Key Points
Question
Among patients with immune-mediated inflammatory diseases undergoing maintenance therapy with infliximab, is proactive therapeutic drug monitoring (TDM) more effective than standard therapy to sustain disease control without disease worsening?
Findings
In this randomized clinical trial that included 458 patients, the proportion of patients with sustained disease control without disease worsening during 52 weeks of follow-up was 74% in the TDM group and 56% in the standard therapy group, a statistically significant difference.
Meaning
Proactive TDM compared with treatment without TDM during maintenance infliximab therapy was more likely to lead to sustained disease control over 52 weeks for patients with immune-mediated inflammatory diseases.
Abstract
Importance
Proactive therapeutic drug monitoring (TDM), consisting of individualized treatment based on scheduled assessments of serum drug levels, has been proposed as an alternative to standard therapy to optimize efficacy and safety of infliximab and other biologic drugs. However, it remains unclear whether proactive TDM improves clinical outcomes during maintenance therapy.
Objective
To assess whether proactive TDM during maintenance therapy with infliximab improves treatment efficacy by preventing disease worsening compared with standard infliximab therapy without TDM.
Design, Setting, and Participants
Randomized, parallel-group, open-label clinical trial including 458 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis undergoing maintenance therapy with infliximab in 20 Norwegian hospitals. Patients were recruited from June 7, 2017, to December 12, 2019. Final follow-up took place on December 14, 2020.
Interventions
Patients were randomized 1:1 to proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 228) or to standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 230).
Main Outcome and Measures
The primary outcome was sustained disease control without disease worsening, defined by disease-specific composite scores or consensus about disease worsening between patient and physician leading to a major change in treatment (switching to another biologic drug, adding an immunosuppressive drug including glucocorticoids, or increasing the infliximab dose), during the 52-week study period.
Results
Among 458 randomized patients (mean age, 44.8 [SD, 14.3] years; 216 women [49.8%]), 454 received their randomly allocated intervention and were included in the full analysis set. The primary outcome of sustained disease control without disease worsening was observed in 167 patients (73.6%) in the TDM group and 127 patients (55.9%) in the standard therapy group. The estimated adjusted difference was 17.6% (95% CI, 9.0%-26.2%; P < .001) favoring TDM. Adverse events were reported in 137 patients (60%) and 142 patients (63%) in the TDM and standard therapy groups, respectively.
Conclusions and Relevance
Among patients with immune-mediated inflammatory diseases undergoing maintenance therapy with infliximab, proactive TDM was more effective than treatment without TDM in sustaining disease control without disease worsening. Further research is needed to compare proactive TDM with reactive TDM, to assess the effects on long-term disease complications, and to evaluate the cost-effectiveness of this approach.
Trial Registration
ClinicalTrials.gov Identifier: NCT03074656
This randomized clinical trial assesses the effect of therapeutic drug monitoring vs standard therapy on sustained disease control without disease worsening among patients with immune-mediated inflammatory diseases (rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis) undergoing maintenance therapy with infliximab.
Introduction
Tumor necrosis factor (TNF) inhibitors have improved outcomes of common chronic immune-mediated inflammatory diseases including rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, and psoriasis. However, treatment failures of TNF inhibitors are common, and 30% to 50% of people who initially respond later become nonresponsive to TNF inhibitors within the first years of therapy.1,2,3 Disease worsening typically impairs quality of life and can increase the risk of irreversible organ damage and disability.1,4,5,6
Observational data have documented variation in serum drug levels of infliximab and other TNF inhibitors, and loss of treatment response has been attributed to subtherapeutic drug levels and development of neutralizing antidrug antibodies.7,8,9,10
Proactive therapeutic drug monitoring (TDM), an individualized treatment strategy based on scheduled assessments of serum drug levels and antidrug antibodies, has been proposed to improve long-term efficacy of TNF inhibitors by optimizing drug concentrations and facilitating early detection of antidrug antibodies. However, due to lack of data from randomized clinical trials, treatment recommendations differ with respect to the use of proactive TDM during maintenance therapy with TNF inhibitors.11,12,13
The 2 randomized Norwegian Drug Monitoring (NOR-DRUM) trials were designed to assess effectiveness of proactive TDM compared with standard therapy with infliximab in immune-mediated inflammatory diseases.14 NOR-DRUM A addressed effectiveness of proactive TDM in achieving remission during infliximab induction.15 The aim of the current NOR-DRUM B trial was to assess the effectiveness of proactive TDM in sustaining disease control during maintenance therapy with infliximab.
