Vonoprazan Study in Patients With Erosive Esophagitis to Evaluate Long-term Safety

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)

The purpose of this study is exploratorily evaluate the effect on gastric mucosal tissue and the safety of long-term administration (260 weeks: 5 years) of vonoprazan 10 mg or 20 mg in patients receiving maintenance treatment after healed erosive esophagitis (EE), and the curative effect of vonoprazan 20 mg versus lansoprazole in patients with EE.

Study Overview

• Status: Completed
• Conditions: Erosive Esophagitis
• Intervention / Treatment: Drug: Vonoprazan; Drug: Lansoprazole

Detailed Description

This is a multicenter, open-label, randomized, parallel-group study to exploratorily evaluate the effect on gastric mucosal tissue and the safety of long-term administration of vonoprazan in maintenance treatment after healed EE, and the curative effect of vonoprazan versus lansoprazole in participants with EE.

Participants endoscopically diagnosed with EE of Los Angeles (LA) Classification Grades A to D at the start of treatment (Week 0 of the healing phase) will be randomly assigned to receive either vonoprazan 20 mg or lansoprazole 30 mg to be taken once daily for up to 8 weeks. Subjects with healed EE as confirmed endoscopically at Week 4 or 8 in the healing phase will enter the maintenance phase.

In the maintenance phase, the vonoprazan group and the lansoprazole group will be administered a starting dose of 10 mg and 15 mg, respectively, once daily up to 260 weeks.

If the principal investigator or investigator judged the effect of vonoprazan 10 mg or lansoprazole 15 mg to be insufficient as the maintenance treatment of EE, vonoprazan and lansoprazole may be increased to 20 mg and 30 mg, respectively.

The research period will consist of two subperiods: healing phase in which participants with EE will receive treatment (for 4 or 8 weeks) and maintenance phase in which participants will receive maintenance treatment (for 260 weeks), and thus, a total of up to 268 weeks. The number of visits will be a maximum of 18 visits. Planned number of research subjects, as the number of research subjects for entry to the maintenance phase, will be 130 participants in the vonoprazan group and 65 participants in the lansoprazole group.

• Study Type: Interventional
• Enrollment (Actual): 208
• Phase: Phase 4

Contacts and Locations

Study Locations

• Japan
  • Fukuoka, Japan
    • Chihaya Hospital
  • Fukuoka, Japan
    • Harada Hospital
  • Fukuoka, Japan
    • Kimura Shiro Clinic
  • Fukuoka, Japan
    • Kyushu University Hospital
  • Fukuoka, Japan
    • Mori Clinic
  • Kumamoto, Japan
    • Hanabata Clinic
  • Kumamoto, Japan
    • Morinaga Ueno Clinic
  • Kyoto, Japan
    • Oki Hospital
  • Oita, Japan
    • Arita Hospital
  • Okayama, Japan
    • Asahigaoka Hospital
  • Okayama, Japan
    • Kawasaki Hospital
  • Shizuoka, Japan
    • Matsuki Clinic
  • Yamagata, Japan
    • Oizumi Medical Clinic
  • Chiba
    • Abiko, Chiba, Japan
      • Tokatsu Tsujinaka Hospital
    • Ichikawa, Chiba, Japan
      • Hohnodai Hospital National Center For Global Health and Medicine
  • Ehime
    • Matsuyama, Ehime, Japan
      • Red Cross Matsuyama Hospital
  • Fukuoka
    • Kama, Fukuoka, Japan
      • Kawakubo Clinic
  • Hokkaido
    • Hakodate, Hokkaido, Japan
      • Hakodate Hospital
  • Hyogo
    • Kobe, Hyogo, Japan
      • Aoyama Medical Clinic
    • Nishinomiya, Hyogo, Japan
      • Hyogo College of Medicine
  • Kagawa
    • Takamatsu, Kagawa, Japan
      • KKR Takamatsu Hospital
  • Miyagi
    • Sendai, Miyagi, Japan
      • Shirane Clinic
    • Sendai, Miyagi, Japan
      • Tohoku University Hospital
  • Oita
    • Beppu, Oita, Japan
      • Shin-Beppu Hospital
  • Okayama
    • Kurashiki, Okayama, Japan
      • Kawasaki Medical University
  • Shiga
    • Otsu, Shiga, Japan
      • Shiga Hospital
    • Otsu, Shiga, Japan
      • Shiga University Of Medical Science Hospital
  • Shimane
    • Izumo, Shimane, Japan
      • Shimane University Hospital
  • Shizuoka
    • Izunokuni, Shizuoka, Japan
      • Juntendo University Shizuoka Hospital
    • Yaizu, Shizuoka, Japan
      • Kohga Hospital
  • Tochigi
    • Otawara, Tochigi, Japan
      • Masuyama Clinic
  • Tokyo
    • Bunkyo-ku, Tokyo, Japan
      • Juntendo University Hospital
    • Ota-ku, Tokyo, Japan
      • Banno Clinic
    • Setagaya-ku, Tokyo, Japan
      • Shimokitazawa Tomo Clinic
    • Shinjyuku-ku, Tokyo, Japan
      • National Center for Global Health and Medicine
    • Shinjyuku-ku, Tokyo, Japan
      • Nippon Medical School Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

