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

Primary Purpose

Non-erosive Gastroesophageal Reflux Disease

Status

Completed

Phase

Phase 3

Locations

Japan

Study Type

Interventional

Intervention

Placebo

TAK-438 10 mg

About this trial

This is an interventional treatment trial for Non-erosive Gastroesophageal Reflux Disease focused on measuring Drug therapy

Eligibility Criteria

20 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
The participant signs and dates a written informed consent form prior to the initiation of any study procedures.
The participant with NERD.
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.
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).
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.
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.
The participant's compliance to the study drug has been good (75% or better) in the run-in period.
The participant has experienced heartburn on at least 2 days in the last 1 week prior to randomization.
The participant has appropriately provided in the patient's diary all the required information during the run-in period.

Exclusion Criteria:

The participant has received any investigational compound within 84 days prior to the first dose of study drug.
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.
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.
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).
Endoscopic examination for entering this study fails to diagnose NERD within 84 days before the start of the run-in period (Visit 1).
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.
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).
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.
The participant has acute gastritis or acute exacerbation of chronic gastritis.
The participant has, or has a history of, Zollinger-Ellison syndrome or gastric acid hypersecretion disorders.
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).
The participant has any other concurrent upper gastrointestinal symptoms more severe than heartburn.
The participant has depression.
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.
The participant has a history of hypersensitivity or allergies to TAK-438 (including the formulation excipients).
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).
The participant requires any excluded medications or treatments.
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.
The participant has any serious neurological, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, endocrinological, or hematologic diseases.
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.
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.
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.
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.

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Experimental

Arm Label

Placebo

TAK-438 10 mg

Arm Description

TAK-438 placebo-matching tablets, orally, once daily after breakfast for 1 week in run-in period followed by TAK-438 placebo-matching tablets, orally, once daily after breakfast for up to 4 weeks in treatment period.

TAK-438 placebo-matching tablets, orally, once daily after breakfast for 1 week in run-in period followed by TAK-438 10 mg tablets, orally, once daily after breakfast for up to 4 weeks in treatment period.

Outcomes

Primary Outcome Measures

Percentage of Days Without Symptoms of Heartburn

Cumulative Rate of Improvement in Symptoms of Heartburn

Heartburn symptoms were collected by participant diaries. Participants recorded the presence and severity (Without symptom [No symptom: 0, No hindrance to daily activities: 1], With symptom [Mild: 2, Moderate: 3, Severe: 4]) of heartburn in a daily participant diary. The score range was 0-4, with the higher scores reflecting the greater severity. Cumulative rate of improvement was calculated as percentage of participants who experienced symptom improvement. Symptom improvement was defined as symptoms experienced on less than 2 days of the last 7 days. The cumulative data was collected between Day 0 and Day 24 and is reported for the following time points: Days 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24. Data not collected were shown as NA = Not Applicable.

Severity of Symptoms of Heartburn

Secondary Outcome Measures

Percentage of Days Without Symptoms of Heartburn in Subgroup Stratified by Response (Improved or Not Improved) at Week 2

Participants recorded the presence and severity of heartburn in a daily participant diary. Percentage of days without heartburn was calculated in each subgroup of the response (improved or not improved) according to Criteria 1, i.e. Improved: the participants experienced heartburn on less than 2 days of the 7 days prior to Week 2 [Day 8 through Day 14]; Not improved: the participants experienced heartburn on 2 days or more of the 7 days prior to Week 2 [Day 8 through Day 14] and Criteria 2, i.e. Improved: the proportion of days the participants experienced heartburn during the treatment period up to Week 2 [Day 14] was lower than that during the run-in period; Not improved: the proportion of days the participants experienced heartburn during the treatment period up to Week 2 [Day 14] was equal to or larger than that during the run-in period.

Cumulative Rate of Improvement in Symptoms of Heartburn in Subgroup Stratified by Response (Improved Per Criteria 1) at Week 2

Participants recorded presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in daily participant diary. The score range was 0-4, with the higher scores reflecting the greater severity. Cumulative rate of improvement was calculated as percentage of participants who experienced symptom improvement. The response was evaluated per Criteria 1, i.e. Improved: the participants experienced heartburn on less than 2 days of the 7 days prior to Week 2 [Day 8 through Day 14]; Not improved: the participants experienced heartburn on 2 days or more of the 7 days prior to Week 2 [Day 8 through Day 14]. Cumulative data was collected between Day 0 and Day 22 and is reported for following time points: Days 0, 1, 2, 3, 4, 5, 6, 7, 8, 11, 15, 16, 17, 18, 19, 20, 21, and 22. Data not collected were shown as NA = Not Applicable.

Cumulative Rate of Improvement in Symptoms of Heartburn in Subgroup Stratified by Response (Not Improved Per Criteria 1) at Week 2

Participants recorded presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in daily participant diary. The score range was 0-4, with the higher scores reflecting the greater severity. Cumulative rate of improvement is calculated as percentage of participants who experienced symptom improvement. The response was evaluated per Criteria 1, i.e. Improved: the participants experienced heartburn on less than 2 days of the 7 days prior to Week 2 [Day 8 through Day 14]; Not improved: the participants experienced heartburn on 2 days or more of the 7 days prior to Week 2 [Day 8 through Day 14]. Cumulative data was collected between Day 0 and Day 24 and is reported for following time points: Days 0, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and 24. Data not collected were shown as NA = Not Applicable.

