OBJECTIVE

We aimed to identify doses of mirogabalin (DS-5565) providing clinically meaningful efficacy with manageable side effects for treatment of diabetic peripheral neuropathic pain (DPNP).

RESEARCH DESIGN AND METHODS

Adults (≥18 years) with type 1 or 2 diabetes, HbA1c ≤10% at screening, and DPNP for ≥6 months were eligible for study participation. Subjects (n = 452) were randomized (2:1:1:1:1:1:1 ratio) to placebo, dose-ranging mirogabalin (5, 10, 15, 20, and 30 mg/day), or pregabalin (300 mg/day) for 5 weeks. The primary end point was weekly change in average daily pain score (ADPS; 0 to 10 numeric rating scale) from baseline to week 5 (minimally meaningful effect, ≥1.0-point decrease versus placebo). ANCOVA was conducted using last observation carried forward, and treatment effect least squares (LS) means were provided for each contrast. Safety assessments included adverse events (AEs), clinical laboratory tests, and electrocardiograms.

RESULTS

LS mean differences in change in ADPS from baseline to week 5 versus placebo were –0.22, –0.53, –0.94, –0.88, and –1.01 for the mirogabalin 5-, 10-, 15-, 20-, and 30-mg/day treatment groups, respectively, and –0.05 in the pregabalin group (P < 0.05 versus placebo for mirogabalin 15, 20, and 30 mg/day). Most frequent AEs (n = 277) were primarily mild to moderate dizziness (9.4%), somnolence (6.1%), and headache (6.1%); otherwise, mirogabalin was well tolerated.

CONCLUSIONS

Mirogabalin 15, 20, and 30 mg/day had statistically significant reductions in ADPS versus placebo, and mirogabalin 30 mg/day also met the criteria of minimally meaningful effect. Mirogabalin may be a promising new treatment option for patients with DPNP.

Diabetic peripheral neuropathic pain (DPNP), a common complication of diabetes, affects up to 50% of patients with diabetic neuropathy (1). DPNP contributes to depression, anxiety, and sleep disorders, which may profoundly impact well-being and quality of life (2,3). Mechanisms underlying DPNP are multifactorial; however, voltage-dependent Ca2+ channels appear to play a central role and represent a key target for pharmacologic intervention (4,5). Voltage-dependent calcium channels are composed of a central pore-forming α1 subunit, a disulfide-linked glycoprotein dimer of α2- and δ-subunits (α2δ), an intracellular β-subunit, and a transmembrane glycoprotein γ-subunit (in some Ca2+-channel types) (6). Ligands for the α2δ-subunit (α2δ-1 and α2δ-2) are thought to exert analgesic effects by reducing Ca2+ influx into neurons throughout the central nervous system (CNS) via a mechanism not yet fully elucidated (4). It is hypothesized that a reduction in Ca2+ influx decreases release of excitatory neurotransmitters such as glutamate, norepinephrine, and substance P, which have been implicated in animal models of induced neuropathic pain (4,79). Recent studies suggest that ligand selectivity for α2δ-1 and α2δ-2 may result in different clinical outcomes. Binding to α2δ-1 appears to contribute to analgesic effects (10,11), whereas binding to α2δ-2 appears to contribute to CNS side effects (10,12).

Nonselective α2δ ligands, gabapentin and pregabalin (13), are first-line treatments for DPNP (14,15); however, of these, only pregabalin is approved by the U.S. Food and Drug Administration for treatment of DPNP (14,16). For many patients with DPNP, pain relief is inadequate and therapy is poorly tolerated (4). Response rates to analgesic monotherapy are only ∼50%, and since efficacy wanes, dose escalation and combination pharmacotherapy are common (2,16). Consequently, there is still a clear unmet need for more effective and better-tolerated treatment options for patients with DPNP.

Mirogabalin (DS-5565; Daiichi Sankyo Co., Ltd., Tokyo, Japan) is a novel, preferentially selective α2δ-1 ligand characterized by high potency and selectivity to the α2δ-1 subunit of voltage-sensitive calcium-channel complexes in the CNS. In vitro experiments using membrane preparations from human and rat α2δ subunit–expressed cells showed that mirogabalin had a slower dissociation rate from α2δ-1 than α2δ-2, in particular, α2δ-1 compared with pregabalin (10). Additionally, mirogabalin showed potent, sustained analgesic effects in streptozotocin-induced diabetic rats with induced pain, and the superior analgesic effects and wider CNS safety margin relative to pregabalin were attributed to its selectivity for and slow dissociation from α2δ-1 compared with pregabalin (10).

Mirogabalin is being developed worldwide as a preferentially selective α2δ-1 ligand intended for the treatment of neuropathic pain. We present efficacy and safety data for mirogabalin from a phase 2, randomized, double-blind, placebo- and active comparator–controlled study with an adaptive trial design conducted in patients with DPNP.

The study was conducted between 28 November 2011 and 7 September 2012 at 80 U.S. sites (ClinicalTrials.gov identifier NCT01496365) (Fig. 1) (for a list of principal investigators, see Supplementary Data). All participating clinical sites received institutional review board approval of the study protocol and study-related documents prior to enrollment, and all subjects provided written informed consent. Details of the adaptive trial design are outlined in Supplementary Data.

Figure 1

Study design.

Figure 1

Study design.

Adults (≥18 years) with type 1 or 2 diabetes and HbA1c ≤10% at screening and on a stable antidiabetic medication regimen for ≥30 days were eligible for study participation. Subjects must have had painful distal symmetric sensorimotor polyneuropathy (17) for ≥6 months based on neurologic history and/or medical examination. Diagnosis included absent or reduced deep tendon reflexes at both ankles. A pain score ≥40 mm on the Short-Form McGill Pain Questionnaire (SF-MPQ) visual analog scale (VAS) at screening and randomization (18) and average daily pain score (ADPS) ≥4 based on the 11-point numeric rating scale (NRS; calculated from a minimum of four pain ratings in daily diary entries during the baseline period) at randomization were required. Additional eligibility criteria included creatinine clearance ≥60 mL/min, stable concomitant medications during the study period, and adequate contraception in women of child-bearing potential during treatment and for 4 weeks after study completion.

