Efficacy and Safety of Vonoprazan Compared to Lansoprazole in the Maintenance Treatment of Erosive Esophagitis

A Randomized, Double-Blind, Double-Dummy, Parallel-group Phase 3 Study to Evaluate the Efficacy and Safety of Oral Once-Daily Administration of TAK-438 10 or 20 mg Compared to Lansoprazole 15 mg in the Maintenance Treatment of Subjects With Endoscopic Healing of Erosive Esophagitis

This is a comparative study of vonoprazan (TAK-438) (10 mg or 20 mg) in participants in whom endoscopic healing of erosive esophagitis has been confirmed with vonoprazan or adequate treatment with a proton pump inhibitor (PPI), to demonstrate the non-inferiority of vonoprazan to lansoprazole in their maintenance treatment (6 months or 24 weeks) as well as to determine the clinically recommended dose for vonoprazan for maintenance therapy in erosive esophagitis.

The drug being tested in this study is called vonoprazan. Vonoprazan is being tested as a maintenance treatment for people with healed erosive esophagitis (EE). This study will look at participants in whom endoscopic healing of erosive esophagitis has been confirmed with vonoprazan or adequate treatment with a proton pump inhibitor (PPI), to demonstrate the non-inferiority of vonoprazan to Lansoprazole in their maintenance treatment (6 months or 24 weeks) as well as to determine the clinically recommended dose for vonoprazan for maintenance therapy in erosive esophagitis.

The study will enroll approximately 693 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the three treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need):

• TAK-438 10 mg
• TAK-438 20 mg
• Lansoprazole 15 mg

Participants with ongoing erosive esophagitis (EE) will receive lansoprazole 30 mg once daily for 4 or 8 weeks (the Healing phase) until healing of EE is confirmed by endoscopy performed at either Week -4 and/or Day 1 before eligible for randomization to maintenance phase. In Maintenance phase, participants with confirming EE healing will be asked to take 2 tablets and a capsule at the same time each morning after breakfast throughout the study. All participants will be asked to record daytime and nighttime (during sleep) subjective symptoms in a diary on a daily basis.

This multi-centre trial will be conducted worldwide. The overall time to participate in this study is 8 months. Participants will make multiple visits to the clinic, and will be contacted by telephone 7-14 days after last dose of study drug for a follow-up assessment.

Inclusion Criteria:

1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.
3. Has been confirmed on endoscopy to have had erosive esophagitis [Los Angeles (LA) classification grades A to D] within 84 days of Day 1.
4. If the participant is not rolled over from TAK-438_303 study, he/she has undergone an open-label Proton pump inhibitor (PPI) treatment (Lansoprazole 30 mg, once daily) of 4 or 8 weeks within the TAK-438_305 protocol.
5. Has been confirmed on endoscopy to have healing of erosive esophagitis. This endoscopy, if not part of the TAK-438_303 study, must have been within the last 14 days prior to randomization, otherwise the endoscopy must be repeated to confirm healing before randomization in the TAK-438_305 study.
6. Is aged 18 years old or older (or the local age of consent if that is older), male or female, at the time of signing an informed consent, and is being treated on an outpatient basis for erosive esophagitis, including those temporarily admitted for examination.
7. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent throughout the duration of the study and for 4 weeks after last dose of study medication.

Exclusion Criteria:

1. Has received any investigational compound (other than study TAK-438_303) within 84 days prior to screening phase.

2. Has received TAK-438 in a previous clinical study (other than study TAK-438_303) or as a therapeutic agent.

3. Is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress.

4. Has, in the judgment of the investigator, clinically significant abnormal hematological parameters of hemoglobin, hematocrit, or erythrocytes at Screening.

5. Has a history or clinical manifestations of significant central nervous system (CNS), cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urological, endocrine or hematological disease.

6. Has a history of hypersensitivity or allergies to TAK-438 or to proton pump inhibitors (PPIs) including any associated excipients.

7. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 1 year prior to the start the screening phase.

8. Is required to take excluded medications.

9. If female, the participant is pregnant or lactating or intending to become pregnant before, during, or within 1 month after participating in this study; or intending to donate ova during such time period.

10. Has participated in another clinical study (other than study TAK-438_303) within the past 30 days from Visit 1.

11. Has co-morbidities that could affect the esophagus (eosinophilic esophagitis, esophageal varices, scleroderma, viral or fungal infection, esophageal strictures), a history of radiotherapy or cryotherapy for the esophagus; those with corrosive or physiochemical injury (with the possible inclusion in the study of those with Schatzki's ring or Barrett's esophagus).

12. Has a history of surgical procedures that may affect the esophagus (eg, fundoplication and mechanical dilatation for esophageal strictures excluding Schatzki's ring) or a history of gastric or duodenal surgery excluding endoscopic removal of benign polyps.

13. Developed acute upper gastrointestinal bleeding, gastric ulcer (a mucosal defect with white coating) or duodenal ulcer (a mucosal defect with white coating), within 30 days before the start of the Screening Phase (Visit 1) (with the possible inclusion of those with gastric or duodenal erosion). Participants requiring non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin treatment along with the concomitant PPI therapy to prevent gastrointestinal (GI) bleeding should not be enrolled.

14. Has Zollinger-Ellison syndrome or gastric acid hypersecretion or a history of gastric acid hypersecretion.

15. Is scheduled for surgery that requires hospitalization or requires surgical treatment during his/her participation in the study.

16. Has a history of malignancy or was treated for malignancy within 5 years before the start of the Screening Phase (visit 1) (the participant may be included in the study if he/she has cured cutaneous basal cell carcinoma or cervical carcinoma in situ).

17. Has acquired immunodeficiency syndrome (AIDS) or hepatitis, including hepatitis virus carriers (hepatitis B surface antigen [HBsAg] or hepatitis C virus (HCV)-antibody-positive) (the participant may be included in the study if he/she is HCV-antigen or HCV-ribonucleic acid [RNA]-negative).

18. Laboratory tests performed on visit 1 revealed any of the following abnormalities in the participant:

    1. Creatinine levels: >2 mg/dL (>177 μmol/L).
    2. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST), or total bilirubin levels: > upper limit of normal (ULN).