Phase 3 Study of TAK-438 10 mg in the Treatment of Non-Erosive Gastroesophageal Reflux Disease (NERD)

A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase 3 Study to Evaluate the Efficacy and Safety of Oral TAK-438 10 mg Once-daily in the Treatment of Non-Erosive Gastroesophageal Reflux Disease

The purpose of this study was to evaluate the efficacy and safety of oral TAK-438 10 mg once-daily in the treatment of non-erosive gastroesophageal reflux disease (NERD).

A phase 3, randomized, double-blind, placebo-controlled, parallel-group, multi-center study will be conducted to verify the superiority of TAK-438 (TAK-438 10 mg, once daily, 4 weeks) to placebo (placebo, once daily, 4 weeks) in participants with non-erosive gastroesophageal reflux disease (NERD).

The study consists of a 1-week, single-blind run-in period and a 4-week, double-blind treatment period. The participants will receive the study drug (TAK-438 placebo tablet) for the 1-week single-blind run-in period. After the run-in period, eligible participants will be randomized into TAK-438 10 mg or placebo treatment groups in a 1:1 ratio. The randomized participants will receive the assigned study drug (TAK-438 10 mg tablet or placebo tablet) for the 4-week double-blind treatment period.

Inclusion Criteria:

1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.

2. The participant signs and dates a written informed consent form prior to the initiation of any study procedures.

3. The participant with NERD.

4. The participant is endoscopically confirmed to have the modified Los Angeles (LA) Classification Grade N or M at the start of the run-in period (Visit 1).

   To allow efficacy evaluation in the participants with Grade N as well as in those with Grade M, the target number of participants in each grade is at least 30% of the total number of participants. Enrollment of patients with either Grade N or M will end when the number of enrolled participants with each grade exceeds 332, or 70% of the total planned number of participants.

5. The participant experiences recurrent heartburn, on at least 2 days a week over the last 3 weeks prior to the start of the run-in period (Visit 1).

6. The participant is either a male or female outpatient with a minimum age of 20 years at the time of informed consent signing. However, participants who are hospitalized only for examination purposes are also allowed to participate.

7. A female participant of childbearing potential agrees to use routinely adequate contraception from signing of informed consent throughout the duration of the study, and for 4 weeks after the last dose of study drug.

8. The participant's compliance to the study drug has been good (75% or better) in the run-in period.

9. The participant has experienced heartburn on at least 2 days in the last 1 week prior to randomization.

10. The participant has appropriately provided in the patient's diary all the required information during the run-in period.

Exclusion Criteria:

1. The participant has received any investigational compound within 84 days prior to the first dose of study drug.

2. The participant has received TAK-438 in a previous clinical study or as a therapeutic agent, except one with experience of receiving TAK-438 as an adjunct therapy for H. pylori eradication, who can be enrolled in this study.

3. The participant 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. The participant has donated at least 400 mL of blood within the 90 days prior to the start of the run-in period (Visit 1).

5. Endoscopic examination for entering this study fails to diagnose NERD within 84 days before the start of the run-in period (Visit 1).

6. The participant has any complications affecting the esophagus, including Barrett's esophagus (3 cm or more, long segment Barrett's esophagus [LSBE]), eosinophilic esophagitis, esophageal varices, scleroderma, viral or fungal infection, and esophageal stenosis; a history of radiation therapy or cryotherapy for the esophagus; or caustic or physiochemical trauma (eg, esophageal sclerotherapy). However, participants with Barrett's mucosa (less than 3 cm, short segment Barrett's esophagus [SSBE]) or Schatzki's ring (a mucosal tissue ring lining the inferior esophageal sphincter) are permitted to participate.

7. The participant has a history of surgery or treatment affecting gastroesophageal reflux, including fundoplication and mechanical dilatation for esophageal stenosis (except Schatzki's ring), or a history of gastric or duodenal surgery (except endoscopic removal of benign polyps).

8. The participant has acute upper gastrointestinal bleeding or gastric or duodenal ulcer, characterized by a defective mucosa with white coating, within 30 days prior to the start of the run-in period (Visit 1). However, participants with gastric or duodenal erosion are permitted to participate.

9. The participant has acute gastritis or acute exacerbation of chronic gastritis.

10. The participant has, or has a history of, Zollinger-Ellison syndrome or gastric acid hypersecretion disorders.

11. The participant has, or has a history of chest pain due to cardiac disease, or has chest pain suspectedly caused by cardiac disease within 1 year prior to the start of the run-in period (Visit 1).

12. The participant has any other concurrent upper gastrointestinal symptoms more severe than heartburn.

13. The participant has depression.

14. The participant has, has a history of, or is suspected of functional upper gastrointestinal disorders, such as functional dyspepsia and functional heartburn diagnosed by the Rome IV criteria.

15. The participant has a history of hypersensitivity or allergies to TAK-438 (including the formulation excipients).

16. The participant has a history or complication of drug abuse (defined as any illicit drug use) or of alcohol abuse within 1 years prior to the start of the run-in period (Visit 1).

17. The participant requires any excluded medications or treatments.

18. The female participant who is pregnant, is lactating, or is intending to become pregnant or to donate ova any time between the informed consent signing and 4 weeks after the last dose of study drug.

19. The participant has any serious neurological, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, endocrinological, or hematologic diseases.

20. The participant needs surgery requiring hospitalization during the course of the study, or surgery requiring hospitalization is scheduled for the participant during the course of the study.

21. The participant has a history of malignancy or is treated for malignancy within 5 years prior to the start of the run-in period (Visit 1). However, participants who have recovered completely from cutaneous basal cell carcinoma or from cervical carcinoma in situ are permitted to participate.

22. The participant has acquired immunodeficiency syndrome (AIDS) or hepatitis, is a human immunodeficiency virus (HIV) carrier, or tested positive for the hepatitis B virus surface antigen (HBsAg) or the hepatitis C virus (HCV) antibody. However, participants who tested negative for HCV antigen or HCV-RNA are permitted to participate.

23. The participant has any of the following abnormal clinical laboratory test values at the start of the run-in period (Visit 1):

    • Creatinine > 2 mg/dL.
    • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > upper limit of normal (ULN).
    • Bilirubin (Total bilirubin) > ULN.