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

Sponsor

Takeda (Industry)

Overall Status

Completed

CT.gov ID

NCT02954848

Collaborator

(none)

484

Enrollment

Locations

Arms

15.4

Actual Duration (Months)

16.1

Patients Per Site

Patients Per Site Per Month

Study Details

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).

Condition or Disease	Intervention/Treatment	Phase
Non-erosive Gastroesophageal Reflux Disease	Drug: Placebo Drug: TAK-438 10 mg	Phase 3

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

484 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Nov 15, 2016

Actual Primary Completion Date :

Feb 25, 2018

Actual Study Completion Date :

Feb 26, 2018

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo 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.	Drug: Placebo TAK-438 placebo-matching tablets
Experimental: TAK-438 10 mg 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.	Drug: Placebo TAK-438 placebo-matching tablets Drug: TAK-438 10 mg TAK-438 tablets

Arm

Intervention/Treatment

Placebo Comparator: Placebo

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.

Drug: Placebo

TAK-438 placebo-matching tablets

Experimental: TAK-438 10 mg

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.

Drug: Placebo

TAK-438 placebo-matching tablets

Drug: TAK-438 10 mg

TAK-438 tablets

Outcome Measures

Primary Outcome Measures

Percentage of Days Without Symptoms of Heartburn [Up to Week 4]
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. Reported data was the percentage of days for each group, calculated by the number of days without heartburn divided by the number of days of treatment period.
Cumulative Rate of Improvement in Symptoms of Heartburn [Day 0 to Day 24]
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 [Up to Week 4]
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 by the number of severity score in daily diaries.

Secondary Outcome Measures

Percentage of Days Without Symptoms of Heartburn in Subgroup Stratified by Response (Improved or Not Improved) at Week 2 [Up to Week 4]
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 [Day 0 to Day 22]
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 [Day 0 to Day 24]
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 [Day 0 to Day 24]
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 [Day 0 to Day 24]
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 [Up to Week 4]
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 [Up to Week 4]
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 [Day 0 to Day 24]
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 [Day 0 to Day 24]
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 [Up to Week 4]
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) [Up to Week 4]
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) [Day 0 to Day 22]
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) [Day 0 to Day 24]
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.
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 M) [Day 0 to Day 22]
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.
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 M) [Day 0 to Day 24]
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) [Day 0 to Day 22]
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) [Day 0 to Day 24]
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.
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 M) [Day 0 to Day 24]
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.
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 M) [Day 0 to Day 23]
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) [Up to Week 4]
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 [Up to Week 4]
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 [Up to Week 4]
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 [Up to Week 4]
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 [Up to Week 4]
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].

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years and Older

Sexes Eligible for Study:

All

Accepts 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.

Contacts and Locations

Locations

	City	State	Country
1	Abiko	Chiba	Japan
2	Yachiyo	Chiba	Japan
3	Kasuya-gun	Fukuoka	Japan
4	Kasuya	Fukuoka	Japan
5	Kitakyushu	Fukuoka	Japan
6	Yukuhashi	Fukuoka	Japan
7	Koriyama	Fukushima	Japan
8	Asahikawa	Hokkaido	Japan
9	Sapporo	Hokkaido	Japan
10	Yokohama	Kanagawa	Japan
11	Suzaki	Kochi	Japan
12	Kitakatsuragi	Nara	Japan
13	Fujimi	Saitama	Japan
14	Hiki-gun	Saitama	Japan
15	Satte	Saitama	Japan
16	Otawara	Tochigi	Japan
17	Arakawa-ku	Tokyo	Japan
18	Nakano-ku	Tokyo	Japan
19	Setagaya-ku	Tokyo	Japan
20	Shibuya-ku	Tokyo	Japan
21	Toshima-ku	Tokyo	Japan
22	Fukuoka		Japan
23	Hiroshima		Japan
24	Kochi		Japan
25	Kumamoto		Japan
26	Nagasaki		Japan
27	Oita		Japan
28	Osaka		Japan
29	Shizuoka		Japan
30	Yamagata		Japan

Sponsors and Collaborators

Takeda

Investigators

Study Director: Study Director, Takeda

Study Documents (Full-Text)

More Information

Publications

None provided.

Responsible Party:

Takeda

ClinicalTrials.gov Identifier:

NCT02954848

Other Study ID Numbers:

Vonoprazan-3001
U1111-1188-1784
JapicCTI-163413

First Posted:

Nov 4, 2016

Last Update Posted:

Aug 2, 2019

Last Verified:

Jun 1, 2019

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Takeda

Drug therapy

Additional relevant MeSH terms:

Gastroesophageal Reflux

Esophagitis, Peptic

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 44 investigative sites in Japan from 15 November 2016 to 26 February 2018.
Pre-assignment Detail	Participants with a diagnosis of non-erosive gastroesophageal reflux disease (NERD) were enrolled and received one tablet of placebo orally, once daily in a run-in period. After that, the participants who met all the entry criteria were randomized in 1:1 ratio to receive TAK-438 10 mg or TAK-438 placebo-matching tablets.

