND

MeSH Terms

Conditions

Arthritis, Rheumatoid

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, PhD

  Reade Rheumatology Research Institute

  PRINCIPAL INVESTIGATOR

• Alfons A Den Broerder, PhD

  Sint Maartenskliniek

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Rheumatologists and patients remain blinded for allocation.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patients with rheumatoid arthritis starting another bDMARD after adalimumab failure (defined as DAS28CRP\>2.9) are randomly assigned to usual care (with randomized switch to etanercept or to a non-TNF-inhibitor) or 'drug concentration' guided switch. When randomized to the usual care group, the treating rheumatologist gets the advice from an independent coworker to switch patients to etanercept 1\*50 mg/week or a non-TNFi (abatacept, rituximab, tocilizumab, or sarilumab), based on random allocation. When randomized to a non-TNFi, the treating rheumatologist will choose the non-TNFi. In the 'drug concentration guided' group, in patients with a concentration \<1.0 mg/L a switch to etanercept (standard dosing regimen of 50mg once a week) is advised by an independent coworker and in patients with a concentration ≥ 1.0 start of a non-TNF-inhibitor (the same drugs and dosing as in usual care group) is advised.

Study Record Dates

• First Submitted: January 8, 2020
• First Posted: February 5, 2020
• Study Start: July 31, 2020
• Primary Completion: May 1, 2024
• Study Completion: May 1, 2024
• Last Updated: November 18, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Six months after the study is published the data will be shared
• Access Criteria: Researchers with demonstrable interest in autoimmunity, biologicals, or therapeutic drug monitoring (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 (2)