Efficacy and safety of neuromodulators combined with proton pump inhibitors for non-erosive reflux disease: A randomized clinical trial

Table 1 Demographic and baseline clinical characteristics, median (interquartile range)/n (%)

Characteristics	FM + LPZ group (n = 82)	P + LPZ group (n = 82)	P value
Age (years), mean (SD)	47.0 (10.8)	46.9 (12.2)	0.941
Female	37 (45.1)	35 (42.7)	0.753
Weight (kg), mean (SD)	66.1 (11.9)	63.5 (10.9)	0.141
Height (cm), mean (SD)	167.8 (8.5)	166.9 (7.0)	0.436
BMI	23.2 (21.1-24.8)	22.8 (20.7-24.6)	0.329
Education level			0.439
Junior high school or below	21 (25.6)	23 (28.0)
Senior high school	16 (19.5)	10 (12.2)
Junior college or higher	45 (54.9)	49 (59.8)
Job category			0.655
Mainly manual labor	9 (11.0)	9 (11.0)
Mainly intellectual labor	33 (40.2)	30 (36.6)
Retired	25 (30.5)	32 (39.0)
Uncertain	15 (18.3)	11 (13.4)
Smoker	14 (17.1)	11 (13.4)	0.515
Alcohol drinker	12 (14.6)	9 (10.9)	0.483
Coffee	6 (7.3)	8 (9.8)	0.576
Spicy food	22 (26.8)	21 (25.6)	0.859
Sweet food	18 (21.9)	14 (17.1)	0.431
Greasy food	16 (19.5)	10 (12.2)	0.199
GerdQ scores	12.0 (10.0-14.0)	12.0 (10.0-15.0)	0.255
GERD-HRQL scores, mean (SD)	13.2 (5.0)	13.6 (4.7)	0.596
GAD-7 scores,	3.0 (1.0-7.0)	3.0 (2.0-5.0)	0.885
PHQ-9 scores	4.0 (1.0-8.0)	4.5 (2.0-8.0)	0.788
GAD-7 ≥ 5 or PHQ-9 ≥ 5	44 (53.7)	45 (54.9)	0.875
PSQI scores, mean (SD)	7.4 (4.4)	7.8 (4.1)	0.596

BMI: Body mass index; GAD-7: Generalized Anxiety Disorder 7-item scale; GerdQ: Gastroesophageal reflux disease questionnaire; GERD-HRQL: Gastroesophageal Reflux Disease Health-Related Quality of Life; PHQ-9: Patient Health Questionnaire-9; PSQI: Pittsburgh Sleep Quality Index; FM: Flupentixol-melitracen; LPZ: Lansoprazole; P + LPZ: Lansoprazole plus placebo.

Table 2 Subgroup analysis of the primary outcome

Subgroup	Number of responsive/total patients		RR (95%CI)	P value for interaction
	FM + LPZ group	P + LPZ group
All patients	71/82	51/82	1.39 (1.15-1.68)
Mood disorders
With anxiety/depression	38/44	27/45	1.44 (1.10-1.88)	0.706
No anxiety/depression	33/38	24/37	1.34 (1.03-1.75)

RR: Relative risk; FM: Flupentixol-melitracen; LPZ: Lansoprazole; P + LPZ: Lansoprazole plus placebo.

Table 3 Symptom scores at baseline, week 2 and week 12 in the per-protocol population, mean (SD)/median (interquartile range)

Variable	Time	FM + LPZ	P + LPZ	P value
GerdQ	Week 0	12.0 (10.0-14.0)	12.0 (10.0-15.0)
	Week 2	6.0 (6.0-8.0)	8.0 (7.0-10.0)	< 0.001
	Week 12	6.0 (6.0-8.0)	8.5 (8.0-10.0)	< 0.001
GAD-7	Week 0	3.0 (1.0-7.0)	3.0 (2.0-5.0)
	Week 2	2.0 (0.0-3.0)	3.0 (2.0-4.0)	< 0.001
	Week 12	2.0 (0.5-3.0)	3.0 (2.0-3.0)	< 0.001
PHQ-9	Week 0	4.0 (1.0-8.0)	4.5 (2.0-8.0)
	Week 2	2.0 (0.0-3.0)	3.5 (2.0-6.0)	< 0.001
	Week 12	2.0 (0.0-4.0)	3.5 (2.0-6.0)	< 0.001
PSQI	Week 0	7.4 (4.4)	7.8 (4.1)
	Week 2	5.4 (3.0)	7.6 (4.0)	< 0.001
	Week 12	4.7 (2.7)	7.7 (4.3)	< 0.001
GERD-HRQL	Week 0	13.2 (5.0)	13.6 (4.7)
	Week 2	3.8 (3.2)	7.7 (4.7)	< 0.001
	Week 12	2.7 (2.5)	7.3 (3.8)	< 0.001

GAD-7: Generalized Anxiety Disorder 7-item scale; GerdQ: Gastroesophageal reflux disease questionnaire; GERD-HRQL: Gastroesophageal Reflux Disease Health-Related Quality of Life; PHQ-9: Patient Health Questionnaire-9; PSQI: Pittsburgh Sleep Quality Index; FM: Flupentixol-melitracen; LPZ: Lansoprazole; P + LPZ: Lansoprazole plus placebo.

Table 4 Cost-effectiveness between the two groups over 12 weeks

Parameters	FM + LPZ group	P + LPZ group
Unit costs (USD)
LPZ (per tablet)	1.1	1.1
FM/placebo (per tablet)	0.1	0.0
Outpatient clinic visit (per visit)	7.0	7.0
Resource utilization (mean per patient)
Initial 2-week therapy (days)	14	14
On-demand therapy (days)	8.2	21.3
Outpatient clinic visits (times)	2	3
Cost-effectiveness
Total cost (USD)	40.6	59.8
CER (USD/treatment response rate)	47.5	95.2
ICER (USD/treatment response rate)	-84.6

Placebo tablets were produced at negligible cost and were therefore not included in the cost calculation. FM: Flupentixol-melitracen; LPZ: Lansoprazole; P + LPZ: Lansoprazole plus placebo; USD: United States dollars; CER: Cost-effectiveness ratio; ICER: Incremental cost-effectiveness ratio.

Table 5 Summary of adverse events during treatment, n (%)

AEs	FM + LPZ (n = 82)	P + LPZ (n = 82)
Patients with AEs	4 (4.9)	2 (2.4)
Constipation	2 (2.4)	0 (0)
Nausea	0 (0)	1 (1.2)
Sleep disturbance	1 (1.2)	1 (1.2)
Increased heart rate	1 (1.2)	0 (0)

FM: Flupentixol-melitracen; LPZ: Lansoprazole; P + LPZ: Lansoprazole plus placebo; AEs: Adverse events.