Exclusion criteria included diagnosis of mononeuropathy, major psychiatric disorders, and known hypersensitivity to pregabalin or gabapentin. Subjects with prior therapeutic failure of pregabalin or gabapentin (considered unresponsive or intolerant to treatment) were excluded; therapeutic failure implied lack of efficacy following full titration to effective doses (e.g., up to 300 mg/day for pregabalin).

Subjects who fulfilled eligibility criteria during the screening period (up to 3 weeks) discontinued analgesic and antidepressant medications (excepting stable doses of selective serotonin-reuptake inhibitors). Duration of the washout period varied according to type of medication(s). Subjects recorded pain scores in a daily diary each morning to assess baseline pain criteria.

The study was designed to identify a dose (or doses) of mirogabalin with meaningful clinical efficacy and manageable side effects for the treatment of DPNP. The 5-week duration of this adaptive study was based on an analysis of seven randomized, placebo-controlled DPNP trials, which showed that 5 weeks was sufficient to detect a statistically meaningful difference in ADPS between pregabalin 300 mg/day and placebo (19). In the 5-week double-blind treatment phase, subjects who met baseline pain criteria were randomly assigned (2:1:1:1:1:1:1) to one of seven treatment groups: placebo, mirogabalin 5 mg/day (once daily at bedtime), mirogabalin 10 mg/day (once daily at bedtime), mirogabalin 15 mg/day (once daily at bedtime), mirogabalin 20 mg/day (10 mg twice daily, in the morning and at bedtime), mirogabalin 30 mg/day (15 mg twice daily, in the morning and at bedtime), or pregabalin 300 mg/day (150 mg twice daily, in the morning and at bedtime). Titration details are described in Fig. 1. No titration was used in mirogabalin 5-, 10-, 15-, and 20-mg/day dosing arms to assess quicker pain relief (20).

The primary efficacy end point was to compare the change in ADPS from baseline to end point (week 5) for mirogabalin versus placebo. ADPS was based on the 11-point NRS (0 [no pain] to 10 [worst possible pain]). Every morning, prior to taking study medication, each subject circled the number best describing his/her pain over the past 24 h. Scores were averaged from the last seven on-treatment entries in subjects’ daily diaries. A minimally meaningful effect was defined as a decrease of at least one point versus placebo on the NRS scale (21).

Secondary efficacy end points included characterizing the dose response of mirogabalin on change from baseline in ADPS; assessing the incidence of responders, by treatment group, defined as the proportion of subjects achieving ≥30 or ≥50% reduction from baseline in ADPS; comparing the effects of mirogabalin versus pregabalin 300 mg/day based on change from baseline in ADPS and responder rate (22); assessing time to meaningful pain relief, defined as number of days from randomization until first pain score that represented a ≥30% decrease from baseline for subjects with a ≥30% decrease in end point ADPS (exploratory analysis); and characterizing the safety and tolerability of mirogabalin based on the overall incidence of adverse events (AEs), AEs of special interest, discontinuations due to AEs, and findings from physical examinations, electrocardiograms (ECGs), and other safety assessments.

Safety assessments, performed at each clinic visit and 1 week after end of treatment, included analysis of AEs, serious AEs (SAEs), and AEs of specific interest among the treatment groups. Additionally, physical examinations, vital signs, neurologic assessments, clinical chemistry, hematology, urinalysis tests, and 12-lead ECGs were conducted at prespecified time points throughout the study.

Statistical Analyses

SAS (version 9.2 or higher) was used to produce all summary tables, figures, and data listings. Unless otherwise specified, analyses were two-sided and performed at the 0.05 level. The full analysis set was defined as all randomized subjects who received ≥1 dose of study medication and had ≥1 postrandomization pain rating, in addition to a baseline value. The per-protocol analysis set, which was used for supportive analyses of the primary parameter, was defined as all subjects who received ≥1 dose of study medication and were sufficiently compliant with the protocol. The safety analysis set included all subjects who received ≥1 dose of study medication.

For the primary analysis, ANCOVA was conducted on the full analysis set, with treatment arm as the factor and baseline ADPS as covariate, to assess if there was an overall treatment difference in end point ADPS (week 5 with last observation carried forward [LOCF]). This was followed by ANCOVA contrasts of mean change from baseline in end point ADPS for each mirogabalin treatment arm with placebo and, for the pregabalin arm with placebo, with P values, corresponding 95% CIs, and treatment effect least squares (LS) means provided for each contrast. Numeric mean changes from baseline in ADPS for each mirogabalin arm were also compared with the numeric mean change from baseline for the pregabalin arm. A baseline observation carried forward (BOCF) method was used for imputation in a sensitivity analysis using ANCOVA.

Assuming a common SD of 2.1 ADPS units and a type 1 error of 0.05, a sample size of 400 subjects would provide 77% statistical power to detect a treatment difference of 1.0 ADPS unit (using change from baseline to week 5 with LOCF) for a mirogabalin treatment arm versus placebo.

Pearson correlation coefficients were computed by treatment group to assess the relationship between VAS and ADPS.

Disposition

A total of 913 subjects were screened, and 452 were randomly assigned to double-blind treatment (Supplementary Fig. 3). Eighty-five percent (383 of 452) of subjects completed the study. Rates of discontinuation were 13.4% in the placebo group; 10.5, 7, 22.8, 17.9, and 10.5% in the mirogabalin 5-, 10-, 15-, 20-, and 30-mg/day treatment groups, respectively; and 26.8% in the pregabalin group. Reasons for discontinuation included AEs (n = 25), withdrawal by subject (n = 19), protocol violation (n = 5), loss to follow-up (n = 3), lack of efficacy (n = 2), and other reasons (n = 15).

Subject Demographics and Baseline Characteristics

Subjects were mostly white (75%), with slightly more men (53.5%) than women (46.5%), and a mean (±SD) age of 60.1 (±9.26) years (Table 1). Most (91.8%) subjects had type 2 diabetes, with a mean HbA1c of 7.4% at baseline and BMI typical of an adult population with diabetes (∼34 kg/m2).

