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High Dose Esomeprazole Na for Prevention of Rebleeding After Successful Endoscopic Therapy of a Bleeding Peptic Ulcer

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ClinicalTrials.gov Identifier: NCT01757275
Recruitment Status : Completed
First Posted : December 28, 2012
Results First Posted : March 8, 2016
Last Update Posted : March 8, 2016
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Prevention
Condition Bleeding Peptic Ulcer
Interventions Drug: Esomeprazole Na
Drug: Cimetidine
Drug: Esomeprazole Mg
Enrollment 239
Recruitment Details

Overall, 239 patients were enrolled from 19 centres in China. The first patient entered the study on 26 February 2013 and the last patient completed the study on 30 December 2014.

Of the 239 patients enrolled into the study, 222 (92.9%) patients were randomised to treatment.

Pre-assignment Details 17 patients were not assigned to treatment, 15 patients did not fulfil the eligibility criteria, 1 was due to patient decision, and 1 patient due to “other” (not enough experimental drug).
Arm/Group Title Esomeprazole Cimetidine
Hide Arm/Group Description Esomeprazole iv 80 mg bolus infusion for 30 min followed by Esomeprazole iv 8 mg/hour for 71.5 hours and esomeprazole oral 40 mg once daily for 27 days Cimetidine iv 200 mg bolus infusion for 30 min followed by Cimetidine iv 60 mg/hour for 71.5 hours and esomeprazole oral 40 mg once daily for 27 days
Period Title: Overall Study
Started 111 111
Completed 102 98
Not Completed 9 13
Reason Not Completed
Lost to Follow-up             1             2
Adverse Event             3             3
Withdrawal by Subject             2             4
Not treated             3             4
Arm/Group Title Esomeprazole Cimetidine Total
Hide Arm/Group Description Esomeprazole iv 80 mg bolus infusion for 30 min followed by Esomeprazole iv 8 mg/hour for 71.5 hours and esomeprazole oral 40 mg once daily for 27 days Cimetidine iv 200 mg bolus infusion for 30 min followed by Cimetidine iv 60 mg/hour for 71.5 hours and esomeprazole oral 40 mg once daily for 27 days Total of all reporting groups
Overall Number of Baseline Participants 108 107 215
Hide Baseline Analysis Population Description
Among 222 randomised patients, 215 patients received iv treatment: 108 patients in the esomeprazole treatment group and 107 patients in the cimetidine treatment group.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Age Number Analyzed 108 participants 107 participants 215 participants
42.4  (12.79) 41.8  (12.96) 42.1  (12.85)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 108 participants 107 participants 215 participants
<=65 years 104 103 207
>65 years 4 4 8
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 108 participants 107 participants 215 participants
Female
25
  23.1%
24
  22.4%
49
  22.8%
Male
83
  76.9%
83
  77.6%
166
  77.2%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Asian/Chinese Number Analyzed 108 participants 107 participants 215 participants
108 107 215
Number of patients with one bleeding ulcer  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 108 participants 107 participants 215 participants
108 107 215
Forrest class   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 108 participants 107 participants 215 participants
Ia 5 4 9
Ib 58 64 122
IIa 33 24 57
IIb 12 15 27
[1]
Measure Description: Forrest classification of PUB (Forrest et al 1974): Ia = arterial bleeding; Ib = oozing bleeding; IIa = non-bleeding visible vessel; IIb = adherent clot.
Bleeding ulcer size  
Mean (Standard Deviation)
Unit of measure:  Mm
Number Analyzed 108 participants 107 participants 215 participants
8.2  (4.8) 8.1  (3.6) 8.1  (4.3)
Ulcer location  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 108 participants 107 participants 215 participants
Stomach 17 8 25
Duodenum 84 89 173
Stomach and Duodenum 7 10 17
Number of patients with ulcers of different sizes  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 108 participants 107 participants 215 participants
<=2 cm 105 106 211
>2 cm 3 1 4
Number of patients with single and multiple ulcers  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 108 participants 107 participants 215 participants
Single 89 89 178
Multiple 19 18 37
1.Primary Outcome
Title Rate of Clinically Significant Rebleeding Within 72 Hours
Hide Description

Diagnostic criteria for clinically significant rebleeding based on either A, B or C:

A) Endoscopy – initiated by clinical signs of bleeding defined as one of B1 or B2 or B3 and endoscopic verification, ie one of A1 or A2.

