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

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ClinicalTrials.gov Identifier: NCT02954848
Recruitment Status : Completed
First Posted : November 4, 2016
Results First Posted : August 2, 2019
Last Update Posted : August 2, 2019
Sponsor:
Information provided by (Responsible Party):
Takeda

Tracking Information
First Submitted Date  ICMJE November 1, 2016
First Posted Date  ICMJE November 4, 2016
Results First Submitted Date  ICMJE February 25, 2019
Results First Posted Date  ICMJE August 2, 2019
Last Update Posted Date August 2, 2019
Actual Study Start Date  ICMJE November 15, 2016
Actual Primary Completion Date February 25, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 16, 2019)
  • Percentage of Days Without Symptoms of Heartburn [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: November 1, 2016)
  • Percentage of Days without Heartburn from Baseline to Week 4 [ Time Frame: Up to Week 4 ]
    Heartburn symptoms will be collected by participant diaries. A participant will record the presence and severity (No symptom, No hindrance to daily activities, Mild, Moderate, Severe) of heartburn in a daily diary. The percentage will be calculated as the number of days with heartburn divided by the number of days of treatment period (from baseline to Week 4).
  • Cumulative Improvement Rate of Heartburn [ Time Frame: Up to Week 4 ]
    Heartburn symptoms will be collected by participant diaries. A participant will record the presence and severity (No symptom, No hindrance to daily activities, Mild, Moderate, Severe) of heartburn in a daily diary. The cumulative improvement rates of heartburn where an event date will be defined as the first day of confirmed improvement in a daily diary.
  • Mean Severity of Heartburn from Baseline to Week 4 [ Time Frame: Up to Week 4 ]
    Heartburn symptoms will be collected by participant diaries. A participant will record the presence and severity (No symptom, No hindrance to daily activities, Mild, Moderate, Severe) of heartburn in a daily diary. The mean severity of heartburn will be calculated by the number of severity score in daily diaries.
Change History Complete list of historical versions of study NCT02954848 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 16, 2019)
  • Percentage of Days Without Symptoms of Heartburn in Subgroup Stratified by Response (Improved or Not Improved) at Week 2 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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].
Original Secondary Outcome Measures  ICMJE
 (submitted: November 1, 2016)
  • Percentage of Days without Heartburn in Subgroup of the Response (improved or not improved) at Week 2 [ Time Frame: Up to Week 4 ]
    Heartburn symptoms will be collected by participant diaries. A participant will record the presence and severity (No symptom, No hindrance to daily activities, Mild, Moderate, Severe) of heartburn in a daily diary. The percentage will be calculated in each subgroup of the Response (improved or not improved) at Week 2 as the number of days with heartburn divided by the number of days between baseline and Week 4.
  • Cumulative Improvement Rate of Heartburn in Subgroup of the Response (improved or not improved) at Week 2 [ Time Frame: Up to Week 4 ]
    Heartburn symptoms will be collected by participant diaries. A participant will record the presence and severity (No symptom, No hindrance to daily activities, Mild, Moderate, Severe) of heartburn in a daily diary. The cumulative improvement rates of heartburn where an event date will be defined as the first day of confirmed improvement in a daily diary.
  • Mean Severity of Heartburn in Subgroup of the Response (improved or not improved) at Week 2 [ Time Frame: Up to Week 4 ]
    Heartburn symptoms will be collected by participant diaries. A participant will record the presence and severity (No symptom, No hindrance to daily activities, Mild, Moderate, Severe) of heartburn in a daily diary. The mean severity of heartburn will be calculated by the number of severity score in daily diaries.
  • Percentage of Days without Heartburn in Subgroup of the Endoscopic Findings (The Modified LA Classification Grade N or M) at Baseline [ Time Frame: Up to Week 4 ]
    Heartburn symptoms will be collected by participant diaries. A participant will record the presence and severity (No symptom, No hindrance to daily activities, Mild, Moderate, Severe) of heartburn in a daily diary. The percentage will be calculated in each subgroup of the Endoscopic Findings (The Modified LA Classification Grade N or M) at Baseline as the number of days with heartburn divided by the number of days between baseline and Week 4. The Modified LA Classification Grade N indicates the participants with normal appearance and Grade M indicates the participants with no mucosal breaks with minimal changes.
  • Cumulative Improvement Rate of Heartburn in Subgroup of the Endoscopic Findings (The Modified LA Classification Grade N or M) at Baseline [ Time Frame: Up to Week 4 ]
