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
|Condition or disease||Intervention/treatment||Phase|
|Rheumatoid Arthritis||Other: Dose reduction to 2mg/L Other: Dose reduction to 5mg/L Drug: Adalimumab||Phase 4|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||89 participants|
|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 Description:||The participants are kept ignorant of the group to which they have been assigned|
|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|
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
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
- 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
- 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
- Number of flares [ Time Frame: after 24 weeks ]Cumulative incidence of flare is calculated in both groups
- Direct medical costs [ Time Frame: after 24 weeks ]Direct medical costs (medication, visits, cost TDM testing) at the separate time points
- 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
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
|Contact: Sadaf Atiqi, MDemail@example.com|
|Contact: Femke Hooijberg, Bscfirstname.lastname@example.org|
|Principal Investigator:||Gertjan Wolbink, PhD||Reade Rheumatology Research Institute|