Mirogabalin in Japanese Patients with Renal Impairment and Pain Associated with Diabetic Peripheral Neuropathy or Post-Herpetic Neuralgia: A Phase III, Open-Label, 14-Week Study

Figures & data

Figure 1 Patient disposition.

Note: ^aOne event each of angina pectoris, hepatitis E, myelitis, and somnolence.

Abbreviations: AE, adverse event; CL_CR, creatinine clearance.

Figure 2 Study design.

Notes: ^aAfter obtaining informed consent, patients who were treated with prohibited concomitant medications (DPNP and PHN) or prohibited concomitant therapies (PHN) underwent a washout period of ≥7 days.

Abbreviations: BID, twice daily; CLCR, creatinine clearance; DPNP, diabetic peripheral neuropathic pain; PHN, post-herpetic neuralgia; QD, once daily.

Table 1 Demographic and Other Baseline Characteristics (Safety Analysis Set)

Parameters	Moderate Renal Impairment (CLCR 30–59 mL/min) n=30	Severe Renal Impairment (CLCR 15–29 mL/min) n=5	Total N=35
Age (years), mean (SD)	73.8 (7.7)	71.0 (4.1)	73.4 (7.3)
<65 years, n (%)	3 (10.0)	0 (0)	3 (8.6)
65–<75 years, n (%)	12 (40.0)	4 (80.0)	16 (45.7)
≥75 years, n (%)	15 (50.0)	1 (20.0)	16 (45.7)
Sex, n (%)
Male	24 (80.0)	4 (80.0)	28 (80.0)
Female	6 (20.0)	1 (20.0)	7 (20.0)
Body mass index (kg/m^2), mean (SD)	22.9 (3.0)	23.7 (4.3)	23.0 (3.1)
Primary disease, n (%)
DPNP^a	24 (80.0)	5 (100.0)	29 (82.9)
PHN	6 (20.0)	0 (0)	6 (17.1)
Duration of primary disease (months), median (range)
DPNP	49.5 (9–139)	60.0 (12–156)	51.0 (9–156)
PHN	14.5 (10–87)	–	14.5 (10–87)
CLCR (mL/min), mean (SD)	51.8 (9.6)	22.0 (6.2)	47.5 (13.9)
Baseline ADPS, mean (SD)	5.7 (1.0)	6.0 (1.3)	5.7 (1.1)
SF-MPQ VAS score, mean (SD)
At screening	58.5 (9.4)	56.6 (10.1)	58.2 (9.4)
At treatment initiation	59.1 (9.1)	62.8 (13.4)	59.6 (9.6)

Notes: ^aAll patients with DPNP had type 2 diabetes, no patients with type 1 diabetes were enrolled. The percentage for each categorical variable was calculated using the “non-missing” n as the denominator. CL_CR was calculated by the Cockcroft-Gault equation. Baseline ADPS was defined as the average of up to 7 available pain scores in the prior 7 days at or before first study treatment.

Abbreviations: ADPS, average daily pain score; CL_CR, creatinine clearance; DPNP, diabetic peripheral neuropathic pain; PHN, post-herpetic neuralgia; SD, standard deviation; SF-MPQ, short-form McGill Pain Questionnaire; VAS, visual analog scale.

Table 2 Summary of TEAEs and ADRs (Safety Analysis Set)

	Moderate Renal Impairment (CLCR 30–59 mL/min) n=30	Severe Renal Impairment (CLCR 15–29 mL/min) n=5	Total N=35
TEAEs
All TEAEs	25 (83.3)	4 (80.0)	29 (82.9)
Serious TEAEs	1 (3.3)	0 (0)	1 (2.9)
Severe TEAEs	1 (3.3)	0 (0)	1 (2.9)
TEAEs leading to discontinuation	4 (13.3)	0 (0)	4 (11.4)
ADRs
All ADRs	9 (30.0)	0 (0)	9 (25.7)
Serious ADRs	0 (0)	0 (0)	0 (0)
Severe ADRs	0 (0)	0 (0)	0 (0)
ADRs leading to discontinuation	1 (3.3)	0 (0)	1 (2.9)
Deaths	0 (0)	0 (0)	0 (0)
Most frequently reported TEAEs (≥5% overall) by preferred term
Nasopharyngitis	6 (20.0)	2 (40.0)	8 (22.9)
Somnolence	4 (13.3)	0 (0)	4 (11.4)
Edema peripheral	2 (6.7)	1 (20.0)	3 (8.6)
Back pain	2 (6.7)	0 (0)	2 (5.7)
Dizziness	2 (6.7)	0 (0)	2 (5.7)
Diarrhea	2 (6.7)	0 (0)	2 (5.7)
Nausea	2 (6.7)	0 (0)	2 (5.7)
Sensory disturbance	2 (6.7)	0 (0)	2 (5.7)

Notes: Data are shown as n (%). The percentage was calculated using the number of patients in the column heading as the denominator. An ADR was defined as a TEAE which was considered related to the study drug (ie, a causal relationship could not be ruled out).