    Heartburn symptoms will be collected by participant diaries. A participant will record the presence and severity (No symptom, No hindrance to daily activities, Mild, Moderate, Severe) of heartburn in a daily diary. The cumulative improvement rates of heartburn where an event date will be defined as the first day of confirmed improvement in a daily diary.
  • Mean Severity of Heartburn in Subgroup of the Endoscopic Findings (The Modified LA Classification Grade N or M) at Baseline [ Time Frame: Up to Week 4 ]
    Heartburn symptoms will be collected by participant diaries. A participant will record the presence and severity (No symptom, No hindrance to daily activities, Mild, Moderate, Severe) of heartburn in a daily diary. The mean severity of heartburn will be calculated by the number of severity score in daily diaries.
  • Percentage of Days without Heartburn in Subgroup of both the Response and the Endoscopic Findings at week 2 [ Time Frame: Up to Week 4 ]
    Heartburn symptoms will be collected by participant diaries. A participant will record the presence and severity (No symptom, No hindrance to daily activities, Mild, Moderate, Severe) of heartburn in a daily diary. The percentage will be calculated in each subgroup (Response; improved and Grade N, Response; not improved and Grade N, Response; improved and Grade M, Response; not improved and Grade M) as the number of days with heartburn divided by the number of days between baseline and Week 4. The Modified LA Classification Grade N indicates the participants with normal appearance and Grade M indicates the participants with no mucosal breaks with minimal changes.
  • Cumulative Improvement Rate of Heartburn in Subgroup of both the Response and the Endoscopic Findings at week 2 [ Time Frame: Up to Week 4 ]
    Heartburn symptoms will be collected by participant diaries. A participant will record the presence and severity (No symptom, No hindrance to daily activities, Mild, Moderate, Severe) of heartburn in a daily diary. The cumulative improvement rates of heartburn where an event date will be defined as the first day of confirmed improvement in a daily diary.
  • Mean Severity of Heartburn in Subgroup of both the Response and the Endoscopic Findings at week 2 [ Time Frame: Up to Week 4 ]
    Heartburn symptoms will be collected by participant diaries. A participant will record the presence and severity (No symptom, No hindrance to daily activities, Mild, Moderate, Severe) of heartburn in a daily diary. The mean severity of heartburn will be calculated by the number of severity score in daily diaries.
  • Percentage of Days without Heartburn with the Participants who stratified by the response (improved or not improved) to acid suppressants in participants who had a medication history. [ Time Frame: Up to Week 4 ]
    Heartburn symptoms will be collected by participant diaries. A participant will record the presence and severity (No symptom, No hindrance to daily activities, Mild, Moderate, Severe) of heartburn in a daily diary. The percentage will be calculated in each subgroup of the Response (improved or not improved) in the participants who had a medication history of any of acid suppressants as the number of days with heartburn divided by the number of days between baseline and Week 4. The acid suppressants includes proton pump inhibitors [PPIs], histamine H2-receptor antagonists [H2RAs], or other agents [anticholinergics or anti-gastrin drugs]
  • Cumulative Improvement Rate of Heartburn with the Participants who stratified by the response (improved or not improved) to acid suppressants in participants who had a medication history. [ Time Frame: Up to Week 4 ]
    Heartburn symptoms will be collected by participant diaries. A participant will record the presence and severity (No symptom, No hindrance to daily activities, Mild, Moderate, Severe) of heartburn in a daily diary. The cumulative improvement rates of heartburn where an event date will be defined as the first day of confirmed improvement in a daily diary.
  • Mean Severity of Heartburnin with the Participants who stratified by the response (improved or not improved) to acid suppressants in participants who had a medication history. [ Time Frame: Up to Week 4 ]
    Heartburn symptoms will be collected by participant diaries. A participant will record the presence and severity (No symptom, No hindrance to daily activities, Mild, Moderate, Severe) of heartburn in a daily diary. The mean severity of heartburn will be calculated by the number of severity score in daily diaries.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase 3 Study of TAK-438 10 mg in the Treatment of Non-Erosive Gastroesophageal Reflux Disease (NERD)
Official Title  ICMJE 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
Brief Summary The purpose of this study was to evaluate the efficacy and safety of oral TAK-438 10 mg once-daily in the treatment of non-erosive gastroesophageal reflux disease (NERD).
Detailed Description

