This phase 3, multicenter, randomized, double-blind, placebo-controlled trial assessed the efficacy and safety of 14 weeks of treatment with mirogabalin 15 mg BID for Chinese patients with DPNP. Mirogabalin elicited significant improvement vs. placebo in the primary endpoint (change from baseline in weekly ADPS at week 14). Results from the secondary endpoints generally supported the efficacy of mirogabalin, although not all improvements met the threshold of statistical significance. Mirogabalin was generally well tolerated, and no novel safety concerns were identified. The majority of TEAEs that occurred more frequently in the mirogabalin group were related to the central nervous system, weight gain, or edema, and are expected class effects of gabapentinoids [18, 23, 24]. TEAEs were mostly mild or moderate and few patients discontinued treatment because of a TEAE.

The ADPS, which was the primary efficacy endpoint in this study, was recommended to be used in clinical trials of neuropathic pain by the Japanese [25], European [26], and the mission of the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) [27] guidelines. Mirogabalin elicited a statistically significant improvement vs. placebo in the ADPS, but this was not reflected in some of the secondary efficacy endpoints, such as the ADPS responder rates and SF-MPQ VAS scores. These inconsistencies may be due to a high placebo response in the present Chinese study compared with a previous phase 3 trial of mirogabalin conducted elsewhere in Asia (primarily in Japan and Korea) [18], which had a similar study design and patient characteristics to the present trial. Both studies found that both placebo and mirogabalin elicited reductions in the weekly ADPS from baseline, but the baseline scores in the placebo group were higher in the present study (6.09 vs. 5.60). The numerically greater reduction in the weekly ADPS (placebo group) from baseline at week 14 in the present study (LS mean − 1.81 vs. − 1.31) may therefore suggest a strong placebo effect in the present study, although the 14-week ADPS values of the placebo groups were similar between studies: 4.30 (present study) vs. 4.26. These abovementioned inconsistencies between Chinese and other Asian populations regarding the placebo effect were also supported by previous studies of pregabalin [28, 29], with respect to both ADPS and SF-MPQ VAS scores. Additionally, both weekly ADPS and VAS scores continued to decrease throughout the treatment period. Both scores remained at consistently lower levels in the mirogabalin group compared with the placebo group soon after treatment initiation and throughout the treatment period. This suggests that mirogabalin has a stronger analgesic effect than placebo, and the difference is not random but corresponds to a pharmacological effect. It is important to note that in our study, the weekly ADPS was assessed using daily pain evaluations, whereas the VAS was evaluated at each study visit, looking back over the past week. Therefore, the ADPS is a more sensitive measure that is affected by daily pain changes, and the favorable ADPS results of our study support the effect of mirogabalin even if there was a contributing placebo effect, although it should also be noted that the ADPS relies on patients’ subjective interpretation of their symptoms. Importantly, in our study, the week 14 ADPS in the mirogabalin group decreased to < 4 (a change of − 2.19), whereas the score in the placebo group did not. Generally, ADPS ≥ 4 is defined as moderate pain, and it is stated that if the severity changes, changing the treatment is clinically meaningful [30]; thus, the reduction of the mean to the lower limit of moderate, ADPS = 4, is clinically meaningful although the difference in the effect size of mirogabalin vs. placebo was reduced due to the placebo effect.

Because there was a slight imbalance in baseline CrCL between treatment groups, with the placebo group having a higher percentage of patients with normal renal function than the mirogabalin group, we performed an additional analysis with adjustment by baseline CrCL as covariate, and a similar tendency was observed in ADPS change from baseline: LS mean difference (95% CI) vs. placebo was − 0.39 (− 0.74, − 0.04); p = 0.0276 (Table S2 in the electronic supplementary material). We found that the ADPS significantly improved with mirogabalin vs. placebo as in the primary analysis. This indicates that the imbalance in baseline CrCL had no influence on the overall greater improvements observed in the ADPS for mirogabalin vs. placebo.

The change from baseline in weekly ADPS was broadly comparable with that of previous studies of mirogabalin and pregabalin (600 mg/day). The LS mean weekly ADPS change from baseline at week 14 (mirogabalin group) in the present study was similar to those of a phase 3 study [18], a study of mirogabalin for postherpetic neuralgia (primarily in Japanese and Korean patients) [31], an 11-week Chinese trial of pregabalin for DPNP [28], and a 14-week Japanese trial of pregabalin for DPNP [29]. The SF-MPQ VAS score data from the present study were consistent with those of the two previous phase 3 Asian (primarily Japanese and Korean) studies of mirogabalin [18, 31]. Regarding the ADSIS, our results were also comparable with those reported for the two previous mirogabalin phase 3 studies for neuropathic pain [18, 31]. Taken together, these data indicate that mirogabalin is effective for treatment of DPNP in the Chinese patient population.