A1: Blood in stomach (this criteria cannot be used during the first 6 hours after primary endoscopic haemostasis). A2: A verified active bleeding from a peptic ulcer (Forrest Ia, Ib).

B) A true clinically based definition, at least two of B1 and/or B2 and/or B3. B1: Vomiting of fresh blood or fresh blood in a gastric tube or haematochezia or melaena after a normal stool. B2: Decrease in Hb >20g/L (or Hct >6%) during 24 hours or an increase in Hb <10g/L (or Hct <3%) despite ≥2 units of blood has been transfused during 24hours. B3: Unstable circulation systolic blood pressure ≤ 90 mmHg or pulse ≥110/min (after have had a stable circulation).

C) Haematemesis. Vomiting significant amounts (>200 ml) of fresh blood as estimated by the investigator.

Time Frame 72 hours
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS). All randomised patients, who started the randomised iv treatment (bolus dose), were included in the FAS.
Arm/Group Title Esomeprazole Cimetidine
Hide Arm/Group Description:
Esomeprazole iv 80 mg bolus infusion for 30 min followed by Esomeprazole iv 8 mg/hour for 71.5 hours and esomeprazole oral 40 mg once daily for 27 days
Cimetidine iv 200 mg bolus infusion for 30 min followed by Cimetidine iv 60 mg/hour for 71.5 hours and esomeprazole oral 40 mg once daily for 27 days
Overall Number of Participants Analyzed 108 107
Measure Type: Number
Unit of Measure: participants
No rebleeding 107 101
Rebleeding 1 6
2.Secondary Outcome
Title Rate of Clinically Significant Rebleeding During 7 Days
Hide Description

Diagnostic criteria for clinically significant rebleeding based on either A, B or C:

A) Endoscopy – initiated by clinical signs of bleeding defined as one of B1 or B2 or B3 and endoscopic verification, ie one of A1 or A2.

A1: Blood in stomach (this criteria cannot be used during the first 6 hours after primary endoscopic haemostasis). A2: A verified active bleeding from a peptic ulcer (Forrest Ia, Ib).

B) A true clinically based definition, at least two of B1 and/or B2 and/or B3. B1: Vomiting of fresh blood or fresh blood in a gastric tube or haematochezia or melaena after a normal stool. B2: Decrease in Hb >20g/L (or Hct >6%) during 24 hours or an increase in Hb <10g/L (or Hct <3%) despite ≥2 units of blood has been transfused during 24hours. B3: Unstable circulation systolic blood pressure ≤ 90 mmHg or pulse ≥110/min (after have had a stable circulation).

C) Haematemesis. Vomiting significant amounts (>200 ml) of fresh blood as estimated by the investigator.

Time Frame 7 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Esomeprazole Cimetidine
Hide Arm/Group Description:
Esomeprazole iv 80 mg bolus infusion for 30 min followed by Esomeprazole iv 8 mg/hour for 71.5 hours and esomeprazole oral 40 mg once daily for 27 days
Cimetidine iv 200 mg bolus infusion for 30 min followed by Cimetidine iv 60 mg/hour for 71.5 hours and esomeprazole oral 40 mg once daily for 27 days
Overall Number of Participants Analyzed 108 107
Measure Type: Number
Unit of Measure: participants
No rebleeding 105 101
Rebleeding 3 6
3.Secondary Outcome
Title Rate of Clinically Significant Rebleeding During 30 Days
Hide Description

Diagnostic criteria for clinically significant rebleeding based on either A, B or C:

A) Endoscopy – initiated by clinical signs of bleeding defined as one of B1 or B2 or B3 and endoscopic verification, ie one of A1 or A2.

A1: Blood in stomach (this criteria cannot be used during the first 6 hours after primary endoscopic haemostasis). A2: A verified active bleeding from a peptic ulcer (Forrest Ia, Ib).