Methods
Study Design and Participants
In this 52-week randomized, open-label, parallel-group, phase 4 superiority trial, patients were recruited and followed up at 20 Norwegian hospitals. The trial was conducted in accordance with the principles of the Declaration of Helsinki and International Conference on Harmonization Guidelines for Good Clinical Practice.16 Patients provided written informed consent. The protocol and the consent form were approved by an independent ethics committee (Regional Committee for Medical and Health Research Ethics). The trial was investigator initiated and funded by the Norwegian Regional Health Authorities. The trial was conducted and analyzed according to the protocol and statistical analysis plan (Supplement 1). A steering group (eAppendix 1 in Supplement 2), including researchers and clinicians representing all relevant specialties, biostatisticians, and patient representatives, planned and conducted the trial.
Adult patients with diagnoses of rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis who had been undergoing maintenance therapy with infliximab (the originator or a biosimilar product) for a minimum of 30 weeks and a maximum of 3 years were potential participants. Inclusion criteria included presence of a clinical indication to continue infliximab therapy but did not include remission. Eligibility criteria are presented in eAppendix 3 in Supplement 2. All Norwegian hospitals providing infliximab for the relevant indications were invited to participate. Patients were recruited by their treating physician and enrolled by study site investigators.
Randomization
Patients were randomized 1:1 to receive either TDM or standard therapy. A computer-generated random block randomization (block sizes of 4, 6, and 8), stratified by diagnosis, prior participation in NOR-DRUM A by randomization group, and TDM prior to inclusion (during the last 3 infusions), was integrated in the electronic data capture software (Viedoc version 4). The study was open label. Group allocation was made available to the study personnel and patients after randomization.
Intervention and Assessments
In the TDM group, infliximab dosing was adjusted according to an algorithm designed to maintain infliximab levels within the therapeutic range of 3 to 8 mg/L (eFigure 1 in Supplement 2).14 At each infusion, serum trough levels of infliximab and antidrug antibodies were measured and results were entered into an interactive web-based case report form. Based on these results, the trial algorithm provided investigating physicians with the recommended infliximab dose and interval. The infliximab dose or interval could be adjusted to reach the therapeutic range. If a patient developed clinically meaningful levels of antidrug antibodies (defined as ≥50 μg/L), the algorithm recommended discontinuation of infliximab.15
In the standard therapy group, administration of infliximab was based on clinical judgement. Adjustments in dosing or intervals between doses were performed at the discretion of investigating physicians. No algorithm was provided to guide dosing adjustments. Levels of infliximab and antidrug antibodies were assessed at each infusion, but the data were not available to study personnel.
Concomitant immunosuppressive treatment initiated prior to inclusion was maintained in both groups. Patients who discontinued infliximab could initiate other medication at the discretion of the treating physician and were assessed at regular study visits until the study was completed.
Data from clinical assessments, blood samples, and patient-reported outcome measures were collected at each infusion visit. Levels of infliximab and antidrug antibodies were measured at the Department of Medical Biochemistry, Oslo University Hospital, Radiumhospitalet, using in-house assays automated on the AutoDELFIA immunoassay platform (PerkinElmer).17
Outcome Measures
The primary outcome was sustained disease control without disease worsening during the study period of 52 weeks. Disease worsening was defined by disease-specific composite scores or a consensus about disease worsening between patient and physician leading to a major change in treatment (switching to another biological drug, adding an immunosuppressive drug including a systemic glucocorticoid, or increasing the infliximab dose for clinical reasons).17 The main composite disease activity measures for the 6 diseases were (1) for rheumatoid arthritis and psoriatic arthritis, the Disease Activity Score in 28 Joints (range, 0-9.4; higher scores indicate worse disease activity; minimum clinically important difference [MCID], 1.2)18,19; (2) for spondyloarthritis, the Ankylosing Spondylitis Disease Activity Score (range, 0.6-7.2; higher scores indicate worse disease activity; MCID, 