Cumulative Rate of Improvement in Symptoms of Heartburn in Subgroup Stratified by Response (Improved Per Criteria 2) at Week 2

Participants recorded presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in daily participant diary. The score range was 0-4, with higher scores reflecting the greater severity. Cumulative rate of improvement calculated as percentage of participants who experienced symptom improvement. Response evaluated per Criteria 2, i.e. Improved: proportion of days participant experienced heartburn during treatment period up to Week 2 [Day 14] was lower than that during run-in period; Not improved: proportion of days participants experienced heartburn during treatment period up to Week 2 [Day 14] was equal to or larger than that during the run-in period. Cumulative data was collected between Day 0 and Day 24 and is reported for following time points: Days 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24. Data not collected were shown as NA=Not Applicable.

Cumulative Rate of Improvement in Symptoms of Heartburn in Subgroup Stratified by Response (Not Improved Per Criteria 2) at Week 2

Participants recorded presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in daily participant diary. The score range was 0-4, with higher scores reflecting the greater severity. Cumulative rate of improvement calculated as percentage of participants who experienced symptom improvement. The response evaluated per Criteria 2, i.e. Improved: proportion of days participant experienced heartburn during treatment period up to Week 2 [Day 14] was lower than that during run-in period; Not improved: proportion of days participants experienced heartburn during treatment period up to Week 2 [Day 14] was equal to or larger than that during run-in period. Cumulative data was collected between Day 0 and Day 24 and is reported for following time points: Days 0, 5, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24. Data not collected shown as NA=Not Applicable.

Severity of Symptoms of Heartburn in Subgroup Stratified by Response (Improved or Not Improved) at Week 2

Participants recorded the presence and severity (Without symptom [No symptom: 0, No hindrance to daily activities: 1], With symptom [Mild: 2, Moderate: 3, Severe: 4]) of heartburn in a daily participant diary. The score range was 0-4, the higher scores indicates greater severity. The severity was calculated in each subgroup of response (improved or not improved) according to Criteria 1, i.e. Improved: participants experienced heartburn on less than 2 days of the 7 days prior to Week 2 [Day 8 through Day 14]; Not improved: participants experienced heartburn on 2 days or more of the 7 days prior to Week 2 [Day 8 through Day 14] and Criteria 2, i.e. Improved: proportion of days the participants experienced heartburn during the treatment period up to Week 2 [Day 14] was lower than that during the run-in period; Not improved: proportion of days the participants experienced heartburn during the treatment period up to Week 2 [Day 14] was equal to or larger than that during the run-in period.

Percentage of Days Without Symptoms of Heartburn in Subgroup Stratified by Endoscopic Findings (the Modified LA Classification Grade N or M) at Baseline

Heartburn symptoms were collected by participant diaries. Participants recorded the presence and severity (Without symptom [No symptom: 0, No hindrance to daily activities: 1], With symptom [Mild: 2, Moderate: 3, Severe: 4]) of heartburn in a daily participant diary. The score range was 0-4, higher scores indicates greater severity. The percentage was calculated in each subgroup of the endoscopic findings where Grade N: normal mucosa; Grade M: minimal changes to the mucosa, such as erythema and/or whitish turbidity; Grade A: non-confluent mucosal breaks <5mm in length; Grade B: non-confluent mucosal breaks ≥5mm in length; Grade C: confluent mucosal breaks <75% circumferential; Grade D: confluent mucosal breaks >75% circumferential.

Cumulative Rate of Improvement in Heartburn in Subgroup Stratified by Endoscopic Findings (the Modified LA Classification Grade N) at Baseline

Participants recorded presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in participant diary. The score range was 0-4, higher scores indicates greater severity. Cumulative rate of improvement calculated as percentage of participants who experienced symptom improvement. Cumulative rate calculated in subgroup of Grade N per modified LA classification. Modified LA classification Grade N: normal mucosa; Grade M: minimal changes to mucosa; Grade A: nonconfluent mucosal breaks <5mm in length; Grade B: non-confluent mucosal breaks ≥5mm in length; Grade C: confluent mucosal breaks <75% circumferential; Grade D: confluent mucosal breaks >75% circumferential. Cumulative data collected between Day 0 and 24 and reported for time points: Days 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and 24. Data not collected shown as NA=Not Applicable.

Cumulative Rate of Improvement in Heartburn in Subgroup Stratified by Endoscopic Findings (the Modified LA Classification Grade M) at Baseline

Participants recorded presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in participant diary. Score range was 0-4, higher scores indicates greater severity. Cumulative rate of improvement calculated as percentage of participants who experienced symptom improvement. Cumulative rate calculated in subgroup of Grade M per modified LA classification. Modified LA classification Grade N: normal mucosa; Grade M: minimal changes to mucosa; Grade A: nonconfluent mucosal breaks <5mm in length; Grade B: non-confluent mucosal breaks ≥5mm in length; Grade C: confluent mucosal breaks <75% circumferential; Grade D: confluent mucosal breaks >75% circumferential. Cumulative data collected between Day 0 and 24 and reported for time points: Days 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and 24. Data not collected shown as NA=Not Applicable.

Severity of Symptoms of Heartburn in Subgroup Stratified by Endoscopic Findings (the Modified LA Classification Grade N or M) at Baseline

Heartburn symptoms were collected by participant diaries. Participants recorded the presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in a daily participant diary. The score range was 0-4, with the higher scores reflecting the greater severity. The severity of heartburn was calculated in each subgroup of the endoscopic findings where Grade N: normal mucosa; Grade M: minimal changes to the mucosa, such as erythema and/or whitish turbidity; Grade A: non-confluent mucosal breaks <5mm in length; Grade B: non-confluent mucosal breaks ≥5mm in length; Grade C: confluent mucosal breaks <75% circumferential; Grade D: confluent mucosal breaks >75% circumferential.