Table 1

Demographics and disease characteristics at baseline (all randomized population)

ParameterPlacebo
(n = 112)Pregabalina
300 mg/day
(n = 56)Mirogabalin
All dose groups
(N = 452)
5 mg/dayb
(n = 57)10 mg/dayb
(n = 57)15 mg/dayb
(n = 57)20 mg/dayc
(n = 56)30 mg/dayd
(n = 57)
Age, years, mean (SD) 60.2 (9.57) 59.5 (9.40) 58.9 (9.85) 60.9 (9.92) 61.4 (8.70) 60.4 (8.59) 59.3 (8.54) 60.1 (9.26) 
Sex, n (%)         
 Male 56 (50.0) 32 (57.1) 27 (47.4) 29 (50.9) 34 (59.6) 32 (57.1) 32 (56.1) 242 (53.5) 
 Female 56 (50.0) 24 (42.9) 30 (52.6) 28 (49.1) 23 (40.4) 24 (42.9) 25 (43.9) 210 (46.5) 
Height, cm, mean (SD) 169.7 (9.89) 171.6 (10.01) 169.3 (10.79) 170.7 (10.25) 173.0 (9.47) 170.5 (10.03) 171.2 (9.60) 170.7 (10.00) 
Weight, kg, mean (SD) 96.2 (19.87) 98.9 (24.87) 97.3 (23.85) 101.9 (22.46) 106.6 (21.70) 103.4 (21.27) 101.5 (20.13) 100.2 (21.96) 
BMI, kg/m2, mean (SD) 33.4 (6.94) 33.5 (7.62) 33.9 (7.68) 34.9 (6.85) 35.8 (7.67) 35.5 (6.87) 34.7 (6.82) 34.4 (7.19) 
Ethnicity, n (%)         
 Hispanic or Latino 18 (16.1) 4 (7.1) 12 (21.1) 12 (21.1) 6 (10.5) 10 (17.9) 10 (17.5) 72 (15.9) 
 Not Hispanic or Latino 94 (83.9) 52 (92.9) 45 (78.9) 45 (78.9) 51 (89.5) 46 (82.1) 47 (82.5) 380 (84.1) 
Race, n (%)         
 American Indian or Alaska Native 1 (0.9) 0 (0.0) 0 (0.0) 1 (1.8) 0 (0.0) 0 (0.0) 0 (0.0) 2 (0.4) 
 Black or African American 27 (24.1) 17 (30.4) 11 (19.3) 9 (15.8) 12 (21.1) 10 (17.9) 8 (14.0) 94 (20.8) 
 Native Hawaiian or Other Pacific Islander 0 (0.0) 2 (3.6) 0 (0.0) 0 (0.0) 0 (0.0) 1 (1.8) 1 (1.8) 4 (0.9) 
 Asian 3 (2.7) 1 (1.8) 0 (0.0) 4 (7.0) 1 (1.8) 1 (1.8) 1 (1.8) 11 (2.4) 
 White 81 (72.3) 36 (64.3) 45 (78.9) 43 (75.4) 44 (77.2) 44 (78.6) 46 (80.7) 339 (75.0) 
 Other 0 (0.0) 0 (0.0) 1 (1.8) 0 (0.0) 0 (0.0) 0 (0.0) 1 (1.8) 2 (0.4) 
HbA1c, %, mean (SD) 7.3 (1.25) 7.5 (1.46) 7.1 (1.23) 7.4 (1.20) 7.5 (1.07) 7.4 (1.19) 7.6 (1.21) 7.4 (1.24) 
Type of diabetes, n (%)         
 Type 1 13 (11.6) 1 (1.8) 4 (7.0) 6 (10.5) 6 (10.5) 2 (3.6) 5 (8.8) 37 (8.2) 
 Type 2 99 (88.4) 55 (98.2) 53 (93.0) 51 (89.5) 51 (89.5) 54 (96.4) 52 (91.2) 415 (91.8) 
Duration of DPNP, years, mean (SD) 5.9 (4.61) 5.7 (5.00) 4.8 (4.05) 4.9 (4.40) 7.7 (6.40) 5.3 (4.39) 6.1 (5.26) 5.8 (4.93) 
ParameterPlacebo
(n = 112)Pregabalina
300 mg/day
(n = 56)Mirogabalin
All dose groups
(N = 452)
5 mg/dayb
(n = 57)10 mg/dayb
(n = 57)15 mg/dayb
(n = 57)20 mg/dayc
(n = 56)30 mg/dayd
(n = 57)
Age, years, mean (SD) 60.2 (9.57) 59.5 (9.40) 58.9 (9.85) 60.9 (9.92) 61.4 (8.70) 60.4 (8.59) 59.3 (8.54) 60.1 (9.26) 
Sex, n (%)         
 Male 56 (50.0) 32 (57.1) 27 (47.4) 29 (50.9) 34 (59.6) 32 (57.1) 32 (56.1) 242 (53.5) 
 Female 56 (50.0) 24 (42.9) 30 (52.6) 28 (49.1) 23 (40.4) 24 (42.9) 25 (43.9) 210 (46.5) 
Height, cm, mean (SD) 169.7 (9.89) 171.6 (10.01) 169.3 (10.79) 170.7 (10.25) 173.0 (9.47) 170.5 (10.03) 171.2 (9.60) 170.7 (10.00) 
Weight, kg, mean (SD) 96.2 (19.87) 98.9 (24.87) 97.3 (23.85) 101.9 (22.46) 106.6 (21.70) 103.4 (21.27) 101.5 (20.13) 100.2 (21.96) 
BMI, kg/m2, mean (SD) 33.4 (6.94) 33.5 (7.62) 33.9 (7.68) 34.9 (6.85) 35.8 (7.67) 35.5 (6.87) 34.7 (6.82) 34.4 (7.19) 
Ethnicity, n (%)         
 Hispanic or Latino 18 (16.1) 4 (7.1) 12 (21.1) 12 (21.1) 6 (10.5) 10 (17.9) 10 (17.5) 72 (15.9) 
 Not Hispanic or Latino 94 (83.9) 52 (92.9) 45 (78.9) 45 (78.9) 51 (89.5) 46 (82.1) 47 (82.5) 380 (84.1) 
Race, n (%)         
 American Indian or Alaska Native 1 (0.9) 0 (0.0) 0 (0.0) 1 (1.8) 0 (0.0) 0 (0.0) 0 (0.0) 2 (0.4) 
 Black or African American 27 (24.1) 17 (30.4) 11 (19.3) 9 (15.8) 12 (21.1) 10 (17.9) 8 (14.0) 94 (20.8) 
 Native Hawaiian or Other Pacific Islander 0 (0.0) 2 (3.6) 0 (0.0) 0 (0.0) 0 (0.0) 1 (1.8) 1 (1.8) 4 (0.9) 
 Asian 3 (2.7) 1 (1.8) 0 (0.0) 4 (7.0) 1 (1.8) 1 (1.8) 1 (1.8) 11 (2.4) 
 White 81 (72.3) 36 (64.3) 45 (78.9) 43 (75.4) 44 (77.2) 44 (78.6) 46 (80.7) 339 (75.0) 
 Other 0 (0.0) 0 (0.0) 1 (1.8) 0 (0.0) 0 (0.0) 0 (0.0) 1 (1.8) 2 (0.4) 
HbA1c, %, mean (SD) 7.3 (1.25) 7.5 (1.46) 7.1 (1.23) 7.4 (1.20) 7.5 (1.07) 7.4 (1.19) 7.6 (1.21) 7.4 (1.24) 
Type of diabetes, n (%)         
 Type 1 13 (11.6) 1 (1.8) 4 (7.0) 6 (10.5) 6 (10.5) 2 (3.6) 5 (8.8) 37 (8.2) 
 Type 2 99 (88.4) 55 (98.2) 53 (93.0) 51 (89.5) 51 (89.5) 54 (96.4) 52 (91.2) 415 (91.8) 
Duration of DPNP, years, mean (SD) 5.9 (4.61) 5.7 (5.00) 4.8 (4.05) 4.9 (4.40) 7.7 (6.40) 5.3 (4.39) 6.1 (5.26) 5.8 (4.93) 