Neuropathic pain is intractable, and the goal of its treatment is not necessarily to eliminate the pain itself, but to reduce it as much as possible and improve activities of daily living and quality of life for patients [32]. Therefore, the EQ-5D-5L and the PGIC are important tools in the evaluation of treatments for neuropathic pain. The present study demonstrated that mirogabalin elicited tangible improvements in quality of life based on the favorable EQ-5D-5L and PGIC results, and such improvements were both statistically and clinically meaningful. With respect to the EQ-5D-5L results, the LS mean difference (95% CI) vs. placebo in EQ-5D-5L index value in a previous study of mirogabalin for central neuropathic pain secondary to spinal cord injury was 0.0287 (− 0.0009, 0.0583) [33] vs. 0.0291 (0.0068, 0.0514) in the present study. Regarding the EQ-5D-5L VAS score, the LS mean difference vs. placebo (95% CI) was 6.2 (2.0, 10.4) in the previous study of mirogabalin for central neuropathic pain [33] vs. 2.8 (0.1, 5.6) in the present study. Quality of life based on the EQ-5D-5L was not assessed in previous phase 3 studies for neuropathic pain [18, 31]; thus, this historical comparison was made with neuropathic pain of different etiologies, which should be noted in interpreting this comparison.

The present study’s PGIC results indicated that the percentage of patients who received mirogabalin and achieved a score of ≤ 3 (“minimally improved” or better) was numerically higher than in previous similar studies: 87.2 vs. 70.3% [18] and 69.0% [31]. Taken together, the above results suggest that mirogabalin not only effectively reduces pain, but also improves quality of life.

The safety results were broadly comparable with those of the previous phase 3 study for DPNP [18], with similar rates of somnolence, dizziness, peripheral edema, and weight gain in patients who received mirogabalin, which are expected class effects of gabapentinoids [24]. However, hyperuricemia as a TEAE was higher in both treatment groups, which was a different trend from the previous research [18]. A recent study reported a relatively high prevalence of hyperuricemia in China [34]. Risk factors for hyperuricemia reported in Chinese studies include high body mass index [35, 35, 36], hypertension [34], and dyslipidemia (high triglycerides, high total cholesterol, high low-density lipoprotein cholesterol, and low high-density lipoprotein cholesterol) [34]. Of the patients who developed hyperuricemia, 38.6% had a history of hyperuricemia or high baseline uric acid, which may explain the relatively high incidence of hyperuricemia in the present study. Notably, patients who developed hyperuricemia did not require any specific treatment or discontinuation/dose interruption of the study drug, most cases were mild and transient, and no severe or serious hyperuricemia TEAEs occurred. Furthermore, the events of hyperuricemia as ADRs were similar between the mirogabalin (n = 2, 1.0%) and placebo groups (n = 1, 0.5%). Thus, mirogabalin treatment raised no new safety concerns in our study, consistent with results from the previous Asian (primarily Japanese and Korean) phase 3 DPNP study [18]. Nevertheless, because hyperuricemia was more common in the mirogabalin group, further study is warranted to confirm whether there is an increased risk of hyperuricemia in Chinese patients with DPNP treated with mirogabalin.

The present study was limited to Chinese patients, so generalization to non-Asian populations may not be valid. Patients with impaired renal function (< 60 ml/min) were excluded, so the safety and efficacy of mirogabalin in Chinese patients with renal disease remains to be determined. The weekly ADPS decreased gradually throughout the study, and it is unclear whether the steady decrease would have continued past 14 weeks of treatment. The lack of efficacy in the secondary outcome measures may not be able to be fully explained by the placebo effect. Neurological examinations such as ankle jerk, vibratory sensation, pain sensation including hyperalgesia, allodynia, muscle strength (ankle dorsiflexion), and gait/station (observation of regular walking, heel-to-toe [tandem] walking, and the Romberg test, each assessed as normal or abnormal) were performed in this study during screening, but these were not performed to evaluate efficacy after study drug administration. Finally, long-term safety and efficacy data of mirogabalin remain to be collected in the Chinese DPNP patient population.