The analysis was performed in the subpopulation of participants in the phase III study who received concomitant α2δ Ca2+ channel ligands. The phase III study was conducted as a multicenter, randomized, placebo-controlled, double-blind, parallel-group study at 75 Japanese sites [13]. It was performed in compliance with the Declaration of Helsinki and Good Clinical Practice guidelines. The 75 participating institutions acquired approval of the protocol from one of the following institutional review boards: Shinagawa East One Medical Clinic Institutional Review Board; Sugiura Clinic Institutional Review Board; and Jimbo Orthopedics Institutional Review Board. Prior to enrollment, all participating patients provided written informed consent to participate in the study. The study was registered with the Japan Primary Registries Network (JPRN-JapicCTI-205134) and the Japan Registry for Clinical Trials (jRCT2080225040).

The phase III study was performed in Japanese patients aged 20 years or older who had been diagnosed with chronic low back pain and had been receiving pain control treatment with NSAIDs or acetaminophen for a minimum of 4 weeks. Patients were excluded if they had symptoms that may have affected the clinical assessment, e.g., radiating pain, numbness, or paralysis extending to the knees. After a 1-week wash-out period, patients underwent a 1-week single-blind placebo patch application (1-week placebo run-in period), after which placebo responders or patients with unstable pain status were excluded. Subsequently, eligible patients (e.g., those with a mean pain VAS score ≥ 40 mm in the 3 days immediately preceding enrollment in the double-blind treatment period) were enrolled in the 2-week double-blind treatment period. Patients were randomized in a 1:1:2 ratio to the 75-mg DF systemic patch group (one active drug patch, one placebo patch), 150-mg group (two active drug patches), or placebo group (two placebo patches). The efficacy and safety of the DF systemic patch (75 or 150 mg) were compared with that of the placebo.

With regard to pre-treatment and concomitant medications and therapies, treatment with α2δ Ca2+ channel ligands, SNRIs, and analgesic adjuncts (e.g., anxiolytics, muscle relaxants, tricyclic antidepressants) or with physiotherapy (e.g., heat therapy, traction therapy, lumbar braces) or alternative therapies (e.g., acupuncture, osteopathy) for low back pain was permitted provided that the dose was not modified and treatment was not initiated from at least 4 weeks prior to the wash-out period and throughout the study period (i.e., the wash-out period, placebo run-in period, and double-blind treatment period). However, pharmacologic treatments, such as opioids, vaccinia virus-inoculated rabbit inflammatory skin extract, and corticosteroids, and surgical treatments that may have affected pain assessment, e.g., lumbar trigger point injections and percutaneous electrical nerve stimulation, were not permitted during the study period.

A total of 538 patients with chronic low back pain were enrolled in the study and randomly allocated to the 75-mg group (n = 136), 150-mg group (n = 135), or placebo group (n = 267). At the end of each day throughout the study period (i.e., the wash-out period, placebo run-in period, and double-blind treatment period), patients rated the average degree of pain at the site of interest (lower back) by using a 100-mm VAS and recorded the value in a patient diary [13].

All 538 patients enrolled in the study were included in the efficacy and safety analysis [13]. In the overall population (full analysis set; FAS), 47 patients were taking concomitant α2δ Ca2+ channel ligands (pregabalin and mirogabalin) and were included in the present subpopulation analysis (75-mg group, n = 14 patients; 150-mg group, n = 11; and placebo group, n = 22).

In the FAS, 114 out of 538 patients took concomitant medications other than α2δ Ca2+ channel ligands for the treatment of chronic low back pain throughout the study period (i.e., the wash-out period, placebo run-in period, and double-blind treatment period). The concomitant medications included muscle relaxants (e.g., eperisone; 48 cases), prostaglandin E1 derivatives (43 cases), vitamin preparations (21 cases), SNRIs (16 cases), Chinese herbal preparations (five cases), and a prostaglandin I2 derivative (one case), whereby some patients took more than one concomitant medication.

The subpopulation analysis included patients in the FAS who were concomitantly treated with an α2δ Ca2+ channel ligand. Although this subpopulation analysis was pre-planned, it was positioned as an exploratory analysis. Tabulation of demographic and baseline characteristics and adverse events (AEs) of the subpopulation were performed post hoc. To evaluate efficacy, in each group (i.e., the 75-mg and 150-mg combination groups and placebo group) the results of the pain VAS scores were used to calculate the least square mean, standard error, and 95% confidence interval (CI) of the change from baseline (i.e., the start of the double-blind treatment period) in the mean 3-day pain VAS score after 2 weeks of treatment and the between-group difference in the least square means of the active treatment combination group (75-mg and 150-mg groups) relative to the placebo group and its 95% CI. The mean 3-day pain VAS score was calculated from the pain VAS scores on the 3 days immediately preceding each specified hospital visit (e.g., the mean 3-day pain VAS score at baseline was the mean of the pain VAS scores on the 3 days immediately preceding the start of the double-blind treatment period). In case of premature discontinuation of participants, the mean of the pain VAS scores on the 3 days immediately preceding the end of the wash-out period were used. SAS® version 9.4 was used for statistical analysis. The subpopulation analysis described in this article was performed for exploratory purposes, so no sample size was determined for the subpopulation analysis and no statistical comparisons were performed between groups.

The subpopulation safety analysis included patients in the safety analysis set (SAF; i.e., those who received the study drug) who were concomitantly treated with the α2δ Ca2+ channel ligand. The incidence rates of adverse events (AEs) and adverse drug reactions (ADRs; i.e., AEs for which a causal relationship could not be ruled out) were tabulated for each group in the subpopulation. Event names of AEs were coded with system organ classes and preferred terms according to the Medical Dictionary for Regulatory Activities version 23.1.