1.1)20,21; (3) for ulcerative colitis, the Partial Mayo Score (range, 0-9; higher scores indicate worse disease activity; MCID, 3)22; (4) for Crohn disease, the Harvey-Bradshaw Index (minimum score, 0, with no upper limit; higher scores indicate worse disease activity; MCID not defined, with 3 points suggested as a clinically meaningful change)23,24; and (5) for psoriasis, the Psoriasis Area and Severity Index (range, 0-72; higher scores indicate worse disease activity; MCID not defined).25 More details regarding the disease activity scores are given in eTable 1 in Supplement 2. Disease worsening was defined as an increase of 1.2 points or more from baseline on the Disease Activity Score in 28 Joints to attain a minimum score of 3.2 for rheumatoid arthritis and psoriatic arthritis, an increase of 1.1 points or more from baseline on the Ankylosing Spondylitis Disease Activity Score to attain a minimum score of 2.1 for spondyloarthritis, an increase of more than 3 points from baseline on the Partial Mayo Score and a score of 5 or greater for ulcerative colitis, an increase of 4 points or more from baseline on the Harvey-Bradshaw Index and a score of 7 points or more for Crohn disease, and an increase of 3 points or more from baseline on the Psoriasis Area and Severity Index and a score of 5 or more for chronic plaque psoriasis.17,18,19,20,21,22,23,24,25
Secondary outcomes assessed across all diagnoses included time to disease worsening, patient and physician global assessments of disease activity (range, 0-100; higher scores indicate worse disease activity; MCID not defined), remission status,15 erythrocyte sedimentation rate (normal range, 0-17 mm/h for women and 0-12 mm/h for men), C-reactive protein (normal range, 0-4 mg/L), and patient-reported outcome measures. Secondary outcomes assessed within each disease included disease worsening, disease-specific disease activity parameters, and patient-reported outcome measures. Details regarding the secondary outcomes are listed in Table 1 and in eTable 1 in Supplement 2.
Table 1. Baseline Participant Characteristics.
| Characteristics | Therapeutic drug monitoring (n = 227) | Standard therapy (n = 227) |
|---|---|---|
| Age, mean (SD), y | 45.1 (14.2) | 44.6 (14.3) |
| Sex, No. (%) | ||
| Women | 117 (51.5) | 99 (43.6) |
| Men | 110 (48.5) | 128 (56.3) |
| Disease duration, median (IQR), y | 6.2 (2.0-15.1) | 5.3 (2.1-12.8) |
| Diagnosis, No. (%) | ||
| Spondyloarthritis | 68 (30.0) | 70 (30.8) |
| Ulcerative colitis | 38 (16.7) | 43 (18.9) |
| Rheumatoid arthritis | 39 (17.2) | 40 (17.6) |
| Crohn disease | 34 (15.0) | 32 (14.1) |
| Psoriatic arthritis | 28 (12.3) | 25 (11.0) |
| Psoriasis | 20 (8.8) | 17 (7.5) |
| Therapy | ||
| Infliximab treatment duration, median (IQR), wk | 40.0 (37.9-61.0) | 39.9 (37.9-61.0) |
| Concomitant immunosuppressive therapy, No. (%)a | 123 (54.2) | 130 (57.3) |
| Concomitant use of glucocorticoids, No. (%) | 15 (6.6) | 13 (5.7) |
| Use of biologic therapy prior to infliximab, No. (%)b | 62 (27.3) | 63 (27.8) |
| Use of tumor necrosis factor inhibitor prior to infliximab, No. (%)c | 62 (27.3) | 61 (26.9) |
| Use of other biologic therapy prior to infliximab, No. (%)d | 6 (2.6) | 12 (5.3) |
| Exposed to therapeutic drug monitoring prior to randomization, No. (%)e | 90 (39.6) | 92 (40.5) |
| Disease activity at baseline | ||
| Erythrocyte sedimentation rate, median (IQR), mm/hf | 7.0 (3.0-12.0) | 5.0 (2.0-11.0) |
| C-reactive protein, median (IQR), mg/Lg | 1.0 (1.0-3.0) | 1.0 (1.0-3.0) |
| Patient global assessment of disease activity, mean (SD)h | 25.8 (21.6) | 22.5 (19.1) |
| Physician global assessment of disease activity, mean (SD)h | 13.8 (15.8) | 11.2 (12.6) |
| Disease-specific characteristics | ||
| Spondyloarthritis | ||
| HLA-B27 positive, No. (%) | 52 (82.5) | 53 (79.1) |
| Ankylosing Spondylitis Disease Activity Score, mean (SD)i | 1.6 (0.8) | 1.5 (0.8) |
| Ulcerative colitis, median (IQR) | ||
| Partial Mayo Scorej | 0.0 (0.0-2.0) | 0.0 (0.0-2.0) |
| Fecal calprotectin level, mg/kgk | 43.0 (15.0-95.0) | 114.0 (25.0-237.0) |
| Rheumatoid arthritis | ||
| Anticitrullinated protein antibody positive, No. (%) | 28 (71.8) | 30 (75.0) |
| Rheumatoid factor positive, No. (%) | 24 (61.5) | 27 (71.1) |
| Disease Activity Score in 28 Joints, mean (SD)l | 2.4 (1.0) | 2.3 (1.2) |
| Crohn disease, median (IQR) | ||
| Harvey-Bradshaw Indexm | 3.0 (1.0-6.0) | 3.0 (1.0-4.0) |
| Fecal calprotectin level, mg/kgk | 51.0 (16.0-113.0) | 67.0 (38.0-120.5) |
| Psoriatic arthritis | ||
| Disease Activity Score in 28 Joints, mean (SD)l | 2.1 (1.1) | 1.6 (1.0) |
| Psoriasis | ||
| Psoriasis Area and Severity Index, mean (SD)n | 2.4 (1.7) | 2.3 (1.4) |
Abbreviations: HLA, human leukocyte antigen; MCID, minimum clinically important difference.
