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
Phase 3 Study of TAK-438 10 mg in the Treatment of Non-Erosive Gastroesophageal Reflux Disease (NERD)
Feb. 26, 2018
484
No obvious differences in demographic characteristics were observed between the TAK-438 10 mg group and the placebo group at baseline.
The percentages of participants with each modified LA Classification grade of NERD evaluated by the PI were comparable between the TAK-438 10 mg group and the placebo group at the baseline: Grade N, 33.5% in the placebo group, 33.9% and in the TAK-438 10 mg group; Grade M, 66.5% in the placebo group, and 66.1% in the TAK-438 10 mg group. Severity scores of symptoms of heartburn at the baseline were comparable between the TAK-438 10 mg group and the placebo group: 1.641 in the placebo group, and 1.765 in the TAK-438 10 mg group.
A total of 721 participants signed the informed consent form, and 484 of them were randomized in the treatment period at 44 sites in Japan. The most common primary reason for being not eligible for randomization was "screen failure" in 216 participants.
In the treatment period, 245 participants were allocated to the placebo group, and 239 were allocated to the TAK-438 10 mg group. Of the 484 randomized participants, 1 in the TAK-438 10 mg group did not received the study medication for the treatment period. The reason for not being treated was "withdrawal by participant". Of the 483 participants who received the study drug for the treatment period, 477 (98.6%) completed the study medication in the treatment period. The number of participants who prematurely discontinued the study drug during the treatment period was 6 (1.2%): 2 (0.8%) in the placebo group, and 4 (1.7%) in the TAK-438 10 mg group. The primary reason for premature discontinuation was "adverse event" in 5 participants (2 in the placebo group, and 3 in the TAK-438 10 mg group) and "withdrawal by participant" in 1 participant in the TAK-438 10 mg group.
The incidence of Treatment emergent adverse events (TEAEs) was 23.3% in the placebo group, and 23.5% in the TAK-438 10 mg group.
The most common TEAE by Preferred Term (PT) was viral upper respiratory tract infection, reported in 4.9% of the participants in the placebo group, and 4.2% of the participants in the TAK-438 10 mg group. The incidences of all the other TEAEs by PT were less than 2%. No remarkable differences were observed in the incidences of TEAEs between the TAK-438 10 mg group and the placebo group. The incidence of drug-related TEAEs was 4.5% in the placebo group, and 5.0% in the TAK-438 10 mg group.
Most of the TEAEs were mild in intensity. No severe TEAEs were reported during the study.
No deaths were reported during the study. After the start of the treatment period, 1 serious adverse event (SAE) was reported in the placebo group, and no SAEs were reported in the TAK-438 10 mg group. The SAE reported in the placebo group was considered by the investigator to be unrelated to the study drug. Two participants in the placebo group, and 3 participants in the TAK-438 10 mg group discontinued the study drug treatment due to a TEAE. After the start of the treatment period, 1 Adverse Events of Special Interests (AESI) was reported in the placebo group, and 1 AESI was reported in the TAK-438 10 mg group.
Mean levels of serum gastrin, pepsinogen I, and pepsinogen II increased after the study drug administration in the TAK-438 10 mg group while no clinically significant changes were observed in the placebo group. No clinically significant changes in laboratory test values and vital signs were observed during the study.
These results indicate that TAK-438 10 mg is relatively safe and well tolerated in patients with NERD and safety profile of TAK-438 10 mg is not remarkably different from that of placebo.
Conclusion:
The safety profile of TAK-438 was not remarkably different from that of placebo, and TAK-438 treatment was safe and well tolerated in patients with NERD.
The median proportion of days without symptoms of heartburn during the treatment period in the Full analysis set (FAS) was 61.50% in the placebo group, and 72.55% in the TAK-438 10 mg group. Although there was no statistically significant difference between the TAK-438 10 mg group and the placebo group (p =0.0643), the proportion of days without symptoms of heartburn during the treatment period was higher in the TAK-438 10 mg group than in the placebo group. However, the superiority of the TAK-438 10 mg treatment to the placebo treatment was indicated in the Per protocol set (PPS); the proportion of days without heartburn was significantly higher in the TAK-438 10 mg group than in the placebo group (p <0.05).
The difference in the cumulative rate of improvement in symptoms of heartburn was statistically significant between the TAK-438 10 mg group and the placebo group either in the FAS or in the PPS, improvement was faster in the TAK-438 10 mg group than in the placebo group.
In the FAS, the severity of symptoms of heartburn was lower in the TAK-438 10 mg group than in the placebo group, although there was no statistically significant difference between the TAK-438 10 mg group and the placebo group (p =0.0826). However, the severity of symptoms of heartburn in the PPS was significantly lower in the TAK-438 10 mg group than in the placebo group (p =0.0476).
