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Efficacy and Safety Study of HZT-501 in Reducing the Risk of Ibuprofen-associated Ulcers

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ClinicalTrials.gov Identifier: NCT00450658
Recruitment Status : Completed
First Posted : March 22, 2007
Results First Posted : June 21, 2011
Last Update Posted : April 29, 2013
Sponsor:
Information provided by (Responsible Party):
Horizon Pharma Ireland, Ltd., Dublin Ireland

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Prevention
Condition Peptic Ulcer
Interventions Drug: HZT-501
Drug: Ibuprofen
Enrollment 627
Recruitment Details A multi-center US study in which 80 sites recruited subjects between March 2007 and February 2008.
Pre-assignment Details Following screening for eligibility and wash-out of restricted medications, subjects were assigned according to the treatment to which they were randomized in a 2:1 ratio (HZT-501:ibuprofen).
Arm/Group Title HZT-501 Ibuprofen
Hide Arm/Group Description HZT-501: Ibuprofen 800mg/Famotidine 26.6mg tablets t.i.d. Ibuprofen 800mg tablets t.i.d.
Period Title: Overall Study
Started 415 212
Completed 272 122
Not Completed 143 90
Reason Not Completed
Adverse Event             24             15
Withdrawal by Subject             43             26
Lost to Follow-up             22             5
UGI ulcer             33             34
misc             21             10
Arm/Group Title HZT-501 Ibuprofen Total
Hide Arm/Group Description HZT-501: Ibuprofen 800mg/Famotidine 26.6mg Ibuprofen 800mg Total of all reporting groups
Overall Number of Baseline Participants 415 212 627
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 415 participants 212 participants 627 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
342
  82.4%
173
  81.6%
515
  82.1%
>=65 years
73
  17.6%
39
  18.4%
112
  17.9%
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 415 participants 212 participants 627 participants
55.3  (9.0) 55.7  (9.5) 55.4  (9.1)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 415 participants 212 participants 627 participants
Female
272
  65.5%
152
  71.7%
424
  67.6%
Male
143
  34.5%
60
  28.3%
203
  32.4%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 415 participants 212 participants 627 participants
415 212 627
1.Primary Outcome
Title Number of Subjects Who Develop Endoscopically-diagnosed Upper Gastrointestinal Ulcers Confirmed by Endoscopy.
Hide Description The primary efficacy endpoint was the number of subjects with upper gastrointestinal (i.e., gastric and/or duodenal) ulcer at any time throughout 24 weeks of treatment. An ulcer was defined as a mucosal break of at least 3 mm in diameter with unequivocal depth. A subject is considered to have completed the study if all scheduled assessments up through the Week 24 visit have been performed.
Time Frame 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized subjects who received at least one dose of study drug and who underwent a baseline endoscopic examination and at least the Week 8 endoscopic examination.
Arm/Group Title HZT-501 Ibuprofen
Hide Arm/Group Description:
HZT-501: Ibuprofen 800mg/Famotidine 26.6mg
Ibuprofen 800mg
Overall Number of Participants Analyzed 380 190
Measure Type: Number
Unit of Measure: participants
40 38
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection HZT-501, Ibuprofen
Comments The primary efficacy endpoint was the proportion of subjects developing UGI (gastric and/or duodenal) ulcers throughout 24 weeks of treatment. A summary including cumulative frequency and percentage with associated 95% confidence intervals was produced for the observational incidences of UGI ulcers at 24 weeks. The cumulative proportion of subjects developing UGI ulcers at 24 weeks was analyzed using the CMH test stratified by use of low-dose aspirin and prior UGI ulcer history at randomization.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0018
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments CMH test stratified by use of low-dose aspirin (Yes/No) and prior upper gastrointestinal ulcer history (Yes/No) at randomization.
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 9.5
Confidence Interval (2-Sided) 95%
3.0 to 15.9
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Number of Subjects Who Develop Endoscopically-diagnosed Gastric Ulcers During the 24-week Treatment Period.
Hide Description The secondary efficacy endpoint was the number of subjects with gastric ulcer at any time throughout 24 weeks of treatment. An ulcer was defined as a mucosal break of at least 3 mm in diameter with unequivocal depth. A subject is considered to have completed the study if all scheduled assessments up through the Week 24 visit have been performed.
Time Frame 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The secondary efficacy endpoint was the number of subjects with gastric ulcer at any time throughout 24 weeks of treatment. An ulcer was defined as a mucosal break of at least 3 mm in diameter with unequivocal depth. A subject is considered to have completed the study if all scheduled assessments up through the Week 24 visit were performed.
Arm/Group Title HZT-501 Ibuprofen
Hide Arm/Group Description:
HZT-501: Ibuprofen 800mg/Famotidine 26.6mg
Ibuprofen 800mg
Overall Number of Participants Analyzed 380 190
Measure Type: Number
Unit of Measure: participants
37 34
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection HZT-501, Ibuprofen
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0051
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments CMH test stratified by use of low-dose aspirin (Yes/No) and prior upper gastrointestinal ulcer history (Yes/No) at randomization.