Concomitant immunosuppressive therapy includes methotrexate, leflunomide, sulfasalazine, and azathioprine.
Biologic therapy includes etanercept, adalimumab, certolizumab pegol, golimumab, abatacept, efalizumab, rituximab, secukinumab, tocilizumab, ustekinumab, vedolizumab, and tofacitinib (targeted synthetic).
Tumor necrosis factor inhibitors include etanercept, adalimumab, certolizumab pegol, and golimumab.
Other biologic therapy includes abatacept, efalizumab, rituximab, secukinumab, tocilizumab, ustekinumab, vedolizumab, and (in 1 patient) tofacitinib (targeted synthetic disease-modifying antirheumatic drug).
Therapeutic drug monitoring prior to randomization was defined as 1 or more assessments of serum drug levels during the last 3 infusions.
The erythrocyte sedimentation rate normal range is 0 to 17 mm/h for women and 0 to 12 mm/h for men.
The C-reactive protein normal range is 0 to 4 mg/L.
Global assessment of disease activity ranges from 0 to 100 on a visual analog scale; 0 indicates no disease activity and 100, highest possible disease activity.
The Ankylosing Spondylitis Disease Activity Score includes total back pain (visual analog scale range, 0-100), patient global assessment of disease activity, peripheral pain/swelling, duration of morning stiffness, and C-reactive protein level. The range is 0.6 to 7.7; higher values indicate worse disease; MCID, 1.1. See eTable 1 in Supplement 2 for details.
The Partial Mayo Score is a disease activity score used for ulcerative colitis that consists of 3 components (rectal bleeding, stool frequency, and physician rating of disease activity) rated from 0 to 3 and summarized for a total score that ranges from 0 to 9. Higher scores indicate worse disease; MCID, 3. See eTable 1 in Supplement 2 for details.
Fecal calprotectin ranges from <50 mg/kg to >2000 mg/kg. Validated cutoff values are still lacking, but a recent consensus agreed on 150 mg/kg as a cutoff to identify endoscopic healing, with levels between 150 and 250 mg/kg as a gray zone.26 See eTable 1 in Supplement 2 for details.
The Disease Activity Score in 28 Joints is a disease activity score used for rheumatoid arthritis and psoriatic arthritis that includes 28 tender and swollen joints count, erythrocyte sedimentation rate, and assessment. Range is 0 to 9.4; higher values indicate worse disease; MCID, 1.2. See eTable 1 in Supplement 2 for details.
The Harvey-Bradshaw Index (HBI) is a disease activity score used for Crohn disease consisting of 5 subdomains: general well-being (0-4), abdominal pain (0-3), number of liquid soft stools per day, abdominal mass (0-3), and number of predefined complications (0-8). The scores of each subdomain are summed to compute the HBI. The minimum value of the HBI is 0, with no upper limit; higher values indicate worse disease; MCID not defined, with 3 points suggested as a clinically meaningful change. See eTable 1 in Supplement 2 for details.
The Psoriasis Area and Severity Index includes measures of redness, thickness, and scaliness of lesions (each graded 0-4), weighted by the area and location of involvement. The score ranges from 0 to 72; higher scores indicate worse disease; MCID not defined. See eTable 1 in Supplement 2 for details.
Development of antidrug antibodies, serum drug levels, infliximab dose, and drug discontinuation were predefined exploratory outcomes. Safety assessments included clinical and laboratory adverse events.27
Sample Size Calculation
The sample size was based on the primary outcome of sustained disease control without disease worsening. Based on the results of a previous trial using standard infliximab therapy and the same primary outcome and disease groups, we assumed a sustained disease control rate of 70% in the standard therapy group.17 A prior randomized trial comparing TDM with standard therapy indicated a potential difference in disease worsening of approximately 10% to 15% in favor of TDM.28 After considering the results of these trials and after thorough discussions between the clinicians and biostatisticians in the steering group, it was decided to design the study to have statistical power to detect a between-group difference of 12.5% (70% vs 82.5%). Using a 2-sided test and a significance level of α = .05, it was estimated that a sample size of 414 patients would be needed to have 85% power to detect this difference. To compensate for attrition, we aimed to include 450 patients.
Statistical Analyses
The primary outcome was analyzed using logistic regression. The model included treatment group and stratification factors as categorical covariates, all of which were treated as additive effects. The intervention difference in the primary outcome was estimated from the logistic regression using the adjusted risk difference, estimating its standard error via the delta method.29 The primary analysis set comprised randomized participants receiving the randomly allocated intervention (received at least 1 dose of infliximab with a recorded treatment decision for the second dose). Patients with less than 26 weeks of follow-up time were treated as having disease worsening.
Missing data on the components defining disease worsening were handled by multiple imputation. A multivariable normal model for the component scores and their lagged values was assumed and used to generate 20 imputations. Pooled estimates were formed using Rubin rules. Alternative approaches to dealing with missing values (complete case analysis, last observation carried forward, and worst/best case imputation) were included as sensitivity analyses, as were analyses adjusting for baseline variables (age, sex, use of concomitant immunosuppressive medication, duration of infliximab treatment, serum infliximab level, and disease activity), adjustments for center (both as random and fixed effects), an analysis excluding disease worsening solely based on patient-physician consensus, and an analysis restricted to patients with high adherence to the protocol (no withdrawal from the study prior to week 52, no deviations from eligibility criteria, no infusion interval longer than 12 weeks, and no physician nonadherence to the study algorithm).
Secondary and exploratory outcomes were analyzed using mixed-effects logistic regression for binary outcomes and linear regression for continuous outcomes with patient-level random intercepts and adjustment for the baseline value. These used the same covariates as above and additionally included time and a time × treatment interaction, with time treated as a categorical variable. Time-to-event end points were analyzed by Cox proportional hazards regression, adjusting for stratification factors and plotted as Kaplan-Meier curves. The proportional hazards assumption (Schoenfeld test) was met. Because of the potential for type I error due to multiple comparisons, findings for analyses other than the primary outcome should be interpreted as exploratory. All analyses were carried out using Stata version 16 (StataCorp) and R version 3.4.4 (R Foundation).
Post Hoc Analyses
Post hoc analyses consisted of analysis of the primary outcome, stratified by use of concomitant immunosuppression therapy, and a between-group comparison of serum infliximab variance at week 52 using an F test. In addition, we tested for a statistical interaction of disease diagnosis on the effects of the intervention on the primary outcome.
Results
Participants
From June 7, 2017, to December 12, 2019, a total of 458 patients with rheumatoid arthritis (n = 80), spondyloarthritis (n = 138), psoriatic arthritis (n = 54), ulcerative colitis (n = 81), Crohn disease (n = 68), or psoriasis (n = 37) undergoing maintenance therapy with infliximab were randomized. Of these, 454 (227 in the TDM group and 227 in the standard therapy group) received at least 1 dose of infliximab, had a recorded treatment decision for the second infliximab infusion, and were included in the primary analysis (Figure 1). A total of 126 and 123 patients in the TDM group and the standard therapy group, respectively, had been participants in NOR-DRUM A.14,15 Of the included patients, 217 (96%) in the TDM group and 220 (97%) in the standard therapy group completed the trial. The 2 groups were balanced overall regarding baseline demographic, clinical, and treatment characteristics (Table 1; eTable 2 in Supplement 2).
Figure 1. Participant Flow in the NOR-DRUM B Trial.
aChronic immune-mediated inflammatory disease included spondyloarthritis, ulcerative colitis, rheumatoid arthritis, Crohn disease, psoriatic arthritis, and psoriasis.
bRandomization was stratified by diagnosis and prior therapeutic drug monitoring.
cPatient had discontinued infliximab prior to randomization.
dMajor protocol violations were prespecified in the statistical analysis plan as follows: deviations from inclusion and/or exclusion criteria, delay in scheduled infusion with an interval between infusions longer than 12 weeks, or investigator nonadherence to study algorithm, defined as discrepancies between recommended and actual dose or interval at more than 1 visit.
eOne patient had both a withdrawal from study prior to week 52 and a prolonged infusion interval.
fPatients for various reasons were not able to adhere to the study routine (eg, did not arrive for scheduled infusions).
gPatients included in the sensitivity analysis had high adherence to the protocol (ie, those who did not withdraw from the study prior to week 52 and had no major protocol violations).
Primary Outcome
Sustained disease control without disease worsening (primary outcome) was achieved in 167 patients (73.6%) in the TDM group and in 127 patients (55.9%) in the standard therapy group. The estimated adjusted difference was 17.6% (95% CI, 9.0%-26.2%; P < .001) in favor of TDM (Figure 2).
Figure 2. Sustained Disease Control With No Disease Worsening (Primary Outcome).
Adjusted difference in the rate of sustained disease control without disease worsening during 52 weeks of follow-up overall (the primary outcome) and by disease subgroup. Size of data markers is proportional to the number of patients in the group. Disease worsening was defined by disease-specific composite scores or a consensus about disease worsening between patient and physician leading to a major change in treatment. Disease worsening according to disease-specific composite measures was defined as follows: for rheumatoid arthritis and psoriatic arthritis, an increase from baseline of 1.2 points or more with a minimum score of 3.2 in the Disease Activity Score in 28 Joints; for spondyloarthritis, an increase from baseline of 1.1 points or more with a minimum score of 2.1 in the Ankylosing Spondylitis Disease Activity Score; for ulcerative colitis, an increase from baseline of more than 3 points with a score of 5 or greater in the Partial Mayo Score; for Crohn disease, an increase from baseline of 4 points or more and a score of 7 or greater in the Harvey-Bradshaw Index; and for psoriasis, an increase from baseline of 3 points or more and a score of 5 or greater in the Psoriasis Area and Severity Index. See Table 1 footnotes for detailed descriptions of the scales and eTable 1 in Supplement 2 for more information.
Sensitivity analyses of the primary outcome (adjustments for baseline variables and center effect, different methods for handling missing data, and an analysis excluding disease worsening solely by patient-physician consensus [see eTable 3 in Supplement 2 for description]) showed consistent results (eTable 4A in Supplement 2).
Secondary Outcomes
The estimated hazard ratio of disease worsening was 2.1 (95% CI, 1.5-2.9) in the standard therapy group compared with the TDM group (Figure 3).
Figure 3. Time to Disease Worsening.
Disease worsening was defined by disease-specific composite scores or a consensus about disease worsening between patient and physician leading to a major change in treatment as defined in the legend of Figure 2. Events that occurred after day 365 (but within the 4-week window of the week 52 visit) were set as having occurred at day 365.
Secondary efficacy outcomes reflecting disease activity, remission status, and patient-reported outcomes at the week 52 visit are summarized in eTable 5 in Supplement 2. There were no significant between-group differences for any of these outcomes other than for the Rheumatoid Arthritis Impact of Disease score.
Treatment Algorithm and Drug Consumption
The mean infliximab dose during the trial was 4.8 mg/kg in both groups (SDs, 1.3 and 1.2). Changes in treatment after disease worsening are described in eTable 6 in Supplement 2. An increase in infliximab dose after disease worsening was more common in the standard therapy group (n = 51 [51%]) than in the TDM group (n = 19 [31.6%]). Infliximab was discontinued in 34 patients (15%) in both groups. In the TDM group, most patients (n = 17) discontinued infliximab because of antidrug antibody formation whereas in the standard therapy group, most patients (n = 22) discontinued because of disease worsening.
Infliximab Levels and Antidrug Antibodies
The median serum level of infliximab was 5.8 mg/L in both groups (IQRs, 4.3-7.5 mg/L in the TDM group and 3.4-8.9 mg/L in the standard therapy group). Serum drug levels are shown in eFigure 2 in Supplement 2.
Seventy patients (30%) in the TDM group and 39 patients (17%) in the standard therapy group had serum infliximab levels within the therapeutic range throughout the study period. Forty-three patients (19%) in the TDM group and 61 patients (27%) in the standard therapy group had low serum infliximab levels (≤2 mg/L) at least once during the study period.
Twenty-one patients (9.2%) in the TDM group and 27 patients (15.0%) in the control group developed clinically significant levels of antidrug antibodies (≥50 μg/L).
Adverse Events
Adverse events were reported in 137 patients (60%) and 142 (63%) patients in the TDM and standard therapy groups, respectively (Table 2). The number of infections was higher in the TDM group (Table 2). Three patients in the standard therapy group and none in the TDM group experienced an infusion reaction.
Table 2. Treatment-Emergent Adverse Events.
| Events | No. (%) of participants | |
|---|---|---|
| Therapeutic drug monitoring (n = 227) | Standard therapy (n = 227) | |
| Serious adverse eventsa | 16 (7) | 18 (8) |
| Adverse events | 137 (60) | 142 (63) |
| Most frequent adverse eventsb | ||
| Upper respiratory tract infectionc | 70 (31) | 58 (26) |
| Rash | 9 (4) | 14 (6) |
| Gastroenteritis | 8 (4) | 8 (4) |
| Herpes virus infection | 8 (4) | 4 |
| Pneumonia | 8 (4) | 4 |
| Most frequent serious adverse eventsd | ||
| Bacterial infectione | 3 (1) | 3 (1) |
| Bone fracture | 1 (<1) | 3 (1) |
| Acute appendicitis | 2 (1) | 1 (<1) |
| Choledocholithiasis | 1 (<1) | 2 (1) |
An adverse event was defined as an unfavorable and unintended sign, symptom, or disease temporally associated with use of the study drug; assessed continuously throughout the study. A serious adverse event was defined as an adverse event resulting in death, a life-threatening condition, hospitalization (initial or prolonged), disability, or permanent damage; assessed continuously throughout the study.
Most frequent adverse events were defined as occurring in more than 5% of the study population.
Upper respiratory tract infection includes common cold, nasopharyngitis, rhinitis, and sinusitis.
Most frequent serious adverse events were defined as occurring in 3 or more patients.
Bacterial infection includes pneumonia (n = 2), liver abscess (n = 1), endocarditis (n = 1), tonsillitis (n = 1), and lower urinary tract infection (n = 1).
Post Hoc Analyses
The effect of TDM on the primary outcome was similar across disease subgroups (P = .91 for interaction). Serum drug levels showed less variation over time in the TDM group; the variance in serum drug levels at week 52 was 20% of that in the standard therapy group (P < .01) (eFigure 2 in Supplement 2). Analysis of the primary outcome stratified by use of concomitant immunosuppression showed similar results (eTable 4B in Supplement 2).
Discussion
Among patients with immune-mediated inflammatory diseases undergoing maintenance therapy with infliximab, proactive TDM was more effective than treatment without TDM in sustaining disease control without disease worsening. This finding was consistent across a range of sensitivity analyses.
A benefit of proactive TDM during maintenance infliximab therapy has been suggested by observational and retrospective studies,30,31 but prior randomized trials addressing proactive TDM of infliximab in patients with inflammatory bowel diseases, the TAILORIX and TAXIT trials, with sample sizes of 122 and 263 patients, respectively, did not demonstrate statistically significant benefits of TDM.28,32 In the TAXIT trial, however, the number of patients with a disease flare, a secondary outcome, was higher in the standard therapy group.
The lack of statistically significant differences in the secondary outcomes reflecting disease activity and patient-reported outcomes assessed at the 52-week visit suggests that patients in both groups may have improved after initial disease worsening, either because infliximab therapy was intensified or because patients’ therapy was changed to another drug. While preventing disease worsening may improve quality of life, delay disease progression, and avoid irreversible organ damage, the association of this study’s primary outcome measure with long-term outcomes is unknown. Similarly, the effectiveness of proactive TDM on long-term outcomes such as irreversible organ damage and disability needs further study.
Although this trial showed that proactive TDM was more effective than standard therapy in sustaining disease control during maintenance therapy with infliximab, the NOR-DRUM A trial did not find that proactive TDM improved remission rates during induction of infliximab therapy.15 These different results regarding the clinical role of TDM during induction of infliximab compared with maintenance therapy are probably related to different mechanisms underlying lack of response/primary treatment failure during the induction period and loss of response/secondary treatment failure during maintenance therapy.1 Proactive TDM might be more important during maintenance therapy, a period during which low drug levels could be an important risk factor for therapeutic failure.33 High drug exposure during induction may diminish potential benefits of TDM during this phase of therapy.
