To assess non-inferiority of s.c. to i.v. CT-P13 in RA.

Patients with active RA and inadequate response to MTX participated in this phase I/III double-blind study at 76 sites. Patients received CT-P13 i.v. 3 mg/kg [week (W) 0 and W2] before randomization (1:1) at W6 to CT-P13 s.c. via pre-filled syringe (PFS) 120 mg biweekly until W28, or CT-P13 i.v. 3 mg/kg every 8 weeks until W22. Randomization was stratified by country, W2 serum CRP and W6 body weight. From W30, all patients received CT-P13 s.c. In a usability sub-study, patients received CT-P13 s.c. via auto-injector (W46–54) then PFS (W56–64). The primary endpoint was change (decrease) from baseline in disease activity score in 28 joints (DAS28)-CRP at W22 (non-inferiority margin: −0.6).

Of 357 patients enrolled, 343 were randomized to CT-P13 s.c. (n = 167) or CT-P13 i.v. (n = 176) at W6. The least-squares mean change (decrease) from baseline (standard error) in DAS28-CRP at W22 was 2.21 (0.22) for CT-P13 s.c. (n = 162) and 1.94 (0.21) for CT-P13 i.v. [n = 168; difference 0.27 (95% CI: 0.02, 0.52)], establishing non-inferiority. Efficacy findings were similar between arms at W54. Safety was similar between arms throughout: 92 (54.8%; CT-P13 s.c.) and 117 (66.9%; CT-P13 i.v.) patients experienced treatment-emergent adverse events (from W6). There were no treatment-related deaths or new safety findings. Usability was similar for CT-P13 s.c. via auto-injector or PFS.

CT-P13 s.c. was non-inferior to CT-P13 i.v. in active RA. The convenience of s.c. administration could benefit patients.

ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT03147248.

• CT-P13
• biosimilar
• immunogenicity
• infliximab
• non-inferiority
• pharmacokinetics
• rheumatoid arthritis
• subcutaneous
• switching

• Antibodies/blood
• Area Under Curve
• Half-Life
• Healthy Volunteers
• Humans
• Infliximab/administration & dosage
• Infliximab/blood
• Infliximab/immunology
• Injections, Intravenous
• Metabolic Clearance Rate
• Models, Biological
• Nonlinear Dynamics
• Single-Blind Method

Evidence supporting treatment intensification in rheumatoid arthritis (RA) is limited and controversial. We explored outcomes of infliximab dose increases and accounted for pre-existing trough levels in patients with active RA.

This study was a retrospective study of 42 RA patients who received increased infliximab following an insufficient response (DAS28 >3.2). Serum concentrations of infliximab and antibodies to infliximab (ATI) and DAS28 and EULAR clinical response parameters were recorded for 1 year. Analyses were performed in three patient groups that were defined by infliximab serum concentration prior to treatment enhancement: no detectable, low (<1.1 μg/mL) or high (≥1.1 μg/mL) drug levels.

No circulating infliximab was detected in 20 patients (47.6%), but 13 (31%) and 9 (21.4%) patients exhibited low and high levels, respectively. ATI was only detected in patients with no detectable drug levels because the drug interferes with ELISA. DAS28 disease activity globally showed a modest improvement after dose escalation, but this improvement did not persist after 6 and 12 months. Infliximab serum levels increased significantly in the high group (p = 0.016), but no increase was achieved in the low and no detectable groups. The three study groups exhibited similar disease activity over time, and no improvement was observed in the non-responder EULAR rates.

These results suggest that the efficacy of an infliximab dose increase is limited, and the response is independent of the infliximab trough serum concentration that is achieved prior to escalation.