For the participants whose symptoms had improved at Week 2 according to either Criteria 1 or 2, the proportions of days without symptoms of heartburn were significantly higher in the TAK-438 10 mg group than in the placebo group (p <0.05).
For the participants with NERD of either Grade N or M, the proportions of days without symptoms of heartburn were higher in the TAK-438 10 mg group than in the placebo group, although there were no statistically significant differences (p >0.05).
For the participants with NERD of Grade M whose symptoms had improved at Week 2 according to Criteria 1, the proportion of days without symptoms of heartburn was significantly higher in the TAK-438 10 mg group than in the placebo group (p <0.05).
For the participants with NERD of Grade N or M whose symptoms had improved at Week 2 according to Criteria 2, the proportions of days without symptoms of heartburn were higher in the TAK-438 10 mg group than in the placebo group. Especially for the participants with NERD of Grade N, the proportion of days without symptoms of heartburn was significantly higher in the TAK-438 10 mg group than in the placebo group (p <0.05).
For the participants who had a medication history of any acid suppressants, and whose symptoms had either improved or not improved by taking acid suppressants, the proportions of days without symptoms of heartburn were higher in the TAK-438 10 mg group than in the placebo group, although there were no statistically significant differences (p >0.05).
Conclusion:
In the FAS, the proportion of days without symptoms of heartburn during the treatment period was higher in the TAK-438 10 mg group than in the placebo group, although there was no statistically significant difference between the TAK-438 10 mg group and the placebo group. However, the superiority of the TAK-438 10 mg treatment to the placebo treatment was indicated in the PPS. There was also statistically significant difference in the cumulative rate of improvement in symptoms of heartburn between the TAK-438 10 mg group and the placebo group. For the participants whose symptoms had improved at Week 2 according to either Criteria 1 or 2, the proportions of days without symptoms of heartburn were significantly higher in the TAK-438 10 mg group than in the placebo group. The above results suggest that TAK-438 treatment is effective in patients with NERD.
Refer to conclusion of "Adverse Events" and "Secondary Outcome Measures" sections.
Yes
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.
version:
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Takeda Pharmaceutical Company Limited
https://www.takeda.com/jp/who-we-are/contact-us/
+81-6-6204-2111
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Takeda Pharmaceutical Company Limited
https://www.takeda.com/jp/who-we-are/contact-us/
+81-6-6204-2111
-
completed
Nov. 15, 2016
484
Interventional
Randomized, double-blind, placebo-controlled, parallel-group, multicenter study
treatment purpose
3
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.
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.
20age old over
No limit
Both
Non-erosive gastroesophageal reflux disease
investigational material(s)
Generic name etc : TAK-438
INN of investigational material : Vonoprazan
Therapeutic category code : 232 Agents for peptic ulcer
Dosage and Administration for Investigational material : 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.
control material(s)
Generic name etc : Placebo
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : 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.
efficacy
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.
efficacy
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.
efficacy
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.
efficacy
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.
efficacy
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 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. 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].
efficacy
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 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. 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].
efficacy
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 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 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 2, i.e. Improved: the proportion of days the participant 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.
efficacy
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 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 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 2, i.e. Improved: the proportion of days the participant 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.
efficacy
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.
efficacy
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.
efficacy
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 was calculated as percentage of participants who experienced symptom improvement. Cumulative rates were 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.
efficacy
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 was calculated as percentage of participants who experienced symptom improvement. Cumulative rates were 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.
efficacy
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.
efficacy
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.
efficacy
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 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]. The modified LA classification Grade N: normal mucosa and Grade M: minimal changes to the mucosa.
efficacy
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 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. Score range was 0-4, higher scores indicates 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]. The modified LA classification Grade N indicates the participants with normal mucosa and Grade M indicates the participants with minimal changes to the mucosa).
efficacy
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 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. Score range was 0-4, higher score indicates 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]. The modified LA classification Grade N indicates the participants with normal mucosa and Grade M indicates the participants with minimal changes to the mucosa).
efficacy
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 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. Score range was 0-4, higher score indicates 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]. The modified LA classification Grade N indicates the participants with normal mucosa and Grade M indicates the participants with minimal changes to the mucosa).
efficacy
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 was calculated as percentage of participants who experienced symptom improvement. Response was evaluated per Criteria 2, i.e. Improved: participants experienced heartburn during the 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.
efficacy
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.
efficacy
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 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 or larger than during run-in period. Modified LA classification Grade N: normal mucosa and Grade M: minimal changes to mucosa.
efficacy
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 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.
efficacy
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.
efficacy
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].
efficacy
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 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 score indicates greater severity. Cumulative rate of improvement was calculated as percentage of participants who experienced symptom improvement. The cumulative improvement rates were 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].
efficacy
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 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 score indicates greater severity. Cumulative rate of improvement was calculated as percentage of participants who experienced symptom improvement. The cumulative improvement rates were 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].
efficacy
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].