Arm/Group Title	Placebo	TAK-438 10 mg
Arm/Group 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.
Period Title: Overall Study
STARTED	245	239
Treated	245	238
COMPLETED	243	234
NOT COMPLETED	2	5

Baseline Characteristics

Arm/Group Title	Placebo	TAK-438 10 mg	Total
Arm/Group 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.	Total of all reporting groups
Overall Participants	245	239	484
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.8 (15.38)	52.8 (14.37)	52.3 (14.88)
Sex: Female, Male (Count of Participants)
Female	140 57.1%	161 67.4%	301 62.2%
Male	105 42.9%	78 32.6%	183 37.8%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (Count of Participants)
Japan	245 100%	239 100%	484 100%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	161.7 (8.62)	160.5 (9.29)	161.1 (8.97)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	59.6 (12.04)	58.7 (11.15)	59.2 (11.61)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	22.67 (3.431)	22.71 (3.375)	22.69 (3.400)
Smoking Classification (Count of Participants)
Never Smoked	124 50.6%	128 53.6%	252 52.1%
Current Smoker	52 21.2%	44 18.4%	96 19.8%
Ex-smoker	69 28.2%	67 28%	136 28.1%
Consumption of Alcohol (Count of Participants)
Drank Every Day	59 24.1%	46 19.2%	105 21.7%
Drank a Couple of Days Per Week	62 25.3%	63 26.4%	125 25.8%
Drank a Couple of Days Per Month	54 22%	54 22.6%	108 22.3%
Never Drank	70 28.6%	76 31.8%	146 30.2%
Consumption of Caffeine (Count of Participants)
Had Caffeine Consumption	192 78.4%	190 79.5%	382 78.9%
Had No Caffeine Consumption	53 21.6%	49 20.5%	102 21.1%
Endoscopic Findings by Principal Investigator (PI) (Count of Participants)
Grade N	82 33.5%	81 33.9%	163 33.7%
Grade M	163 66.5%	158 66.1%	321 66.3%
Endoscopic Findings by Central Adjudication Committee (CAC) (Count of Participants)
Grade M	168 68.6%	157 65.7%	325 67.1%
Grade N	77 31.4%	82 34.3%	159 32.9%
Barrett's Mucosa (Count of Participants)
Yes (Less than 3 cm)	56 22.9%	51 21.3%	107 22.1%
No	189 77.1%	188 78.7%	377 77.9%
Esophageal Hiatal Hernia (Count of Participants)
Yes (2 cm or More)	17 6.9%	18 7.5%	35 7.2%
Yes (Less than 2 cm)	82 33.5%	85 35.6%	167 34.5%
No	146 59.6%	136 56.9%	282 58.3%
Severity of Symptoms, Heartburn (score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on a scale]	1.641 (0.5747)	1.765 (0.6171)	1.702 (0.5986)
Severity of Symptoms, Regurgitation (score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on a scale]	1.074 (0.8398)	1.109 (0.9092)	1.091 (0.8739)
Use of Proton Pump Inhibitors (PPIs) Within 180 Days Prior to Informed Consent (IC) (Count of Participants)
Yes	45 18.4%	55 23%	100 20.7%
No	200 81.6%	184 77%	384 79.3%
Use of H2-Receptor Antagonists (H2RA) Within 180 Days Prior to IC (Count of Participants)
Yes	29 11.8%	28 11.7%	57 11.8%
No	216 88.2%	211 88.3%	427 88.2%
Use of Other Agents (Anticholinergics or Anti-gastrin Drugs) within 180 Days Prior to IC (Count of Participants)
Yes	24 9.8%	22 9.2%	46 9.5%
No	221 90.2%	217 90.8%	438 90.5%
Response to Acid Suppressants (Count of Participants)
Heartburn has been Resolved	31 12.7%	45 18.8%	76 15.7%
Heartburn has not been Resolved but Relieved	52 21.2%	43 18%	95 19.6%
Heartburn has Remained Unchanged	8 3.3%	5 2.1%	13 2.7%
Response to Acid Suppressants (Count of Participants)
Improved	83 33.9%	88 36.8%	171 35.3%
Not Improved	8 3.3%	5 2.1%	13 2.7%
History of H. pylori Eradication (Count of Participants)
Within the Last Year	2 0.8%	1 0.4%	3 0.6%
More than One Year Before	58 23.7%	49 20.5%	107 22.1%
No	185 75.5%	189 79.1%	374 77.3%
Serological Determination for H. pylori (Count of Participants)
Positive	37 15.1%	28 11.7%	65 13.4%
Negative	208 84.9%	209 87.4%	417 86.2%
Gastrin (pg/mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [pg/mL]	91.6 (53.29)	103.1 (182.68)	97.3 (133.83)
Ratio of Pepsinogen I to Pepsinogen II (ratio) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ratio]	7.63 (2.722)	7.57 (2.442)	7.60 (2.585)
Factors and Improvement: Physical Factors, Kyphosis (Count of Participants)
Yes	4 1.6%	8 3.3%	12 2.5%
No	241 98.4%	231 96.7%	472 97.5%
Factors and Improvement: Physical Factors, Evident Obesity (Count of Participants)
Yes	14 5.7%	15 6.3%	29 6%
No	231 94.3%	224 93.7%	455 94%
Factors and Improvement: Movement, Forward Flexion (Count of Participants)
Yes	105 42.9%	83 34.7%	188 38.8%
No	140 57.1%	156 65.3%	296 61.2%
Factors and Improvement: Movement, Lying in Bed (Count of Participants)
Yes	99 40.4%	89 37.2%	188 38.8%
No	146 59.6%	150 62.8%	296 61.2%
Factors and Improvement: Movement, Other (Count of Participants)
Yes	13 5.3%	12 5%	25 5.2%
No	232 94.7%	227 95%	459 94.8%
Factors and Improvement: Diet, Fatty Foods (Fried Foods, Stodge, etc.) (Count of Participants)
Yes	165 67.3%	156 65.3%	321 66.3%
No	80 32.7%	83 34.7%	163 33.7%
Factors and Improvement: Diet, Carbohydrates (Grains, Potatoes, etc.) (Count of Participants)
Yes	115 46.9%	90 37.7%	205 42.4%
No	130 53.1%	149 62.3%	279 57.6%
Factors and Improvement: Diet, Sweet Foods (Chocolate, etc.) (Count of Participants)
Yes	87 35.5%	78 32.6%	165 34.1%
No	158 64.5%	161 67.4%	319 65.9%
Factors and Improvement: Diet, Acidic Foods (Citrus Fruits, Carb. Beverage) (Count of Participants)
Yes	79 32.2%	66 27.6%	145 30%
No	166 67.8%	173 72.4%	339 70%
Factors and Improvement: Diet, Spices (Pepper, Curry, etc.) (Count of Participants)
Yes	83 33.9%	77 32.2%	160 33.1%
No	162 66.1%	162 67.8%	324 66.9%
Factors and Improvement: Diet, Other (Count of Participants)
Yes	5 2%	13 5.4%	18 3.7%
No	240 98%	226 94.6%	466 96.3%
Factors and Improvement: Habits, Smoking (Count of Participants)
Yes	29 11.8%	19 7.9%	48 9.9%
No	216 88.2%	220 92.1%	436 90.1%
Factors and Improvement: Habits, Caffeine Ingestion (Count of Participants)
Yes	112 45.7%	112 46.9%	224 46.3%
No	133 54.3%	127 53.1%	260 53.7%
Factors and Improvement: Habits, Drinking Alcohol (Count of Participants)
Yes	79 32.2%	68 28.5%	147 30.4%
No	166 67.8%	171 71.5%	337 69.6%
Factors and Improvement: Above Factors are NA or cannot be Specified (Count of Participants)
Yes	4 1.6%	8 3.3%	12 2.5%
No	241 98.4%	231 96.7%	472 97.5%
Factors and Improvement: Improving Lifestyle (Count of Participants)
Yes	84 34.3%	97 40.6%	181 37.4%
No	161 65.7%	142 59.4%	303 62.6%