B) A true clinically based definition, at least two of B1 and/or B2 and/or B3. B1: Vomiting of fresh blood or fresh blood in a gastric tube or haematochezia or melaena after a normal stool. B2: Decrease in Hb >20g/L (or Hct >6%) during 24 hours or an increase in Hb <10g/L (or Hct <3%) despite ≥2 units of blood has been transfused during 24hours. B3: Unstable circulation systolic blood pressure ≤ 90 mmHg or pulse ≥110/min (after have had a stable circulation).

C) Haematemesis. Vomiting significant amounts (>200 ml) of fresh blood as estimated by the investigator.

Time Frame 30 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Esomeprazole Cimetidine
Hide Arm/Group Description:
Esomeprazole iv 80 mg bolus infusion for 30 min followed by Esomeprazole iv 8 mg/hour for 71.5 hours and esomeprazole oral 40 mg once daily for 27 days
Cimetidine iv 200 mg bolus infusion for 30 min followed by Cimetidine iv 60 mg/hour for 71.5 hours and esomeprazole oral 40 mg once daily for 27 days
Overall Number of Participants Analyzed 108 107
Measure Type: Number
Unit of Measure: participants
No rebleeding 105 101
Rebleeding 3 6
4.Secondary Outcome
Title Number of Patients With Endoscopic Re-treatment Within 72 Hours
Hide Description [Not Specified]
Time Frame 72 hours
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Esomeprazole Cimetidine
Hide Arm/Group Description:
Esomeprazole iv 80 mg bolus infusion for 30 min followed by Esomeprazole iv 8 mg/hour for 71.5 hours and esomeprazole oral 40 mg once daily for 27 days
Cimetidine iv 200 mg bolus infusion for 30 min followed by Cimetidine iv 60 mg/hour for 71.5 hours and esomeprazole oral 40 mg once daily for 27 days
Overall Number of Participants Analyzed 108 107
Measure Type: Number
Unit of Measure: participants
No re-treatment 108 106
Re-treatment 0 1
5.Secondary Outcome
Title Number of Patients With Endoscopic Re-treatment Within 30 Days
Hide Description [Not Specified]
Time Frame 30 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Esomeprazole Cimetidine
Hide Arm/Group Description:
Esomeprazole iv 80 mg bolus infusion for 30 min followed by Esomeprazole iv 8 mg/hour for 71.5 hours and esomeprazole oral 40 mg once daily for 27 days
Cimetidine iv 200 mg bolus infusion for 30 min followed by Cimetidine iv 60 mg/hour for 71.5 hours and esomeprazole oral 40 mg once daily for 27 days
Overall Number of Participants Analyzed 108 107
Measure Type: Number
Unit of Measure: participants
No re-treatment 106 106
Re-treatment 2 1
6.Secondary Outcome
Title Number of Patients With Surgery Due to Rebleeding Within 72 Hours
Hide Description [Not Specified]
Time Frame within 72 hours
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Esomeprazole Cimetidine
Hide Arm/Group Description:
Esomeprazole iv 80 mg bolus infusion for 30 min followed by Esomeprazole iv 8 mg/hour for 71.5 hours and esomeprazole oral 40 mg once daily for 27 days
Cimetidine iv 200 mg bolus infusion for 30 min followed by Cimetidine iv 60 mg/hour for 71.5 hours and esomeprazole oral 40 mg once daily for 27 days
Overall Number of Participants Analyzed 108 107
Measure Type: Number
Unit of Measure: participants
No surgery 108 107
Surgery 0 0
7.Secondary Outcome
Title Number of Patients With Surgery Due to Rebleeding Within 30 Days
Hide Description [Not Specified]
Time Frame within 30 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Esomeprazole Cimetidine
Hide Arm/Group Description:
Esomeprazole iv 80 mg bolus infusion for 30 min followed by Esomeprazole iv 8 mg/hour for 71.5 hours and esomeprazole oral 40 mg once daily for 27 days
