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Using Adalimumab Serum Concentration to Choose a Subsequent Biological DMARD in Rheumatoid Arthritis Patients Failing Adalimumab Treatment (ADDORA-switch)

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ClinicalTrials.gov Identifier: NCT04251741
Recruitment Status : Recruiting
First Posted : February 5, 2020
Last Update Posted : October 14, 2020
Sponsor:
Collaborators:
ZonMw: The Netherlands Organisation for Health Research and Development
Sint Maartenskliniek
Information provided by (Responsible Party):
Reade Rheumatology Research Institute

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).

Condition or disease Intervention/treatment Phase
Rheumatoid Arthritis Diagnostic Test: Adalimumab trough concentration Other: Usual care Phase 4

Detailed Description:

Over the last decades biopharmaceuticals such as agents against tumor necrosis factor (TNF), are frequently prescribed to optimize rheumatoid arthritis treatment. Although TNFi such as adalimumab, etanercept and infliximab, have improved the treatment of rheumatoid arthritis, a proportion of patients discontinue the treatment because of inefficacy or intolerance.

Where TNFi have failed, mainly two treatment approaches are available: switch to another TNFi or to a biological with a different mode of action (notably rituximab, abatacept or tocilizumab) or to a target synthetic DMARDs. The EULAR recommendation for the management of rheumatoid arthritis advocate that any biologic agent including a subsequent TNFi can be used with equal chance for effect in case of non-response to a previous TNFi. This recommendation is based on three randomized controlled trails, but it should be noted that systematic reviews also including non-randomized controlled studies sometimes concluded that non-TNFi are more effective after TNFi failure than a second TNFi.

Of note, currently there are no strong predictors available for response to bDMARDS in RA. This study focuses on non-response after adalimumab, as this is the most prescribed TNFi worldwide.

Although it seems that indeed on a group level response to a non-TNFi is comparable to a second TNFi after the first TNFi has failed, using therapeutic drug monitoring could identify subgroups of patient who would benefit more from either a non-TNFi or a TNF-i as next treatment. The underlying pathophysiological mechanisms for this hypothesis are explored in this study.

Nonresponse on adalimumab in RA can have different causes. Firstly, the patient might not be sensitive to TNF blockade at all, or the patient develops this trait later on (primary nonresponse or secondary nonresponse). In these patients, switching to a non-TNFi might conceptually be superior to starting a second TNFi. However, in other patients nonresponse (either primary or secondary) might be caused by inefficient drug concentration because of development of antidrug antibodies against adalimumab. In these patients a TNFi might be just as effective as a non-TNFi, as these patients have drug- but not class failure. Thus, testing of adalimumab levels might be helpful in channelling patients to their most optimal treatment.

Above mentioned hypothesis has been tested in three studies (5) of which one concerned adalimumab in RA. This study showed that response to a second TNFi was indeed higher in patients with antidrug antibodies (ADA) and low adalimumab levels, and lower in patients with adequate adalimumab levels. However, a diagnostic study comparing a serum concentration guided versus usual care switching strategy has not yet been performed.

In this multi-centre, double blinded randomized controlled trial it will be evaluated whether clinical outcome after switching to a subsequent biological treatment is superior with a switching strategy using adalimumab concentration compared to usual care switching strategy.

Patients with rheumatoid arthritis starting another bDMARD (biologic disease modifying antirheumatic drugs) after adalimumab failure (defined as DAS28-CRP >2.9) are randomly assigned to usual care (with randomized switch to etanercept or to a non-TNFi) or 'drug concentration' guided switch.