Percentage of Days Without Symptoms of Heartburn Stratified by Subgroup of Both the Response at Week 2 and the Endoscopic Findings (the Modified LA Classification Grade N or M)

Heartburn symptoms were collected by participant diaries. Participants recorded the presence and severity (Without symptom [No symptom: 0, No hindrance to daily activities: 1], With symptom [Mild: 2, Moderate: 3, Severe: 4]) of heartburn in a daily participant diary. The score range was 0-4, higher scores indicates greater severity. The percentage was calculated in each subgroup (response; Grade N and improved, response; Grade N and not improved, response; Grade M and improved, response; Grade M and not improved) according to Criteria 1 and 2. The modified LA classification Grade N indicates the participants with normal mucosa and Grade M indicates the participants with minimal changes to the mucosa.

Cumulative Rate of Improvement in Symptoms of Heartburn in Subgroup Stratified by Both the Response (Improved Per Criteria 1) at Week 2 and the Endoscopic Findings (the Modified LA Classification Grade N)

Participants recorded the presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in participant diary. Score range was 0-4, higher scores indicates greater severity. Cumulative rate of improvement calculated as percentage of participants who experienced symptom improvement. Response was evaluated per Criteria 1, i.e. Improved: participants experienced heartburn on less than 2 days of 7 days prior to Week 2 [Day 8 through Day 14]; Not improved: participants experienced heartburn on 2 days or more of the 7 days prior to Week 2 [Day 8 through Day 14]. Modified LA classification Grade N: normal mucosa and Grade M: minimal changes to the mucosa. Cumulative data was collected between Day 0 and Day 22 and is reported for following time points: Days 0, 1, 2, 3, 4, 5, 6, 7, 8, 11, 19, 20, and 22. Data not collected were shown as NA=Not Applicable.

Cumulative Rate of Improvement in Symptoms of Heartburn in Subgroup Stratified by Both the Response (Not Improved Per Criteria 1) at Week 2 and the Endoscopic Findings (the Modified LA Classification Grade N)

Participants recorded presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in participant diary. Score range was 0-4, higher scores indicates greater severity. Cumulative rate of improvement calculated as percentage of participants who experienced symptom improvement. Response was evaluated per Criteria 1, i.e. Improved: participants experienced heartburn on less than 2 days of 7 days prior to Week 2 [Day 8 through Day 14]; Not improved: participants experienced heartburn on 2 days or more of 7 days prior to Week 2 [Day 8 through Day 14]. Modified LA classification Grade N indicates participants with normal mucosa and Grade M indicates participants with minimal changes to mucosa). Cumulative data was collected between Day 0 and Day 22 and is reported for following time points: Days 0, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 and 22. Data not collected were shown as NA=Not Applicable.

Participants recorded presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in participant diary. Score range was 0-4, higher score indicates greater severity. Cumulative rate of improvement calculated as percentage of participants who experienced symptom improvement. Response was evaluated per Criteria 1, i.e. Improved: participants experienced heartburn on less than 2 days of 7 days prior to Week 2 [Day 8 through Day 14]; Not improved: participants experienced heartburn on 2 days or more of 7 days prior to Week 2 [Day 8 through Day 14]. Modified LA classification Grade N indicates participants with normal mucosa and Grade M indicates participants with minimal changes to mucosa). Cumulative data collected between Day 0 and Day 22 and is reported for following time points: Days 0, 1, 2, 3, 4, 5, 6, 7, 8, 11, 15, 16, 17, 18, 20, 21 and 22. Data not collected were shown as NA=Not Applicable.

Participants recorded presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in a daily participant diary. Score range was 0-4, higher score indicates greater severity. Cumulative rate of improvement calculated as percentage of participants who experienced symptom improvement. Response evaluated per Criteria 1, i.e. Improved: participants experienced heartburn on < 2 days of the 7 days prior to Week 2 [Day 8 to 14]; Not improved: participants experienced heartburn on >= 2 days of 7 days prior to Week 2 [Day 8 to 14]. Modified LA classification Grade N indicates participants with normal mucosa and Grade M indicates participants with minimal changes to mucosa). Cumulative data collected between Day 0 and 24 and reported for following time points: Days 0, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24. Data not collected were shown as NA=Not Applicable.

Cumulative Rate of Improvement in Symptoms of Heartburn in Subgroup Stratified by Both the Response (Improved Per Criteria 2) at Week 2 and the Endoscopic Findings (the Modified LA Classification Grade N)

Participants recorded presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in participant diary. Score range was 0-4, higher score indicates greater severity. Cumulative rate of improvement calculated as percentage of participants who experienced symptom improvement. Response was evaluated per Criteria 2, i.e. Improved: participants experienced heartburn during treatment period up to Week 2 [Day 14] was lower than during run-in period; Not improved: participants experienced heartburn during treatment period up to Week 2 [Day 14] was equal to or larger than during run-in period. Modified LA classification Grade N: normal mucosa and Grade M: minimal changes to mucosa). Cumulative data collected between Day 0 and 22 and reported for following time points: Days 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, and 22. Data not collected shown as NA=Not Applicable.

Cumulative Rate of Improvement in Symptoms of Heartburn in Subgroup Stratified by Both the Response (Not Improved Per Criteria 2) at Week 2 and the Endoscopic Findings (the Modified LA Classification Grade N)

Participants recorded presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in participant diary. Score range was 0-4, higher score indicates greater severity. Cumulative rate of improvement was calculated as percentage of participants who experienced symptom improvement. Response was evaluated per Criteria 2, i.e. Improved: participants experienced heartburn during treatment period up to Week 2 [Day 14] was lower than during run-in period; Not improved: participants experienced heartburn during treatment period up to Week 2 [Day 14] was equal to or larger than during run-in period. Modified LA classification Grade N: normal mucosa and Grade M: minimal changes to mucosa. Cumulative data was collected between Day 0 and Day 24 and is reported for following time points: Days 0, 5, 9, 11, 12, 13, 14, 19, 20, 21, 22, 23, and 24. Data not collected were shown as NA=Not Applicable.

