Comparative Efficacy & Safety Study of D961H Versus Placebo for the Prevention of Gastric and Duodenal Ulcers With Low-dose Aspirin

A Phase III Multinational, Multicenter, Randomized, Double-blind, Parallel-group, Comparative Efficacy and Safety Study of D961H (20 mg Once Daily) Versus Placebo for Prevention of Gastric and/or Duodenal Ulcers Associated With Continuous Low-dose Aspirin (LDA) Use

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01069939

Enrollment

427

Registered

2010-02-17

Start date

2010-02-28

Completion date

2011-11-30

Last updated

2012-11-22

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Prevention

Keywords

Gastric ulcer, Duodenal ulcer, Low-dose aspirin

Brief summary

To assess the efficacy of D961H 20 mg once daily (q.d.) versus placebo in continuous treatment involving patients with a history of gastric and/or duodenal ulcers receiving daily Low-dose aspirin therapy by evaluating time from randomisation to occurrence of gastric and/or duodenal ulcers.

Interventions

DRUGEsomeprazole

20mg, capsule, 72 weeks

DRUGPlacebo

Placebo, capsule, 72 weeks

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

PREVENTION

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

20 Years to No maximum

Healthy volunteers

Inclusion criteria

* Provision of written informed consent before starting the study-related procedures and examinations * Patients who have the history of gastric and/or duodenal ulcer. * A diagnosis of a chronic condition (angina pectoris, myocardial infarction and ischemic cerebrovascular disorder, etc., requiring prevention of thrombosis or embolism) which requires taking the prescribed LDA during the study treatment period.

Exclusion criteria

* Having gastric or duodenal ulcer (except for ulcer scar). * History of esophageal, gastric or duodenal surgery, except for simple closure of perforation.

Design outcomes

Primary

Measure	Time frame	Description
Time From Randomization to Occurrence of Gastric and/or Duodenal Ulcers up to Data Cut-off Date for Interim Analysis.	From randomisation to up to 48 weeks (Maximum follow-up period at the interim analysis)	Assessments for occurrence of gastric and/or duodenal ulcers were performed every 12 weeks after randomisation. The numbers of participants with recurrence of gastric and/or duodeal ulcers were analysed every 12 weeks up to 48 weeks.

Secondary

Measure	Time frame	Description
Change in Degree of Gastric Mucosal Lesion by Modified Lanza Scale From Baseline to Last Measurement up to Week 48	Up to 48 weeks (Baseline to last measurement)	Modified Lanza scale attributes the degree of gastric mucosal lesion, graded on a 5 point scale (0=No hemorrhage, no erosion, 1=One hemorrhage or one erosions, 2=2-10 hemorrhages or erosions, 3=11-25 hemorrhages or erosions, 4=More than 25 hemorrhages or erosions, or ulcer). Higher scores indicate greater severity of gastric mucosal lesion.
Number of Participants With Reflux Esophagitis Evaluated by the LA Classification up to Week 48.	12, 24, 36 and 48 weeks	Endoscopy was conducted at 12, 24, 36 and 48 weeks after randomisation. At the endoscopy, participants was evaluated whether they have reflux esophagitis or not.
Change in the Severity of Epigastric Pain From Baseline to Last Measurement up to Week 48	Up to 48 weeks (Baseline to last measurement)	The severity of epigastric pain at baseline and the last measurement up to 48 weeks was obtained (None, Mild, Moderate, Severe). If the value at the last was better in a participant, the participant was categorized into Improved. If the value was same, categorised into Unchanged. If the value was worsened, categorise into Worsened.
Change in the Severity of Heartburn From Baseline to Last Measurement up to Week 48.	Up to 48 weeks (Baseline to last measurement)	The severity of heartburn at baseline and the last measurement up to 48 weeks was obtained (None, Mild, Moderate, Severe). If the value at the last was better in a participant, the participant was categorized into Improved. If the value was same, categorised into Unchanged. If the value was worsened, categorise into Worsened.
Change in the Severity of Anorexia From Baseline to Last Measurement up to Week 48	Up to 48 weeks (Baseline to last measurement)	The severity of anorexia at baseline and the last measurement up to 48 weeks was obtained (None, Mild, Moderate, Severe). If the value at the last was better in a participant, the participant was categorized into Improved. If the value was same, categorised into Unchanged. If the value was worsened, categorise into Worsened.
Change in the Severity of Nausea and/or Vomiting From Baseline to Last Measurement up to Week 48	Up to 48 weeks (Baseline to last measurement)	The severity of Nausea and/or Vomiting at baseline and the last measurement up to 48 weeks was obtained (None, Mild, Moderate, Severe). If the value at the last was better in a participant, the participant was categorized into Improved. If the value was same, categorised into Unchanged. If the value was worsened, categorise into Worsened.
Change in the Severity of Discomfort in the Stomach From Baseline to Last Measurement up to Week 48	Up to 48 weeks (Baseline to last measurement)	The severity of Discomfort in the stomach at baseline and the last measurement up to 48 weeks was obtained (None, Mild, Moderate, Severe). If the value at the last was better in a participant, the participant was categorized into Improved. If the value was same, categorised into Unchanged. If the value was worsened, categorise into Worsened.
Number of Participants With Adverse Events	Up to 70 weeks at the longest	Participants who had at least adverse events (AE) which occurred after receiving study drug were counted.
Change in the Severity of Abdomen Enlarged Feeling From Baseline to Last Measurement up to Week	Up to 48 weeks (Baseline to last measurement)	The severity of abdomen enlarged feeling at baseline and the last measurement up to 48 weeks was obtained (None, Mild, Moderate, Severe). If the value at the last was better in a participant, the participant was categorized into Improved. If the value was same, categorised into Unchanged. If the value was worsened, categorise into Worsened.

