Maintenance for healed erosive esophagitis: Phase III comparison of vonoprazan with lansoprazole

Table 1 Demographic and other baseline characteristics in the randomized set (n = 607)¹

Characteristic	LPZ 15 mg (n = 201)	VPZ 10 mg (n = 202)	VPZ 20 mg (n = 204)
Age, yr	57.8 ± 12.9	55.5 ± 13.8	56.8 ± 13.6
Gender, male	140 (69.7)	160 (79.2)	160 (78.4)
Height, cm	163.5 ± 10.2	165.5 ± 9.3	165.6 ± 9.3
Weight, kg	67.0 ± 13.4	68.2 ± 12.3	69.0 ± 13.1
Erosive esophagitis grade, investigator-assessed
LA Grade A/B	160 (79.6)	162 (80.2)	161 (78.9)
LA Grade C/D	41 (20.4)	40 (19.8)	43 (21.1)
Esophageal hiatal hernia
≥ 2 cm	31 (15.4)	45 (22.3)	46 (22.5)
< 2 cm	105 (52.2)	100 (49.5)	113 (55.4)
None	65 (32.3)	57 (28.2)	44 (21.6)
H. pylori infection status
Positive	29 (14.4)	37 (18.3)	23 (11.3)
Negative	172 (85.6)	165 (81.7)	181 (88.7)
CYP2C19 genotype
Extensive metabolizers	162 (80.6)	169 (84.1)	169 (83.3)
Poor metabolizers	39 (19.4)	32 (15.9)	34 (16.7)

¹Values expressed as mean ± SD, or n (%). LA: Los Angeles; LPZ: Lansoprazole; SD: Standard deviation; VPZ: Vonoprazan.

Table 2 Recurrence rate of erosive esophagitis: Intergroup differences and non-inferiority test

Endpoint	LPZ 15 mg		VPZ 10 mg	VPZ 20 mg
Week 24 (primary endpoint)1	16.8% (33/196)		5.1% (10/197)	2.0% (4/201)
Week 12 (secondary endpoint)1	12.2% (24/196)		2.5% (5/197)	1.0% (2/201)
Comparison	Difference and 95%CI (%)		Non-inferiority, P value	Fisher exact test, P value2
Week 24 (primary endpoint)
VPZ 10 mg vs LPZ 15 mg		-11.8 [-17.83, -5.69]	< 0.0001	0.0002
VPZ 20 mg vs LPZ 15 mg		-14.8 [-20.43, -9.26]	< 0.0001	< 0.0001
VPZ 10 mg vs VPZ 20 mg		-3.1 [-6.71, 0.54]	N/A	0.1090
Week 12 (secondary endpoint)
VPZ 10 mg vs LPZ 15 mg		-9.7 [-14.80, -4.62]	< 0.0001	N/A
VPZ 20 mg vs LPZ 15 mg		-11.2 [-16.04, -6.46]	< 0.0001	N/A
VPZ 10 mg vs VPZ 20 mg		-1.5 [-4.13, 1.05]	N/A	N/A

¹Values expressed as percentages with number of subjects in parentheses;

²Post hoc analysis. CI: Confidence interval; LPZ: Lansoprazole; VPZ: Vonoprazan; N/A: Not applicable.

Table 3 Recurrence rate of erosive esophagitis within 24 wk: sub-group analysis according to baseline characteristics

	LPZ 15 mg		VPZ 10 mg			VPZ 20 mg
	Estimate (%)1	Estimate (%)1	Difference2 and 95%CI (%)	Fisher exact test, P value3	Estimate (%)1	Difference2 and 95%CI (%)	Fisher exact test, P value3
Age (yr)
< 65	14.4 (19/132)	4.3 (6/139)	-10.1 [-16.95, -3.20]	0.0056	0.0 (0/136)	-14.4 [-20.38, -8.41]	< 0.0001
≥ 65 to < 75	21.7 (10/46)	7.0 (3/43)	-14.8 [-28.91, -0.62]	0.0711	7.0 (3/43)	-14.8 [-28.91, -0.62]	0.0711
≥ 75	22.2 (4/18)	6.7 (1/15)	-15.6 [-38.54, 7.43]	0.3457	4.5 (1/22)	-17.7 [-38.76, 3.41]	0.1554
Sex
Male	13.9 (19/137)	6.3 (10/159)	-7.6 [-14.49, -0.67]	0.0321	1.3 (2/159)	-12.6 [-18.65, -6.57]	< 0.0001
Female	23.7 (14/59)	0.0 (0/38)	-23.7 [-34.58, -12.87]	0.0007	4.8 (2/42)	-19.0 [-31.59, -6.35]	0.0120
Smoking classification
Never smoked	22.4 (17/76)	1.9 (1/54)	-20.5 [-30.55, -10.48]	0.0006	5.0 (3/60)	-17.4 [-28.24, -6.50]	0.0062
Current smoker	20.0 (8/40)	6.6 (4/61)	-13.4 [-27.31, 0.42]	0.0588	0.0 (0/57)	-20.0 [-32.40, -7.60]	0.0005
Ex-smoker	10.0 (8/80)	6.1 (5/82)	-3.9 [-12.27, 4.47]	0.3998	1.2 (1/84)	-8.8 [-15.78, -1.84]	0.0160
Erosive esophagitis grade4
LA Grade A/B	11.0 (17/155)	3.1 (5/159)	-7.8 [-13.44, -2.21]	0.0075	1.3 (2/158)	-9.7 [-14.92, -4.48]	0.0002
LA Grade C/D	39.0 (16/41)	13.2 (5/38)	-25.9 [-44.26, -7.47]	0.0114	4.7 (2/43)	-34.4 [-50.58, -18.17]	0.0001
CYP2C19 genotype
Extensive metabolizers	19.6 (31/158)	5.4 (9/166)	-14.2 [-21.28, -7.11]	0.0001	1.8 (3/168)	-17.8 [-24.34, -11.33]	< 0.0001
Poor metabolizers	5.3 (2/38)	3.2 (1/31)	-2.0 [-11.48, 7.40]	1.0000	3.0 (1/33)	-2.2 [-11.43, 6.97]	1.0000
H. pylori infection status
Positive	3.7 (1/27)	2.7 (1/37)	-1.0 [-9.84, 7.83]	1.0000	0.0 (0/27)	-3.7 [-10.83, 3.42]	1.0000
Negative	18.9 (32/169)	5.6 (9/160)	-13.3 [-20.21, -6.41]	0.0003	2.2 (4/179)	-16.7 [-22.99. -10.41]	< 0.0001