Data regarding disease status, functioning, adverse events and use of co-medication/rescue medication will be collected during this study.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 84 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

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 a secondary randomization schedule. 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.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Rheumatologists and patients remain blinded for allocation.
Primary Purpose: Treatment
Official Title: Using Adalimumab Serum Concentration to Choose a Subsequent Biological DMARD in Rheumatoid Arthritis Patients Failing Adalimumab Treatment: a Blinded Randomized Superiority Trial
Actual Study Start Date : March 1, 2020
Estimated Primary Completion Date : February 1, 2022
Estimated Study Completion Date : February 1, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Adalimumab

Arm Intervention/treatment
Active Comparator: Usual care group
Based on a secondary randomization schedule patients are treated with etanercept or a non-TNFi (abatacept, rituximab, tocilizumab, or sarilumab)
Other: Usual care
In the usual care group, switch to subsequent biological is based on secondary randomisation

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




Primary Outcome Measures :
  1. mean time weighted DAS28-CRP [ Time Frame: 24 weeks ]
    difference in mean time weighted DAS28-CRP between the two groups


Secondary Outcome Measures :
  1. Good or moderate response according the EULAR response criteria [ Time Frame: 12 en 24 weeks ]
    Percentage of patients with good or moderate response according the EULAR response criteria

  2. Minimal disease activity (DAS28-CRP<2.9) [ Time Frame: 24 weeks ]
    Percentage of patients with minimal disease activity (DAS28-CRP<2.9)

  3. Non-responders [ Time Frame: 24 weeks ]
    Percentage of patients with no response according to EULAR response criteria

  4. Number of adverse events [ Time Frame: 24 weeks ]
    The number of adverse events

  5. Severity of adverse events [ Time Frame: 24 weeks ]
    Severity of adverse events

  6. Cumulative dose co-medication [ Time Frame: 24 weeks ]
    Cumulative dose of co-medication

  7. Times co-medication is used [ Time Frame: 24 weeks ]
    Number of times co-medication is used

  8. Cumulative dose of rescue medication [ Time Frame: 24 weeks ]
    Cumulative dose of rescue medication

  9. Times rescue medication is used [ Time Frame: 24 weeks ]
    Number of times co-medication is used



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

  • 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)
  • who has agreed to participate (written informed consent);
  • age 18 years or older.

Exclusion Criteria:

  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04251741


Contacts
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Contact: Sadaf Atiqi, MD 0031-202421641 s.atiqi@reade.nl
Contact: Maike Wientjes, MSc 0031 24 365 9180 m.wientjes@maartenskliniek.nl

Locations
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Netherlands
Sint Maartenskliniek Recruiting
Ubbergen, Gelderland, Netherlands, 6574NA
Contact: Maike Wientjes, Msc    0031 24 365 9180    m.wientjes@maartenskliniek.nl   
Reade Rheumatology Research Institute Recruiting
Amsterdam, Noord- Holland, Netherlands, 1056AB
Contact: Sadaf Atiqi, MD    0031-202421641    s.atiqi@reade.nl   
Contact: Femke Hooijberg, Bsc    0031-202421633    f.hooijberg@reade.nl   
Sponsors and Collaborators
Reade Rheumatology Research Institute
ZonMw: The Netherlands Organisation for Health Research and Development
Sint Maartenskliniek
Investigators
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Principal Investigator: Gertjan Wolbink, PhD Reade Rheumatology Research Institute
Principal Investigator: Alfons A Den Broerder, PhD Sint Maartenskliniek
Publications:
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Responsible Party: Reade Rheumatology Research Institute
ClinicalTrials.gov Identifier: NCT04251741    
Other Study ID Numbers: ADDORA-switch
First Posted: February 5, 2020    Key Record Dates
Last Update Posted: October 14, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: To avoid duplication of research, the gathered data will be shared once all desirable data analysis have been performed and the results are published
Supporting Materials: Study Protocol
Statistical Analysis Plan (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

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Reade Rheumatology Research Institute:
Adalimumab
Rheumatoid arthritis
Therapeutic Drug Monitoring
Drug level
Switching
Failure
Non-response
Subsequent biological
Additional relevant MeSH terms:
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Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Adalimumab
Anti-Inflammatory Agents
Antirheumatic Agents