Countries

Japan, South Korea, Taiwan

Participant flow

Recruitment details

First participant enrolled on 4 February 2010. On 20 May 2011, the efficacy analysis was completed based on positive results of an interim analysis so that the efficacy data in this report are at the interim analysis. To evaluate the safety, the study was continued. The last participant completed the study on 9 November 2011.

Pre-assignment details

Out of 914 enrolled participants, 430 participants were assigned , but 484 participants were not assigned. The major reasons of no assignment were 'Did not meet eligibility criteria' (462 participants) and 'Voluntary discontinuation by participant' (21 participants). After 366 participants were randomised, the interim analysis was done.

Participants by arm

Arm	Count
Esomeprazole 20mg Esomeprazole 20mg once daily oral	213
Placebo Placebo once daily oral	214
Total	427

Withdrawals & dropouts

Period	Reason	FG000	FG001
Randomised and Included in the Analyses	Adverse Event	17	22
Randomised and Included in the Analyses	Eligibility criteria not fulfilled	4	3
Randomised and Included in the Analyses	Lack of Efficacy	0	1
Randomised and Included in the Analyses	Lost to Follow-up	1	1
Randomised and Included in the Analyses	Physician Decision	0	2
Randomised and Included in the Analyses	Protocol Violation	0	1
Randomised and Included in the Analyses	Removal	1	0
Randomised and Included in the Analyses	Study-specific withdrawal criteria	7	33
Randomised and Included in the Analyses	Use of prohibited concomitant drug	4	2
Randomised and Included in the Analyses	Withdrawal by Subject	15	12

Baseline characteristics

Characteristic	Esomeprazole 20mg	Placebo	Total
Age, Customized <=64years	85 Participants	71 Participants	156 Participants
Age, Customized >=75 years	46 Participants	54 Participants	100 Participants
Age, Customized Between 65 and 74 years	82 Participants	89 Participants	171 Participants
Helicobacter pylori status Negative	117 Participants	116 Participants	233 Participants
Helicobacter pylori status Positive	93 Participants	93 Participants	186 Participants
Region of Enrollment Japan	160 Participants	160 Participants	320 Participants
Region of Enrollment Korea, Republic of	31 Participants	33 Participants	64 Participants
Region of Enrollment Taiwan	22 Participants	21 Participants	43 Participants
Sex: Female, Male Female	43 Participants	46 Participants	89 Participants
Sex: Female, Male Male	170 Participants	168 Participants	338 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	70 / 214	53 / 213
serious Total, serious adverse events	17 / 214	15 / 213

Outcome results

Primary

Time From Randomization to Occurrence of Gastric and/or Duodenal Ulcers up to Data Cut-off Date for Interim Analysis.

Assessments for occurrence of gastric and/or duodenal ulcers were performed every 12 weeks after randomisation. The numbers of participants with recurrence of gastric and/or duodeal ulcers were analysed every 12 weeks up to 48 weeks.

Time frame: From randomisation to up to 48 weeks (Maximum follow-up period at the interim analysis)

Population: Participants not taking investigational drug were not included. In total 364 participants were included in the efficacy evaluation at the interim analysis. 24 of the 364 total participants had an occurrence of gastric and/or duodenal ulcers by the 48-week assessment.

Arm	Measure	Group	Value (NUMBER)
Esomeprazole 20mg	Time From Randomization to Occurrence of Gastric and/or Duodenal Ulcers up to Data Cut-off Date for Interim Analysis.	0 - 12 weeks	1 Participants
Esomeprazole 20mg	Time From Randomization to Occurrence of Gastric and/or Duodenal Ulcers up to Data Cut-off Date for Interim Analysis.	13 - 24 weeks	1 Participants
Esomeprazole 20mg	Time From Randomization to Occurrence of Gastric and/or Duodenal Ulcers up to Data Cut-off Date for Interim Analysis.	25 - 36 weeks	0 Participants
Esomeprazole 20mg	Time From Randomization to Occurrence of Gastric and/or Duodenal Ulcers up to Data Cut-off Date for Interim Analysis.	37 - 48 weeks	0 Participants
Placebo	Time From Randomization to Occurrence of Gastric and/or Duodenal Ulcers up to Data Cut-off Date for Interim Analysis.	37 - 48 weeks	0 Participants
Placebo	Time From Randomization to Occurrence of Gastric and/or Duodenal Ulcers up to Data Cut-off Date for Interim Analysis.	0 - 12 weeks	16 Participants
Placebo	Time From Randomization to Occurrence of Gastric and/or Duodenal Ulcers up to Data Cut-off Date for Interim Analysis.	25 - 36 weeks	2 Participants
Placebo	Time From Randomization to Occurrence of Gastric and/or Duodenal Ulcers up to Data Cut-off Date for Interim Analysis.	13 - 24 weeks	4 Participants

Comparison: The above two groups were compared.p-value: <0.00196.65% CI: [0.02, 0.41]Log Rank

Secondary

Change in Degree of Gastric Mucosal Lesion by Modified Lanza Scale From Baseline to Last Measurement up to Week 48

Modified Lanza scale attributes the degree of gastric mucosal lesion, graded on a 5 point scale (0=No hemorrhage, no erosion, 1=One hemorrhage or one erosions, 2=2-10 hemorrhages or erosions, 3=11-25 hemorrhages or erosions, 4=More than 25 hemorrhages or erosions, or ulcer). Higher scores indicate greater severity of gastric mucosal lesion.