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 8.2
Confidence Interval (2-Sided) 95%
1.9 to 14.4
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Number of Subjects Who Develop Endoscopically-diagnosed Duodenal Ulcers During the 24-week Treatment Period.
Hide Description The secondary efficacy endpoint was the number of subjects with duodenal ulcer at any time throughout the 24 weeks of treatment. An ulcer was defined as a mucosal break of at least 3 mm in diameter with unequivocal depth. A subject is considered to have completed the study if all scheduled assessments up through the Week 24 visit have been performed.
Time Frame 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title HZT-501 Ibuprofen
Hide Arm/Group Description:
HZT-501: Ibuprofen 800mg/Famotidine 26.6mg
Ibuprofen 800mg
Overall Number of Participants Analyzed 380 190
Measure Type: Number
Unit of Measure: participants
3 9
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection HZT-501, Ibuprofen
Comments The secondary efficacy endpoint was the proportion of subjects developing duodenal ulcers throughout 24 weeks of treatment. A summary including cumulative frequency and percentage with associated 95% confidence intervals was produced for the observational incidences of duodenal ulcers at 24 weeks. The cumulative proportion of subjects developing duodenal ulcers at 24 weeks was analyzed using the CMH test stratified by use of low-dose aspirin and prior UGI ulcer history at randomization.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0017
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments CMH test stratified by use of low-dose aspirin and prior UGI ulcer history at randomization.
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 3.9
Confidence Interval (2-Sided) 95%
0.8 to 7.1
Estimation Comments [Not Specified]
4.Secondary Outcome
Title The Incidence Rate of NSAID-associated Serious Gastrointestinal Complications.
Hide Description The secondary efficacy endpoint was the number of subjects developing a NSAID-associated serious GI complication at any time throughout 6 months of treatment. A NSAID-associated serious GI complication was defined as a perforation of ulcers, gastric outlet obstruction due to ulcers, and/or GI bleeding.
Time Frame 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized subjects who received at least one dose of study drug and who underwent a baseline endoscopic exam. Subjects were assigned according to the treatment to which they received.
Arm/Group Title HZT-501 Ibuprofen
Hide Arm/Group Description:
HZT-501: Ibuprofen 800mg/Famotidine 26.6mg
Ibuprofen 800mg
Overall Number of Participants Analyzed 415 212
Measure Type: Number
Unit of Measure: participants
0 0
Time Frame Randomization through 24 weeks.
Adverse Event Reporting Description Safety Population: All randomized subjects who received at least one dose of study drug and who underwent a baseline endoscopic examination. Subjects were assigned to the treatment to which they received; 2:1 randomization, HZT-501:ibuprofen.
 
Arm/Group Title HZT-501 Ibuprofen
Hide Arm/Group Description HZT-501: Ibuprofen 800mg/Famotidine 26.6mg Ibuprofen 800mg
All-Cause Mortality
HZT-501 Ibuprofen
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
HZT-501 Ibuprofen
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   11/415 (2.65%)      4/212 (1.89%)    
Cardiac disorders     
coronary artery disease  1  0/415 (0.00%)  0 1/212 (0.47%)  1
Gastrointestinal disorders     
esophageal ulcer  1  1/415 (0.24%)  1 0/212 (0.00%)  0
inguinal hernia  1  1/415 (0.24%)  1 0/212 (0.00%)  0
General disorders     
chest pain  1  1/415 (0.24%)  1 0/212 (0.00%)  0
edema peripheral  1  0/415 (0.00%)  0 1/212 (0.47%)  1
non-cardiac chest pain  1  1/415 (0.24%)  1 1/212 (0.47%)  1
Infections and infestations     
abscess  1  1/415 (0.24%)  1 0/212 (0.00%)  0
diverticulitis  1  1/415 (0.24%)  1 0/212 (0.00%)  0
infection  1  1/415 (0.24%)  1 0/212 (0.00%)  0
Injury, poisoning and procedural complications     
wrist fracture  1  1/415 (0.24%)  1 0/212 (0.00%)  0
Musculoskeletal and connective tissue disorders     
osteoarthritis  1  1/415 (0.24%)  1 0/212 (0.00%)  0
osteonecrosis  1  0/415 (0.00%)  0 1/212 (0.47%)  1