a150 mg twice daily.

bOnce-daily dosing.

c10 mg twice daily.

d15 mg twice daily.

Mean duration of DPNP was 5.8 years across all treatment arms (range, 4.8 to 7.7 years). Gabapentin was previously used by 31.3% of placebo recipients, 24.6% of mirogabalin recipients (all treatment arms combined), and 17.9% of pregabalin recipients. Previous pregabalin use was 4.5, 5.6, and 12.5%, respectively.

Efficacy

A total of 433 subjects were included in the full analysis set, providing at least 80% of statistical power. At baseline, mean ADPS was 7.0 in the placebo arm, 6.7 across all five mirogabalin treatment arms, and 6.6 in the pregabalin arm. This indicates that pain was classified in all treatment groups similarly as moderate/severe (i.e., ADPS ≥4) according to the NRS or Likert scale (22).

Mean changes in ADPS from baseline to week 5 were –1.9 in the placebo group; –2.0, –2.3, –2.7, –2.6, and –2.8 in the mirogabalin 5-, 10-, 15-, 20-, and 30-mg/day treatment groups, respectively; and –1.8 in the pregabalin group (Supplementary Table 4). In subjects receiving mirogabalin, LS mean differences in change in ADPS from baseline to week 5 versus placebo were –0.22, –0.53, –0.94, –0.88, and –1.01 for the mirogabalin 5-, 10-, 15-, 20-, and 30-mg/day treatment groups, respectively, and –0.05 for pregabalin 300 mg/day. These differences were statistically significant (P < 0.05) versus placebo at the mirogabalin 15-, 20-, and 30-mg/day dose levels (Fig. 2A). These changes began at week 1 and continued through week 5 (P < 0.05). The LS mean differences for pregabalin 300 mg/day were statistically significant versus placebo group at weeks 1 and 2 (P < 0.05) but not at weeks 3, 4, or 5 (P = NS).

Figure 2

Mean change from baseline in ADPS by week and treatment group (full analysis set) (A) and proportion of patients with ≥30 and ≥50% reductions in ADPS at week 5 compared with baseline (LOCF) (B). LS mean differences in change in ADPS from baseline to week 5 versus placebo were –0.22, –0.53, –0.94, –0.88, and –1.01 for the mirogabalin 5-, 10-, 15-, 20-, and 30-mg/day treatment groups, respectively. These differences were statistically significant (P < 0.05) versus placebo at the mirogabalin 15-, 20-, and 30-mg/day dose levels, beginning at week 1 and continuing through week 5 (P < 0.05). The LS mean differences for pregabalin 300 mg/day were statistically significant versus placebo group at weeks 1 and 2 (P < 0.05) but not at weeks 3, 4, or 5 (P = NS).

Figure 2

Mean change from baseline in ADPS by week and treatment group (full analysis set) (A) and proportion of patients with ≥30 and ≥50% reductions in ADPS at week 5 compared with baseline (LOCF) (B). LS mean differences in change in ADPS from baseline to week 5 versus placebo were –0.22, –0.53, –0.94, –0.88, and –1.01 for the mirogabalin 5-, 10-, 15-, 20-, and 30-mg/day treatment groups, respectively. These differences were statistically significant (P < 0.05) versus placebo at the mirogabalin 15-, 20-, and 30-mg/day dose levels, beginning at week 1 and continuing through week 5 (P < 0.05). The LS mean differences for pregabalin 300 mg/day were statistically significant versus placebo group at weeks 1 and 2 (P < 0.05) but not at weeks 3, 4, or 5 (P = NS).

