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Vonoprazan study In patients with erosive esophagitis to evaluate long-term safety: A study to evaluate the safety of long-term administration of vonoprazan in maintenance treatment in patients with erosive esophagitis (EE)

Vonoprazan study in patients with erosive esophagitis to evaluate long-term safety (VISION Study)

202

The main patient characteristics were as follows: age (mean +- SD) was 60.4 +- 11.81 years in the vonoprazan group (135 subjects), of which 80 subjects (59.3%) were =< 65 years, and 61.5 +- 12.16 years in the lansoprazole group (67 subjects), of which 35 subjects (52.2%) were =<65 years; there were 97 male subjects (71.9%) in the vonoprazan group and 41 male subjects (61.2%) in the lansoprazole group; BMI (mean +- SD) was 25.31 +- 3.721 kg/m^2 in the vonoprazan group, of which 69 subjects (51.1%) had a BMI of >=18.5 to <25.0 kg/m2, and 24.85 +- 3.325 kg/m^2 in the lansoprazole group, of which 38 subjects (56.7%) had a BMI of >=18.5 to <25.0 kg/m^2; as for history of alcohol drinking, 44 subjects (32.6%) in the vonoprazan group and 16 subjects (23.9%) in the lansoprazole group did not drink alcohol; 110 subjects (81.5%) in the vonoprazan group and 48 subjects (71.6%) in the lansoprazole group had caffeine consumption; and the severity of the disease by esophagoscopy at the start of the healing phase was Grade A in 63 subjects (46.7%), Grade B in 49 subjects (36.3%), Grade C in 18 subjects (13.3%), and Grade D in 5 subjects (3.7%) in the vonoprazan group, and Grade A in 33 subjects (49.3%), Grade B in 25 subjects (37.3%), Grade C in 8 subjects (11.9%), and Grade D in 1 subject (1.5%) in the lansoprazole group.

In this study, consent was obtained from 302 subjects of which 209 were randomized. The Safety Data Analysis Set in the healing phase included 208 subjects (139 subjects in the vonoprazan group and 69 subjects in the lansoprazole group), excluding 1 subject who discontinued the study before the start of the treatment. The Safety Data Analysis Set in the maintenance phase included 202 subjects (135 subjects in the vonoprazan group and 67 subjects in the lansoprazole group), excluding 3 subjects who discontinued the study during the healing phase and 3 subjects who did not meet the inclusion/exclusion criteria at the start of the maintenance phase. In total, 158 subjects (105 subjects in the vonoprazan group and 53 subjects in the lansoprazole group) completed the treatment at Week 206 of the maintenance phase.

Overview of TEAEs reported in the research period and display of TEAEs: In the Safety Data Analysis Set in the healing phase, adverse events occurred in 128 subjects (92.1%) in the vonoprazan group (139 subjects) and 65 subjects (94.2%) in the lansoprazole group (69 subjects) during the research period. Common adverse events (Preferred Terms) that occurred during the research period were "gastric polyps" in 62 subjects (44.6%), "nasopharyngitis" in 49 subjects (35.3%), and "gastric mucosal lesion" in 30 subjects (21.6%) in the vonoprazan group, and "gastric polyps" in 31 subjects (44.9%), "nasopharyngitis" in 29 subjects (42.0%), and "gastric mucosal lesion" in 17 subjects (24.6%) in the lansoprazole group. Brief Summary (continued): Regarding the safety, incidences of TEAEs and serious TEAEs in the maintenance phase were comparable to those in the lansoprazole group.