In the NOR-DRUM A trial of TDM during induction therapy, TDM significantly reduced the rate of infusion reactions compared with standard therapy.15 This effect was confirmed in the present trial, with no infusion reactions in the TDM group compared with 3 infusion reactions in the standard therapy group. Patients susceptible to infusion reactions may have discontinued infliximab before they could be included in the study, possibly explaining the low number of infusion reactions.
The following additional considerations should be noted. First, this trial showed that TDM improved infliximab treatment by preventing disease flares without increasing drug consumption. Additional research is needed to establish whether proactive TDM during maintenance therapy is cost-effective. Second, these data cannot be extrapolated to biologics with different immunogenicity profiles. Third, standard therapy was defined as therapy without TDM according to clinical practice and treatment guidelines for the included disease groups.12,13,34 Reactive TDM, in which serum drug level and antidrug antibody measurements are performed only when a therapeutic failure is likely, was not included in this trial. Further studies are needed to compare effectiveness and cost-effectiveness of proactive and reactive TDM.
Strengths of this study include the randomized design, the large number of included patients, and the high retention rate.
Limitations
This study has several limitations. First, the trial was open-label. Definitions of disease worsening in each diagnosis were based on well-established measures of disease activity with predefined cut points.18,19,20,21,22,23,24,25,35,36,37 However, disease activity composite measures included both objective and subjective assessments, and disease worsening by patient-physician consensus was integrated in the definition. Biased outcome assessment due to lack of blinding is possible. Consistent with this, the number of disease-worsening events based on patient-physician consensus was higher in the standard therapy group. Second, the trial did not have statistical power to test the effectiveness of TDM separately in each of the 6 disease groups. These diseases have inherent differences, and findings may not be completely generalizable across groups. Third, the proactive TDM strategy used in this trial was based on available data when the study was being planned and after consultation with key opinion leaders in the international advisory board. The therapeutic range defined for serum infliximab was consistent with prior studies and clinical guidelines.11,12,13,28,30,32,34,38,39,40 However, some patients might benefit from higher drug levels than prescribed in this study. Fourth, MCIDs have not been established for 2 of the disease activity parameters defining the primary outcome. Fifth, whereas infliximab levels are comparable between assays, reporting of antidrug antibodies is assay dependent and not currently standardized. The cutoff of 50 μg/L was established after considering observational data from the main study centers showing that antidrug antibodies exceeding this level were rarely transient. In the NOR-DRUM A trial of TDM during induction therapy, only 1 patient with an antidrug antibody level above 50 μg/L regained measurable drug levels, supporting this cutoff.15
Conclusions
Among patients with immune-mediated inflammatory diseases undergoing maintenance therapy with infliximab, proactive TDM was more effective than treatment without TDM in sustaining disease control without disease worsening. Further research is needed to compare proactive TDM with reactive TDM, to assess the effects on long-term disease complications, and to evaluate the cost-effectiveness of this approach.
Trial Protocol and Statistical Analysis Plan
eAppendix 1. The NOR-DRUM Steering Group
eAppendix 2. Principal Investigators From Each Study Center
eAppendix 3. Eligibility Criteria
eTable 1. Details of Study Endpoints
eTable 2. Demographic and Baseline Characteristics in Disease Subgroups
eTable 3. Disease Worsening According to Different Parts of the Definition
eTable 4. Sensitivity Analyses of the Primary Endpoint
eTable 5. Results Secondary Endpoints
eTable 6. Change in Treatment at Disease Worsening
eFigure 1. Treatment Algorithm in the Therapeutic Drug Monitoring Group
eFigure 2. Serum Infliximab Level
eReferences
Data Sharing Statement
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol and Statistical Analysis Plan
eAppendix 1. The NOR-DRUM Steering Group
eAppendix 2. Principal Investigators From Each Study Center
eAppendix 3. Eligibility Criteria
eTable 1. Details of Study Endpoints
eTable 2. Demographic and Baseline Characteristics in Disease Subgroups
eTable 3. Disease Worsening According to Different Parts of the Definition
eTable 4. Sensitivity Analyses of the Primary Endpoint
eTable 5. Results Secondary Endpoints
eTable 6. Change in Treatment at Disease Worsening
eFigure 1. Treatment Algorithm in the Therapeutic Drug Monitoring Group
eFigure 2. Serum Infliximab Level
eReferences
Data Sharing Statement