LS mean differences in change in ADPS from baseline to week 5 versus pregabalin 300 mg/day were –0.17, –0.47, –0.89, –0.83, and –0.96 for the mirogabalin 5-, 10-, 15-, 20-, and 30-mg/day treatment groups, respectively. These differences were statistically significant (P < 0.05) versus the pregabalin 300-mg/day group at the 15- and 30-mg/day dose levels.

Results of the sensitivity analysis (BOCF) were generally similar to that of the primary analysis (LOCF) except that the mirogabalin 10-mg/day group was significantly different versus placebo whereas the mirogabalin 20-mg/day group was not. LS mean differences in change in ADPS from baseline to week 5 versus placebo were –0.53, –0.93, –0.98, –0.58, and –1.18 for the mirogabalin 5-, 10-, 15-, 20-, and 30-mg/day treatment groups, respectively. These differences were statistically significant (P < 0.05) versus placebo at the 10-, 15-, and 30-mg/day dose levels.

The proportion of responders, defined as subjects who achieved ≥30 or ≥50% reduction in ADPS from baseline to week 5, are shown by treatment group in Fig. 2B. Fifty-six to 67% of subjects achieved ≥30% reduction in ADPS in the top four mirogabalin treatment arms (i.e., 10, 15, 20, and 30 mg/day); 39–44% of subjects achieved ≥50% reduction in ADPS in the top three mirogabalin treatment arms (i.e., 15, 20, and 30 mg/day); and 23% of subjects achieved ≥75% reduction in ADPS in the mirogabalin 30-mg/day group (data not shown). There was a positive correlation between VAS and ADPS from randomization (Supplementary Fig. 5) to week 5 (LOCF), with r values ranging from 0.792 to 0.859 in all treatment groups at week 5.

Median time to meaningful pain relief was 30, 16, 20, and 16 days in the mirogabalin 10-, 15-, 20-, and 30-mg/day groups, compared with 36 days in the placebo group (P < 0.05 for all comparisons). Median values could not be calculated for the mirogabalin 5-mg/day or pregabalin 300-mg/day groups because >50% of the subjects in each group did not achieve ≥30% pain reduction from baseline. When meaningful pain relief was defined in terms of a ≥50% responder rate, the mirogabalin 15-, 20-, and 30-mg/day groups continued to demonstrate a shorter time to pain relief than the placebo group (P < 0.05 for all comparisons).

Safety and Tolerability

A total of 435 subjects were included in the safety analysis. AEs occurring in ≥5% of subjects in any treatment group are shown in Table 2. Most AEs were mild. Headache was the only severe AE that was reported in >1 subject (one in the mirogabalin 5-mg/day group and one in the mirogabalin 20-mg/day group).