• clinical efficacy
• dose increase
• infliximab
• rheumatoid arthritis

• adalimumab
• pharmacodynamics
• pharmacokinetic-pharmacodynamic modelling
• pharmacokinetics
• rheumatoid arthritis

• DMARDs (biologic)
• Rheumatoid Arthritis
• Treatment

• Administration, Oral
• Antirheumatic Agents/therapeutic use
• Arthritis, Rheumatoid/drug therapy
• Biological Products/therapeutic use
• Contraindications
• Drug Therapy, Combination
• Humans
• Immunosuppressive Agents/therapeutic use
• Methotrexate/therapeutic use
• Tumor Necrosis Factor-alpha/antagonists & inhibitors

• 18475 Arthritis Research UK
• 18475 Versus Arthritis

• Adolescent
• Adult
• Aged
• Antibodies, Monoclonal/adverse effects
• Antibodies, Monoclonal/blood
• Antibodies, Monoclonal/immunology
• Antibodies, Monoclonal/therapeutic use
• Antibody Formation
• Antirheumatic Agents/adverse effects
• Antirheumatic Agents/blood
• Antirheumatic Agents/immunology
• Antirheumatic Agents/therapeutic use
• Double-Blind Method
• Female
• Humans
• Immunoglobulin G/adverse effects
• Immunoglobulin G/blood
• Immunoglobulin G/immunology
• Immunoglobulin G/therapeutic use
• Infliximab
• Male
• Middle Aged
• Prospective Studies
• Severity of Illness Index
• Spondylitis, Ankylosing/blood
• Spondylitis, Ankylosing/drug therapy
• Spondylitis, Ankylosing/immunology
• Treatment Outcome
• Young Adult

AIM: To study the safety and effectiveness associated with accelerated infliximab infusion protocols in patients with inflammatory bowel disease (IBD).

METHODS: Original protocols and infusion rates were developed for the administration of infliximab over 90-min and 60-min. Then the IBD patients on stable maintenance infliximab therapy were offered accelerated infusions. To be eligible for the study, patients needed a minimum of four prior infusions. An initial infusion of 90-min was given to each patient; those tolerating the accelerated infusion were transitioned to a 60-min infusion protocol at their next and all subsequent visits. Any patient having significant infusion reactions would be reverted to the standard 120-min protocol. A change in a patient’s dose mandated a single 120-min infusion before accelerated infusions could be administered again.

RESULTS: The University of Virginia Medical Center's Institutional Review Board approved this study. Fifty IBD patients treated with infliximab 5 mg/kg, 7.5 mg/kg and 10 mg/kg were offered accelerated infusions. Forty-six patients consented to participate in the study. Nineteen (41.3%) were female, five (10.9%) were African American and nine (19.6%) had ulcerative colitis. The mean age was 42.6 years old. Patients under age 18 were excluded. Ten patients used immunosuppressive drugs concurrently out of which six were taking azathioprine, three were taking 6-mercaptopurine and one was taking methotrexate. One of the 46 study patients used corticosteroid therapy for his IBD. Seventeen of the patients used prophylactic medications prior to receiving infusions; six patients received corticosteroids as pre-medication. Four patients had a history of distant transfusion reactions to infliximab. These reactions included shortness of breath, chest tightness, flushing, pruritus and urticaria. These patients all took prophylactic medications before receiving infusions. 46 patients (27 males and 19 females) received a total of fifty 90-min infusions and ninety-three 60-min infusions. No infusion reactions were reported. There were no adverse events, including drug-related infections. None of the patients developed cancer of any type during the study timeframe. Total cost savings for administration of the both 90-min and 60-min accelerated infusions compared to standard 120-min infusions was estimated to be $53 632 ($116 965 vs $63 333, P = 0.001). One hundred and eighteen hours were saved in the administration of the accelerated infusions (17 160 min vs 10 080 min, P = 0.001). In the study population, overweight females [body mass index (BMI) > 25.00 kg/m²] were found to have statistically higher BMIs than overweight males (mean BMI 35.07 ± 2.66 kg/m²vs 30.08 ± 0.99 kg/m², P = 0.05), finding which is of significance since obesity was described as being one of the risk factors for Crohn’s disease.

CONCLUSION: We are the first US group to report substantial cost savings, increased safety and patient satisfaction associated with accelerated infliximab infusion.

