Treatment response to sleep, pain, and mood disturbance and their correlation with sleep disturbance in adult patients with moderate-to-severe primary restless legs syndrome: Pooled analyses from 3 trials of gabapentin enacarbil

Figures & data

Table I. Baseline characteristics of the mITT population.

	No-to-moderate sleep disturbance (n = 372)			Severe-to-very severe sleep disturbance (n = 299)
Characteristic	Placebo (n = 135)	GEn 600 mg (n = 88)	GEn 1200 mg (n = 149)	Placebo (n = 109)	GEn 600 mg (n = 73)	GEn 1200 mg (n = 117)
Age at screening, mean years (SD)	48.6 (12.60)	48.2 (13.06)	49.0 (13.11)	50.1 (11.96)	48.0 (12.35)	52.8 (11.60)
Sex, n (%)
Female	82 (61)	51 (58)	79 (53)	69 (63)	45 (62)	74 (63)
Male	53 (39)	37 (42)	70 (47)	40 (37)	28 (38)	43 (37)
White race, n (%)	130 (96)	84 (95)	141 (95)	104 (95)	68 (93)	115 (98)
Mean IRLS total score at baseline, points (SD)	20.3 (3.50)	20.1 (3.43)	20.1 (3.22)	26.5 (4.07)	27.2 (3.76)	27.3 (4.18)
Mean IRLS: item 4 (severity of sleep disturbance) score at baseline, points (SD)	1.6 (0.61)	1.7 (0.48)	1.7 (0.53)	3.2 (0.38)	3.2 (0.40)	3.2 (0.43)
Mean IRLS: item 9 (daily affairs) score at baseline, points (SD)	1.1 (0.94)	1.2 (0.83)	1.0 (0.89)	1.8 (1.03)	1.9 (0.96)	1.9 (1.04)
Mean IRLS: item 10 (severity of mood disturbance) score at baseline, points (SD)	1.3 (0.89)	1.1 (0.83)	1.2 (0.84)	1.9 (1.01)	1.9 (1.00)	1.9 (1.02)
Average daily RLS pain score at baseline, points (SD)	3.6 (2.18)^a	3.5 (2.38)^b	3.4 (2.19)^c	4.2 (2.62)^d	4.7 (2.76)^e	4.7 (2.55)^f
Duration of RLS symptoms, mean (SD)	14.3 (13.83)	12.0 (12.30)	13.0 (12.66)	13.4 (11.91)	15.3 (13.28)	16.1 (15.58)^f
≥ 1 Prior RLS treatment, n (%)^g	31 (23)^a	21 (24)^h	37 (25)	58 (53)	29 (40)	46 (40)^f

GEn = gabapentin enacarbil; IRLS = International restless legs scale; mITT = modified intent-to-treat; RLS = restless legs syndrome; SD = standard deviation.

^an = 133; ^bn = 87; ^cn = 148; ^dn = 108; ^en = 71; ^fn = 116; ^g Includes patients whose treatment terminated prior to the month before the start of study drug and who received treatment within the month of the start of study drug or within the previous month; ^hn = 86.

Table II. Baseline POMS subscale scores of the mITT population.

	No-to-moderate sleep disturbance			Severe-to-very severe sleep disturbance
POMS subscale item, mean (SD)	Placebo (n = 135)	GEn 600 mg (n = 86)	GEn 1200 mg (n = 148)	Placebo (n = 108)	GEn 600 mg (n = 73)	GEn 1200 mg (n = 117)
Anger–hostility	3.9 (3.05)	3.8 (2.98)	4.1 (2.91)	5.5 (4.32)	5.4 (4.23)	5.6 (4.28)
Confusion–bewilderment	4.4 (2.54)	4.5 (2.50)	4.4 (2.51)	5.4 (3.34)	5.2 (3.26)	5.7 (3.51)
Depression–dejection	3.0 (2.90)	2.9 (3.06)	2.8 (2.92)	4.0 (3.64)	4.0 (4.62)	4.5 (4.35)
Fatigue–inertia	7.6 (3.90)	7.4 (4.46)	7.4 (3.85)	10.6 (4.42)	10.4 (4.95)	11.1 (4.90)
Tension–anxiety	4.6 (3.13)	4.2 (3.55)	4.3 (2.89)	5.9 (3.83)	5.4 (4.21)	6.3 (4.38)
Total mood disturbance	16.2 (15.48)	15.2 (15.44)	15.3 (13.95)	24.8 (18.62)	24.4 (20.18)	26.8 (20.71)
Vigor–activity	7.2 (4.12)	7.6 (3.65)	7.6 (3.91)	6.6 (4.13)	6.0 (3.73)	6.3 (3.98)

GEn = gabapentin enacarbil; mITT = modified intent-to-treat; POMS = Profile of Mood States; SD = standard deviation.

Figure 1. LS mean changes from baseline per week in the IRLS total score for (A) patients with no-to-moderate sleep disturbance or (B) patients with severe-to-very severe sleep disturbance. *P < 0.05; **P < 0.01; ***P < 0.001 for GEn (600 mg or 1200 mg) versus placebo. GEn = gabapentin enacarbil; IRLS = International Restless Legs Scale; LS = least squares.

Figure 2. Proportion of patients with (A) no-to-moderate sleep disturbance or (B) severe-to-very severe disturbance who stated that they were ‘much’ or ‘very much’ improved on the investigator-rated CGI-I, by visit. *P < 0.01, **P < 0.001 for GEn (600 mg or 1200 mg) versus placebo. CGI-I = Clinical Global Impression–Improvement; GEn = gabapentin enacarbil.