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

   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 (See Table 9.b)

8. Participants who have been determined to be appropriate as subjects for maintenance treatment of EE by the principal investigator or investigator

Exclusion Criteria:

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

    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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vonoprazan group; 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	Drug: Vonoprazan; Vonoprazan fumarate 10 mg or 20 mg capsules
Active Comparator: Lansoprazole group; 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	Drug: Lansoprazole; Lansoprazole 15 mg or 30 mg capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Malignant Alteration of Epithelial Cells	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.	Time Frame: Up to Week 268 (Week 260 in Maintenance Phase)
Number of Participants With Parietal Cell Protrusion/Hyperplasia	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.	Up to Week 268 (Week 260 in Maintenance Phase)
Number of Participants With Foveolar Hyperplasia	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.	Up to Week 268 (Week 260 in Maintenance Phase)
Number of Participants With Enterochromaffin-like-cell Hyperplasia	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.	Up to Week 268 (Week 260 in Maintenance Phase)
Number of Participants With G-cell Hyperplasia	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.	Up to Week 268 (Week 260 in Maintenance Phase)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Recurrence of Erosive Esophagitis (EE)	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.	Up to Week 268 (Week 260 in Maintenance Phase)
Percentage of Participants Who Healed EE at the End of Healing Phase	Percentage of participants who healed EE at the end of healing phase was reported.	Up to Week 8
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) in 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 TEAE is defined as an adverse event with an onset that occurs after receiving study drug.	260 weeks (Baseline, up to the end of Maintenance Phase)
Number of Participants With Fundic Gland Polyp	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.	Up to Week 268 (Week 260 in Maintenance Phase)
Number of Participants With Hyperplastic Polyp	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.	Up to Week 268 (Week 260 in Maintenance Phase)
Number of Participants With Cobblestone Mucosa	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.	Up to Week 268 (Week 260 in Maintenance Phase)
Number of Participants With Multiple White and Flat Elevated Lesions	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.	Up to Week 268 (Week 260 in Maintenance Phase)
Number of Participants With Black Spots	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.	Up to Week 268 (Week 260 in Maintenance Phase)
Number of Participants With Inflammation (Mononuclear Infiltration) in Greater Curvature of Middle Gastric Body	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.	Up to Week 268 (Week 260 in Maintenance Phase)
Number of Participants With Inflammation (Mononuclear Infiltration) in Greater Curvature of Antrum	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.	Up to Week 268 (Week 260 in Maintenance Phase)
Number of Participants With Neutrophilic Infiltration in Greater Curvature of Middle Gastric Body	Numbers of participants with neutrophilic 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.	Up to Week 268 (Week 260 in Maintenance Phase)
Number of Participants With Neutrophilic Infiltration in Greater Curvature of Antrum	Numbers of participants with neutrophilic 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.	Up to Week 268 (Week 260 in Maintenance Phase)
Number of Participants With Atrophy in Greater Curvature of Middle Gastric Body	Numbers of participants with atrophy 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.	Up to Week 268 (Week 260 in Maintenance Phase)
Number of Participants With Atrophy in Greater Curvature of Antrum	Numbers of participants with atrophy 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.	Up to Week 268 (Week 260 in Maintenance Phase)
Number of Participants With Intestinal Metaplasia in Greater Curvature of Middle Gastric Body	Numbers of participants with intestinal metaplasia 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.	Up to Week 268 (Week 260 in Maintenance Phase)
Number of Participants With Intestinal Metaplasia in Greater Curvature of Antrum	Numbers of participants with intestinal metaplasia 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.	Up to Week 268 (Week 260 in Maintenance Phase)
Number of Participants With Presence of H.Pylori in Greater Curvature of Middle Gastric Body	Numbers of participants with presence of H.pylori 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.	Up to Week 268 (Week 260 in Maintenance Phase)
Number of Participants With Presence of H.Pylori in Greater Curvature of Antrum	Numbers of participants with presence of H.pylori 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.	Up to Week 268 (Week 260 in Maintenance Phase)
Number of Participants With Gastric Polyp	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.	Up to Week 268 (Week 260 in Maintenance Phase)

Collaborators and Investigators

• Sponsor: Takeda
• Investigators: Study Director: Study Director, Takeda

Publications and helpful links

Helpful Links

• To obtain more information on the study, click here/on this link

Study record dates

Study Major Dates

• Study Start (Actual): March 20, 2016
• Primary Completion (Actual): March 5, 2022
• Study Completion (Actual): March 5, 2022

Study Registration Dates

• First Submitted: February 8, 2016
• First Submitted That Met QC Criteria: February 8, 2016
• First Posted (Estimated): February 10, 2016

Study Record Updates

• Last Update Posted (Estimated): December 13, 2023
• Last Update Submitted That Met QC Criteria: December 10, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Esophagitis
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Esophageal Diseases; Esophagitis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Gastrointestinal Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Dexlansoprazole; Lansoprazole
• Other Study ID Numbers: Vonoprazan-4003; U1111-1178-8948 (Registry Identifier: WHO); JapicCTI-163153 (Registry Identifier: JapicCTI)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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.
• IPD Sharing Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No