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

• Sponsor: Horizon Pharma Ireland, Ltd., Dublin Ireland (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00450658
• Collaborator: (none)
• Enrollment: 627
• Arms: 2
• Duration (Months): 19.1

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate whether HZT-501 is effective in reducing the rate of development of ibuprofen-associated ulcers in patients who require long-term daily use of ibuprofen.

Condition or Disease	Intervention/Treatment	Phase
Peptic Ulcer	Drug: HZT-501; Drug: Ibuprofen	Phase 3

Detailed Description

HZT-501 is a combination product including ibuprofen and the acid reducing agent famotidine. The study is designed to determine whether the combination product reduces the rate of ulcer development in subjects who require long-term daily use of ibuprofen.

Subjects will be assigned randomly, in approximately a 2:1 ratio, to treatment with either HZT-501 (ibuprofen 800 mg/famotidine 26.6 mg) or ibuprofen (800 mg) three times daily for a 24 week treatment period or until they develop either an endoscopically-diagnosed upper gastrointestinal ulcer and/or prohibitive toxicity. Subjects will visit the study center for Screening and at Weeks 4, 8, 16, and 24. Physical exams will be performed, and clinical laboratory measurements made, at selected times during the study. Endoscopic exams will be performed during Screening and at Weeks 8, 16, and 24. Subjects will be contacted four weeks following study completion.

Study Design

• Study Type: Interventional
• Actual Enrollment: 627 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: A Randomized, Double-Blind, Phase 3 Study of the Efficacy and Safety of HZT-501 in Subjects Requiring NSAID Treatment
• Study Start Date: Mar 1, 2007
• Actual Primary Completion Date: Sep 1, 2008
• Actual Study Completion Date: Oct 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 HZT-501: Ibuprofen 800mg/Famotidine 26.6mg	Drug: HZT-501; HZT-501: Ibuprofen 800mg/famotidine 26.6mg orally 3 times daily for 24 weeks
Active Comparator: 2 Ibuprofen 800mg	Drug: Ibuprofen; Ibuprofen 800mg orally 3 times daily for 24 weeks

Outcome Measures

Primary Outcome Measures

1. Number of Subjects Who Develop Endoscopically-diagnosed Upper Gastrointestinal Ulcers Confirmed by Endoscopy. [24 weeks]

   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.

Secondary Outcome Measures

1. Number of Subjects Who Develop Endoscopically-diagnosed Gastric Ulcers During the 24-week Treatment Period. [24 weeks]

   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.

2. Number of Subjects Who Develop Endoscopically-diagnosed Duodenal Ulcers During the 24-week Treatment Period. [24 weeks]

   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.

3. The Incidence Rate of NSAID-associated Serious Gastrointestinal Complications. [24 weeks]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Expected to require daily administration of a nonsteroidal anti-inflammatory drug (NSAID) for at least the coming six months for conditions such as osteoarthritis, rheumatoid arthritis, chronic low back pain, chronic regional pain syndrome, and chronic soft tissue pain.

• Did not use a NSAID within the 30 days prior to study entry

Exclusion Criteria:

• History of erosive esophagitis

• History of any of the following serious gastrointestinal complications:

• perforation of ulcers,

• gastric outlet obstruction due to ulcers,

• gastrointestinal bleeding.

• Active cardiac, renal, and/or hepatic disease

• Current Helicobacter pylori (H. pylori) infection

• Use of an acid suppressant agent, misoprostol, or more than 325 mg/day of aspirin within the 14 days prior to study entry.

• Uncontrolled diabetes

• Uncontrolled hypertension

• Positive pregnancy test at screening

• Positive test at Screening for human immunodeficiency virus (HIV), hepatitis B, or hepatitis C.

• Currently participating, or participation within 30 days prior to study entry, in an investigational drug study

Please note that there are other additional criteria. The study center will determine if patients meet all of the criteria.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Horizon Pharma Ireland, Ltd., Dublin Ireland

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Horizon Pharma Ireland, Ltd., Dublin Ireland
• ClinicalTrials.gov Identifier: NCT00450658
• Other Study ID Numbers: HZ-CA-301
• First Posted: Mar 22, 2007
• Last Update Posted: Apr 29, 2013
• Last Verified: Apr 1, 2013

• Keywords provided by Horizon Pharma Ireland, Ltd., Dublin Ireland: ibuprofen; famotidine; ulcers; NSAIDS; pain; arthritis; chronic regional pain syndrome; chronic soft tissue pain; osteoarthritis; rheumatoid arthritis; chronic low back pain
• Additional relevant MeSH terms: Peptic Ulcer; Ulcer; Ibuprofen

Study Results

Participant Flow

Recruitment Details	A multi-center US study in which 80 sites recruited subjects between March 2007 and February 2008.
Pre-assignment Detail	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
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

Baseline Characteristics

Arm/Group Title	HZT-501	Ibuprofen	Total
Arm/Group Description	HZT-501: Ibuprofen 800mg/Famotidine 26.6mg	Ibuprofen 800mg	Total of all reporting groups
Overall Participants	415	212	627
Age (Count of Participants)
<=18 years	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 (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.3 (9.0)	55.7 (9.5)	55.4 (9.1)
Sex: Female, Male (Count of Participants)
Female	272 65.5%	152 71.7%	424 67.6%
Male	143 34.5%	60 28.3%	203 32.4%
Region of Enrollment (participants) [Number]
United States	415 100%	212 100%	627 100%