Participants recorded presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in participant diary. Score range was 0-4, higher score indicates greater severity. Cumulative rate of improvement calculated as percentage of participants who experienced symptom improvement. Response was evaluated per Criteria 2, i.e. Improved: participants experienced heartburn during treatment period up to Week 2 [Day 14] was lower than during run-in period; Not improved: participants experienced heartburn during treatment period up to Week 2 [Day 14] was equal or larger than during run-in period. Modified LA classification Grade N: normal mucosa and Grade M: minimal changes to mucosa. Cumulative data collected between Day 0 and 24 and reported for following time points: Days 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24. Data not collected shown as NA=Not Applicable.

Participants recorded presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe: 4]) of heartburn in participant diary. Score range was 0-4, higher score indicates greater severity. Cumulative rate of improvement calculated as percentage of participants who experienced symptom improvement. Response was evaluated per Criteria 2, i.e. Improved: participants experienced heartburn during treatment period up to Week 2 [Day 14] was lower than during run-in period; Not improved: participants experienced heartburn during treatment period up to Week 2 [Day 14] was equal to or larger than during run-in period. Modified LA classification Grade N: normal mucosa and Grade M: minimal changes to mucosa). Cumulative data was collected between Day 0 and Day 23 and is reported for following time points: Days 0, 9, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, and 23. Data not collected shown as NA=Not Applicable.

Severity of Symptoms of Heartburn in Subgroup Stratified by Both the Response at Week 2 and the Endoscopic Findings (the Modified LA Classification Grade N or M)

Heartburn symptoms were collected by participant diaries. Participants recorded the presence and severity (Without symptom [No symptom: 0, No hindrance to daily activities: 1], With symptom [Mild: 2, Moderate: 3, Severe: 4]) of heartburn in a daily participant diary. The score range was 0-4, with the higher scores reflecting the greater severity. The mean severity of heartburn was calculated in each subgroup (response; Grade N and improved, response; Grade N and not improved, response; Grade M and improved, response; Grade M and not improved) according to criteria 1 and 2. The modified LA classification Grade N indicates the participants with normal mucosa and Grade M indicates the participants with minimal changes to the mucosa.

Percentage of Days Without Symptoms of Heartburn in Subgroup Stratified by Response (Improved or Not Improved) to Acid Suppressants in Participants Who Had a Medication History

Heartburn symptoms were collected by participant diaries. Participants recorded the presence and severity (Without symptom [No symptom: 0, No hindrance to daily activities: 1], With symptom [Mild: 2, Moderate: 3, Severe: 4]) of heartburn in a daily participant diary. The score range was 0-4, higher score indicates greater severity. The percentage was calculated in each subgroup of the response (improved or not improved) in the participants who had a medication history of any of acid suppressants. The acid suppressants include proton pump inhibitors [PPIs], histamine H2-receptor antagonists [H2RAs], or other agents [anticholinergics or anti-gastrin drugs].

Cumulative Rate of Improvement in Symptoms of Heartburn in Subgroup Stratified by Response (Improved) to Acid Suppressants in Participants Who Had a Medication History

Participants recorded presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in participant diary. Score range was 0-4, higher score indicates greater severity. Cumulative rate of improvement calculated as percentage of participants who experienced symptom improvement. Cumulative improvement rate calculated in each subgroup of the response (improved or not improved) in participants who had medication history of any of acid suppressants. Acid suppressants include proton pump inhibitors [PPIs], histamine H2-receptor antagonists [H2RAs], or other agents [anticholinergics or anti-gastrin drugs]. Cumulative data collected between Day 0 and Day 23 and is reported for following time points: Days 0, 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 and 23. Data not collected were shown as NA=Not Applicable.

Cumulative Rate of Improvement in Symptoms of Heartburn in Subgroup Stratified by Response (Not Improved) to Acid Suppressants in Participants Who Had a Medication History

Participants recorded presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in participant diary. Score range was 0-4, higher score indicates greater severity. Cumulative rate of improvement calculated as percentage of participants who experienced symptom improvement. Cumulative improvement rate calculated in each subgroup of the response (improved or not improved) in participants who had medication history of any of acid suppressants. Acid suppressants include proton pump inhibitors [PPIs], histamine H2-receptor antagonists [H2RAs], or other agents [anticholinergics or anti-gastrin drugs]. Cumulative data was collected between Day 0 and Day 23 and is reported for following time points: Days 0, 1, 5, 9, 16, 19, and 20. Data not collected were shown as NA=Not Applicable.

Severity of Symptoms of Heartburn in Subgroup Stratified by Response (Improved or Not Improved) to Acid Suppressants in Participants Who Had a Medication History

Heartburn symptoms were collected by participant diaries. Participants recorded the presence and severity (Without symptom [No symptom: 0, No hindrance to daily activities: 1], With symptom [Mild: 2, Moderate: 3, Severe: 4]) of heartburn in a daily participant diary. The score range was 0-4, with the higher scores reflecting the greater severity. The mean severity of heartburn was calculated in each subgroup of the response (improved or not improved) in the participants who had a medication history of any of acid suppressants. The acid suppressants include proton pump inhibitors [PPIs], histamine H2-receptor antagonists [H2RAs], or other agents [anticholinergics or anti-gastrin drugs].