- Gastric mucosa histopathology -- Presence or absence of malignant alteration of epithelial cells In both vonoprazan and lansoprazole groups, malignant alteration was not observed at all time points from the start of the healing phase to Week 260 of the maintenance phase. -- Presence or absence of prominence/hyperplasia of wall cells Numbers of subjects with prominent/hyperplasia of wall cells were 99 subjects (97.1%) in the vonoprazan group and 45 subjects (86.5%) in the lansoprazole group at Week 260 of the maintenance phase. -- Presence or absence of hyperplasia of crypt epithelial cells Numbers of subjects with hyperplasia of crypt epithelial cells were 15 subjects (14.7%) in the vonoprazan group and 1 subject (1.9%) in the lansoprazole group at Week 260 of the maintenance phase. -- Presence or absence of proliferation of endocrine cells The proliferation of endocrine cells was observed in 5 subjects (4.9%) in the vonoprazan group and 4 subjects (7.7%) in the lansoprazole group at Week 260 of the maintenance phase. -- Presence or absence of hyperplasia of G cells Numbers of subjects with hyperplasia of G cells were 87 subjects (85.3%) in the vonoprazan group and 40 subjects (76.9%) in the lansoprazole group at Week 260 of the maintenance phase.

- Endoscopic EE recurrence rates during the maintenance phase The EE recurrence rates were 4 subjects (3.8%; 95% CI, 1.1 - 9.6) in the vonoprazan group and 6 subjects (11.3%; 95% CI, 4.3 - 23.0) in the lansoprazole group at Week 260 of the maintenance phase. - EE healing rates during the healing phase In the Full Analysis Set in the healing phase, EE healing rate [95% CI] was 1.4% (2/139 subjects) [0.2 - 5.1] in the vonoprazan group and 0.0% (0/69 subjects) [0.0 - 5.2] in the lansoprazole group at Week 8 of the healing phase. - Endoscopic findings -- Presence or absence of fundic gland polyp In the Safety Data Analysis Set in the maintenance phase, the numbers of subjects who had endoscopically confirmed "fundic gland polyp" were 75 (72.1%) in the vonoprazan group and 45 (84.9%) in the lansoprazole group at Week 260 of the maintenance phase. -- Presence or absence of hyperplastic polyp In the Safety Data Analysis Set in the maintenance phase, the numbers of subjects with endoscopically confirmed hyperplastic polyp were 24 (23.1%) in the vonoprazan group and 6 (11.3%) in the lansoprazole group at Week 260 of the maintenance phase. -- Presence or absence of cobblestone mucosa In the Safety Data Analysis Set in the maintenance phase, the numbers of subjects who had endoscopically confirmed cobblestone mucosa were 23 (22.1%) in the vonoprazan group and 8 (15.1%) in the lansoprazole group at Week 260 of the maintenance phase. -- Presence or absence of multiple white flat elevation In the Safety Data Analysis Set in the maintenance phase, the numbers of subjects who had endoscopically confirmed multiple white flat elevation were 8 (7.7%) in the vonoprazan group and 9 (17.0%) in the lansoprazole group at Week 260 of the maintenance phase. -- Presence or absence of black spots In the Safety Data Analysis Set in the maintenance phase, the numbers of subjects who had endoscopically confirmed black spots were 8 (7.7%) in the vonoprazan group and 7 (13.2%) in the lansoprazole group at Week 260 of the maintenance phase. - Histological evaluation of gastritis according to the Sydney classification -- Inflammation (mononuclear infiltration) In the Safety Data Analysis Set in the maintenance phase, the numbers of subjects who had inflammation (mononuclear infiltration) of the greater curvature of the middle gastric body by histological evaluation of gastritis according to Sydney classification were 15 (14.7%) in the vonoprazan group and 9 (17.3%) in the lansoprazole group at Week 260 of the maintenance phase. The numbers of subjects with inflammation (mononuclear cell infiltration) of the greater curvature of the antrum were 11 (10.8%) in the vonoprazan group and 9 (17.3%) in the lansoprazole group at Week 260 of the maintenance phase. -- Activity (neutrophilic infiltration) In the Safety Data Analysis Set in the maintenance phase, the numbers of subjects who had activity (neutrophilic infiltration) of the greater curvature of the middle gastric body by histological evaluation of gastritis according to Sydney classification were 1 (1.0%) in the vonoprazan group and 0 (0.0%) in the lansoprazole group at Week 260 of the maintenance phase. The numbers of subjects with activity (neutrophilic infiltration) of the greater curvature of the antrum were 0 (0.0%) in both the vonoprazan group and the lansoprazole group at Week 260 of the maintenance phase. -- Atrophy In the Safety Data Analysis Set in the maintenance phase, the numbers of subjects who had atrophy of the greater curvature of the middle gastric body by histological evaluation of gastritis according to Sydney classification were 0 (0.0%) in both the vonoprazan group and the lansoprazole group at Week 260 of the maintenance phase. The numbers of subjects with atrophy of the greater curvature of the antrum were 7 (6.9%) in the vonoprazan group and 7 (13.5%) in the lansoprazole group at Week 260 of the maintenance phase. -- Intestinal metaplasia In the Safety Data Analysis Set in the maintenance phase, the numbers of subjects with intestinal metaplasia in the greater curvature of the middle gastric body based on histological evaluation of gastritis according to the Sydney classification were 0 (0.0%) in the both the vonoprazan group and the lansoprazole group at Week 260 of the maintenance phase. The numbers of subjects with intestinal metaplasia in the greater curvature of the antrum were 6 (5.9%) in the vonoprazan group and 6 (11.5%) in the lansoprazole group at Week 260 of the maintenance phase. -- H. pylori In the Safety Data Analysis Set in the maintenance phase, the number of subjects with H. pylori in the greater curvature of the middle gastric body based on histological evaluation of gastritis according to the Sydney classification was 0 (0.0%) at Week 260 in both the vonoprazan group (135 subjects) and the lansoprazole group (67 subjects). The number of subjects with H. pylori in the greater curvature of the gastric antrum was 0 (0.0%) in both the vonoprazan group and the lansoprazole group at Week 260 of the maintenance phase. - Incidence of gastric polyp In the Safety Data Analysis Set in the maintenance phase, the incidences of gastric polyp were 82 subjects (78.8%) in the vonoprazan group at Week 260 of the maintenance phase, 46 patients (86.8%) in the lansoprazole group.