Table 2

Most frequent AEs (>5%) by system organ class and preferred term

System organ class, preferred term, n (%)Placebo
(n = 108)Pregabalin
300 mg/daya
(n = 50)Mirogabalin
5 mg/dayb
(n = 55)10 mg/dayb
(n = 56)15 mg/dayb
(n = 53)20 mg/dayc
(n = 56)30 mg/dayd
(n = 57)All
(n = 277)
Number of AEs 117 69 64 80 110 89 88 431 
Nervous system disorders 8 (7.4) 11 (22.0) 9 (16.4) 11 (19.6) 12 (22.6) 19 (33.9) 21 (36.8) 72 (26.0) 
 Dizziness 2 (1.9) 3 (6.0) 0 (0.0) 7 (12.5) 6 (11.3) 4 (7.1) 9 (15.8) 26 (9.4) 
 Headache 4 (3.7) 2 (4.0) 6 (10.9) 4 (7.1) 1 (1.9) 5 (8.9) 1 (1.8) 17 (6.1) 
 Somnolence 1 (0.9) 4 (8.0) 1 (1.8) 1 (1.8) 3 (5.7) 5 (8.9) 7 (12.3) 17 (6.1) 
 Balance disorder 0 (0.0) 2 (4.0) 0 (0.0) 0 (0.0) 1 (1.9) 3 (5.4) 3 (5.3) 7 (2.5) 
Gastrointestinal disorders 10 (9.3) 5 (10.0) 7 (12.7) 11 (19.6) 9 (17.0) 6 (10.7) 5 (8.8) 38 (13.7) 
 Constipation 2 (1.9) 1 (2.0) 1 (1.8) 5 (8.9) 2 (3.8) 1 (1.8) 3 (5.3) 12 (4.3) 
 Nausea 2 (1.9) 1 (2.0) 2 (3.6) 4 (7.1) 2 (3.8) 2 (3.6) 1 (1.8) 11 (4.0) 
 Diarrhea 3 (2.8) 0 (0.0) 3 (5.5) 3 (5.4) 1 (1.9) 1 (1.8) 0 (0.0) 8 (2.9) 
 Vomiting 4 (3.7) 0 (0.0) 1 (1.8) 3 (5.4) 2 (3.8) 1 (1.8) 1 (1.8) 8 (2.9) 
General disorders and administration site conditions 12 (11.1) 8 (16.0) 3 (5.5) 5 (8.9) 12 (22.6) 6 (10.7) 10 (17.5) 36 (13.0) 
 Edema peripheral 1 (0.9) 4 (8.0) 2 (3.6) 4 (7.1) 2 (3.8) 3 (5.4) 2 (3.5) 13 (4.7) 
 Fatigue 2 (1.9) 2 (4.0) 0 (0.0) 2 (3.6) 4 (7.5) 2 (3.6) 2 (3.5) 10 (3.6) 
Investigations 10 (9.3) 5 (10.0) 4 (7.3) 6 (10.7) 5 (9.4) 8 (14.3) 5 (8.8) 28 (10.1) 
 Weight increased 1 (0.9) 0 (0.0) 0 (0.0) 1 (1.8) 0 (0.0) 3 (5.4) 1 (1.8) 5 (1.8) 
Infections and infestations 8 (7.4) 6 (12.0) 2 (3.6) 7 (12.5) 5 (9.4) 8 (14.3) 5 (8.8) 27 (9.7) 
 Urinary tract infection 5 (4.6) 4 (8.0) 2 (3.6) 2 (3.6) 0 (0.0) 4 (7.1) 0 (0.0) 8 (2.9) 
Metabolism and nutrition disorders 6 (5.6) 3 (6.0) 3 (5.5) 3 (5.4) 4 (7.5) 3 (5.4) 2 (3.5) 15 (5.4) 
 Hyperglycemia 1 (0.9) 0 (0.0) 0 (0.0) 3 (5.4) 2 (3.8) 0 (0.0) 1 (1.8) 6 (2.2) 
Injury, poisoning, and procedural complicationse 8 (7.4) 3 (6.0) 2 (3.6) 5 (8.9) 1 (1.9) 2 (3.6) 2 (3.5) 12 (4.3) 
 Fall 1 (0.9) 1 (2.0) 1 (1.8) 3 (5.4) 0 (0.0) 0 (0.0) 0 (0.0) 4 (1.4) 
System organ class, preferred term, n (%)Placebo
(n = 108)Pregabalin
300 mg/daya
(n = 50)Mirogabalin
5 mg/dayb
(n = 55)10 mg/dayb
(n = 56)15 mg/dayb
(n = 53)20 mg/dayc
(n = 56)30 mg/dayd
(n = 57)All
(n = 277)
Number of AEs 117 69 64 80 110 89 88 431 
Nervous system disorders 8 (7.4) 11 (22.0) 9 (16.4) 11 (19.6) 12 (22.6) 19 (33.9) 21 (36.8) 72 (26.0) 
 Dizziness 2 (1.9) 3 (6.0) 0 (0.0) 7 (12.5) 6 (11.3) 4 (7.1) 9 (15.8) 26 (9.4) 
 Headache 4 (3.7) 2 (4.0) 6 (10.9) 4 (7.1) 1 (1.9) 5 (8.9) 1 (1.8) 17 (6.1) 
 Somnolence 1 (0.9) 4 (8.0) 1 (1.8) 1 (1.8) 3 (5.7) 5 (8.9) 7 (12.3) 17 (6.1) 
 Balance disorder 0 (0.0) 2 (4.0) 0 (0.0) 0 (0.0) 1 (1.9) 3 (5.4) 3 (5.3) 7 (2.5) 
Gastrointestinal disorders 10 (9.3) 5 (10.0) 7 (12.7) 11 (19.6) 9 (17.0) 6 (10.7) 5 (8.8) 38 (13.7) 
 Constipation 2 (1.9) 1 (2.0) 1 (1.8) 5 (8.9) 2 (3.8) 1 (1.8) 3 (5.3) 12 (4.3) 
 Nausea 2 (1.9) 1 (2.0) 2 (3.6) 4 (7.1) 2 (3.8) 2 (3.6) 1 (1.8) 11 (4.0) 
 Diarrhea 3 (2.8) 0 (0.0) 3 (5.5) 3 (5.4) 1 (1.9) 1 (1.8) 0 (0.0) 8 (2.9) 
 Vomiting 4 (3.7) 0 (0.0) 1 (1.8) 3 (5.4) 2 (3.8) 1 (1.8) 1 (1.8) 8 (2.9) 
General disorders and administration site conditions 12 (11.1) 8 (16.0) 3 (5.5) 5 (8.9) 12 (22.6) 6 (10.7) 10 (17.5) 36 (13.0) 
 Edema peripheral 1 (0.9) 4 (8.0) 2 (3.6) 4 (7.1) 2 (3.8) 3 (5.4) 2 (3.5) 13 (4.7) 
 Fatigue 2 (1.9) 2 (4.0) 0 (0.0) 2 (3.6) 4 (7.5) 2 (3.6) 2 (3.5) 10 (3.6) 
Investigations 10 (9.3) 5 (10.0) 4 (7.3) 6 (10.7) 5 (9.4) 8 (14.3) 5 (8.8) 28 (10.1) 
 Weight increased 1 (0.9) 0 (0.0) 0 (0.0) 1 (1.8) 0 (0.0) 3 (5.4) 1 (1.8) 5 (1.8) 
Infections and infestations 8 (7.4) 6 (12.0) 2 (3.6) 7 (12.5) 5 (9.4) 8 (14.3) 5 (8.8) 27 (9.7) 
 Urinary tract infection 5 (4.6) 4 (8.0) 2 (3.6) 2 (3.6) 0 (0.0) 4 (7.1) 0 (0.0) 8 (2.9) 
Metabolism and nutrition disorders 6 (5.6) 3 (6.0) 3 (5.5) 3 (5.4) 4 (7.5) 3 (5.4) 2 (3.5) 15 (5.4) 
 Hyperglycemia 1 (0.9) 0 (0.0) 0 (0.0) 3 (5.4) 2 (3.8) 0 (0.0) 1 (1.8) 6 (2.2) 
Injury, poisoning, and procedural complicationse 8 (7.4) 3 (6.0) 2 (3.6) 5 (8.9) 1 (1.9) 2 (3.6) 2 (3.5) 12 (4.3) 
 Fall 1 (0.9) 1 (2.0) 1 (1.8) 3 (5.4) 0 (0.0) 0 (0.0) 0 (0.0) 4 (1.4) 

a150 mg twice daily.

bOnce-daily dosing.

c10 mg twice daily.

d15 mg twice daily.

eAEs were grouped by Medical Dictionary for Regulatory Activity terms.

