Efficacy and Safety of a New Sustained-release Pregabalin Formulation Compared With Immediate-release Pregabalin in Patients With Peripheral Neuropathic Pain: A Randomized Noninferiority Phase 3 Trial

Abstract

Objective: This study investigated whether a new sustained-release (SR) pregabalin formulation is noninferior to immediate-release (IR) pregabalin in alleviating peripheral neuropathic pain in Korean patients.

Materials and methods: This was a randomized, double-blind, active-controlled phase 3 study of patients with diabetic peripheral neuropathy or postherpetic neuralgia from 41 sites in South Korea in 2017-2018. Eligible patients were randomized (1:1) to receive once-daily SR pregabalin or twice-daily IR pregabalin (150 to 600 mg/d) in a double-dummy manner for 12 weeks according to a stratified permuted block randomization scheme. The primary endpoint was the Daily Pain Rating Scale score at the end of treatment, averaged from the last 7 available scores.

Results: A total of 319 of 371 (86.0%) randomized patients completed the 12-week treatment (SR pregabalin: n=154; IR pregabalin: n=165; per-protocol set: n=296). The least square mean difference between both groups for the primary endpoint was 0.06 (SE 0.19); (95% confidence interval -0.31 to 0.42), with the lower limit of the confidence interval above the pre-specified margin (-0.78; Pnoninferiority<0.0001). Drug-related treatment-emergent adverse events (TEAEs) were comparable between both groups. The incidence of drug-related TEAEs leading to treatment discontinuation was low (SR pregabalin: 2.7%; IR pregabalin: 1.1%). No serious drug-related TEAEs or deaths occurred.

Discussion: The results demonstrate that the new once-daily SR pregabalin formulation is noninferior to twice-daily IR pregabalin in reducing peripheral neuropathic pain and is well tolerated in Korean patients with diabetic peripheral neuropathy or postherpetic neuralgia after 12 weeks of treatment.

FIGURE 1

Study design. D indicates day; DPN, diabetic peripheral neuropathy; IR, immediate-release; PHN, postherpetic neuralgia; SR, sustained-release.

FIGURE 2

Patient disposition during the study period. FAS indicates full analysis set; IR, immediate-release; PPS, per-protocol set; SAF, safety analysis set; SR, sustained-release.

FIGURE 3

Difference in mean DPRS score at the end of treatment between SR pregabalin and IR pregabalin groups (per-protocol set). †Mixed-effects model for repeated measures included visit, baseline DPRS score (averaged from the last 7 available DPRS scores during the placebo run-in period), stratification factor (diabetic peripheral neuropathy and postherpetic neuralgia), and treatment group as fixed effects, as well as visit-by-baseline score interaction and visit-by-treatment group interaction. CI indicates confidence interval; DPRS, Daily Pain Rating Scale; IR, immediate-release; LS, least square; NI, noninferiority; SR, sustained-release.

FIGURE 4

A, Change from baseline in mean DPRS score at each visit (per-protocol set). Points represent LS mean values; error bars represent SE. †Mixed-effects model for repeated measures included visit, baseline DPRS score (averaged from the last 7 available DPRS scores during the placebo run-in period), stratification factor (diabetic peripheral neuropathy and postherpetic neuralgia), and treatment group as fixed effects, as well as visit-by-baseline score interaction and visit-by-treatment group interaction. B, Proportion of responders† each visit (per-protocol set). †Defined as having ≥30% reduction in mean DPRS score from baseline. DPRS indicates Daily Pain Rating Scale; IR, immediate-release; LS, least square; SR, sustained-release.