¹Data expressed as percentages with number of subjects in parentheses;

²Calculated for difference between VPZ group and LPZ 15 mg group;

³Post hoc analysis;

⁴LA Classification Grade of erosive esophagitis by principal investigator at baseline. CI: Confidence interval; LA: Los Angeles; LPZ: Lansoprazole; VPZ: Vonoprazan.

Table 4 Summary of treatment-emergent adverse events during maintenance treatment n (%)

	LPZ 15 mg (n = 201)		VPZ 10 mg (n = 202)		VPZ 20 mg (n = 204)
	Events	Patients	Events	Patients	Events	Patients
Any TEAE	166	103 (51.2)	220	109 (54.0)	212	120 (58.8)
Drug-related TEAE	30	23 (11.4)	26	21 (10.4)	23	21 (10.3)
TEAE leading to study discontinuation	10	8 (4.0)	5	5 (2.5)	8	8 (3.9)
Any serious TEAE	4	4 (2.0)	5	5 (2.5)	4	4 (2.0)
Death	0	0 (0.0)	0	0 (0.0)	0	0 (0.0)
TEAEs reported in ≥ 2% of patients in any group, irrespective of causal relationship to study medication, during maintenance treatment.
TEAE (preferred term)	LPZ 15 mg		VPZ 10 mg		VPZ 20 mg
Nasopharyngitis	28 (13.9)		34 (16.8)		27 (13.2)
Diarrhea	11 (5.5)		6 (3.0)		5 (2.5)
Upper respiratory tract inflammation	3 (1.5)		8 (4.0)		4 (2.0)
Elevated blood creatinine phosphokinase	2 (1.0)		4 (2.0)		6 (2.9)
Elevated blood triglycerides	6 (3.0)		1 (0.5)		5 (2.5)
Fall	1 (0.5)		8 (4.0)		2 (1.0)
Gastroenteritis	1 (0.5)		5 (2.5)		5 (2.5)
Back pain	1 (0.5)		3 (1.5)		5 (2.5)
Constipation	4 (2.0)		2 (1.0)		3 (1.5)
Elevated ALT1	1 (0.5)		3 (1.5)		4 (2.0)
Contusion	1 (0.5)		5 (2.5)		2 (1.0)
Seasonal allergy	2 (1.0)		4 (2.0)		2 (1.0)
Bronchitis	2 (1.0)		5 (2.5)		0 (0.0)
Dizziness	1 (0.5)		4 (2.0)		2 (1.0)
Abnormal liver function test2	1 (0.5)		2 (1.0)		4 (2.0)
Abnormal hepatic function2	1 (0.5)		0 (0.0)		4 (2.0)
Periodontitis	0 (0.0)		4 (2.0)		1 (0.5)

¹Recorded as a special-interest adverse event (SIAE) if ALT > 3 × the upper limit of normal (ULN);

²Recorded as a SIAE if total bilirubin > 2 × ULN in two consecutive measurements. ALT: Alanine aminotransferase; LPZ: Lansoprazole; TEAE: Treatment-emergent adverse event; VPZ: Vonoprazan.

Table 5 Histopathology of gastric mucosa: neuroendocrine cell density (/mm²)

	LPZ 15 mg		VPZ 10 mg		VPZ 20 mg
	n	Mean (SD)	n	Mean (SD)	n	Mean (SD)
Epithelial cells (× 103)
Baseline	28	1.58 (0.4831)	29	1.82 (0.3188)	28	1.74 (0.3943)
Week 24	24	1.63 (0.2689)	26	1.71 (0.4304)	28	1.54 (0.4744)
Grimelius-positive cells (× 102)
Baseline	28	0.716 (0.3997)	29	0.705 (0.5562)	28	0.656 (0.3778)
Week 24	24	1.06 (0.2676)	26	1.07 (0.3858)	28	0.943 (0.4260)
Chromogranin A-positive cells (× 102)
Baseline	28	1.35 (0.6625)	29	1.25 (0.7250)	28	1.35 (0.7073)
Week 24	24	1.35 (0.2962)	26	1.31 (0.4595)	28	1.20 (0.5041)
Synaptophysin-positive cells (× 102)
Baseline	28	1.73 (0.7005)	29	1.73 (0.8123)	28	1.83 (0.9076)
Week 24	24	1.58 (0.3716)	26	1.55 (0.4490)	28	1.45 (0.6173)
Ki-67-positive cells (× 102)
Baseline	28	1.44 (0.8192)	29	1.10 (0.6624)	28	1.32 (0.5513)
Week 24	24	1.14 (0.5037)	26	1.09 (0.4075)	28	1.05 (0.4853)

LPZ: Lansoprazole; SD: Standard deviation; VPZ: Vonoprazan.