Cimetidine iv 200 mg bolus infusion for 30 min followed by Cimetidine iv 60 mg/hour for 71.5 hours and esomeprazole oral 40 mg once daily for 27 days
Overall Number of Participants Analyzed 108 107
Measure Type: Number
Unit of Measure: participants
No surgery 108 106
Surgery 0 1
8.Secondary Outcome
Title Number of Blood Units Transfused Within 72 Hours
Hide Description [Not Specified]
Time Frame within 72 hours
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Esomeprazole Cimetidine
Hide Arm/Group Description:
Esomeprazole iv 80 mg bolus infusion for 30 min followed by Esomeprazole iv 8 mg/hour for 71.5 hours and esomeprazole oral 40 mg once daily for 27 days
Cimetidine iv 200 mg bolus infusion for 30 min followed by Cimetidine iv 60 mg/hour for 71.5 hours and esomeprazole oral 40 mg once daily for 27 days
Overall Number of Participants Analyzed 108 107
Measure Type: Number
Unit of Measure: blood units
14 21
9.Secondary Outcome
Title Number of Blood Units Transfused Within 30 Days
Hide Description [Not Specified]
Time Frame within 30 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Esomeprazole Cimetidine
Hide Arm/Group Description:
Esomeprazole iv 80 mg bolus infusion for 30 min followed by Esomeprazole iv 8 mg/hour for 71.5 hours and esomeprazole oral 40 mg once daily for 27 days
Cimetidine iv 200 mg bolus infusion for 30 min followed by Cimetidine iv 60 mg/hour for 71.5 hours and esomeprazole oral 40 mg once daily for 27 days
Overall Number of Participants Analyzed 108 107
Measure Type: Number
Unit of Measure: blood units
18 21
Time Frame AEs will be collected from the time of the first administration of IP until the end of study, up to 35 days. SAEs will be collected from signed inform consent until the end of the study, up to 36 days.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Esomeprazole Cimetidine
Hide Arm/Group Description Esomeprazole iv 80 mg bolus infusion for 30 min followed by Esomeprazole iv 8 mg/hour for 71.5 hours and esomeprazole oral 40 mg once daily for 27 days Cimetidine iv 200 mg bolus infusion for 30 min followed by Cimetidine iv 60 mg/hour for 71.5 hours and esomeprazole oral 40 mg once daily for 27 days
All-Cause Mortality
Esomeprazole Cimetidine
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Esomeprazole Cimetidine
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   5/110 (4.55%)      5/105 (4.76%)    
Gastrointestinal disorders     
Duodenal ulcer haemorrhage * 1  2/110 (1.82%)  2 2/105 (1.90%)  2
Gastric ulcer haemorrhage * 1  1/110 (0.91%)  1 0/105 (0.00%)  0
Gastrointestinal haemorrhage * 1  0/110 (0.00%)  0 1/105 (0.95%)  1
Infections and infestations     
Bronchitis * 1  0/110 (0.00%)  0 1/105 (0.95%)  1
Investigations     
Blood fibrinogen decreased * 1  1/110 (0.91%)  1 0/105 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Lung neoplasm malignant * 1  1/110 (0.91%)  1 0/105 (0.00%)  0
Psychiatric disorders     
Persecutory delusion * 1  0/110 (0.00%)  0 1/105 (0.95%)  1
Renal and urinary disorders     
Nephrolithiasis * 1  0/110 (0.00%)  0 1/105 (0.95%)  1
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Esomeprazole Cimetidine
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   22/110 (20.00%)      20/105 (19.05%)    
Blood and lymphatic system disorders     
Anaemia * 1  0/110 (0.00%)  1/105 (0.95%) 
Haemorrhagic anaemia * 1  0/110 (0.00%)  1/105 (0.95%) 
Cardiac disorders     
Myocardial ischaemia * 1  0/110 (0.00%)  1/105 (0.95%) 
Palpitations * 1  0/110 (0.00%)  1/105 (0.95%) 
Gastrointestinal disorders     
Duodenal ulcer haemorrhage * 1  2/110 (1.82%)  2/105 (1.90%) 