Overall rates of AEs of special interest, including CNS effects, cardiac conduction abnormalities, arrhythmias, edema, visual disorders, and potential for abuse, were low. CNS effects were observed in 2.8% of subjects in the placebo group, 14.1% of subjects in the mirogabalin groups (all arms combined), and 12.0% of subjects in the pregabalin group. Dizziness and somnolence were the most commonly observed CNS effects; most were mild in severity and resolved before study end. The incidence of somnolence increased with increasing doses of mirogabalin. Cardiac conduction abnormalities occurred in two subjects. One subject in the mirogabalin 15-mg/day group experienced mild bundle branch block, and one subject in the placebo group experienced mild QT prolongation. Arrhythmias were observed in four subjects. Two subjects in the mirogabalin 30-mg/day group experienced mild bradycardia (n = 1) and mild syncope (n = 1). One subject in the mirogabalin 15-mg/day group had a mild increase in heart rate, and one subject in the pregabalin group experienced moderate bradycardia. Overall incidence of edema was 1.0% in the placebo group, 5.1% in the mirogabalin groups (all arms combined), and 10% in the pregabalin group. Peripheral edema was most common in all groups and most cases of edema resolved by study end. Mildly blurred vision was the most commonly reported visual disorder, occurring in 1.9% of subjects in the placebo group, 1.8% of subjects in the mirogabalin groups, and 4.0% of subjects in the pregabalin 300-mg/day group. With regard to abuse potential, one subject in the mirogabalin 30-mg/day group experienced moderate euphoria that resolved after 9 days. The event was considered related to study drug, and the patient was discontinued from the study.

The most common AEs related to study drug were increased blood creatinine phosphokinase levels (1.9%) in the placebo group; dizziness (7.6%) and somnolence (5.1%) in the mirogabalin groups (all arms combined); and somnolence (8.0%), balance disorder (4.0%), fatigue (4.0%), and peripheral edema (4.0%) in the pregabalin 300-mg/day group.

No deaths occurred during the study. SAEs occurred in 1% of subjects in the placebo group, 2.9% of subjects in the mirogabalin groups, and no subjects in the pregabalin group. Only one SAE was considered related to study medication. A 73-year-old white man with a medical history of obesity, uric acid elevation, and hypertension experienced acute elevations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin after receiving mirogabalin 15 mg/day. Hepatic ultrasound, performed 6 days after abnormal laboratory findings were observed, showed fatty infiltration and a 1.5-cm gallstone. No signs of bile stasis or dilation of the biliary tract were noted. The subject took the last dose of study drug on day 35; total bilirubin returned to normal (0.6 mg/dL) 6 days after the last dose, and all elevated liver function test results resolved 14 days after the last dose. The patient was asymptomatic throughout the course of events.

Twenty-four subjects discontinued the study because of ≥1 AEs: 2 (1.9%) subjects in the placebo group (hyperglycemia, feeling hot), 20 (7.2%) subjects in the mirogabalin groups (dizziness, somnolence, and nausea were most common), and 2 (4.0%) subjects in the pregabalin group (disturbance in attention, peripheral edema, fluid retention).

There was no notable difference in ECGs, physical examination, or neurologic examinations and no clinically significant trends in hematology, biochemistry, or clinical laboratory test values over time. One subject in the pregabalin 300-mg/day group and two subjects in the mirogabalin 15-mg/day group experienced ALT level ≥3× the upper limit of normal (ULN) and AST level ≥3× ULN, one of whom also had a concomitant total bilirubin level ≥2× ULN (case described above). No trends for ALT/AST elevations ≥3× ULN were observed across treatment groups.

This phase 2, randomized, double-blind, placebo- and active comparator–controlled adaptive study demonstrated that mirogabalin was effective in reducing pain and was generally well tolerated in subjects with DPNP at doses ranging from 5 to 30 mg/day. Beginning at week 1, the highest three mirogabalin dosing groups (15, 20, and 30 mg/day) had significantly greater mean reductions from baseline to week 5 in ADPS compared with placebo, and one dosing group (30 mg/day) met the criteria for minimally clinically meaningful effect (i.e., a decrease ≥1.0 point versus placebo). These data are compelling given the study population had DPNP for a mean of 5.8 years, which is longer than those who participated in pregabalin trials, where subjects were excluded if the duration of DPNP was >5 years (20,2325). Analysis of responders, defined as subjects who attained ≥30 or ≥50% reduction from baseline in ADPS, were generally supportive of a mirogabalin treatment effect compared with placebo, as improvements relative to placebo were statistically significant at 15-, 20-, and 30-mg/day dose levels using one or both responder definitions. Furthermore, median time to clinically meaningful pain relief, calculated as time to reach ≥30% reduction from baseline ADPS, was significantly shorter (44–56%) than placebo in the mirogabalin 15-, 20-, and 30-mg/day groups.

The efficacy and safety of pregabalin for the treatment of DPNP have been evaluated extensively. Freeman et al. (19) pooled and analyzed efficacy and safety data from seven randomized, placebo-controlled pregabalin trials. Trials ranged in duration from 5 to 13 weeks; included pregabalin 150-, 300-, and 600-mg/day treatment arms (administered either twice daily or three times daily); and excluded those who had DPNP longer than 5 years. Overall, pregabalin showed variable and inconsistent reductions in ADPS and statistically significant increases in the proportion of responders. In pregabalin 150-, 300-, and 600-mg/day groups, LS mean differences in change from baseline to week 5 in ADPS were –1.98, –2.44, and –2.75 versus placebo (–1.47; P ≤ 0.01 for all comparisons, LOCF). The proportion of subjects who achieved ≥50% reductions in ADPS from baseline to end point were 27, 39, and 47% versus placebo (22%), respectively (P < 0.0001 for pregabalin 300 and 600 mg/day).

It is noteworthy that no statistically significant differences were observed between pregabalin 300 mg/day and placebo in ADPS or proportion of responders at end point in the current study. Numeric improvements were observed in ADPS and the proportion of responders in the pregabalin 300-mg/day group at end point, but differences were not statistically significant versus placebo. Of note, statistically significant differences in ADPS were observed between pregabalin 300 mg/day and placebo at weeks 1 and 2, but not at weeks 3, 4, and 5.

This was not an unexpected finding, as pregabalin has shown inconsistent efficacy results previously, similar to what was observed in the current study. For example, in the pregabalin (Lyrica) registration program, pregabalin 300 mg/day showed approximately comparable efficacy to placebo in two of five DPNP trials, and of the three studies that evaluated pregabalin 600 mg/day, results were positive in two and negative in the other (26). Additionally, recent evidence suggests that baseline comorbidities may predict response to pregabalin. A post hoc analysis of data pooled from 16 placebo-controlled trials of pregabalin in patients with DPNP or postherpatic neuralgia (N = 4,527) demonstrated that the presence of comorbid sleep disturbance at baseline may, in part, predict substantial pain relief in response to pregabalin treatment (27). It is not known what role, if any, baseline comorbidities had on response to pregabalin treatment in the current study. The high placebo effect observed in the current study may have also contributed to the lack of statistically significant differences between the pregabalin 300 mg/day and placebo arms. Placebo effect is common in clinical trials of DPNP (28). In the analysis of pregabalin DPNP trials conducted by Freeman et al. (19), the average placebo response was –1.47. In our study, the placebo response was somewhat higher at –1.86, which may have made it harder for pregabalin to separate from placebo. However, and most notably, despite the magnitude of the placebo response, mirogabalin separated from placebo in a dose-dependent manner, reaching statistical significance at the highest three dose levels.

Mirogabalin is a novel, preferentially selective α2δ-1 ligand with a unique binding profile that may translate to clinically meaningful differences in both efficacy and safety. A slower dissociation rate from α2δ-1 than α2δ-2 may provide a wider therapeutic index with fewer CNS AEs (10). In support of this premise, mirogabalin demonstrated a balanced safety profile across all study treatments; no deaths occurred during the study, and there was a low overall rate of both AEs and AEs of special interest, including weight gain, edema, and balance disorder. The most common AEs of dizziness and somnolence are expected based on the mechanism of action of mirogabalin. Dizziness and somnolence are also observed with pregabalin, with dizziness appearing to be dose related (19). Of note, the incidence of these AEs were somewhat lower in the current study compared with analysis of pregabalin DPNP trials conducted by Freeman et al. (19), where the incidences were 23.3 and 14.3%, respectively. In addition to safety and tolerability, mirogabalin also has several appealing convenience characteristics compared with current treatment options, including a potential for once-daily dosing without titration and bedtime administration. Bedtime administration is beneficial because pain tends to worsen at night, and nighttime dosing may limit the frequency and severity of dizziness and somnolence during the day.

The current study has a few limitations that should be considered. First, the uniqueness of the study design precludes direct comparisons to other studies. Differences in study duration, patient populations, and other variables can greatly impact efficacy; therefore, comparisons must be made with caution. Second, the 5-week duration of the study may have been too short to observe the full magnitude of pain reduction or the placebo response. Third, the proportion of subjects with type 1 diabetes was relatively low in the mirogabalin 30 mg/day group (1.8%), and it is unknown whether this impacted the results. Low incidences of subjects with type 1 diabetes is consistent with other clinical development programs (26). Fourth, pregabalin 300 mg/day was administered as 150 mg twice daily, and it is unknown whether other pregabalin dosing regimens would have resulted in a similar response (29). Overall, ∼6% of subjects had received gabapentin previously, and ∼25% had received pregabalin previously. It is difficult to speculate if this, combined with the high placebo response, may have contributed to the low efficacy observed with pregabalin in the current study. However, a post hoc analysis of subjects with and without previous exposure to gabapentinoids did not show differences in efficacy results (data not shown). Last, durability of pain relief was not assessed, and long-term studies are needed to determine whether reductions in ADPS observed with mirogabalin persist over time.

In summary, results of the first clinical trial using an adaptive design in patients with DPNP show that mirogabalin was effective and well tolerated in this patient population at doses ranging from 5 to 30 mg/day. Overall efficacy and safety data suggest that mirogabalin, given either once or twice daily with or without titration, provides analgesic effects with a potentially wider safety margin compared with current first-line treatments for DPNP. Three of the mirogabalin arms (15, 20, and 30 mg/day) had statistically significant reductions in ADPS versus placebo at week 5 and one (30 mg/day) met the criteria of “minimally meaningful effect,” defined as a ≥1.0-point decrease versus placebo. In addition, statistically significant reductions in ADPS versus placebo were observed as early as week 1 in the mirogabalin 15-, 20-, and 30-mg/day groups and continued through week 5 despite a high placebo response rate. Finally, 56–67% of subjects achieved ≥30% reduction in ADPS in the top four mirogabalin treatment arms (i.e., 10, 15, 20, and 30 mg/day). Although phase 3 studies are needed to confirm and further these results, these multiple lines of evidence, when taken together, suggest that mirogabalin may be a promising new treatment option for patients with DPNP.

Acknowledgments. The authors acknowledge editorial assistance provided by Drs. W. Lesley R. Castro and Lynn Brown, both at ApotheCom, which was funded by Daiichi Sankyo, Inc. The authors also acknowledge Julie Pitcher, RN, BSN, Biostatistics and Data Operations Department at Daiichi Sankyo Pharma Development, Edison, NJ.

Duality of Interest. A.V. has received research funding from Daiichi Sankyo for the conduct of the study. J.R. has served on scientific advisory boards and received honorarium or consulting fees from Sanofi, Novo Nordisk, Eli Lilly, GlaxoSmithKline, Takeda, Merck, Daiichi Sankyo, Janssen, Novartis, Boehringer Ingelheim, MannKind, Halozyme, Intarcia, and Lexicon and received grants/research support from Merck, Pfizer, Sanofi, Novo Nordisk, Roche, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Takeda, Novartis, AstraZeneca, Amylin, Janssen, Daiichi Sankyo, MannKind, Boehringer Ingelheim, Intarcia, and Lexicon. K.F. and C.H. are employees of Daiichi Sankyo Pharma Development, and D.M. is an employee of Daiichi Sankyo Development Ltd. No other potential conflicts of interest relevant to this article were reported.

Author Contributions. A.V., J.R., U.S., K.F., and D.M. interpreted the data and critically reviewed and edited the paper. C.H. interpreted the data, critically reviewed and edited the paper, and provided the analyses. All authors had access to the data. A.V. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Prior Presentation. Parts of this study were presented at the Annual Meeting of the American Academy of Neurology, Philadelphia, PA, 26 April–3 May 2014 and at the 74th Scientific Sessions of the American Diabetes Association, San Francisco, CA, 13–17 June 2014.

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Supplementary data