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

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

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Non-erosive Gastroesophageal Reflux Disease
Intervention  ICMJE
  • Drug: Placebo
    TAK-438 placebo-matching tablets
  • Drug: TAK-438 10 mg
    TAK-438 tablets
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Placebo
  • 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.
    Interventions:
    • Drug: Placebo
    • Drug: TAK-438 10 mg
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 25, 2018)
484
Original Estimated Enrollment  ICMJE
 (submitted: November 1, 2016)
474
Actual Study Completion Date  ICMJE February 26, 2018
Actual Primary Completion Date February 25, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
  2. The participant signs and dates a written informed consent form prior to the initiation of any study procedures.
  3. The participant with NERD.
  4. The participant is endoscopically confirmed to have the modified Los Angeles (LA) Classification Grade N or M at the start of the run-in period (Visit 1).

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

  5. The participant experiences recurrent heartburn, on at least 2 days a week over the last 3 weeks prior to the start of the run-in period (Visit 1).
  6. The participant is either a male or female outpatient with a minimum age of 20 years at the time of informed consent signing. However, participants who are hospitalized only for examination purposes are also allowed to participate.
  7. A female participant of childbearing potential agrees to use routinely adequate contraception from signing of informed consent throughout the duration of the study, and for 4 weeks after the last dose of study drug.
  8. The participant's compliance to the study drug has been good (75% or better) in the run-in period.
  9. The participant has experienced heartburn on at least 2 days in the last 1 week prior to randomization.
  10. The participant has appropriately provided in the patient's diary all the required information during the run-in period.

Exclusion Criteria:

  1. The participant has received any investigational compound within 84 days prior to the first dose of study drug.
  2. The participant has received TAK-438 in a previous clinical study or as a therapeutic agent, except one with experience of receiving TAK-438 as an adjunct therapy for H. pylori eradication, who can be enrolled in this study.
  3. The participant is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress.
  4. The participant has donated at least 400 mL of blood within the 90 days prior to the start of the run-in period (Visit 1).
  5. Endoscopic examination for entering this study fails to diagnose NERD within 84 days before the start of the run-in period (Visit 1).
  6. The participant has any complications affecting the esophagus, including Barrett's esophagus (3 cm or more, long segment Barrett's esophagus [LSBE]), eosinophilic esophagitis, esophageal varices, scleroderma, viral or fungal infection, and esophageal stenosis; a history of radiation therapy or cryotherapy for the esophagus; or caustic or physiochemical trauma (eg, esophageal sclerotherapy). However, participants with Barrett's mucosa (less than 3 cm, short segment Barrett's esophagus [SSBE]) or Schatzki's ring (a mucosal tissue ring lining the inferior esophageal sphincter) are permitted to participate.
  7. The participant has a history of surgery or treatment affecting gastroesophageal reflux, including fundoplication and mechanical dilatation for esophageal stenosis (except Schatzki's ring), or a history of gastric or duodenal surgery (except endoscopic removal of benign polyps).
  8. The participant has acute upper gastrointestinal bleeding or gastric or duodenal ulcer, characterized by a defective mucosa with white coating, within 30 days prior to the start of the run-in period (Visit 1). However, participants with gastric or duodenal erosion are permitted to participate.
  9. The participant has acute gastritis or acute exacerbation of chronic gastritis.
  10. The participant has, or has a history of, Zollinger-Ellison syndrome or gastric acid hypersecretion disorders.
  11. The participant has, or has a history of chest pain due to cardiac disease, or has chest pain suspectedly caused by cardiac disease within 1 year prior to the start of the run-in period (Visit 1).
  12. The participant has any other concurrent upper gastrointestinal symptoms more severe than heartburn.
  13. The participant has depression.
  14. The participant has, has a history of, or is suspected of functional upper gastrointestinal disorders, such as functional dyspepsia and functional heartburn diagnosed by the Rome IV criteria.
  15. The participant has a history of hypersensitivity or allergies to TAK-438 (including the formulation excipients).
  16. The participant has a history or complication of drug abuse (defined as any illicit drug use) or of alcohol abuse within 1 years prior to the start of the run-in period (Visit 1).
  17. The participant requires any excluded medications or treatments.
  18. The female participant who is pregnant, is lactating, or is intending to become pregnant or to donate ova any time between the informed consent signing and 4 weeks after the last dose of study drug.
  19. The participant has any serious neurological, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, endocrinological, or hematologic diseases.
  20. The participant needs surgery requiring hospitalization during the course of the study, or surgery requiring hospitalization is scheduled for the participant during the course of the study.
  21. The participant has a history of malignancy or is treated for malignancy within 5 years prior to the start of the run-in period (Visit 1). However, participants who have recovered completely from cutaneous basal cell carcinoma or from cervical carcinoma in situ are permitted to participate.
  22. The participant has acquired immunodeficiency syndrome (AIDS) or hepatitis, is a human immunodeficiency virus (HIV) carrier, or tested positive for the hepatitis B virus surface antigen (HBsAg) or the hepatitis C virus (HCV) antibody. However, participants who tested negative for HCV antigen or HCV-RNA are permitted to participate.
  23. The participant has any of the following abnormal clinical laboratory test values at the start of the run-in period (Visit 1):

    • Creatinine > 2 mg/dL.
    • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > upper limit of normal (ULN).
    • Bilirubin (Total bilirubin) > ULN.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 20 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Japan
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02954848
Other Study ID Numbers  ICMJE Vonoprazan-3001
U1111-1188-1784 ( Other Identifier: WHO )
JapicCTI-163413 ( Registry Identifier: JapicCTI )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.
Responsible Party Takeda
Study Sponsor  ICMJE Takeda
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Study Director Takeda
PRS Account Takeda
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP