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Efficacy and Safety Study of HZT-501 in Subjects Requiring Nonsteroidal Anti-Inflammatory Drug (NSAID) Treatment

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ClinicalTrials.gov Identifier: NCT00450216
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 Ulcer
Interventions Drug: Ibuprofen/famotidine
Drug: Ibuprofen
Enrollment 906
Recruitment Details  
Pre-assignment Details  
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 607 299
Completed 433 170
Not Completed 174 129
Reason Not Completed
Adverse Event             38             23
Withdrawal by Subject             48             26
Lost to Follow-up             16             9
upper gastrointestinal (UGI) ulcer             51             51
misc             21             20
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 607 299 906
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 607 participants 299 participants 906 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
500
  82.4%
240
  80.3%
740
  81.7%
>=65 years
107
  17.6%
59
  19.7%
166
  18.3%
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 607 participants 299 participants 906 participants
55.5  (9.2) 55.9  (9.3) 55.6  (9.2)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 607 participants 299 participants 906 participants
Female
416
  68.5%
208
  69.6%
624
  68.9%
Male
191
  31.5%
91
  30.4%
282
  31.1%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 607 participants 299 participants 906 participants
607 299 906
1.Primary Outcome
Title Number of Participants Who Develop Endoscopically-diagnosed Gastric Ulcers
Hide Description The primary efficacy endpoint was the number of participants 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 participant is considered to have completed the study if all scheduled assessments up through the Week 24 visit have been performed.
Time Frame 24 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug and who underwent a baseline endoscopic examination and at least the Week 8 endoscopic examination. Participants were assigned according to the treatment to which they were randomized; 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
Overall Number of Participants Analyzed 550 262
Measure Type: Number
Unit of Measure: participants
55 52
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection HZT-501, Ibuprofen
Comments The primary efficacy endpoint was the number of participants developing gastric 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 gastric ulcers at 24 weeks. The cumulative number of participants developing gastric ulcers at 24 weeks was analyzed using the Cochran-Mantel-Haenszel (CMH) test stratified by use of low-dose aspirin and prior UGI ulcer history.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments CMH test stratified by use of low-dose aspirin (yes/no) and prior upper gastrointestinal (UGI) ulcer history (yes/no) at randomization.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 9.8
Confidence Interval (2-Sided) 95%
4.4 to 15.3
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Number of Participants Who Develop Endoscopically-diagnosed Upper Gastrointestinal (UGI) Ulcers During the 24-week Treatment Period.
Hide Description The secondary efficacy endpoint was the number of participants with UGI (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 participant is considered to have completed the study if all scheduled assessments up through the Week 24 visit have been performed.
Time Frame 24 weeks
Show Outcome Measure DataHide 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 550 262
Measure Type: Number
Unit of Measure: participants
63 61
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection HZT-501, Ibuprofen
Comments The secondary efficacy endpoint was the number of participants developing UGI (i.e., 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 number of participants developing UGI ulcers at 24 weeks was analyzed using the CMH test stratified by use of low-dose aspirin and prior UGI ulcer history.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments CMH test stratified by use of low-dose aspirin (yes/no) and prior UGI ulcer history (yes/no) at randomization.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 11.8
Confidence Interval (2-Sided) 95%
6.1 to 17.6
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Number of Participants Who Develop Endoscopically-diagnosed Duodenal Ulcers During the 24-week Treatment Period.
Hide Description The secondary efficacy endpoint was the number of participants with 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 participant is considered to have completed the study if all scheduled assessments up through the Week 24 visit have been performed.
Time Frame 24 weeks
Show Outcome Measure DataHide 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 550 262
Measure Type: Number
Unit of Measure: participants
8 14
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection HZT-501, Ibuprofen
Comments The secondary efficacy endpoint was the number of participants 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 number of participants developing duodenal ulcers at 24 weeks was analyzed using the CMH test stratified by use of low-dose aspirin and prio UGI ulcer history at randomization.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0006
Comments CMH test stratified by use of low-dose aspirin (yes/no) and prior UGI ulcer history (yes/no) at randomization.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 3.8
Confidence Interval (2-Sided) 95%
1.0 to 6.8
Estimation Comments [Not Specified]
4.Secondary Outcome
Title The Number of Participants Developing Non-steroidal Anti-inflammatory (NSAID)Associated Serious Gastrointestinal Complications (Perforation of Ulcers, Gastric Outlet Obstruction Due to Ulcers, Gastrointestinal Bleeding)
Hide Description The secondary efficacy endpoint was the number of participants developing a NSAID-associated serious gastrointestinal complication at any time throughout 24 weeks of treatment. A NSAID-associated serious gastrointestinal complication was defined as a perforation of ulcers, gastric outlet obstruction due to ulcers, and/or gastrointestinal bleeding.