Full Information

NCT ID

NCT02954848

First Posted

November 1, 2016

Last Updated

June 16, 2019

Sponsor

Takeda

1. Study Identification

Unique Protocol Identification Number

NCT02954848

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

June 2019

Overall Recruitment Status

Completed

Study Start Date

November 15, 2016 (Actual)

Primary Completion Date

February 25, 2018 (Actual)

Study Completion Date

February 26, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Takeda

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

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).

Detailed Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Non-erosive Gastroesophageal Reflux Disease

Keywords

Drug therapy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

484 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Arm Title

TAK-438 10 mg

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

TAK-438 placebo-matching tablets

Intervention Type

Drug

Intervention Name(s)

TAK-438 10 mg

Intervention Description

TAK-438 tablets

Primary Outcome Measure Information:

Title

Percentage of Days Without Symptoms of Heartburn

Description

Time Frame

Up to Week 4

Title

Cumulative Rate of Improvement in Symptoms of Heartburn

Description

Time Frame

Day 0 to Day 24

Title

Severity of Symptoms of Heartburn

Description

Time Frame

Up to Week 4

Secondary Outcome Measure Information:

Title

Percentage of Days Without Symptoms of Heartburn in Subgroup Stratified by Response (Improved or Not Improved) at Week 2

Description

Time Frame

Up to Week 4

Title

Cumulative Rate of Improvement in Symptoms of Heartburn in Subgroup Stratified by Response (Improved Per Criteria 1) at Week 2

Description

Time Frame

Day 0 to Day 22

Title

Cumulative Rate of Improvement in Symptoms of Heartburn in Subgroup Stratified by Response (Not Improved Per Criteria 1) at Week 2

Description

Participants recorded presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in daily participant diary. The score range was 0-4, with the higher scores reflecting the greater severity. Cumulative rate of improvement is calculated as percentage of participants who experienced symptom improvement. The response was evaluated per Criteria 1, i.e. Improved: the participants experienced heartburn on less than 2 days of the 7 days prior to Week 2 [Day 8 through Day 14]; Not improved: the participants experienced heartburn on 2 days or more of the 7 days prior to Week 2 [Day 8 through Day 14]. Cumulative data was collected between Day 0 and Day 24 and is reported for following time points: Days 0, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and 24. Data not collected were shown as NA = Not Applicable.

Time Frame

Day 0 to Day 24

Title

Cumulative Rate of Improvement in Symptoms of Heartburn in Subgroup Stratified by Response (Improved Per Criteria 2) at Week 2

Description

Participants recorded presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in daily participant diary. The score range was 0-4, with higher scores reflecting the greater severity. Cumulative rate of improvement calculated as percentage of participants who experienced symptom improvement. Response evaluated per Criteria 2, i.e. Improved: proportion of days participant experienced heartburn during treatment period up to Week 2 [Day 14] was lower than that during run-in period; Not improved: proportion of days participants experienced heartburn during treatment period up to Week 2 [Day 14] was equal to or larger than that during the run-in period. Cumulative data was collected between Day 0 and Day 24 and is reported for following time points: Days 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24. Data not collected were shown as NA=Not Applicable.

Time Frame

Day 0 to Day 24

Title

Cumulative Rate of Improvement in Symptoms of Heartburn in Subgroup Stratified by Response (Not Improved Per Criteria 2) at Week 2

Description

Participants recorded presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in daily participant diary. The score range was 0-4, with higher scores reflecting the greater severity. Cumulative rate of improvement calculated as percentage of participants who experienced symptom improvement. The response evaluated per Criteria 2, i.e. Improved: proportion of days participant experienced heartburn during treatment period up to Week 2 [Day 14] was lower than that during run-in period; Not improved: proportion of days participants experienced heartburn during treatment period up to Week 2 [Day 14] was equal to or larger than that during run-in period. Cumulative data was collected between Day 0 and Day 24 and is reported for following time points: Days 0, 5, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24. Data not collected shown as NA=Not Applicable.

Time Frame

Day 0 to Day 24

Title

Severity of Symptoms of Heartburn in Subgroup Stratified by Response (Improved or Not Improved) at Week 2

Description

Time Frame

Up to Week 4

Title

Percentage of Days Without Symptoms of Heartburn in Subgroup Stratified by Endoscopic Findings (the Modified LA Classification Grade N or M) at Baseline

Description

Heartburn symptoms were collected by participant diaries. Participants recorded the presence and severity (Without symptom [No symptom: 0, No hindrance to daily activities: 1], With symptom [Mild: 2, Moderate: 3, Severe: 4]) of heartburn in a daily participant diary. The score range was 0-4, higher scores indicates greater severity. The percentage was calculated in each subgroup of the endoscopic findings where Grade N: normal mucosa; Grade M: minimal changes to the mucosa, such as erythema and/or whitish turbidity; Grade A: non-confluent mucosal breaks <5mm in length; Grade B: non-confluent mucosal breaks ≥5mm in length; Grade C: confluent mucosal breaks <75% circumferential; Grade D: confluent mucosal breaks >75% circumferential.

Time Frame

Up to Week 4

Title

Cumulative Rate of Improvement in Heartburn in Subgroup Stratified by Endoscopic Findings (the Modified LA Classification Grade N) at Baseline

Description

Participants recorded presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in participant diary. The score range was 0-4, higher scores indicates greater severity. Cumulative rate of improvement calculated as percentage of participants who experienced symptom improvement. Cumulative rate calculated in subgroup of Grade N per modified LA classification. Modified LA classification Grade N: normal mucosa; Grade M: minimal changes to mucosa; Grade A: nonconfluent mucosal breaks <5mm in length; Grade B: non-confluent mucosal breaks ≥5mm in length; Grade C: confluent mucosal breaks <75% circumferential; Grade D: confluent mucosal breaks >75% circumferential. Cumulative data collected between Day 0 and 24 and reported for time points: Days 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and 24. Data not collected shown as NA=Not Applicable.

Time Frame

Day 0 to Day 24

Title

Cumulative Rate of Improvement in Heartburn in Subgroup Stratified by Endoscopic Findings (the Modified LA Classification Grade M) at Baseline

Description

Participants recorded presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in participant diary. Score range was 0-4, higher scores indicates greater severity. Cumulative rate of improvement calculated as percentage of participants who experienced symptom improvement. Cumulative rate calculated in subgroup of Grade M per modified LA classification. Modified LA classification Grade N: normal mucosa; Grade M: minimal changes to mucosa; Grade A: nonconfluent mucosal breaks <5mm in length; Grade B: non-confluent mucosal breaks ≥5mm in length; Grade C: confluent mucosal breaks <75% circumferential; Grade D: confluent mucosal breaks >75% circumferential. Cumulative data collected between Day 0 and 24 and reported for time points: Days 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and 24. Data not collected shown as NA=Not Applicable.

Time Frame

Day 0 to Day 24

Title

Severity of Symptoms of Heartburn in Subgroup Stratified by Endoscopic Findings (the Modified LA Classification Grade N or M) at Baseline

Description

Heartburn symptoms were collected by participant diaries. Participants recorded the presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in a daily participant diary. The score range was 0-4, with the higher scores reflecting the greater severity. The severity of heartburn was calculated in each subgroup of the endoscopic findings where Grade N: normal mucosa; Grade M: minimal changes to the mucosa, such as erythema and/or whitish turbidity; Grade A: non-confluent mucosal breaks <5mm in length; Grade B: non-confluent mucosal breaks ≥5mm in length; Grade C: confluent mucosal breaks <75% circumferential; Grade D: confluent mucosal breaks >75% circumferential.

Time Frame

Up to Week 4

Title

Percentage of Days Without Symptoms of Heartburn Stratified by Subgroup of Both the Response at Week 2 and the Endoscopic Findings (the Modified LA Classification Grade N or M)

Description

Heartburn symptoms were collected by participant diaries. Participants recorded the presence and severity (Without symptom [No symptom: 0, No hindrance to daily activities: 1], With symptom [Mild: 2, Moderate: 3, Severe: 4]) of heartburn in a daily participant diary. The score range was 0-4, higher scores indicates greater severity. The percentage was calculated in each subgroup (response; Grade N and improved, response; Grade N and not improved, response; Grade M and improved, response; Grade M and not improved) according to Criteria 1 and 2. The modified LA classification Grade N indicates the participants with normal mucosa and Grade M indicates the participants with minimal changes to the mucosa.

Time Frame

Up to Week 4

Title

Description

Participants recorded the presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in participant diary. Score range was 0-4, higher scores indicates greater severity. Cumulative rate of improvement calculated as percentage of participants who experienced symptom improvement. Response was evaluated per Criteria 1, i.e. Improved: participants experienced heartburn on less than 2 days of 7 days prior to Week 2 [Day 8 through Day 14]; Not improved: participants experienced heartburn on 2 days or more of the 7 days prior to Week 2 [Day 8 through Day 14]. Modified LA classification Grade N: normal mucosa and Grade M: minimal changes to the mucosa. Cumulative data was collected between Day 0 and Day 22 and is reported for following time points: Days 0, 1, 2, 3, 4, 5, 6, 7, 8, 11, 19, 20, and 22. Data not collected were shown as NA=Not Applicable.

Time Frame

Day 0 to Day 22

Title

Description

Participants recorded presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in participant diary. Score range was 0-4, higher scores indicates greater severity. Cumulative rate of improvement calculated as percentage of participants who experienced symptom improvement. Response was evaluated per Criteria 1, i.e. Improved: participants experienced heartburn on less than 2 days of 7 days prior to Week 2 [Day 8 through Day 14]; Not improved: participants experienced heartburn on 2 days or more of 7 days prior to Week 2 [Day 8 through Day 14]. Modified LA classification Grade N indicates participants with normal mucosa and Grade M indicates participants with minimal changes to mucosa). Cumulative data was collected between Day 0 and Day 22 and is reported for following time points: Days 0, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 and 22. Data not collected were shown as NA=Not Applicable.

Time Frame

Day 0 to Day 24

Title

Description

Participants recorded presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in participant diary. Score range was 0-4, higher score indicates greater severity. Cumulative rate of improvement calculated as percentage of participants who experienced symptom improvement. Response was evaluated per Criteria 1, i.e. Improved: participants experienced heartburn on less than 2 days of 7 days prior to Week 2 [Day 8 through Day 14]; Not improved: participants experienced heartburn on 2 days or more of 7 days prior to Week 2 [Day 8 through Day 14]. Modified LA classification Grade N indicates participants with normal mucosa and Grade M indicates participants with minimal changes to mucosa). Cumulative data collected between Day 0 and Day 22 and is reported for following time points: Days 0, 1, 2, 3, 4, 5, 6, 7, 8, 11, 15, 16, 17, 18, 20, 21 and 22. Data not collected were shown as NA=Not Applicable.