Outcome Measures

1. Primary Outcome

Title	Percentage of Days Without Symptoms of Heartburn
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. Reported data was the percentage of days for each group, calculated by the number of days without heartburn divided by the number of days of treatment period.
Time Frame	Up to Week 4

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS) included participants who were randomized and received at least one dose of the study drug.

Arm/Group Title	Placebo	TAK-438 10 mg
Arm/Group 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.
Measure Participants	245	238
Median (Full Range) [percentage of days]	61.50	72.55

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0643
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	3.800
	Confidence Interval	(2-Sided) 95% 0.000 to 10.600
	Parameter Dispersion	Type: Value:
	Estimation Comments	The point estimate of the median difference between the treatment groups was calculated using the Hodges-Lehmann estimation.

2. Primary Outcome

Title	Cumulative Rate of Improvement in Symptoms of Heartburn
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. 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.
Time Frame	Day 0 to Day 24

Outcome Measure Data

Analysis Population Description
FAS included participants who were randomized and received at least one dose of the study drug.

Arm/Group Title	Placebo	TAK-438 10 mg
Arm/Group 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.
Measure Participants	245	238
Day 0	0.0 0%	0.0 0%
Day 1	14.7 6%	23.1 9.7%
Day 2	15.9 6.5%	24.4 10.2%
Day 3	16.3 6.7%	25.2 10.5%
Day 4	17.6 7.2%	26.1 10.9%
Day 5	18.8 7.7%	28.2 11.8%
Day 6	19.2 7.8%	30.4 12.7%
Day 7	20.0 8.2%	32.5 13.6%
Day 8	21.2 8.7%	32.9 13.8%
Day 9	23.7 9.7%	34.2 14.3%
Day 10	NA NaN	35.5 14.9%
Day 11	25.7 10.5%	38.5 16.1%
Day 12	27.3 11.1%	41.1 17.2%
Day 13	29.0 11.8%	44.6 18.7%
Day 14	30.6 12.5%	46.7 19.5%
Day 15	31.4 12.8%	48.9 20.5%
Day 16	34.3 14%	49.7 20.8%
Day 17	36.3 14.8%	51.0 21.3%
Day 18	38.4 15.7%	54.4 22.8%
Day 19	40.0 16.3%	55.7 23.3%
Day 20	42.7 17.4%	59.0 24.7%
Day 21	44.7 18.2%	59.5 24.9%
Day 22	48.6 19.8%	62.7 26.2%
Day 23	51.3 20.9%	66.1 27.7%
Day 24	NA NaN	71.3 29.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	Log Rank
	Comments

3. Primary Outcome

Title	Severity of Symptoms of Heartburn
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 a daily participant diary. The score range was 0-4, with the higher scores reflecting the greater severity. The severity of heartburn was calculated by the number of severity score in daily diaries.
Time Frame	Up to Week 4

Outcome Measure Data

Analysis Population Description
FAS included participants who were randomized and received at least one dose of the study drug.

Arm/Group Title	Placebo	TAK-438 10 mg
Arm/Group 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.
Measure Participants	245	238
Median (Full Range) [score on a scale]	1.140	1.070

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0826
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.1100
	Confidence Interval	(2-Sided) 95% -0.2400 to 0.0100
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percentage of Days Without Symptoms of Heartburn in Subgroup Stratified by Response (Improved or Not Improved) at Week 2
Description	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.
Time Frame	Up to Week 4

Outcome Measure Data

Analysis Population Description
FAS included participants who were randomized and received at least one dose of the study drug. Number analyzed is the number of participants who were evaluable at each category.

Arm/Group Title	Placebo	TAK-438 10 mg
Arm/Group 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.
Measure Participants	245	238
Criteria 1, Improved	92.00	96.00
Criteria 1, Not Improved	50.95	48.05
Criteria 2, Improved	71.40	81.15
Criteria 2, Not Improved	39.30	24.15

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for criteria 1, improved response
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0478
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	3.300
	Confidence Interval	(2-Sided) 95% 0.000 to 5.300
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for criteria 1, not improved response
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.8963
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.000
	Confidence Interval	(2-Sided) 95% -6.100 to 6.000
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for criteria 2, improved response
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0120
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	5.200
	Confidence Interval	(2-Sided) 95% 0.000 to 10.700
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for criteria 2, not improved response
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0871
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-4.700
	Confidence Interval	(2-Sided) 95% -17.400 to 0.000
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Cumulative Rate of Improvement in Symptoms of Heartburn in Subgroup Stratified by Response (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 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.
Time Frame	Day 0 to Day 22

Outcome Measure Data

Analysis Population Description
FAS included participants who were randomized and received at least one dose of the study drug. Number analyzed is the number of participants who were evaluable at each category.