Time Frame 24 weeks
Show Outcome Measure DataHide 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 550 262
Measure Type: Number
Unit of Measure: particpants
3 0
Time Frame Randomization to 28 weeks.
Adverse Event Reporting Description Safety Population: All randomized participants who received at least one dose of study drug and who underwent a baseline endoscopic examination. Participants 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 (%) Affected / at Risk (%)
Total   22/607 (3.62%)   13/299 (4.35%) 
Blood and lymphatic system disorders     
esoinophilia  2  0/607 (0.00%)  1/299 (0.33%) 
Cardiac disorders     
cardio-respiratory arrest  1  0/607 (0.00%)  2/299 (0.67%) 
coronary artery disease  1  0/607 (0.00%)  1/299 (0.33%) 
Gastrointestinal disorders     
abdominal hernia  1  1/607 (0.16%)  0/299 (0.00%) 
hemorrhoid hemorrhage  1  1/607 (0.16%)  0/299 (0.00%) 
hemorrhoids  1  1/607 (0.16%)  0/299 (0.00%) 
General disorders     
chest pain  1  2/607 (0.33%)  1/299 (0.33%) 
multi-organ failure  1  0/607 (0.00%)  1/299 (0.33%) 
non-cardiac chest pain  1  1/607 (0.16%)  0/299 (0.00%) 
Hepatobiliary disorders     
cholecystitis  1  1/607 (0.16%)  0/299 (0.00%) 
Infections and infestations     
bronchits  1  0/607 (0.00%)  1/299 (0.33%) 
cellulits  1  2/607 (0.33%)  0/299 (0.00%) 
pneumonia  1  1/607 (0.16%)  2/299 (0.67%) 
upper respiratory tract infection  1  0/607 (0.00%)  1/299 (0.33%) 
Injury, poisoning and procedural complications     
alcohol poisoning  1  1/607 (0.16%)  0/299 (0.00%) 
drug toxicity  1  0/607 (0.00%)  1/299 (0.33%) 
road traffic accident  1  0/607 (0.00%)  1/299 (0.33%) 
traumatic brain injury  1  2/607 (0.33%)  1/299 (0.33%) 
Investigations     
blood creatinine increased  1  1/607 (0.16%)  0/299 (0.00%) 
Metabolism and nutrition disorders     
dehydration  1  2/607 (0.33%)  0/299 (0.00%) 
hypoglycemia  1  0/607 (0.00%)  1/299 (0.33%) 
Musculoskeletal and connective tissue disorders     
myositis  1  0/607 (0.00%)  1/299 (0.33%) 
osteoarthritis  1  0/607 (0.00%)  1/299 (0.33%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
benign neoplasm  1  0/607 (0.00%)  1/299 (0.33%) 
Nervous system disorders     
migraine  1  1/607 (0.16%)  0/299 (0.00%) 
syncope  1  0/607 (0.00%)  1/299 (0.33%) 
Psychiatric disorders     
bipolar disorder  1  0/607 (0.00%)  1/299 (0.33%) 
depression  1  1/607 (0.16%)  1/299 (0.33%) 
major depression  1  1/607 (0.16%)  0/299 (0.00%) 
schizoaffective disorder  1  1/607 (0.16%)  0/299 (0.00%) 
Renal and urinary disorders     
calculus ureteric  1  1/607 (0.16%)  0/299 (0.00%) 
renal failure acute  1  3/607 (0.49%)  0/299 (0.00%) 
Reproductive system and breast disorders     
menorrhagia  1  1/607 (0.16%)  0/299 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
dyspnea  1  1/607 (0.16%)  0/299 (0.00%) 
dyspnea exertional  1  0/607 (0.00%)  1/299 (0.33%) 
Vascular disorders     
hypertension  1  1/607 (0.16%)  0/299 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (9.1)
2
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 (%) Affected / at Risk (%)
Total   342/607 (56.34%)   184/299 (61.54%) 
Blood and lymphatic system disorders     
anemia  1  13/607 (2.14%)  2/299 (0.67%) 
Gastrointestinal disorders     
abdominal distension  1  4/607 (0.66%)  5/299 (1.67%) 
abdominal pain  1  8/607 (1.32%)  4/299 (1.34%) 
abdominal pain upper  1  20/607 (3.29%)  7/299 (2.34%) 
abdominal tenderness  1  5/607 (0.82%)  4/299 (1.34%) 
constipation  1  27/607 (4.45%)  13/299 (4.35%) 
diarrhea  1  30/607 (4.94%)  13/299 (4.35%) 
dry mouth  1  6/607 (0.99%)  2/299 (0.67%) 
dyspepsia  1  31/607 (5.11%)  23/299 (7.69%) 
flatulence  1  8/607 (1.32%)  2/299 (0.67%) 
gastritis  1  3/607 (0.49%)  4/299 (1.34%) 
gastroesophageal reflux disease  1  10/607 (1.65%)  8/299 (2.68%) 
nausea  1  40/607 (6.59%)  13/299 (4.35%) 
stomach discomfort  1  14/607 (2.31%)  4/299 (1.34%) 
toothache  1  3/607 (0.49%)  3/299 (1.00%) 
vomiting  1  15/607 (2.47%)  8/299 (2.68%) 
General disorders     
edema peripheral  1  14/607 (2.31%)  6/299 (2.01%) 
fatigue  1  2/607 (0.33%)  4/299 (1.34%) 
Infections and infestations     
bronchitis  1  13/607 (2.14%)  4/299 (1.34%) 
gastroenteritis viral  1  8/607 (1.32%)  1/299 (0.33%) 
herpes zoster  1  3/607 (0.49%)  3/299 (1.00%) 
influenza  1  9/607 (1.48%)  7/299 (2.34%) 
nasopharyngitis  1  12/607 (1.98%)  8/299 (2.68%) 
pneumonia  1  3/607 (0.49%)  4/299 (1.34%) 
sinusitis  1  12/607 (1.98%)  11/299 (3.68%) 
upper respiratory tract infection  1  23/607 (3.79%)  10/299 (3.34%) 
urinary tract infection  1  14/607 (2.31%)  9/299 (3.01%) 
viral upper respiratory tract infection  1  3/607 (0.49%)  3/299 (1.00%) 
Injury, poisoning and procedural complications     
contusion  1  2/607 (0.33%)  4/299 (1.34%) 
fall  1  5/607 (0.82%)  4/299 (1.34%) 
Investigations     
blood pressure increased  1  6/607 (0.99%)  2/299 (0.67%) 
Musculoskeletal and connective tissue disorders     
arthralgia  1  11/607 (1.81%)  6/299 (2.01%) 
back pain  1  8/607 (1.32%)  1/299 (0.33%) 
muscle spasms  1  6/607 (0.99%)  2/299 (0.67%) 
neck pain  1  1/607 (0.16%)  3/299 (1.00%) 
pain in extremity  1  7/607 (1.15%)  3/299 (1.00%) 
Nervous system disorders     
dizziness  1  9/607 (1.48%)  5/299 (1.67%) 
headache  1  23/607 (3.79%)  9/299 (3.01%) 
syncope  1  3/607 (0.49%)  3/299 (1.00%) 
Psychiatric disorders     
insomnia  1  7/607 (1.15%)  1/299 (0.33%) 
Respiratory, thoracic and mediastinal disorders     
cough  1  12/607 (1.98%)  9/299 (3.01%) 
epistaxis  1  7/607 (1.15%)  0/299 (0.00%) 
pharyngolaryngeal pain  1  8/607 (1.32%)  4/299 (1.34%) 
sinus congestion  1  3/607 (0.49%)  4/299 (1.34%) 
Vascular disorders     
hypertension  1  21/607 (3.46%)  7/299 (2.34%) 
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: NCT00450216     History of Changes
Other Study ID Numbers: HZ-CA-303
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