Time Frame

Day 0 to Day 22

Title

Description

Participants recorded presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in a daily participant diary. Score range was 0-4, higher score indicates greater severity. Cumulative rate of improvement calculated as percentage of participants who experienced symptom improvement. Response evaluated per Criteria 1, i.e. Improved: participants experienced heartburn on < 2 days of the 7 days prior to Week 2 [Day 8 to 14]; Not improved: participants experienced heartburn on >= 2 days of 7 days prior to Week 2 [Day 8 to 14]. Modified LA classification Grade N indicates participants with normal mucosa and Grade M indicates participants with minimal changes to mucosa). Cumulative data collected between Day 0 and 24 and reported for following time points: Days 0, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24. Data not collected were shown as NA=Not Applicable.

Time Frame

Day 0 to Day 24

Title

Description

Participants recorded presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in participant diary. Score range was 0-4, higher score indicates greater severity. Cumulative rate of improvement calculated as percentage of participants who experienced symptom improvement. Response was evaluated per Criteria 2, i.e. Improved: participants experienced heartburn during treatment period up to Week 2 [Day 14] was lower than during run-in period; Not improved: participants experienced heartburn during treatment period up to Week 2 [Day 14] was equal to or larger than during run-in period. Modified LA classification Grade N: normal mucosa and Grade M: minimal changes to mucosa). Cumulative data collected between Day 0 and 22 and reported for following time points: Days 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, and 22. Data not collected shown as NA=Not Applicable.

Time Frame

Day 0 to Day 22

Title

Description

Participants recorded presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in participant diary. Score range was 0-4, higher score indicates greater severity. Cumulative rate of improvement was calculated as percentage of participants who experienced symptom improvement. Response was evaluated per Criteria 2, i.e. Improved: participants experienced heartburn during treatment period up to Week 2 [Day 14] was lower than during run-in period; Not improved: participants experienced heartburn during treatment period up to Week 2 [Day 14] was equal to or larger than during run-in period. Modified LA classification Grade N: normal mucosa and Grade M: minimal changes to mucosa. Cumulative data was collected between Day 0 and Day 24 and is reported for following time points: Days 0, 5, 9, 11, 12, 13, 14, 19, 20, 21, 22, 23, and 24. Data not collected were shown as NA=Not Applicable.

Time Frame

Day 0 to Day 24

Title

Description

Participants recorded presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in participant diary. Score range was 0-4, higher score indicates greater severity. Cumulative rate of improvement calculated as percentage of participants who experienced symptom improvement. Response was evaluated per Criteria 2, i.e. Improved: participants experienced heartburn during treatment period up to Week 2 [Day 14] was lower than during run-in period; Not improved: participants experienced heartburn during treatment period up to Week 2 [Day 14] was equal or larger than during run-in period. Modified LA classification Grade N: normal mucosa and Grade M: minimal changes to mucosa. Cumulative data collected between Day 0 and 24 and reported for following time points: Days 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24. Data not collected shown as NA=Not Applicable.

Time Frame

Day 0 to Day 24

Title

Description

Participants recorded presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe: 4]) of heartburn in participant diary. Score range was 0-4, higher score indicates greater severity. Cumulative rate of improvement calculated as percentage of participants who experienced symptom improvement. Response was evaluated per Criteria 2, i.e. Improved: participants experienced heartburn during treatment period up to Week 2 [Day 14] was lower than during run-in period; Not improved: participants experienced heartburn during treatment period up to Week 2 [Day 14] was equal to or larger than during run-in period. Modified LA classification Grade N: normal mucosa and Grade M: minimal changes to mucosa). Cumulative data was collected between Day 0 and Day 23 and is reported for following time points: Days 0, 9, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, and 23. Data not collected shown as NA=Not Applicable.

Time Frame

Day 0 to Day 23

Title

Severity of Symptoms of Heartburn in Subgroup Stratified by Both the Response at Week 2 and the Endoscopic Findings (the Modified LA Classification Grade N or M)

Description

Heartburn symptoms were collected by participant diaries. Participants recorded the presence and severity (Without symptom [No symptom: 0, No hindrance to daily activities: 1], With symptom [Mild: 2, Moderate: 3, Severe: 4]) of heartburn in a daily participant diary. The score range was 0-4, with the higher scores reflecting the greater severity. The mean severity of heartburn was calculated in each subgroup (response; Grade N and improved, response; Grade N and not improved, response; Grade M and improved, response; Grade M and not improved) according to criteria 1 and 2. The modified LA classification Grade N indicates the participants with normal mucosa and Grade M indicates the participants with minimal changes to the mucosa.

Time Frame

Up to Week 4

Title

Percentage of Days Without Symptoms of Heartburn in Subgroup Stratified by Response (Improved or Not Improved) to Acid Suppressants in Participants Who Had a Medication History

Description

Heartburn symptoms were collected by participant diaries. Participants recorded the presence and severity (Without symptom [No symptom: 0, No hindrance to daily activities: 1], With symptom [Mild: 2, Moderate: 3, Severe: 4]) of heartburn in a daily participant diary. The score range was 0-4, higher score indicates greater severity. The percentage was calculated in each subgroup of the response (improved or not improved) in the participants who had a medication history of any of acid suppressants. The acid suppressants include proton pump inhibitors [PPIs], histamine H2-receptor antagonists [H2RAs], or other agents [anticholinergics or anti-gastrin drugs].

Time Frame

Up to Week 4

Title

Cumulative Rate of Improvement in Symptoms of Heartburn in Subgroup Stratified by Response (Improved) to Acid Suppressants in Participants Who Had a Medication History

Description

Participants recorded presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in participant diary. Score range was 0-4, higher score indicates greater severity. Cumulative rate of improvement calculated as percentage of participants who experienced symptom improvement. Cumulative improvement rate calculated in each subgroup of the response (improved or not improved) in participants who had medication history of any of acid suppressants. Acid suppressants include proton pump inhibitors [PPIs], histamine H2-receptor antagonists [H2RAs], or other agents [anticholinergics or anti-gastrin drugs]. Cumulative data collected between Day 0 and Day 23 and is reported for following time points: Days 0, 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 and 23. Data not collected were shown as NA=Not Applicable.

Time Frame

Up to Week 4

Title

Cumulative Rate of Improvement in Symptoms of Heartburn in Subgroup Stratified by Response (Not Improved) to Acid Suppressants in Participants Who Had a Medication History

Description

Participants recorded presence and severity (Without symptom [No symptom:0, No hindrance to daily activities:1], With symptom [Mild:2, Moderate:3, Severe:4]) of heartburn in participant diary. Score range was 0-4, higher score indicates greater severity. Cumulative rate of improvement calculated as percentage of participants who experienced symptom improvement. Cumulative improvement rate calculated in each subgroup of the response (improved or not improved) in participants who had medication history of any of acid suppressants. Acid suppressants include proton pump inhibitors [PPIs], histamine H2-receptor antagonists [H2RAs], or other agents [anticholinergics or anti-gastrin drugs]. Cumulative data was collected between Day 0 and Day 23 and is reported for following time points: Days 0, 1, 5, 9, 16, 19, and 20. Data not collected were shown as NA=Not Applicable.

Time Frame

Up to Week 4

Title

Severity of Symptoms of Heartburn in Subgroup Stratified by Response (Improved or Not Improved) to Acid Suppressants in Participants Who Had a Medication History

Description

Heartburn symptoms were collected by participant diaries. Participants recorded the presence and severity (Without symptom [No symptom: 0, No hindrance to daily activities: 1], With symptom [Mild: 2, Moderate: 3, Severe: 4]) of heartburn in a daily participant diary. The score range was 0-4, with the higher scores reflecting the greater severity. The mean severity of heartburn was calculated in each subgroup of the response (improved or not improved) in the participants who had a medication history of any of acid suppressants. The acid suppressants include proton pump inhibitors [PPIs], histamine H2-receptor antagonists [H2RAs], or other agents [anticholinergics or anti-gastrin drugs].

Time Frame

Up to Week 4

10. Eligibility

Sex

All

Minimum Age & Unit of Time

20 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements. The participant signs and dates a written informed consent form prior to the initiation of any study procedures. The participant with NERD. 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. 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). 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. 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. The participant's compliance to the study drug has been good (75% or better) in the run-in period. The participant has experienced heartburn on at least 2 days in the last 1 week prior to randomization. The participant has appropriately provided in the patient's diary all the required information during the run-in period. Exclusion Criteria: The participant has received any investigational compound within 84 days prior to the first dose of study drug. 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. 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. 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). Endoscopic examination for entering this study fails to diagnose NERD within 84 days before the start of the run-in period (Visit 1). 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. 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). 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. The participant has acute gastritis or acute exacerbation of chronic gastritis. The participant has, or has a history of, Zollinger-Ellison syndrome or gastric acid hypersecretion disorders. 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). The participant has any other concurrent upper gastrointestinal symptoms more severe than heartburn. The participant has depression. 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. The participant has a history of hypersensitivity or allergies to TAK-438 (including the formulation excipients). 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). The participant requires any excluded medications or treatments. 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. The participant has any serious neurological, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, endocrinological, or hematologic diseases. 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. 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. 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. 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Study Director

Organizational Affiliation

Takeda

Official's Role

Study Director

Facility Information:

City

Abiko

State/Province

Chiba

Country

Japan

City

Yachiyo

State/Province

Chiba

Country

Japan

City

Kasuya-gun

State/Province

Fukuoka

Country

Japan

City

Kasuya

State/Province

Fukuoka

Country

Japan

City

Kitakyushu

State/Province

Fukuoka

Country

Japan

City

Yukuhashi

State/Province

Fukuoka

Country

Japan

City

Koriyama

State/Province

Fukushima

Country

Japan

City

Asahikawa

State/Province

Hokkaido

Country

Japan

City

Sapporo

State/Province

Hokkaido

Country

Japan

City

Yokohama

State/Province

Kanagawa

Country

Japan

City

Suzaki

State/Province

Kochi

Country

Japan

City

Kitakatsuragi

State/Province

Nara

Country

Japan

City

Fujimi

State/Province

Saitama

Country

Japan

City

Hiki-gun

State/Province

Saitama

Country

Japan

City

Satte

State/Province

Saitama

Country

Japan

City

Otawara

State/Province

Tochigi

Country

Japan

City

Arakawa-ku

State/Province

Tokyo

Country

Japan

City

Nakano-ku

State/Province

Tokyo

Country

Japan

City

Setagaya-ku

State/Province

Tokyo

Country

Japan

City

Shibuya-ku

State/Province

Tokyo

Country

Japan

City

Toshima-ku

State/Province

Tokyo

Country

Japan

City

Fukuoka

Country

Japan

City

Hiroshima

Country

Japan

City

Kochi

Country

Japan

City

Kumamoto

Country

Japan

City

Nagasaki

Country

Japan

City

Oita

Country

Japan

City

Osaka

Country

Japan

City

Shizuoka

Country

Japan

City

Yamagata

Country

Japan

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.

Citations:

PubMed Identifier

31770139

Citation

Kinoshita Y, Sakurai Y, Takabayashi N, Kudou K, Araki T, Miyagi T, Iwakiri K, Ashida K. Efficacy and Safety of Vonoprazan in Patients With Nonerosive Gastroesophageal Reflux Disease: A Randomized, Placebo-Controlled, Phase 3 Study. Clin Transl Gastroenterol. 2019 Nov;10(11):e00101. doi: 10.14309/ctg.0000000000000101.

Results Reference

derived

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

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