Figure 3. LS mean changes from baseline per week in the average daily RLS pain score for patients with (A) no-to-moderate sleep disturbance or (B) severe-to-very severe sleep disturbance. *P < 0.05; **P < 0.01; ***P <0.001 for GEn (600 mg or 1200 mg) versus placebo. GEn = gabapentin enacarbil; LS = least squares; RLS = restless legs syndrome.

Table III. POMS subscale score treatment differences in the change from baseline to week 12.

	Treatment comparison
	GEn 600 mg versus placebo		GEn 1200 mg versus placebo
POMS item	LS mean treatment difference (SE)	P value ^a	LS mean treatment difference (SE)	P value
No-to-moderate sleep disturbance group
Anger–hostility	− 0.6 (0.39)	0.098	− 0.5 (0.33)	0.109
Confusion–bewilderment	− 0.6 (0.32)	0.081	− 0.5 (0.28)	0.057
Depression–dejection	− 0.9 (0.37)	0.015	− 0.9 (0.32)	0.005
Fatigue–inertia	− 0.9 (0.56)	0.103	− 1.2 (0.48)	0.012
Tension–anxiety	− 0.4 (0.36)	0.279	− 0.1 (0.32)	0.639
Total mood disturbance	− 4.2 (1.96)	0.032	− 4.9 (1.69)	0.004
Vigor–activity	1.0 (0.55)	0.081	1.7 (0.48)	< 0.001
Severe-to-very severe sleep disturbance group
Anger–hostility	0.1 (0.50)	0.838	− 0.3 (0.45)	0.568
Confusion–bewilderment	− 0.4 (0.39)	0.344	− 0.6 (0.34)	0.108
Depression–dejection	0.3 (0.43)	0.554	− 0.1 (0.38)	0.703
Fatigue–inertia	− 0.4 (0.69)	0.610	− 0.9 (0.61)	0.156
Tension–anxiety	− 0.2 (0.48)	0.687	− 0.4 (0.42)	0.346
Total mood disturbance	− 1.0 (2.47)	0.679	− 4.4 (2.19)	0.045
Vigor–activity	0.7 (0.66)	0.282	2.2 (0.59)	< 0.001

GEn = gabapentin enacarbil; LS = least squares; POMS = Profile of Mood States; SE = standard error.

^aP values are for GEn (600 mg or 1200 mg) versus placebo.

Figure 4. LS mean changes from baseline per week for the score of item 4 (severity of sleep disturbance) on the IRLS for patients with (A) no-to-moderate sleep disturbance or (B) severe-to-very severe sleep disturbance. *P < 0.05; **P < 0.01; ***P < 0.001 for GEn (600 mg or 1200 mg) versus placebo. GEn = gabapentin enacarbil; IRLS = International Restless Legs Scale; LS = least squares.

Figure 5. LS mean changes from baseline per week for the score of item 9 (daily affairs) of the IRLS for patients with (A) no-to-moderate sleep disturbance or (B) severe-to-very severe sleep disturbance. *P < 0.05; **P < 0.01; ***P < 0.001 for GEn (600 mg or 1200 mg) versus placebo. GEn = gabapentin enacarbil; IRLS = International Restless Legs Scale; LS = least square.

Figure 6. LS mean changes from baseline per week for the score of item 10 (severity of mood disturbance) of the IRLS for patients with (A) no-to-moderate sleep disturbance or (B) severe-to-very severe sleep disturbance. *P < 0.05; **P < 0.01; ***P < 0.001 for GEn (600 mg or 1200 mg) versus placebo. GEn = gabapentin enacarbil; IRLS = International Restless Legs Scale; LS = least squares.

Table IV. Most frequent treatment-emergent adverse events reported in at least 5% of the safety population.

Adverse event, n (%)	Placebo (n = 135)	GEn 600 mg (n = 89)	GEn 1200 mg (n = 151)
Patients with no-to-moderate sleep disturbance
Any	103 (76.3)	72 (80.9)	124 (82.1)
Dizziness	10 (7.4)	13 (14.6)	36 (23.8)
Somnolence	6 (4.4)	16 (18.0)	32 (21.2)
Headache	14 (10.4)	10 (11.2)	24 (15.9)
Nasopharyngitis	11 (8.1)	8 (9.0)	11 (7.3)
Fatigue	8 (5.9)	3 (3.4)	9 (6.0)
Upper respiratory tract infection	7 (5.2)	8 (9.0)	3 (2.0)
Diarrhea	7 (5.2)	3 (3.4)	7 (4.6)
Nausea	5 (3.7)	3 (3.4)	8 (5.3)
Sedation	1 (0.7)	1 (1.1)	8 (5.3)

	(n = 110)	(n = 74)	(n = 118)
Patients with severe-to-very severe sleep disturbance
Any	80 (72.7)	60 (81.1)	103 (87.3)
Somnolence	6 (5.5)	16 (21.6)	29 (24.6)
Headache	13 (11.8)	9 (12.2)	16 (13.6)
Dizziness	1 (0.9)	9 (12.2)	23 (19.5)
Nausea	7 (6.4)	6 (8.1)	11 (9.3)
Nasopharyngitis	5 (4.5)	6 (8.1)	10 (8.5)
Fatigue	3 (2.7)	5 (6.8)	9 (7.6)
Back pain	6 (5.5)	5 (6.8)	3 (2.5)
Constipation	6 (5.5)	2 (2.7)	6 (5.1)
Insomnia	1 (0.9)	6 (8.1)	3 (2.5)
Muscle spasms	3 (2.7)	4 (5.4)	1 (0.8)
Sinusitis	0	4 (5.4)	2 (1.7)
Toothache	1 (0.9)	4 (5.4)	0

GEn = gabapentin enacarbil.