Efficacy and Safety of Oral Once-Daily Vonoprazan (TAK-438) in Participants With Erosive Esophagitis

A Randomized, Double-Blind, Double-Dummy Phase 3 Study to Evaluate the Efficacy and Safety of Oral Once-Daily Administration of TAK-438 20 mg Compared to Lansoprazole 30 mg in the Treatment of Subjects With Erosive Esophagitis

The purpose of the study is to demonstrate the efficacy of vonoprazan (TAK-438) versus lansoprazole in the treatment of erosive esophagitis classified as Los Angeles (LA) classification grades A to D at Week 8.

Study Overview

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

Detailed Description

The drug being tested in this study is called vonoprazan. Vonoprazan is being tested to treat people who have erosive esophagitis. This study will look at mucosal healing of people who take vonoprazan versus lansoprazole.

This study will enroll approximately 480 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need):

• Vonoprazan 20 mg
• Lansoprazole 30 mg

All participants will be asked to take one tablet and one capsule at the same time each day 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-center trial will be conducted worldwide. The overall time to participate in this study is up to 11 weeks. 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.

• Study Type: Interventional
• Enrollment (Actual): 481
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Beijing, China
  • Beijing, China, 100050
    • Beijing Friendship Hospital, Capital Medical University
  • Chongqing, China
    • The Second Affiliated Hospital of Chongqing Medical University
  • Hangzhou, China
    • 1st Affiliated Hospital of Zhejiang University
  • Nanchang, China
    • The First Affiliated Hospital of Nanchang University
  • Nanjing, China, 210008
    • The Affiliated DrumTower Hospital of Nanjing University
  • Tianjin, China
  • Beijing
    • Beijing, Beijing, China, 100029
      • China-Japan Friendship Hospital
    • Beijing, Beijing, China, 100032
      • Peking Union Medical College Hospital
    • Beijing, Beijing, China, 100020
      • Beijing Chao Yang Hospital
    • Beijing, Beijing, China, 100370
      • Beijing Tongren Hospital, Capital Medical Univeristy
    • Beijing, Beijing, China, 100700
      • PLA.The Military General Hospital of Beijing
  • Fujian
    • Fuzhou, Fujian, China, 350100
      • Fuzhou General hospital of Nanjing Military Command
  • Guangdong
    • Guangzhou, Guangdong, China, 510080
      • The First Affiliated Hospital, Sun Yat-sen University
    • Guangzhou, Guangdong, China, 510080
      • Guangdong General Hospital
  • Hubei
    • Wuhan, Hubei, China, 430022
      • Union Hospital of Tongji Medical College of Huazhong Science and Techology University
    • Wuhan, Hubei, China, 430030
      • Tongji Hospital, Tongji Medical College, Huazhong University of Science & Techology
  • Hunan
    • Changsha, Hunan, China, 410011
      • The 2nd Xiangya Hospital Central South University
    • Chenzhou, Hunan, China, 432000
      • Chenzhou No.1 people's Hospital
  • Jiangsu
    • Changzhou City, Jiangsu, China, 213003
      • The First People's Hospital of Changzhou
    • Nanjing, Jiangsu, China, 210029
      • Jiangsu Province People's Hospital
  • Jilin
    • Changchun, Jilin, China, 130041
      • No.2 Hospital Affiliated to Jilin University
    • Jilin, Jilin, China, 132011
      • Jilin Central Hospital
  • Ningxia
    • Yinchuan, Ningxia, China, 750004
      • General Hospital of Ningxia Medical University
  • Shanghai
    • Shanghai, Shanghai, China, 200032
      • Zhongshan Hospital Fudan University
    • Shanghai, Shanghai, China, 200025
      • Ruijin Hospital, Shanghai Jiaotong Uni. School of Med.
    • Shanghai, Shanghai, China, 200065
      • Tongji Hospital of Tongji University
  • Tianjin
    • Tianjin, Tianjin, China, 300052
      • Tianjin Medical University General Hospital
    • Tianjin, Tianjin, China, 300211
      • The 2nd Hospital of Tianjin Medical University
  • Yunnan
    • Kunming, Yunnan, China, 650032
      • The First Affiated Hospital of Kunming Medical College
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310016
      • Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine
    • Hangzhou, Zhejiang, China, 310009
      • 2nd Affiliated Hospital, Zhejiang Univ. School of Medicine
• Korea, Republic of
  • Busan, Korea, Republic of, 49241
    • Pusan National University Hospital
  • Daegu, Korea, Republic of, 42415
    • Yeungnam University Hospital
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center
  • Seoul, Korea, Republic of, 02447
    • Kyung Hee University Hospital
  • Seoul, Korea, Republic of, 02841
    • Korea University Anam Hospital
  • Seoul, Korea, Republic of, 06351
    • Samsung Medical Center
  • Seoul, Korea, Republic of, 03181
    • Kangbuk Samsung Hospital
  • Seoul, Korea, Republic of, 06591
    • The Catholic University of Korea, Seoul St. Marys Hospital
  • Gyeonggi-do
    • Seongnam-si, Gyeonggi-do, Korea, Republic of, 13620
      • Seoul National University Bundang Hospital
    • Seoul, Gyeonggi-do, Korea, Republic of, 03080
      • Seoul National University Hospital
  • Gyeongsangbuk-do
    • Daegu, Gyeongsangbuk-do, Korea, Republic of, 41404
      • Kyungpook National University Medical Center
  • Jeollabuk-do
    • Iksan-si, Jeollabuk-do, Korea, Republic of, 54538
      • Wonkwang University School of Medicine & Hospital
• Malaysia
  • Kelantan, Malaysia, 16150
    • Hospital Universiti Sains Malaysia
  • Kuala Lumpur, Malaysia, 50586
    • Hospital Kuala Lumpur
  • Kuala Lumpur, Malaysia, 59100
    • University Malaya Medical Centre
  • Kedah
    • Alor Setar, Kedah, Malaysia, 5460
      • Hospital Sultana Bahiyah
  • Kelantan
    • Kota Bahru, Kelantan, Malaysia, 15586
      • Hospital Raja Perempuan Zainab Ii
  • Pahang
    • Kuantan, Pahang, Malaysia, 25100
      • Hospital Tengku Ampuan Afzan
  • Sabah
    • Kota Kinabalu, Sabah, Malaysia, 88586
      • Hospital Queen Elizabeth
  • Selangor
    • Ampang, Selangor, Malaysia, 68000
      • Hospital Ampang
• Taiwan
  • Kaohsiung, Taiwan, 807
    • Kaohsiung Medical University Chung-Ho Memorial Hospital
  • Kaohsiung, Taiwan, 833
    • Kaohsiung Chang Gung Memorial Hospital
  • Kaohsiung, Taiwan, 824
    • E-Da Hospital
  • Taichung, Taiwan, 402
    • Chung Shan Medical University Hospital
  • Taichung, Taiwan, 333
    • China Medical University Hospital
  • Taichung, Taiwan, 407
    • Cheng Ching General Hospital-Chung Kang Branch
  • Tainan, Taiwan, 704
    • National Cheng Kung University Hospital
  • Taipei, Taiwan, 100
    • National Taiwan University Hospital
  • Taipei, Taiwan, 114
    • Tri-Service General Hospital
  • Taipei, Taiwan, 112
    • Taipei Veterans General Hospital
  • Taipei City, Taiwan, 110
    • Taipei Medical University Hospital
  • Taoyuan County, Taiwan, 333
    • Chang Gung Memorial Hospital, Linkou

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 in an endoscopy to have erosive esophagitis, ie, the Los Angeles (LA) classification grades A to D within 7 days of the start of the Day 1 (Visit 2).

   Note: The recruitment goal is to ensure that those with LA classification grade C/D will account for more than 30% of all participants enrolled (144/480), with no further recruitment of those with grade A/B considered when they account for more than 70% (336/480) of all participants.

4. 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 admitted temporarily for examination.
5. 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.

Exclusion Criteria:

1. Has received any investigational compound within 84 days prior to the start of the Observation phase.
2. Has received TAK-438 in a previous clinical study or as a therapeutic agent.
3. Is an immediate family member, study site employee, or is in a dependant 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 serious central nerve system (CNS), cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urological, endocrine or hematological disease.

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

   *D-mannitol, crystalline cellulose, hydroxypropyl cellulose, fumaric acid, croscarmellose sodium, magnesium stearate, hypromellose, macrogol 6000, titanium oxide, yellow iron sesquioxide and iron sesquioxide.

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 Observation Phase (Visit 1).
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 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 Observation Phase (Visit 1) (with the possible inclusion of those with gastric or duodenal erosion).
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 Observation 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) positive, 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 at the start of the Early Observation Phase (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).
19. Is active in the Screening Period after the closure of enrollment identified by the Sponsor or the number of participants randomized with LA classification A/B or C/D have reached the required sample size.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vonoprazan 20 mg; Vonoprazan 20 mg, tablet, orally, once daily and lansoprazole placebo-matching capsule, orally, once daily for up to 8 weeks.	Drug: Vonoprazan; Vonoprazan tablets; Other Names: TAK-438; Drug: Lansoprazole Placebo; Lansoprazole placebo-matching capsules
Active Comparator: Lansoprazole 30 mg; Lansoprazole 30 mg, capsule, orally, once daily and vonoprazan placebo-matching tablet, orally, once daily for up to 8 weeks.	Drug: Lansoprazole; Lansoprazole capsules; Other Names: Prevacid; Drug: Vonoprazan Placebo; Vonoprazan placebo-matching tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Endoscopic Healing of Erosive Esophagitis During the 8-Week Treatment Phase	Endoscopic healing is defined as participants endoscopically diagnosed as Los Angeles classification grade O during the treatment phase. Grade O indicates there are no mucosal breaks in the mucosa.	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Endoscopic Healing of Erosive Esophagitis After 2 Weeks and 4 Weeks of Treatment	Endoscopic healing is defined as participants endoscopically diagnosed as Los Angeles classification grade O during the treatment phase. Grade O indicates there are no mucosal breaks in the mucosa.	Week 2 and Week 4
Number of Participants Reporting Who Had One or More Treatment-emergent Adverse Event (TEAE)	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.	On or after the start of study drug (Day 1) to 14 days after the last dose of study medication (up to 10 weeks)
Number of Participants With Markedly 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 10 weeks)
Number of Participants With Markedly 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 10 weeks)
Number of Participants With Markedly Abnormal Vital Sign Measurements	Number of participants with any markedly abnormal vital signs measurements is reported. Vital signs included body temperature (oral, tympanic, or infra-axillary measurement), sitting blood pressure (5 minutes), and pulse. °C = degrees Celsius, mmHg = millimeters of mercury, bpm = beats per minute.	From Day 1 to 14 days after the last dose of study medication (up to 10 weeks)
Change From Baseline in Serum Gastrin	The change between the serum gastrin values collected at Weeks 2, 4, and 8 relative to baseline.	Baseline and Weeks 2, 4, and 8
Change From Baseline in Serum Pepsinogen I	The change between the serum pepsinogen I values collected at Weeks 2, 4, and 8 relative to baseline.	Baseline and Weeks 2, 4, and 8
Change From Baseline in Serum Pepsinogen II	The change between the serum pepsinogen II values collected at Weeks 2, 4, and 8 relative to baseline.	Baseline and Weeks 2, 4, and 8

Collaborators and Investigators

• Sponsor: Takeda

Publications and helpful links

General Publications

• Xiao Y, Zhang S, Dai N, Fei G, Goh KL, Chun HJ, Sheu BS, Chong CF, Funao N, Zhou W, Chen M. Phase III, randomised, double-blind, multicentre study to evaluate the efficacy and safety of vonoprazan compared with lansoprazole in Asian patients with erosive oesophagitis. Gut. 2020 Feb;69(2):224-230. doi: 10.1136/gutjnl-2019-318365. Epub 2019 Aug 13.

Study record dates

Study Major Dates

• Study Start (Actual): March 24, 2015
• Primary Completion (Actual): July 27, 2017
• Study Completion (Actual): July 27, 2017

Study Registration Dates

• First Submitted: March 9, 2015
• First Submitted That Met QC Criteria: March 9, 2015
• First Posted (Estimate): March 17, 2015

Study Record Updates

• Last Update Posted (Actual): June 3, 2019
• Last Update Submitted That Met QC Criteria: February 22, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: Drug therapy
• 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: TAK-438_303; U1111-1138-4788 (Registry Identifier: UTN (WHO)); CTR20150040 (Registry Identifier: CNDA CTR)

Drug and device information, study documents

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