Abbreviations: ADR, adverse drug reaction; AE, adverse event; CLCR, creatinine clearance; TEAE, treatment-emergent AE.

Table 3 Efficacy Outcomes (Efficacy Analysis Set)

	Moderate Renal Impairment (CLCR 30–59 mL/min) n=30	Severe Renal Impairment (CLCR 15–29 mL/min) n=5	Total N=35
ADPS, baseline, mean (SD)	5.7 (1.0)	6.0 (1.3)	5.7 (1.1)
Week 14 change from baseline (imputed), LS mean [95% CI]	−1.8 [−2.5, −1.1]	−2.1 [−3.8, −0.4]	−1.9 [−2.8, −1.0]
ADPS responder rate^a
≥30% reduction in ADPS at Week 14, n (%) [95% CI]	13 (43.3) [27.4, 60.8]	2 (40.0) [11.8, 76.9]	15 (42.9) [28.0, 59.1]
≥50% reduction in ADPS at Week 14, n (%) [95% CI]	8 (26.7) [14.2, 44.4]	2 (40.0) [11.8, 76.9]	10 (28.6) [16.3, 45.1]
SF-MPQ, baseline, mean (SD)
Sensory score	7.7 (4.3)	8.6 (8.8)	7.8 (5.0)
Week 14/LOCF change from baseline	−5.1 (4.4)	−1.8 (2.5)	−4.6 (4.3)
Affective score	1.3 (1.5)	2.6 (2.7)	1.5 (1.7)
Week 14/LOCF change from baseline	−1.0 (1.6)	−0.8 (0.5)	−1.0 (1.5)
Total score	9 (5.3)	11.2 (11.4)	9.3 (6.3)
Week 14/LOCF change from baseline	−6.1 (5.4)	−2.6 (2.7)	−5.6 (5.2)
VAS (mm)	59.1 (9.1)	62.8 (13.4)	59.6 (9.6)
Week 14/LOCF change from baseline	−20.8 (17.7)	−26.0 (22.8)	−21.5 (18.2)
Present pain intensity	1.9 (1.0)	2 (0.7)	1.9 (0.9)
Week 14/LOCF change from baseline	−0.8 (0.8)	−0.2 (0.8)	−0.7 (0.8)
PGIC^a,b
Much improved or better (≤2) at Week 14, n (%) [95% CI]	11 (36.7) [21.9, 54.5]	1 (20.0) [3.6, 62.4]	12 (34.3) [20.8, 50.8]
Minimally improved or better (≤3) at Week 14, n (%) [95% CI]	23 (76.7) [59.1, 88.2]	4 (80.0) [37.6, 96.4]	27 (77.1) [61.0, 87.9]
ADSIS, baseline^c, mean (SD)	3.5 (1.8)	3.8 (3.4)	3.5 (2.1)
Week 14/LOCF change from baseline	−1.4 (1.6)	−0.5 (0.7)	−1.3 (1.5)

Notes: ^aThe 95% CI was calculated using the Wilson score method without continuity correction. ^bFor patients who were missing PGIC data at Week 14 but who had data prior to Week 14, the LOCF approach was used. Patients who had no PGIC data throughout the study were regarded as non-responders. ^cBaseline ADSIS was defined as the average of up to 7 available sleep interference scores in the previous 7 days at or before first study treatment.

Abbreviations: ADPS, average daily pain score; ADSIS, average daily sleep interference score; CI, confidence interval; CL_CR, creatinine clearance; LOCF, last observation carried forward; LS, least squares; PGIC, patient global impression of change; SD, standard deviation; SF-MPQ, short-form McGill Pain Questionnaire; VAS, visual analog scale.

Figure 3 Time course of average daily pain scores^a (efficacy analysis set).

Notes: ^aData are shown as least squares mean ± SE. The MI method using pattern mixture model with different shifting parameters according to the reason for treatment discontinuation was applied. The MMRM with CL_CR group, week and CL_CR group-by-week as fixed effects and baseline ADPS as a covariate was performed to estimate the least squares means and the corresponding SE for each week.

Abbreviations: ADPS, average daily pain score; CL_CR, creatinine clearance; MI, multiple imputation; MMRM, mixed-effects model with repeated measures; RI, renal impairment; SE, standard error.