Arm/Group Title	Placebo	TAK-438 10 mg
Arm/Group 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.
Measure Participants	245	238
Day 0	0.0 0%	0.0 0%
Day 1	43.4 17.7%	55.6 23.3%
Day 2	47.0 19.2%	58.6 24.5%
Day 3	48.2 19.7%	60.6 25.4%
Day 4	51.8 21.1%	62.6 26.2%
Day 5	55.4 22.6%	67.7 28.3%
Day 6	56.6 23.1%	72.7 30.4%
Day 7	59.0 24.1%	77.8 32.6%
Day 8	62.7 25.6%	78.8 33%
Day 11	NA NaN	80.8 33.8%
Day 15	NA NaN	81.8 34.2%
Day 16	63.9 26.1%	NA NaN
Day 17	65.1 26.6%	NA NaN
Day 18	NA NaN	83.8 35.1%
Day 19	66.3 27.1%	NA NaN
Day 20	69.2 28.2%	87.6 36.7%
Day 21	70.6 28.8%	NA NaN
Day 22	75.5 30.8%	93.8 39.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0025
	Comments
	Method	Log Rank
	Comments

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description
FAS included participants who were randomized and received at least one dose of the study drug. Number analyzed is the number of participants who were evaluable at each category.

Arm/Group Title	Placebo	TAK-438 10 mg
Arm/Group 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.
Measure Participants	245	238
Day 0	0.0 0%	0.0 0%
Day 9	3.7 1.5%	2.2 0.9%
Day 10	NA NaN	4.4 1.8%
Day 11	6.8 2.8%	8.1 3.4%
Day 12	9.3 3.8%	12.6 5.3%
Day 13	11.7 4.8%	18.5 7.7%
Day 14	14.2 5.8%	22.2 9.3%
Day 15	15.4 6.3%	25.2 10.5%
Day 16	19.1 7.8%	26.7 11.2%
Day 17	21.6 8.8%	28.9 12.1%
Day 18	24.7 10.1%	33.3 13.9%
Day 19	26.6 10.9%	35.6 14.9%
Day 20	29.2 11.9%	38.7 16.2%
Day 21	31.5 12.9%	39.5 16.5%
Day 22	34.9 14.2%	41.7 17.4%
Day 23	39.2 16%	47.0 19.7%
Day 24	NA NaN	55.1 23.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.1059
	Comments
	Method	Log Rank
	Comments

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description
FAS included participants who were randomized and received at least one dose of the study drug. Number analyzed is the number of participants who were evaluable at each category.

Arm/Group Title	Placebo	TAK-438 10 mg
Arm/Group 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.
Measure Participants	245	238
Day 0	0.0 0%	0.0 0%
Day 1	21.4 8.7%	31.6 13.2%
Day 2	23.2 9.5%	33.3 13.9%
Day 3	23.8 9.7%	34.5 14.4%
Day 4	25.6 10.4%	35.6 14.9%
Day 5	26.2 10.7%	38.5 16.1%
Day 6	26.8 10.9%	41.4 17.3%
Day 7	28.0 11.4%	44.3 18.5%
Day 8	29.8 12.2%	44.9 18.8%
Day 9	32.1 13.1%	46.0 19.2%
Day 10	NA NaN	47.8 20%
Day 11	34.5 14.1%	51.8 21.7%
Day 12	36.9 15.1%	54.1 22.6%
Day 13	38.7 15.8%	57.6 24.1%
Day 14	NA NaN	58.2 24.4%
Day 15	39.3 16%	60.0 25.1%
Day 16	42.3 17.3%	61.1 25.6%
Day 17	45.3 18.5%	62.3 26.1%
Day 18	47.1 19.2%	65.2 27.3%
Day 19	48.3 19.7%	66.3 27.7%
Day 20	50.9 20.8%	69.5 29.1%
Day 21	52.4 21.4%	70.1 29.3%
Day 22	56.7 23.1%	71.9 30.1%
Day 23	NA NaN	74.5 31.2%
Day 24	NA NaN	78.7 32.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0004
	Comments
	Method	Log Rank
	Comments

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description
FAS included participants who were randomized and received at least one dose of the study drug. Number analyzed is the number of participants who were evaluable at each category.

Arm/Group Title	Placebo	TAK-438 10 mg
Arm/Group 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.
Measure Participants	245	238
Day 0	0.0 0%	0.0 0%
Day 5	2.6 1.1%	NA NaN
Day 9	5.2 2.1%	1.6 0.7%
Day 11	6.5 2.7%	NA NaN
Day 12	NA NaN	4.9 2.1%
Day 13	7.8 3.2%	8.2 3.4%
Day 14	13.0 5.3%	14.8 6.2%
Day 15	14.3 5.8%	18.0 7.5%
Day 16	16.9 6.9%	NA NaN
Day 17	NA NaN	19.7 8.2%
Day 18	19.5 8%	24.6 10.3%
Day 19	22.1 9%	26.2 11%
Day 20	24.9 10.2%	29.7 12.4%
Day 21	27.9 11.4%	NA NaN
Day 22	31.3 12.8%	37.0 15.5%
Day 23	41.1 16.8%	42.7 17.9%
Day 24	NA NaN	50.9 21.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.5393
	Comments
	Method	Log Rank
	Comments

9. Secondary Outcome

Title	Severity of Symptoms of Heartburn in Subgroup Stratified by Response (Improved or Not Improved) at Week 2
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 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.
Time Frame	Up to Week 4

Outcome Measure Data

Analysis Population Description
FAS included participants who were randomized and received at least one dose of the study drug. Number analyzed is the number of participants who were evaluable at each category.

Arm/Group Title	Placebo	TAK-438 10 mg
Arm/Group 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.
Measure Participants	245	238
Criteria 1, Improved	0.420	0.310
Criteria 1, Not Improved	1.430	1.420
Criteria 2, Improved	0.960	0.675
Criteria 2, Not Improved	1.610	1.740

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for criteria 1, improved response
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0505
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.1000
	Confidence Interval	(2-Sided) 95% -0.2100 to 0.0000
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for criteria 1, not improved response
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.8138
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.0200
	Confidence Interval	(2-Sided) 95% -0.1200 to 0.1500
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for criteria 2, improved response
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0129
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.1500
	Confidence Interval	(2-Sided) 95% -0.2800 to -0.0300
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for criteria 2, not improved response
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0765
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.1700
	Confidence Interval	(2-Sided) 95% -0.0100 to 0.3600
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description
FAS included participants who were randomized and received at least one dose of the study drug. Number analyzed is the number of participants who had endoscopic findings.

Arm/Group Title	Placebo	TAK-438 10 mg
Arm/Group 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.
Measure Participants	245	238
Grade N	64.15	76.70
Grade M	60.70	67.90

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for Grade N of endoscopic findings
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.1490
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	6.500
	Confidence Interval	(2-Sided) 95% -1.900 to 15.300
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for Grade M of endoscopic findings
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.2146
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	3.600
	Confidence Interval	(2-Sided) 95% -1.400 to 10.700
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description
FAS included participants who were randomized and received at least one dose of the study drug. Number analyzed is the number of participants who were evaluable at each category.

Arm/Group Title	Placebo	TAK-438 10 mg
Arm/Group 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.
Measure Participants	245	238
Day 0	0.0 0%	0.0 0%
Day 1	18.3 7.5%	22.2 9.3%
Day 2	NA NaN	23.5 9.8%
Day 3	19.5 8%	24.7 10.3%
Day 4	NA NaN	27.2 11.4%
Day 5	23.2 9.5%	29.7 12.4%
Day 6	24.4 10%	32.3 13.5%
Day 7	26.8 10.9%	36.0 15.1%
Day 8	28.0 11.4%	37.3 15.6%
Day 9	29.3 12%	41.0 17.2%
Day 11	34.1 13.9%	43.5 18.2%
Day 12	36.6 14.9%	47.3 19.8%
Day 13	NA NaN	51.1 21.4%
Day 14	NA NaN	54.8 22.9%
Day 15	NA NaN	57.3 24%
Day 16	39.0 15.9%	NA NaN
Day 17	40.2 16.4%	58.6 24.5%
Day 18	43.9 17.9%	61.1 25.6%
Day 19	46.3 18.9%	63.6 26.6%
Day 20	47.7 19.5%	66.3 27.7%
Day 21	49.1 20%	67.7 28.3%
Day 22	52.1 21.3%	73.4 30.7%
Day 23	NA NaN	78.7 32.9%
Day 24	NA NaN	89.4 37.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0059
	Comments
	Method	Log Rank
	Comments

12. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description
FAS included participants who were randomized and received at least one dose of the study drug. Number analyzed is the number of participants who were evaluable at each category.

Arm/Group Title	Placebo	TAK-438 10 mg
Arm/Group 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.
Measure Participants	245	238
Day 0	0.0 0%	0.0 0%
Day 1	12.9 5.3%	23.6 9.9%
Day 2	14.7 6%	24.9 10.4%
Day 3	NA NaN	25.5 10.7%
Day 4	16.6 6.8%	NA NaN
Day 5	NA NaN	27.5 11.5%
Day 6	NA NaN	29.4 12.3%
Day 7	NA NaN	30.7 12.8%
Day 8	17.8 7.3%	NA NaN
Day 9	20.9 8.5%	NA NaN
Day 10	NA NaN	32.7 13.7%
Day 11	21.5 8.8%	35.9 15%
Day 12	22.7 9.3%	37.9 15.9%
Day 13	25.2 10.3%	41.2 17.2%
Day 14	27.6 11.3%	42.5 17.8%
Day 15	28.8 11.8%	44.4 18.6%
Day 16	31.9 13%	45.7 19.1%
Day 17	34.4 14%	47.0 19.7%
Day 18	35.6 14.5%	51.0 21.3%
Day 19	36.9 15.1%	51.6 21.6%
Day 20	40.3 16.4%	55.1 23.1%
Day 21	42.6 17.4%	NA NaN
Day 22	47.0 19.2%	57.1 23.9%
Day 23	50.8 20.7%	59.6 24.9%
Day 24	NA NaN	63.3 26.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0153
	Comments
	Method	Log Rank
	Comments

13. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description
FAS included participants who were randomized and received at least one dose of the study drug. Number analyzed is the number of participants who had endoscopic findings.

Arm/Group Title	Placebo	TAK-438 10 mg
Arm/Group 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.
Measure Participants	245	238
Grade N	1.070	0.850
Grade M	1.180	1.110

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for Grade N of endoscopic findings
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0757
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.1800
	Confidence Interval	(2-Sided) 95% -0.4300 to 0.0200
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for Grade M of endoscopic findings
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.3837
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.0700
	Confidence Interval	(2-Sided) 95% -0.2200 to 0.0900
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description
FAS included participants who were randomized and received at least one dose of the study drug. Number analyzed is the number of participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	TAK-438 10 mg
Arm/Group 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.
Measure Participants	245	238
Criteria 1, Grade N and Improved	93.00	92.90
Criteria 1, Grade N and Not Improved	53.60	53.60
Criteria 1, Grade M and Improved	89.30	96.40
Criteria 1, Grade M and Not Improved	49.05	44.40
Criteria 2, Grade N and Improved	69.00	79.30
Criteria 2, Grade N and Not Improved	50.00	22.95
Criteria 2, Grade M and Improved	73.30	82.10
Criteria 2, Grade M and Not Improved	33.90	25.00

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for Criteria 1, Grade N and improved response
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.6631
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.000
	Confidence Interval	(2-Sided) 95% -5.000 to 3.500
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for Criteria 1, Grade N and not improved response
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.5627
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	3.200
	Confidence Interval	(2-Sided) 95% -7.100 to 13.900
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for Criteria 1, Grade M and improved response
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0042
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	3.700
	Confidence Interval	(2-Sided) 95% 0.000 to 8.000
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for Criteria 1, Grade M and not improved response
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.6452
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.700
	Confidence Interval	(2-Sided) 95% -9.400 to 6.400
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for Criteria 2, Grade N and improved response
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0376
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	7.400
	Confidence Interval	(2-Sided) 95% 0.000 to 17.800
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for Criteria 2, Grade N and not improved response
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.1600
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-13.000
	Confidence Interval	(2-Sided) 95% -35.700 to 3.600
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for Criteria 2, Grade M and improved response
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.1032
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	3.600
	Confidence Interval	(2-Sided) 95% 0.000 to 10.700
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for Criteria 2, Grade M and not improved response
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.2613
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-3.300
	Confidence Interval	(2-Sided) 95% -14.300 to 0.200
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	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)
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

Outcome Measure Data

Analysis Population Description
FAS included participants who were randomized and received at least one dose of the study drug. Number analyzed is the number of participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	TAK-438 10 mg
Arm/Group 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.
Measure Participants	245	238
Day 0	0.0 0%	0.0 0%
Day 1	53.6 21.9%	46.2 19.3%
Day 2	NA NaN	48.7 20.4%
Day 3	57.1 23.3%	51.3 21.5%
Day 4	NA NaN	56.4 23.6%
Day 5	67.9 27.7%	61.5 25.7%
Day 6	71.4 29.1%	66.7 27.9%
Day 7	78.6 32.1%	74.4 31.1%
Day 8	82.1 33.5%	76.9 32.2%
Day 11	NA NaN	79.5 33.3%
Day 19	85.7 35%	NA NaN
Day 20	NA NaN	82.9 34.7%
Day 22	89.3 36.4%	100.0 41.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.9970
	Comments
	Method	Log Rank
	Comments

16. Secondary Outcome

Title	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)
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

Outcome Measure Data

Analysis Population Description
FAS included participants who were randomized and received at least one dose of the study drug. Number analyzed is the number of participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	TAK-438 10 mg
Arm/Group 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.
Measure Participants	245	238
Day 0	0.0 0%	0.0 0%
Day 9	1.9 0.8%	7.3 3.1%
Day 11	9.3 3.8%	9.8 4.1%
Day 12	13.0 5.3%	17.1 7.2%
Day 13	NA NaN	24.4 10.2%
Day 14	NA NaN	31.7 13.3%
Day 15	NA NaN	36.6 15.3%
Day 16	16.7 6.8%	NA NaN
Day 17	18.5 7.6%	39.0 16.3%
Day 18	24.1 9.8%	43.9 18.4%
Day 19	25.9 10.6%	48.8 20.4%
Day 20	27.9 11.4%	51.2 21.4%
Day 21	30.1 12.3%	53.8 22.5%
Day 22	32.4 13.2%	NA NaN
Day 23	NA NaN	63.0 26.4%
Day 24	NA NaN	81.5 34.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0125
	Comments
	Method	Log Rank
	Comments

17. Secondary Outcome

Title	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 M)
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

Outcome Measure Data

Analysis Population Description
FAS included participants who were randomized and received at least one dose of the study drug. Number analyzed is the number of participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	TAK-438 10 mg
Arm/Group 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.
Measure Participants	245	238
Day 0	0.0 0%	0.0 0%
Day 1	38.2 15.6%	61.7 25.8%
Day 2	43.6 17.8%	65.0 27.2%
Day 3	NA NaN	66.7 27.9%
Day 4	49.1 20%	NA NaN
Day 5	NA NaN	71.7 30%
Day 6	NA NaN	76.7 32.1%
Day 7	NA NaN	80.0 33.5%
Day 8	52.7 21.5%	NA NaN
Day 11	NA NaN	81.7 34.2%
Day 15	NA NaN	83.3 34.9%
Day 16	54.5 22.2%	NA NaN
Day 17	56.4 23%	NA NaN
Day 18	NA NaN	86.7 36.3%
Day 20	60.8 24.8%	90.5 37.9%
Day 21	63.0 25.7%	NA NaN
Day 22	68.3 27.9%	NA NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0004
	Comments
	Method	Log Rank
	Comments

18. Secondary Outcome

Title	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 M)
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

Outcome Measure Data

Analysis Population Description
FAS included participants who were randomized and received at least one dose of the study drug. Number analyzed is the number of participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	TAK-438 10 mg
Arm/Group 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.
Measure Participants	245	238
Day 0	0.0 0%	0.0 0%
Day 9	4.6 1.9%	NA NaN
Day 10	NA NaN	3.2 1.3%
Day 11	5.6 2.3%	7.4 3.1%
Day 12	7.4 3%	10.6 4.4%
Day 13	11.1 4.5%	16.0 6.7%
Day 14	14.8 6%	18.1 7.6%
Day 15	16.7 6.8%	20.2 8.5%
Day 16	20.4 8.3%	22.3 9.3%
Day 17	23.1 9.4%	24.5 10.3%
Day 18	25.0 10.2%	28.7 12%
Day 19	26.9 11%	29.8 12.5%
Day 20	29.9 12.2%	33.2 13.9%
Day 21	32.2 13.1%	NA NaN
Day 22	36.2 14.8%	36.4 15.2%
Day 23	42.0 17.1%	40.1 16.8%
Day 24	NA NaN	45.6 19.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.7999
	Comments
	Method	Log Rank
	Comments

19. Secondary Outcome

Title	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)
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

Outcome Measure Data

Analysis Population Description
FAS included participants who were randomized and received at least one dose of the study drug. Number analyzed is the number of participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	TAK-438 10 mg
Arm/Group 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.
Measure Participants	245	238
Day 0	0.0 0%	0.0 0%
Day 1	25.4 10.4%	29.5 12.3%
Day 2	NA NaN	31.1 13%
Day 3	27.1 11.1%	32.8 13.7%
Day 4	NA NaN	36.1 15.1%
Day 5	28.8 11.8%	39.3 16.4%
Day 6	30.5 12.4%	42.6 17.8%
Day 7	33.9 13.8%	47.5 19.9%
Day 8	35.6 14.5%	49.2 20.6%
Day 9	NA NaN	52.5 22%
Day 11	40.7 16.6%	55.7 23.3%
Day 12	44.1 18%	59.0 24.7%
Day 13	NA NaN	62.3 26.1%
Day 14	NA NaN	63.9 26.7%
Day 15	NA NaN	67.2 28.1%
Day 16	47.5 19.4%	NA NaN
Day 17	49.2 20.1%	68.9 28.8%
Day 18	54.2 22.1%	72.1 30.2%
Day 19	55.9 22.8%	73.8 30.9%
Day 20	NA NaN	77.5 32.4%
Day 21	NA NaN	79.4 33.2%
Day 22	58.1 23.7%	84.5 35.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0059
	Comments
	Method	Log Rank
	Comments

20. Secondary Outcome

Title	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)
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

Outcome Measure Data

Analysis Population Description
FAS included participants who were randomized and received at least one dose of the study drug. Number analyzed is the number of participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	TAK-438 10 mg
Arm/Group 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.
Measure Participants	245	238
Day 0	0.0 0%	0.0 0%
Day 5	8.7 3.6%	NA NaN
Day 9	13.0 5.3%	5.3 2.2%
Day 11	17.4 7.1%	NA NaN
Day 12	NA NaN	10.5 4.4%
Day 13	NA NaN	15.8 6.6%
Day 14	NA NaN	26.3 11%
Day 19	21.7 8.9%	31.6 13.2%
Day 20	26.3 10.7%	NA NaN
Day 21	30.9 12.6%	NA NaN
Day 22	35.9 14.7%	39.2 16.4%
Day 23	NA NaN	59.5 24.9%
Day 24	NA NaN	100.0 41.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.5520
	Comments
	Method	Log Rank
	Comments

21. Secondary Outcome

Title	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 M)
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

Outcome Measure Data

Analysis Population Description
FAS included participants who were randomized and received at least one dose of the study drug. Number analyzed is the number of participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	TAK-438 10 mg
Arm/Group 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.
Measure Participants	245	238
Day 0	0.0 0%	0.0 0%
Day 1	19.3 7.9%	32.7 13.7%
Day 2	22.0 9%	34.5 14.4%
Day 3	NA NaN	35.4 14.8%
Day 4	24.8 10.1%	NA NaN
Day 5	NA NaN	38.1 15.9%
Day 6	NA NaN	40.7 17%
Day 7	NA NaN	42.5 17.8%
Day 8	26.6 10.9%	NA NaN
Day 9	30.3 12.4%	NA NaN
Day 10	NA NaN	45.2 18.9%
Day 11	31.2 12.7%	49.7 20.8%
Day 12	33.0 13.5%	51.5 21.5%
Day 13	35.8 14.6%	55.1 23.1%
Day 15	36.7 15%	56.0 23.4%
Day 16	39.4 16.1%	57.8 24.2%
Day 17	43.2 17.6%	58.7 24.6%
Day 18	NA NaN	61.4 25.7%
Day 19	44.1 18%	62.3 26.1%
Day 20	48.2 19.7%	65.1 27.2%
Day 21	50.6 20.7%	NA NaN
Day 22	56.1 22.9%	NA NaN
Day 23	NA NaN	69.0 28.9%
Day 24	NA NaN	75.2 31.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0175
	Comments
	Method	Log Rank
	Comments

22. Secondary Outcome

Title	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 M)
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

Outcome Measure Data

Analysis Population Description
FAS included participants who were randomized and received at least one dose of the study drug. Number analyzed is the number of participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	TAK-438 10 mg
Arm/Group 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.
Measure Participants	245	238
Day 0	0.0 0%	0.0 0%
Day 9	1.9 0.8%	NA NaN
Day 12	NA NaN	2.4 1%
Day 13	3.7 1.5%	4.8 2%
Day 14	11.1 4.5%	9.5 4%
Day 15	13.0 5.3%	14.3 6%
Day 16	16.7 6.8%	NA NaN
Day 17	NA NaN	16.7 7%
Day 18	20.4 8.3%	23.8 10%
Day 19	22.3 9.1%	NA NaN
Day 20	24.3 9.9%	29.1 12.2%
Day 21	26.5 10.8%	NA NaN
Day 22	29.0 11.8%	36.2 15.1%
Day 23	43.2 17.6%	NA NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.7505
	Comments
	Method	Log Rank
	Comments

23. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description
FAS included participants who were randomized and received at least one dose of the study drug. Number analyzed is the number of participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	TAK-438 10 mg
Arm/Group 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.
Measure Participants	245	238
Criteria 1, Grade N and Improved	0.510	0.430
Criteria 1, Grade N and Not Improved	1.375	1.240
Criteria 1, Grade M and Improved	0.420	0.280
Criteria 1, Grade M and Not Improved	1.430	1.520
Criteria 2, Grade N and Improved	1.000	0.640
Criteria 2, Grade N and Not Improved	1.460	1.695
Criteria 2, Grade M and Improved	0.890	0.710
Criteria 2, Grade M and Not Improved	1.645	1.790

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for Criteria 1, Grade N and improved response
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.7845
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.0300
	Confidence Interval	(2-Sided) 95% -0.2300 to 0.1600
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for Criteria 1, Grade N and not improved response
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.4456
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Wilcoxon Rank-Sum Test
	Estimated Value	-0.1100
	Confidence Interval	(2-Sided) 95% -0.3300 to 0.1700
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for Criteria 1, Grade M and improved response
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0200
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.1500
	Confidence Interval	(2-Sided) 95% -0.2900 to -0.0200
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for Criteria 1, Grade M and not improved response
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.4673
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.0600
	Confidence Interval	(2-Sided) 95% -0.1000 to 0.2200
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for Criteria 2, Grade N and improved response
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0095
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.2900
	Confidence Interval	(2-Sided) 95% -0.5300 to -0.0700
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for Criteria 2, Grade N and not improved response
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.1650
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.3100
	Confidence Interval	(2-Sided) 95% -0.1600 to 0.7100
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for Criteria 2, Grade M and improved response
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.2475
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.0800
	Confidence Interval	(2-Sided) 95% -0.2400 to 0.0700
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for Criteria 2, Grade M and not improved
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.2367
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.1300
	Confidence Interval	(2-Sided) 95% -0.0900 to 0.3200
	Parameter Dispersion	Type: Value:
	Estimation Comments

24. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description
FAS included participants who were randomized and received at least one dose of the study drug. Number analyzed is the number of participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	TAK-438 10 mg
Arm/Group 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.
Measure Participants	245	238
Improved	61.30	71.40
Not Improved	49.30	80.80

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for improved response
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.1885
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	5.500
	Confidence Interval	(2-Sided) 95% -2.700 to 14.300
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for not improved response
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.2337
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Wilcoxon Rank-Sum Test
	Estimated Value	25.600
	Confidence Interval	(2-Sided) 95% -19.200 to 75.000
	Parameter Dispersion	Type: Value:
	Estimation Comments

25. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description
FAS included participants who were randomized and received at least one dose of the study drug. Number analyzed is the number of participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	TAK-438 10 mg
Arm/Group 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.
Measure Participants	245	238
Day 0	0.0 0%	0.0 0%
Day 1	13.3 5.4%	25.0 10.5%
Day 2	15.7 6.4%	26.2 11%
Day 4	18.1 7.4%	NA NaN
Day 5	20.5 8.4%	NA NaN
Day 6	21.7 8.9%	27.3 11.4%
Day 7	NA NaN	28.5 11.9%
Day 8	22.9 9.3%	29.6 12.4%
Day 9	25.3 10.3%	NA NaN
Day 10	NA NaN	30.8 12.9%
Day 11	NA NaN	35.4 14.8%
Day 12	26.5 10.8%	NA NaN
Day 13	NA NaN	41.2 17.2%
Day 14	28.9 11.8%	42.3 17.7%
Day 15	30.1 12.3%	43.5 18.2%
Day 16	31.3 12.8%	NA NaN
Day 17	32.6 13.3%	NA NaN
Day 18	33.8 13.8%	46.9 19.6%
Day 19	35.0 14.3%	NA NaN
Day 20	36.3 14.8%	49.4 20.7%
Day 21	NA NaN	50.8 21.3%
Day 22	41.6 17%	54.5 22.8%
Day 23	48.9 20%	61.0 25.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0811
	Comments
	Method	Log Rank
	Comments

26. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description
FAS included participants who were randomized and received at least one dose of the study drug. Number analyzed is the number of participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	TAK-438 10 mg
Arm/Group 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.
Measure Participants	245	238
Day 0	0.0 0%	0.0 0%
Day 1	25.0 10.2%	40.0 16.7%
Day 5	NA NaN	60.0 25.1%
Day 9	NA NaN	80.0 33.5%
Day 16	37.5 15.3%	NA NaN
Day 19	NA NaN	100.0 41.8%
Day 20	50.0 20.4%	NA NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0288
	Comments
	Method	Log Rank
	Comments

27. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description
FAS included participants who were randomized and received at least one dose of the study drug. Number analyzed is the number of participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	TAK-438 10 mg
Arm/Group 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.
Measure Participants	245	238
Improved	1.150	1.040
Not Improved	1.280	1.030

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for improved response
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.1488
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.1700
	Confidence Interval	(2-Sided) 95% -0.4200 to 0.0400
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-438 10 mg
	Comments	Statistical analysis for not improved response
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.3778
	Comments
	Method	Wilcoxon Rank-Sum Test
	Comments

Method of Estimation	Estimation Parameter	Wilcoxon Rank-Sum Test
	Estimated Value	-0.4400
	Confidence Interval	(2-Sided) 95% -1.5700 to 0.6900
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

	Placebo		TAK-438 10 mg
Time Frame	Up to Week 4
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Arm/Group Title	Placebo		TAK-438 10 mg
Arm/Group 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.
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/245 (0%)		0/238 (0%)
Serious Adverse Events
	Placebo		TAK-438 10 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/245 (0.4%)		0/238 (0%)
Gastrointestinal disorders
Colitis ulcerative	1/245 (0.4%)		0/238 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		TAK-438 10 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/245 (4.9%)		10/238 (4.2%)
Infections and infestations
Viral upper respiratory tract infection	12/245 (4.9%)		10/238 (4.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.

Results Point of Contact

Name/Title	Medical Director
Organization	Takeda
Phone	+1-877-825-3327
Email	trialdisclosures@takeda.com

Responsible Party:

Takeda

ClinicalTrials.gov Identifier:

NCT02954848

Other Study ID Numbers:

Vonoprazan-3001
U1111-1188-1784
JapicCTI-163413

First Posted:

Nov 4, 2016

Last Update Posted:

Aug 2, 2019

Last Verified:

Jun 1, 2019