rotator cuff syndrome  1  1/415 (0.24%)  1 0/212 (0.00%)  0
Nervous system disorders     
transient ischemic attack  1  1/415 (0.24%)  1 0/212 (0.00%)  0
Psychiatric disorders     
schizoaffective disorder  1  1/415 (0.24%)  1 0/212 (0.00%)  0
suicide attempt  1  1/415 (0.24%)  1 0/212 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
asthma  1  1/415 (0.24%)  1 0/212 (0.00%)  0
bronchospasm  1  1/415 (0.24%)  1 0/212 (0.00%)  0
chronic obstructive pulmonary disease  1  1/415 (0.24%)  1 0/212 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 9.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 1%
HZT-501 Ibuprofen
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   220/415 (53.01%)      116/212 (54.72%)    
Blood and lymphatic system disorders     
anemia  1  3/415 (0.72%)  5/212 (2.36%) 
Eye disorders     
vision blurred  1  2/415 (0.48%)  4/212 (1.89%) 
Gastrointestinal disorders     
abdominal distension  1  5/415 (1.20%)  2/212 (0.94%) 
abdominal pain  1  7/415 (1.69%)  4/212 (1.89%) 
abdominal pain upper  1  14/415 (3.37%)  6/212 (2.83%) 
constipation  1  15/415 (3.61%)  8/212 (3.77%) 
diarrhea  1  17/415 (4.10%)  9/212 (4.25%) 
dyspepsia  1  17/415 (4.10%)  18/212 (8.49%) 
flatulence  1  6/415 (1.45%)  0/212 (0.00%) 
gastritis  1  7/415 (1.69%)  3/212 (1.42%) 
gastroesophageal reflux  1  9/415 (2.17%)  8/212 (3.77%) 
nausea  1  19/415 (4.58%)  11/212 (5.19%) 
stomach discomfort  1  4/415 (0.96%)  4/212 (1.89%) 
vomiting  1  8/415 (1.93%)  1/212 (0.47%) 
General disorders     
edema peripheral  1  6/415 (1.45%)  3/212 (1.42%) 
influenza like illness  1  4/415 (0.96%)  0/212 (0.00%) 
Infections and infestations     
bronchitis  1  12/415 (2.89%)  2/212 (0.94%) 
gastroenteritis  1  4/415 (0.96%)  0/212 (0.00%) 
gastroenteritis viral  1  2/415 (0.48%)  3/212 (1.42%) 
influenza  1  8/415 (1.93%)  1/212 (0.47%) 
nasopharyngitis  1  13/415 (3.13%)  6/212 (2.83%) 
sinusits  1  9/415 (2.17%)  3/212 (1.42%) 
upper respiratory tract infection  1  16/415 (3.86%)  11/212 (5.19%) 
urinary tract infection  1  3/415 (0.72%)  3/212 (1.42%) 
Investigations     
blood creatinine increased  1  4/415 (0.96%)  0/212 (0.00%) 
Musculoskeletal and connective tissue disorders     
arthralgia  1  2/415 (0.48%)  3/212 (1.42%) 
back pain  1  10/415 (2.41%)  3/212 (1.42%) 
muscle spasms  1  4/415 (0.96%)  0/212 (0.00%) 
musculoskeletal pain  1  5/415 (1.20%)  3/212 (1.42%) 
pain in extremity  1  7/415 (1.69%)  1/212 (0.47%) 
Nervous system disorders     
headache  1  11/415 (2.65%)  8/212 (3.77%) 
Psychiatric disorders     
depression  1  4/415 (0.96%)  2/212 (0.94%) 
insomnia  1  4/415 (0.96%)  4/212 (1.89%) 
Respiratory, thoracic and mediastinal disorders     
asthma  1  5/415 (1.20%)  0/212 (0.00%) 
cough  1  7/415 (1.69%)  1/212 (0.47%) 
dyspnea  1  1/415 (0.24%)  3/212 (1.42%) 
pharyngolaryngeal pain  1  8/415 (1.93%)  2/212 (0.94%) 
sinus congestion  1  3/415 (0.72%)  3/212 (1.42%) 
Skin and subcutaneous tissue disorders     
rash  1  3/415 (0.72%)  3/212 (1.42%) 
Vascular disorders     
hypertension  1  11/415 (2.65%)  4/212 (1.89%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 9.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS 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.
PI reserves the right to publish or otherwise make public the Study results provided that such communication occurs only after (i) the results of the multicenter Study in its entirety have been publicly disclosed by, or with consent of the sponsor or (ii) 18 months after conclusion of the Study at all sites, whichever comes first. Following this, PI can publish, present or use any non-confidential study results following Sponsor review. PI will not make public raw data or Case Reports.
Results Point of Contact
Name/Title: Amy Grahn, MS Senior Vice President, Clinical Development and Operations
Organization: Horizon Pharma, Inc.
Phone: 224-383-3012
Responsible Party: Horizon Pharma Ireland, Ltd., Dublin Ireland
ClinicalTrials.gov Identifier: NCT00450658     History of Changes
Other Study ID Numbers: HZ-CA-301
First Submitted: March 19, 2007
First Posted: March 22, 2007
Results First Submitted: May 17, 2011
Results First Posted: June 21, 2011
Last Update Posted: April 29, 2013