Diarrhoea * 1  2/110 (1.82%)  1/105 (0.95%) 
Melaena * 1  1/110 (0.91%)  2/105 (1.90%) 
Constipation * 1  1/110 (0.91%)  1/105 (0.95%) 
Abdominal distension * 1  1/110 (0.91%)  0/105 (0.00%) 
Dry mouth * 1  1/110 (0.91%)  0/105 (0.00%) 
Dyspepsia * 1  1/110 (0.91%)  0/105 (0.00%) 
Gastric ulcer haemorrhage * 1  1/110 (0.91%)  0/105 (0.00%) 
Gastrointestinal haemorrhage * 1  0/110 (0.00%)  1/105 (0.95%) 
Gastrointestinal motility disorder * 1  0/110 (0.00%)  1/105 (0.95%) 
General disorders     
Pyrexia * 1  2/110 (1.82%)  2/105 (1.90%) 
Asthenia * 1  0/110 (0.00%)  1/105 (0.95%) 
Non-cardiac chest pain * 1  0/110 (0.00%)  1/105 (0.95%) 
Hepatobiliary disorders     
Cholelithiasis * 1  0/110 (0.00%)  1/105 (0.95%) 
Hepatic function abnormal * 1  0/110 (0.00%)  1/105 (0.95%) 
Infections and infestations     
Bronchitis * 1  0/110 (0.00%)  1/105 (0.95%) 
Nasopharyngitis * 1  1/110 (0.91%)  0/105 (0.00%) 
Upper respiratory tract infection * 1  0/110 (0.00%)  1/105 (0.95%) 
Injury, poisoning and procedural complications     
Laceration * 1  0/110 (0.00%)  1/105 (0.95%) 
Ligament sprain * 1  0/110 (0.00%)  1/105 (0.95%) 
Investigations     
Blood fibrinogen decreased * 1  1/110 (0.91%)  0/105 (0.00%) 
Haematocrit decreased * 1  0/110 (0.00%)  1/105 (0.95%) 
Haemoglobin decreased * 1  0/110 (0.00%)  1/105 (0.95%) 
Liver function test abnormal * 1  1/110 (0.91%)  0/105 (0.00%) 
Neutrophil count increased * 1  1/110 (0.91%)  0/105 (0.00%) 
Neutrophil percentage increased * 1  1/110 (0.91%)  0/105 (0.00%) 
Red blood cell count decreased * 1  0/110 (0.00%)  1/105 (0.95%) 
White blood cell count increased * 1  1/110 (0.91%)  0/105 (0.00%) 
Metabolism and nutrition disorders     
Hypochloraemia * 1  1/110 (0.91%)  0/105 (0.00%) 
Hypokalaemia * 1  1/110 (0.91%)  0/105 (0.00%) 
Hyponatraemia * 1  1/110 (0.91%)  0/105 (0.00%) 
Musculoskeletal and connective tissue disorders     
Back pain * 1  1/110 (0.91%)  0/105 (0.00%) 
Gouty arthritis * 1  1/110 (0.91%)  0/105 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Lung neoplasm malignant * 1  1/110 (0.91%)  0/105 (0.00%) 
Nervous system disorders     
Dizziness * 1  1/110 (0.91%)  1/105 (0.95%) 
Headache * 1  0/110 (0.00%)  1/105 (0.95%) 
Psychiatric disorders     
Agitation * 1  1/110 (0.91%)  0/105 (0.00%) 
Persecutory delusion * 1  0/110 (0.00%)  1/105 (0.95%) 
Renal and urinary disorders     
Nephrolithiasis * 1  0/110 (0.00%)  1/105 (0.95%) 
Reproductive system and breast disorders     
Haematospermia * 1  1/110 (0.91%)  0/105 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Cough * 1  2/110 (1.82%)  0/105 (0.00%) 
Oropharyngeal pain * 1  0/110 (0.00%)  1/105 (0.95%) 
Pleurisy * 1  0/110 (0.00%)  1/105 (0.95%) 
Skin and subcutaneous tissue disorders     
Ecchymosis * 1  0/110 (0.00%)  1/105 (0.95%) 
Erythema * 1  1/110 (0.91%)  0/105 (0.00%) 
Rash * 1  1/110 (0.91%)  0/105 (0.00%) 
Rash maculo-papular * 1  0/110 (0.00%)  1/105 (0.95%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA
No hypothesis testing was performed in this study and, as such, no formal statistical comparisons were made. Two patients who were initially randomised to receive cimetidine treatment actually received esomeprazole treatment.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Huifang Chen
Organization: AstraZeneca
Phone: +86 21 60301335
Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT01757275     History of Changes
Other Study ID Numbers: D961DC00007
First Submitted: December 21, 2012
First Posted: December 28, 2012
Results First Submitted: December 16, 2015
Results First Posted: March 8, 2016
Last Update Posted: March 8, 2016