The incidences of prominence/hyperplasia of wall cells and hyperplasia of G cells were consistently high after the start of the maintenance phase in both groups. The incidence of hyperplasia of crypt epithelial cells was low during the maintenance phase in both groups; however, it tended to be higher in the vonoprazan group than in the lansoprazole group. The incidence of proliferation of endocrine cells was low during the maintenance phase in both groups, but increased at Week 260 of the maintenance phase.

April. 07, 2023

Jan. 24, 2018

https://www.dovepress.com/rationale-and-design-of-the-vision-study-a-randomized-open-label-study-peer-reviewed-fulltext-article-CEG

Yes

Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

Takeda Pharmaceutical Company Limited

https://www.takeda.com/who-we-are/contact-us/

smb.Japanclinicalstudydisclosure@takeda.com

Takeda Pharmaceutical Company Limited

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smb.Japanclinicalstudydisclosure@takeda.com

completed

Mar. 20, 2016

Interventional

Multicenter, open-label, randomized, parallel-group study

treatment purpose

4

< At the start of healing phase >
1. Participants endoscopically diagnosed with EE of grades A to D by the LA Classification Grading System at the start of treatment (Week 0 of the healing phase)
2. Participants with H. pylori negative
3. Participants who, in the opinion of the principal investigator or investigator, are capable of understanding the content of the clinical research and complying with the research protocol requirements.
4. Participants who can sign and date an informed consent form and information sheet prior to the conduction of the clinical research procedures.
5. Male or female participants aged 20 years or older at the time of informed consent
6. Therapeutic category: Ambulatory

< At the start of maintenance phase >
7. Participants who have endoscopically confirmed EE healing* (mucous membrane disorder is not observed) at completion of the healing phase (Week 4 or 8 of the healing phase)
* Participants who are classified as grade 0 according to severity classification of EE
8. Participants who have been determined to be appropriate as subjects for maintenance treatment of EE by the principal investigator or investigator

< At the start of healing phase >
1. Participants with concurrent peptic ulcer (except scarred stage) or Zollinger-Ellison syndrome
2. Participants who received treatment with PPIs (including vonoprazan) within 4 weeks (Week -4 to Week 0) prior to the start of healing phase (Week 0 of the healing phase)
3. Participants with a history of H. pylori eradication.
4. Participants who have received surgery or treatment affecting gastroesophageal reflux (fundoplication or dilation for esophageal stenosis [excluding Schatzki's ring], etc.)
5. Participants with an esophagus-related complication (eosinophilic esophagitis, esophageal varices, scleroderma, viral or fungal infection, esophageal stenosis, etc.), a history of radiotherapy or cryotherapy of the esophagus, a caustic or physiochemical trauma (esophageal sclerotherapy, etc.). However, participants with Schatzki's ring (mucosal tissue ring around inferior esophageal sphincter) or Barrett's esophagus are allowed to be included.
6. Participants with clinically apparent hepatic impairment (e.g., AST or ALT levels at the time of informed consent: >1.5 times the upper limit of normal (ULN).
7. Participants with renal impairment or renal failure [creatinine clearance (CCr) <30 mL/min, etc.]
8. Participants with a history of hypersensitivity or allergy for PPIs.
9. Participants with a history of gastrectomy, gastrointestinal resection, or vagotomy
10. Participants with a malignant tumor
11. Participants who are pregnant, breast-feeding, possibly pregnant, or planning to become pregnant
12. Participants with one of the diseases listed under administration contraindication in the vonoprazan or lansoprazole package insert
13. Participants planning to take prohibited concomitant medications during the research period
14. Participants participating in other clinical studies
15. Participants who have been determined to be inappropriate as subjects in the study by the principal investigator or investigator

<At the start of maintenance phase >
16. Participants who have taken PPIs other than the study drug or the control drug during the healing phase
17. Participants who have been determined to be inappropriate as subjects in the study by the principal investigator or investigator

Both

Erosive esophagitis

investigational material(s)
Generic name etc : Vonoprazan
INN of investigational material : Vonoprazan
Therapeutic category code : 232 Agents for peptic ulcer
Dosage and Administration for Investigational material : Vonoprazan 20 mg administered orally once daily in the healing phase + vonoprazan 10 mg (as the initial dose and adjusted to vonoprazan 10 mg or 20 mg) administered orally once daily in the maintenance phase

control material(s)
Generic name etc : Lansoprazole
INN of investigational material : Lansoprazole
Therapeutic category code : 232 Agents for peptic ulcer
Dosage and Administration for Investigational material : Lansoprazole 30 mg administered orally once daily in the healing phase + lansoprazole 15 mg (as the initial dose and adjusted to lansoprazole 15 mg or 30 mg) administered orally once daily in the maintenance phase

1. Number of Participants with Malignant Alteration of Epithelial Cells
Timeframe: Up to Week 268 (Week 260 in Maintenance Phase)
Numbers of participants with Malignant alteration of epithelial cells for Vonoprazan group and Lansoprazole group at Week 268 (Week 260 in Maintenance Phase) were reported as the endpoint for gastric mucosa histopathology. The number analyzed is the number of participants with data available for analysis.

2. Number of Participants with Parietal Cell Protrusion/Hyperplasia
Timeframe: Up to Week 268 (Week 260 in Maintenance Phase)
Numbers of participants with parietal cell protrusion/hyperplasia for Vonoprazan group and Lansoprazole group at Week 268 (Week 260 in Maintenance Phase) were reported as the endpoint for gastric mucosa histopathology. The number analyzed is the number of participants with data available for analysis.

3. Number of Participants with Foveolar Hyperplasia
Timeframe: Up to Week 268 (Week 260 in Maintenance Phase)
Numbers of participants with foveolar hyperplasia for Vonoprazan group and Lansoprazole group at Week 268 (Week 260 in Maintenance Phase) were reported as the endpoint for gastric mucosa histopathology. The number analyzed is the number of participants with data available for analysis.

4. Number of Participants with Enterochromaffin-like-cell Hyperplasia
Timeframe: Up to Week 268 (Week 260 in Maintenance Phase)
Numbers of participants with enterochromaffin-like-cell hyperplasia for Vonoprazan group and Lansoprazole group at Week 268 (Week 260 in Maintenance Phase) were reported as the endpoint for gastric mucosa histopathology. The number analyzed is the number of participants with data available for analysis.

5. Number of Participants with G-cell Hyperplasia
Timeframe: Up to Week 268 (Week 260 in Maintenance Phase)
Numbers of participants with G-cell hyperplasia for Vonoprazan group and Lansoprazole group at Week 268 (Week 260 in Maintenance Phase) were reported as the endpoint for gastric mucosa histopathology. The number analyzed is the number of participants with data available for analysis.

1. Percentage of Participants with Recurrence of Erosive Esophagitis (EE)
Time Frame: Up to Week 268 (Week 260 in Maintenance Phase)
Erosive esophagitis recurrence is defined as endoscopically confirmed to have erosive esophagitis (LA classification grades O and A to D) during the Maintenance Phase. The LA classification graded as follows- Grade O: normal mucosa; Grade A: nonconfluent mucosal breaks <5 mm in length; Grade B: nonconfluent mucosal breaks >=5mm in length; Grade C: confluent mucosal breaks <75% circumferential; Grade D: confluent mucosal breaks >75% circumferential.

2. Percentage of Participants who Healed EE at the End of the Healing Phase
Time Frame: Up to Week 8
Percentage of participants who healed EE at the end of healing phase was reported.

3. Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) in Maintenance Phase
Time Frame: 260 weeks (Baseline, up to the end of Maintenance Phase)
Number of participants reporting one or more TEAEs in Maintenance Phase was reported. An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.

4. Number of Participants with Fundic Gland Polyp
Timeframe: Up to Week 268 (Week 260 in Maintenance Phase)
Numbers of participants with fundic gland polyp for Vonoprazan group and Lansoprazole group at Week 268 (Week 260 in Maintenance Phase) were reported as the endpoint for endoscopic findings. The number analyzed is the number of participants with data available for analysis.

5. Number of Participants with Hyperplastic Polyp
Timeframe: Up to Week 268 (Week 260 in Maintenance Phase)
Numbers of participants with hyperplastic polyp for Vonoprazan group and Lansoprazole group at Week 268 (Week 260 in Maintenance Phase) were reported as the endpoint for endoscopic findings. The number analyzed is the number of participants with data available for analysis.

6. Number of Participants with Cobblestone Mucosa
Timeframe: Up to Week 268 (Week 260 in Maintenance Phase)
Numbers of participants with cobblestone mucosa for Vonoprazan group and Lansoprazole group at Week 268 (Week 260 in Maintenance Phase) were reported as the endpoint for endoscopic findings. The number analyzed is the number of participants with data available for analysis.

7. Number of Participants with Multiple White and Flat Elevated Lesions
Timeframe: Up to Week 268 (Week 260 in Maintenance Phase)
Numbers of participants with multiple white and flat elevated lesions for Vonoprazan group and Lansoprazole group at Week 268 (Week 260 in Maintenance Phase) were reported as the endpoint for endoscopic findings. The number analyzed is the number of participants with data available for analysis.

8. Number of Participants with Black Spots
Timeframe: Up to Week 268 (Week 260 in Maintenance Phase)
Numbers of participants with black spots for Vonoprazan group and Lansoprazole group at Week 268 (Week 260 in Maintenance Phase) were reported as the endpoint for endoscopic findings. The number analyzed is the number of participants with data available for analysis.

9. Number of Participants with Inflammation (Mononuclear Infiltration) in Greater Curvature of Middle Gastric Body
Timeframe: Up to Week 268 (Week 260 in Maintenance Phase)
Numbers of participants with inflammation (mononuclear infiltration) in greater curvature of the middle gastric body for Vonoprazan group and Lansoprazole group at Week 268 (Week 260 in Maintenance Phase) were reported as histological assessment of gastritis.

10. Number of Participants with Inflammation (Mononuclear Infiltration) in Greater Curvature of Antrum
Timeframe: Up to Week 268 (Week 260 in Maintenance Phase)
Numbers of participants with inflammation (mononuclear infiltration) in greater curvature of the antrum for Vonoprazan group and Lansoprazole group at Week 268 (Week 260 in Maintenance Phase) were reported as histological assessment of gastritis.

11. Number of Participants with Neutrophilic Infiltration in Greater Curvature of Middle Gastric Body
Timeframe: Up to Week 268 (Week 260 in Maintenance Phase)
Numbers of participants with neutrophilic infiltration in greater curvature of middle gastric body for Vonoprazan group and Lansoprazole group at Week 268 (Week 260 in Maintenance Phase) were reported as histological assessment of gastritis.

12. Number of Participants with Neutrophilic Infiltration in Greater Curvature of Antrum
Timeframe: Up to Week 268 (Week 260 in Maintenance Phase)
Numbers of participants with neutrophilic infiltration in greater curvature of antrum for Vonoprazan group and Lansoprazole group at Week 268 (Week 260 in Maintenance Phase) were reported as histological assessment of gastritis.

13. Number of Participants with Atrophy in Greater Curvature of Middle Gastric Body
Timeframe: Up to Week 268 (Week 260 in Maintenance Phase)
Numbers of participants with atrophy in greater curvature of middle gastric body for Vonoprazan group and Lansoprazole group at Week 268 (Week 260 in Maintenance Phase) were reported as histological assessment of gastritis.

14. Number of Participants with Atrophy in Greater Curvature of Antrum
Timeframe: Up to Week 268 (Week 260 in Maintenance Phase)
Numbers of participants with atrophy in greater curvature of antrum for Vonoprazan group and Lansoprazole group at Week 268 (Week 260 in Maintenance Phase) were reported as histological assessment of gastritis.

15. Number of Participants with Intestinal Metaplasia in Greater Curvature of Middle Gastric Body
Timeframe: Up to Week 268 (Week 260 in Maintenance Phase)
Numbers of participants with intestinal metaplasia in greater curvature of middle gastric body for Vonoprazan group and Lansoprazole group at Week 268 (Week 260 in Maintenance Phase) were reported as histological assessment of gastritis.

16. Number of Participants with Intestinal Metaplasia in Greater Curvature of Antrum
Timeframe: Up to Week 268 (Week 260 in Maintenance Phase)
Numbers of participants with intestinal metaplasia in greater curvature of antrum for Vonoprazan group and Lansoprazole group at Week 268 (Week 260 in Maintenance Phase) were reported as histological assessment of gastritis.

17. Number of Participants with Presence of H.pylori in Greater Curvature of Middle Gastric Body
Timeframe: Up to Week 268 (Week 260 in Maintenance Phase)
Numbers of participants with presence of H.pylori in greater curvature of middle gastric body for Vonoprazan group and Lansoprazole group at Week 268 (Week 260 in Maintenance Phase) were reported as histological assessment of gastritis.

18. Number of Participants with Presence of H.pylori in Greater Curvature of Antrum
Timeframe: Up to Week 268 (Week 260 in Maintenance Phase)
Numbers of participants with presence of H.pylori in greater curvature of antrum for Vonoprazan group and Lansoprazole group at Week 268 (Week 260 in Maintenance Phase) were reported as histological assessment of gastritis.

19. Number of Participants with Gastric Polyp
Timeframe: Up to Week 268 (Week 260 in Maintenance Phase)
Numbers of participants with gastric polyp for Vonoprazan group and Lansoprazole group at Week 268 (Week 260 in Maintenance Phase) were reported. The number analyzed is the number of participants with data available for analysis.

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Jan. 20, 2016