• Infliximab
• Accelerated infusion
• Crohn’s disease
• Ulcerative colitis
• Obesity

• Adult
• Aged
• Antibodies, Monoclonal/therapeutic use
• Antibodies, Monoclonal, Humanized/therapeutic use
• Antirheumatic Agents/therapeutic use
• Arthritis, Rheumatoid/drug therapy
• Drug Therapy, Combination
• Female
• Humans
• Infliximab
• Male
• Middle Aged
• Retreatment
• Tacrolimus/therapeutic use
• Treatment Outcome

To characterize primary failure to infliximab and determine the efficacy of switching to tocilizumab in patients with rheumatoid arthritis (RA), we examined 24 RA patients who had started on infliximab therapy (3 mg/kg) as their first biological agent. Nine of the 24 patients were found to be primary nonresponders, defined as patients who had never achieved a 20% clinical improvement according to the American College of Rheumatology criteria (ACR20) during induction therapy. The remaining 15 patients had achieved an ACR20 response to infliximab, without any relapses, for at least the first 14 weeks. A higher baseline health assessment questionnaire score was markedly associated with primary unresponsiveness to infliximab (p = 0.0005). Six of the 9 primary nonresponders showed rapid clearance of infliximab: their trough concentrations of infliximab were under 1 μg/ml. The other 3 were classified as exhibiting the residual type of unresponsiveness, which was defined as unresponsiveness in patients who maintained serum infliximab levels above 1 μg/ml. Human antichimeric antibody was not detected in the rapid-clearance nonresponders. Dose escalation (5 mg/kg) was insufficiently effective. Primary nonresponders to infliximab were started on tocilizumab therapy (8 mg/kg, every 4 weeks), and their responses were assessed after 24 weeks of this second attempt at therapy. All the nonresponders, except for a single rapid-clearance patient, had achieved an ACR20 clinical improvement at the time of assessment. In conclusion, primary nonresponders to infliximab can be classified into rapid-clearance and residual types, based on their trough concentrations of infliximab, but both types of nonresponders seem to benefit from an early decision to discontinue infliximab therapy and switch to tocilizumab.

Adjustment of infliximab dosage for individuals may be useful in improving therapeutic response in rheumatoid arthritis (RA). Herein, we aimed to determine whether measurement of infliximab serum concentration modifies the therapeutic decision and improves the control of disease activity.

RA patients routinely treated with infliximab were included in an observational open-label study. On visit 1 (V1), according to the disease activity, a preliminary therapeutic decision was selected among four therapeutic options and a blood sample was collected to measure trough serum infliximab concentration. The final therapeutic decision, based on both disease activity and serum infliximab concentration assessed at V1, was applied at the following infusion (V2). Clinical and biological evaluations were performed at V3 and V4 and compared with those at V1.

We included 24 patients. The final therapeutic decision differed from the preliminary decision for 12 patients (50%). For patients with increased infliximab dosage at V2, mean disease activity score for 28 joints (DAS28) decreased by about 20% at V3 or V4 as compared with V1 (P < 0.05). Decreased DAS28 was correlated with increased serum infliximab concentration (P < 0.02).

The measurement of infliximab trough concentration modifies the therapeutic decision for RA patients and helps improve control of disease activity. Therapeutic drug monitoring of infliximab in RA may be useful for individual dosage adjustment.

• adalimumab
• antibodies
• certolizumab
• crohn’s disease
• infliximab
• monoclonal
• practice guideline

• Anti-Inflammatory Agents/adverse effects
• Anti-Inflammatory Agents/pharmacology
• Anti-Inflammatory Agents/therapeutic use
• Antibodies, Monoclonal/adverse effects
• Antibodies, Monoclonal/pharmacology
• Antibodies, Monoclonal/therapeutic use
• Crohn Disease/drug therapy
• Humans
• Infliximab
• Remission Induction/methods
• Severity of Illness Index
• Treatment Outcome
• Tumor Necrosis Factor-alpha/antagonists & inhibitors

• Antibodies, Monoclonal/pharmacokinetics
• Antibodies, Monoclonal/therapeutic use
• Arthritis, Rheumatoid/drug therapy
• Crohn Disease/drug therapy
• Humans
• Infliximab
• Pharmacokinetics
• Treatment Outcome
• Tumor Necrosis Factor-alpha/immunology