Randomized Crossover Comparison of Injection Site Pain with 40 mg/0.4 or 0.8 mL Formulations of Adalimumab in Patients with Rheumatoid Arthritis

Introduction Adalimumab, an anti-tumor necrosis factor antibody, is currently available in a 40 mg/0.8 mL formulation. The objective of this analysis was to evaluate injection site-related pain, safety, and tolerability of a 40 mg/0.4 mL formulation of adalimumab that had fewer excipients, a smaller volume, and a delivery presentation with a smaller gauge needle, versus the current 40 mg/0.8 mL formulation in patients with rheumatoid arthritis (RA). Methods Two identically designed, phase 2, randomized, single-blind, two-period crossover studies were conducted in Belgium and the Czech Republic (Study 1) and Australia, Canada, and Germany (Study 2). In both studies, adults with RA [biologic-naive or current users of 40 mg/0.8 mL adalimumab with an average injection site-related pain rating ≥3 cm on a visual analog scale (VAS; 0–10 cm)] were randomized to receive 40 mg/0.8 mL or 40 mg/0.4 mL adalimumab at visit 1. After 1–2 weeks (depending on patient medication schedule), patients received the other formulation at visit 2. A pain VAS [McGill Pain Questionnaire (MPQ-SF)] and the Draize scale were evaluated immediately after injection and 15 min postinjection. The primary endpoint was immediate pain after injection. Results 64 and 61 patients were randomized in Studies 1 and 2, respectively. Both studies found a clinically relevant and statistically significant lower immediate pain after injection for the 40 mg/0.4 mL versus the 40 mg/0.8 mL formulation. The mean difference on the VAS for the pooled data (−2.48 cm) was also clinically relevant. Most other endpoints in both studies favored the 40 mg/0.4 mL formulation, and its tolerability and safety profile were consistent with 40 mg/0.8 mL adalimumab. Conclusion A 40 mg/0.4 mL adalimumab formulation was well tolerated and associated with less injection site-related pain than the 40 mg/0.8 mL adalimumab formulation. Trial registration ClinicalTrials.gov identifier, NCT01561313 and NCT01502423. Funding AbbVie. Electronic supplementary material The online version of this article (doi:10.1007/s40744-016-0041-3) contains supplementary material, which is available to authorized users.

INTRODUCTION Adalimumab (Humira Ò ; AbbVie, North Chicago, IL, USA) is a fully human, highly specific, high-affinity anti-tumor necrosis factor a monoclonal antibody approved for the treatment of patients with rheumatoid arthritis (RA) as well as other immunemediated inflammatory diseases in over 90 countries worldwide [1][2][3].
Adalimumab is administered via subcutaneous injection. In placebo-controlled clinical trials in adult patients with RA, the most common adverse event (AE) with adalimumab was injection site reactions, including erythema and/ or itching, hemorrhage, related pain, and swelling [4][5][6][7][8]. The overall incidence of such reactions was 20.3% in patients who received adalimumab versus 13.8% who received placebo; these reactions are the most commonly reported AE across all indications [4].
Pain related to subcutaneous injection can be influenced by various factors, including the inactive ingredients of the formulation (e.g., citrate buffer) [9][10][11], injection volume [12,13], and needle size and sharpness [14]. A 40 mg/0.4 mL formulation of adalimumab was developed to address pain associated with injection. The active ingredient in both formulations remains adalimumab derived from the same master cell bank using identical isolation processes [15]. The 40 mg/0.4 mL formulation differs from the current formulation of adalimumab in that it has fewer excipients (Supplementary Table 1); particularly, there is no citrate buffer.
Further, the citrate-free formulation has a higher concentration of adalimumab that allows a smaller injection volume (40 mg adalimumab delivered in 0.4 mL instead of 0.8 mL), and the 40 mg/0.4 mL formulation is delivered via a syringe that has a smaller (29 vs 27 gauge) needle than the 40 mg/0.8 mL formulation.
This report details the results of two phase 2, randomized crossover studies in patients with RA that assessed injection site-related pain, safety, and tolerability of the 40 mg/0.4 mL adalimumab formulation versus the 40 mg/ 0.8 mL formulation.

Study Designs
Two phase 2, randomized, single-blind, twoperiod crossover studies of identical design were conducted (Fig. 1). Study

Statistical Methods
Based on a prior investigation, it was reasonable to assume a mean pain level of 3.00 and 2.00 cm on the 10-cm VAS for 40 mg/0.8 mL and 40 mg/ 0.4 mL formulations, respectively, with a standard deviation of 2.60 for the difference. From this assumption, it was estimated that a two-sided level a = 0.05 test for superiority with 83% power would require a total of 60 patients.
Injection site pain was analyzed in the crossover intent-to-treat population, defined as all patients who were randomized and completed both periods and received study drug in each period of the study. to the respective sequences of 40 mg/0.8 mL to 40 mg/0.4 mL and 40 mg/0.4 mL to 40 mg/ 0.8 mL formulation (Fig. 2). One randomized patient in each study discontinued before receiving the first dose of study drug; one patient in Study 1 discontinued (due to pharyngitis) after receipt of the first dose of study drug (Fig. 2).
Demographic and clinical characteristics at baseline within each study were similar between the sequence groups, with the exception of age and duration of RA in Study 1 ( Table 1).   ANOVA analysis of variance, cITT crossover intent-to-treat, RA rheumatoid arthritis, SD standard deviation a P\0.05 for difference between sequence groups using one-way ANOVA b Calculated as (date of first study drug-date of diagnosis of RA)/365.25 c P B 0.001 for difference between sequence groups using one-way ANOVA d Only for patients currently receiving adalimumab e Assessed on a 10-cm visual analog scale at screening (0 cm = no pain; 10 cm = worst possible pain)

Other Endpoints
Injection-related pain 15 min after injection was significantly lower for the 40 mg/0.4 mL versus the 40 mg/0.8 mL formulation in Study 2 but not in Study 1 (Table 3). For the pooled population, the mean difference in pain 15 min      AE adverse event a n = 62; one patient discontinued the study before receiving the 40 mg/0.4 mL formulation The MCID has been reported to range between 1.0 and 1.6 cm in settings of acute pain [19][20][21], and between 0.5 and 1.1 cm in observational studies of chronic pain in patients with RA [22].
Most other patient-reported endpoints were statistically significantly in favor of the 40 mg/ 0.4 mL formulation immediately after injection in Study 1 and at both time points after injection for Study 2. As observed for the primary and most other endpoints, differences between formulations were of larger magnitude