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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Erosive Esophagitis

Intervention / Treatment
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* Drug: Vonoprazan
* Drug: Lansoprazole
* Drug: Vonoprazan Placebo
* Drug: Lansoprazole Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements. 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. Has been confirmed on endoscopy to have had erosive esophagitis [Los Angeles (LA) classification grades A to D] within 84 days of Day 1. 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. 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. 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. 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: Has received any investigational compound (other than study TAK-438_303) within 84 days prior to screening phase. Has received TAK-438 in a previous clinical study (other than study TAK-438_303) or as a therapeutic agent. 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. Has, in the judgment of the investigator, clinically significant abnormal hematological parameters of hemoglobin, hematocrit, or erythrocytes at Screening. Has a history or clinical manifestations of significant central nervous system (CNS), cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urological, endocrine or hematological disease. Has a history of hypersensitivity or allergies to TAK-438 or to proton pump inhibitors (PPIs) including any associated excipients. 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. Is required to take excluded medications. 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. Has participated in another clinical study (other than study TAK-438_303) within the past 30 days from Visit 1. 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). 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. 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. Has Zollinger-Ellison syndrome or gastric acid hypersecretion or a history of gastric acid hypersecretion. Is scheduled for surgery that requires hospitalization or requires surgical treatment during his/her participation in the study. 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). 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). Laboratory tests performed on visit 1 revealed any of the following abnormalities in the participant: Creatinine levels: >2 mg/dL (>177 μmol/L). Alanine aminotransferase (ALT) or aspartate aminotransferase (AST), or total bilirubin levels: > upper limit of normal (ULN).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vonoprazan 10 mg<br>Lansoprazole 30 mg, capsules or tablets, orally, once, daily, for up to 4 or 8 weeks or until confirmed healing of erosive esophagitis (EE) in healing phase for participants with ongoing EE. Vonoprazan 10 mg, tablets, orally, once, daily, and Vonoprazan 20 mg, placebo-matching tablets, orally, once, daily, and Lansoprazole 15 mg placebo-matching, capsules, orally, once, daily, for up to 24 weeks in maintenance phase for participants with confirmed EE healing. | Drug: Vonoprazan<br>* Vonoprazan tablets<br>* Other names: TAK-438;Drug: Lansoprazole<br>* Lansoprazole capsules or tablets<br>* Other names: Prevacid;Drug: Vonoprazan Placebo<br>* Vonoprazan placebo-matching tablets<br>Drug: Lansoprazole Placebo<br>* Lansoprazole placebo-matching capsules<br>|
| Experimental: Vonoprazan 20 mg<br>Lansoprazole 30 mg, capsules or tablets, orally, once, daily, for up to 4 or 8 weeks or until confirmed healing of erosive esophagitis (EE) in healing phase for participants with ongoing EE. Vonoprazan 20 mg, tablets, orally, once, daily, and Vonoprazan 10 mg, placebo-matching tablets, orally, once, daily, and Lansoprazole 15 mg, placebo-matching capsules, orally, once, daily, for up to 24 weeks in maintenance phase for participants with confirmed EE healing | Drug: Vonoprazan<br>* Vonoprazan tablets<br>* Other names: TAK-438;Drug: Lansoprazole<br>* Lansoprazole capsules or tablets<br>* Other names: Prevacid;Drug: Vonoprazan Placebo<br>* Vonoprazan placebo-matching tablets<br>Drug: Lansoprazole Placebo<br>* Lansoprazole placebo-matching capsules<br>|
| Active Comparator: Lansoprazole 15 mg<br>Lansoprazole 30 mg, capsules or tablets, orally, once, daily, for up to 4 or 8 weeks or until confirmed healing of erosive esophagitis (EE) in healing phase for participants with ongoing EE. Lansoprazole 15 mg, capsules, orally, once, daily, and Vonoprazan 10 mg, placebo-matching tablets, orally, once, daily, and Vonoprazan 20 mg, placebo-matching tablets, orally, once, daily, for up to 24 weeks in maintenance phase for participants with confirmed EE healing. | Drug: Lansoprazole<br>* Lansoprazole capsules or tablets<br>* Other names: Prevacid;Drug: Vonoprazan Placebo<br>* Vonoprazan placebo-matching tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Recurrence of Erosive Esophagitis as Confirmed on Endoscopy After the 24-week Maintenance Phase | Erosive esophagitis recurrence is defined as participants endoscopically confirmed to have erosive esophagitis (Los Angeles [LA] classification grades A to D) during the Maintenance Phase (24 weeks). Grade A: >/=1 mucosal breaks </=5 mm, none of which extends between the tops of the mucosal folds; Grade B: >/=1 mucosal breaks >5 mm, none of which extends between the tops of two mucosal folds; Grade C: mucosal breaks that extend between the tops of two or more mucosal folds, but which involve <75% of esophageal circumference; Grade D: mucosal breaks which involve >/=75% of esophageal circumference. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Recurrence of Erosive Esophagitis After 12 Weeks of Treatment in the Maintenance Phase | Erosive esophagitis recurrence is defined as endoscopically confirmed to have erosive esophagitis (LA classification grades A to D) during the Maintenance Phase (12 weeks). Grade A: >/=1 mucosal breaks </=5 mm, none of which extends between the tops of the mucosal folds; Grade B: >/=1 mucosal breaks >5 mm, none of which extends between the tops of two mucosal folds; Grade C: mucosal breaks that extend between the tops of two or more mucosal folds, but which involve <75% of esophageal circumference; Grade D: mucosal breaks which involve >/=75% of esophageal circumference. | 12 weeks | 
| Number of Participants With Adverse Events (AEs) | An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product; 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. | From Day 1 to 14 days after the last dose of study medication (up to 26 weeks) | 
| Number of Participants With Abnormal Clinical Laboratory Findings | Clinical laboratory safety tests included chemistry, hematology and urinalysis. Number of participants with any markedly abnormal values in laboratory tests collected throughout study is reported. ALT = alanine aminotransferase, AST = aspartate aminotransferase, GGT = gamma-glutamyl transferase, CPK = creatine phosphokinase, BUN = blood urea nitrogen, LLN = lower limit of normal or lower reference limit, ULN = upper limit of normal or upper reference limit, g/L = grams per liter, U/L = units per liter, mmol/L = millimoles per liter, pmol/L = picomoles per liter. | From Day 1 to 14 days after the last dose of study medication (up to 26 weeks) | 
| Number of Participants With Abnormal Electrocardiogram (ECG) Findings | Number of participants with any markedly abnormal 12-lead ECG findings is reported. bpm = beats per minute, msec = milliseconds, CHG= change from baseline. | From Day 1 to 14 days after the last dose of study medication (up to 26 weeks) | 
| Number of Participants With Abnormal Vital Sign Measurements | The percentage of participants with any markedly abnormal vital sign measurements including (body temperature, blood pressure and pulse), mmHg = millimeters of mercury. | From Day 1 to 14 days after the last dose of study medication (up to 26 weeks) | 
| Change From Baseline in Serum Gastrin |  | Baseline and Weeks 4, 12 and 24 | 
| Change From Baseline in Serum Pepsinogen I |  | Baseline and Weeks 4, 12 and 24 | 
| Change From Baseline in Serum Pepsinogen II |  | Baseline and Weeks 4, 12 and 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug therapy