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Adalimumab Dose Reduction Aiming Low Serum Concentration With Control of Disease Activity (ADDORA-low)

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ClinicalTrials.gov Identifier: NCT04222920
Recruitment Status : Recruiting
First Posted : January 10, 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:
Several prior studies have shown that dose reduction or discontinuation of tumor necrosis factor (TNF)-inhibitors, like adalimumab, is possible in substantial number of patients with a rheumatic disease without an increase in disease activity. Prior studies showed that patients with concentrations higher than 5 mg/L are overexposed to adalimumab and can safely reduce the dose. In the first phase of treatment, an adalimumab concentration of 5mg/L is needed to achieve adequate clinical response. However to control disease activity after 28 weeks, lower concentration than 5 mg/L are probably sufficient. Recent published data suggest that concentrations of 0.1-0.5 mg/L are enough to control TNF blockade in this state. Yet, a study which investigates the lowest effective drug serum concentration is missing so far. The hypothesis is that serum adalimumab concentration of 2 mg/L is sufficient to control disease activity.

Condition or disease Intervention/treatment Phase
Rheumatoid Arthritis Other: Dose reduction to 2mg/L Other: Dose reduction to 5mg/L Drug: Adalimumab Phase 4

Detailed Description:

Biological agents are frequently prescribed to optimize rheumatoid arthritis care. In order to prevent joint destruction it is necessary to maintain remission or low disease activity. Up to now clinicians used to continue the initial treatment regimen to maintain remission or low disease activity. Since biologic therapy is expensive, and is associated with patient burden as dose dependant risk for serious infections, multiple studies have been performed to show that a large proportion of patients with rheumatoid arthritis with stable low disease activity can reduce their dose without relapse of disease. In addition the latest European and American recommendations pose to reduce the dosage or to discontinue the bDMARDs in case of persistent remission or low disease activity. Yet, there are no recommendations on how this should be carried out.

Currently, most clinicians use Disease Activity Score in 28 joints (DAS28) and the Clinical Disease Activity Index (CDAI) to monitor dose reduction strategies. Although disease activity guided dose reduction is safe and cost-effective, a relatively novel strategy is dose reduction using serum drug concentrations (therapeutic drug monitoring). Most biologics are characterized by wide variation in pharmacokinetics between patients, resulting in wide range of drug concentrations when administered at the labeled dose. Therapeutic drug monitoring can be a valuable tool for optimizing the dosage of biopharmaceuticals and improving patient care on individual level. In other autoimmune diseases, such as inflammatory bowel disease, it is thought to be superior to empirical dose reduction and is already applied in clinical practice.

The rationale behind therapeutic drug monitoring is that medication dose correlates with serum drug levels and drug concentration correlates with therapeutic effect. The latter notion is demonstrated for adalimumb by Pouw et al. Adalimumab serum concentration in a range 5-8 mg/L is sufficient for adequate response. In the first phase of treatment, drug concentration must be high enough to control immunogenicity. To control disease activity in the 2nd phase (after 28 weeks), lower concentrations than 5 mg/L are probably sufficient. Our study group illustrated in 2018 that reducing adalimumab dose by prolonging the dosing interval with 50%, is non-inferior to continuation in patients with adalimumab levels > 8mg/L. In addition, recent published data suggest that concentrations of 0.1-0.5 mg/L are enough to control TNF in this phase. Since around 70% of the patients have adalimumab concentration above 5 mg/l, while an adalimumab concentration of 5 mg/L is enough for adequate response (7), a large extent of patients might thus be overexposed.

The hypothesis is that 1/ tapering adalimumab in RA patient doing well after 28 weeks using TDM aiming at 5mg/l (and disease activity measurement) results in maintenance of disease control and lower adalimumab use, and that 2/ tapering to a lower target drug level of 2 mg/L is non inferior to the higher 5mg/l target with respect to disease activity control and safety, and superior in adalimumab reduction. Tapering to achieve these lower targets (for example direct doubling of interval in patients with levels > 10 mg/L) might result in the lowest effective drug dose.

Disease activity after dose reduction, aiming adalimumab concentration of 2 mg/L or 5 mg/L, in rheumatoid arthritis patients treated with adalimumab for at least 28 weeks and a serum adalimumab concentration above 5 mg/L, will be evaluated in this multi-centre, randomized, single blinded trail. Patients with an adalimumab concentration above 5mg/L will be randomly assigned to dose reduction by extending their dosing interval aiming a drug level of 2 mg/L or aiming a drug level of 5 mg/L. A newly developed algorithm is used to determine the interval prolongation for each patient

Data regarding disease status, functioning, adalimumab serum concentrations, anti-drug antibodies and medical costs will be collected during this study.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 89 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Patients with rheumatoid arthritis treated with adalimumab for at least 28 weeks and a serum adalimumab concentration above 5 mg/L will be randomly assigned to dose reduction by extending their dosing interval aiming a drug level of 2 mg/L or aiming a drug level of 5 mg/L
Masking: Single (Participant)
Masking Description: The participants are kept ignorant of the group to which they have been assigned
Primary Purpose: Treatment
Official Title: Adalimumab Dose Reduction Aiming Low Serum Concentration With Control of Disease Activity: a Single Blind, Non-inferiority, Randomised Clinical 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
Experimental: Low serum drug concentration
Adalimumab dose reduction aiming a drug level of 2 mg/L
Other: Dose reduction to 2mg/L
Adalimumab dose reduction aiming drug concentration of 2mg/L

Drug: Adalimumab
Adalimumab

Active Comparator: High serum drug concentration
Adalimumab dose reduction aiming a drug level of 5 mg/L
Other: Dose reduction to 5mg/L
Adalimumab dose reduction aiming drug concentration of 5mg/L

Drug: Adalimumab
Adalimumab




Primary Outcome Measures :
  1. Mean time weighted DAS28-CRP [ Time Frame: after 24 weeks ]
    The difference in mean time weighted DAS28-CRP after 28 weeks between dose reduction aiming serum adalimumab concentration of 5mg/L and 2mg/L


Secondary Outcome Measures :
  1. Mean time weighted DAS28-CRP [ Time Frame: after 12 weeks ]
    The difference in mean time weighted DAS28-CRP after 28 weeks between dose reduction aiming serum adalimumab concentration of 5mg/L and 2mg/L

  2. Number of flares [ Time Frame: after 24 weeks ]
    Cumulative incidence of flare is calculated in both groups

  3. Direct medical costs [ Time Frame: after 24 weeks ]
    Direct medical costs (medication, visits, cost TDM testing) at the separate time points

  4. Drug levels [ Time Frame: after 12 and 24 weeks ]
    The difference in drug levels between the measured drug level and the predicted drug level with the (newly developed) algorithm at different timepoints



Information from the National Library of Medicine

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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 ACR 1987 or ACR/EULAR 2010
  • Treated for at least 28 weeks with adalimumab
  • Adalimumab trough concentration >5mg/L
  • 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;
  • other disease that might flare if adalimumab is tapered like psoriasis, inflammatory bowel disease

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): NCT04222920


Contacts
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Contact: Sadaf Atiqi, MD 0031-202421641 s.atiqi@reade.nl
Contact: Femke Hooijberg, Bsc 0031202421633 f.hooijberg@reade.nl

Locations
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Netherlands
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
Publications:
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Responsible Party: Reade Rheumatology Research Institute
ClinicalTrials.gov Identifier: NCT04222920    
Other Study ID Numbers: ADDORA-low
First Posted: January 10, 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 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
Dose reduction
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