Outcome Measures

1. Primary Outcome

Title	Number of Subjects Who Develop Endoscopically-diagnosed Upper Gastrointestinal Ulcers Confirmed by Endoscopy.
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

Outcome Measure Data

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
Arm/Group Description	HZT-501: Ibuprofen 800mg/Famotidine 26.6mg	Ibuprofen 800mg
Measure Participants	380	190
Number [participants]	40 9.6%	38 17.9%

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
Statistical Test of Hypothesis	p-Value	0.0018
	Comments
	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
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Subjects Who Develop Endoscopically-diagnosed Gastric Ulcers During the 24-week Treatment Period.
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

Outcome Measure Data

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
Arm/Group Description	HZT-501: Ibuprofen 800mg/Famotidine 26.6mg	Ibuprofen 800mg
Measure Participants	380	190
Number [participants]	37 8.9%	34 16%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	HZT-501, Ibuprofen
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0051
	Comments
	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
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Number of Subjects Who Develop Endoscopically-diagnosed Duodenal Ulcers During the 24-week Treatment Period.
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	HZT-501	Ibuprofen
Arm/Group Description	HZT-501: Ibuprofen 800mg/Famotidine 26.6mg	Ibuprofen 800mg
Measure Participants	380	190
Number [participants]	3 0.7%	9 4.2%

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
Statistical Test of Hypothesis	p-Value	0.0017
	Comments
	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
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	The Incidence Rate of NSAID-associated Serious Gastrointestinal Complications.
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

Outcome Measure Data

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
Arm/Group Description	HZT-501: Ibuprofen 800mg/Famotidine 26.6mg	Ibuprofen 800mg
Measure Participants	415	212
Number [participants]	0 0%	0 0%

Adverse Events

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
Arm/Group Description	HZT-501: Ibuprofen 800mg/Famotidine 26.6mg		Ibuprofen 800mg
All Cause Mortality
	HZT-501		Ibuprofen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	HZT-501		Ibuprofen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/415 (2.7%)		4/212 (1.9%)
Cardiac disorders
coronary artery disease	0/415 (0%)	0	1/212 (0.5%)	1
Gastrointestinal disorders
esophageal ulcer	1/415 (0.2%)	1	0/212 (0%)	0
inguinal hernia	1/415 (0.2%)	1	0/212 (0%)	0
General disorders
chest pain	1/415 (0.2%)	1	0/212 (0%)	0
edema peripheral	0/415 (0%)	0	1/212 (0.5%)	1
non-cardiac chest pain	1/415 (0.2%)	1	1/212 (0.5%)	1
Infections and infestations
abscess	1/415 (0.2%)	1	0/212 (0%)	0
diverticulitis	1/415 (0.2%)	1	0/212 (0%)	0
infection	1/415 (0.2%)	1	0/212 (0%)	0
Injury, poisoning and procedural complications
wrist fracture	1/415 (0.2%)	1	0/212 (0%)	0
Musculoskeletal and connective tissue disorders
osteoarthritis	1/415 (0.2%)	1	0/212 (0%)	0
osteonecrosis	0/415 (0%)	0	1/212 (0.5%)	1
rotator cuff syndrome	1/415 (0.2%)	1	0/212 (0%)	0
Nervous system disorders
transient ischemic attack	1/415 (0.2%)	1	0/212 (0%)	0
Psychiatric disorders
schizoaffective disorder	1/415 (0.2%)	1	0/212 (0%)	0
suicide attempt	1/415 (0.2%)	1	0/212 (0%)	0
Respiratory, thoracic and mediastinal disorders
asthma	1/415 (0.2%)	1	0/212 (0%)	0
bronchospasm	1/415 (0.2%)	1	0/212 (0%)	0
chronic obstructive pulmonary disease	1/415 (0.2%)	1	0/212 (0%)	0
Other (Not Including Serious) Adverse Events
	HZT-501		Ibuprofen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	220/415 (53%)		116/212 (54.7%)
Blood and lymphatic system disorders
anemia	3/415 (0.7%)		5/212 (2.4%)
Eye disorders
vision blurred	2/415 (0.5%)		4/212 (1.9%)
Gastrointestinal disorders
abdominal distension	5/415 (1.2%)		2/212 (0.9%)
abdominal pain	7/415 (1.7%)		4/212 (1.9%)
abdominal pain upper	14/415 (3.4%)		6/212 (2.8%)
constipation	15/415 (3.6%)		8/212 (3.8%)
diarrhea	17/415 (4.1%)		9/212 (4.2%)
dyspepsia	17/415 (4.1%)		18/212 (8.5%)
flatulence	6/415 (1.4%)		0/212 (0%)
gastritis	7/415 (1.7%)		3/212 (1.4%)
gastroesophageal reflux	9/415 (2.2%)		8/212 (3.8%)
nausea	19/415 (4.6%)		11/212 (5.2%)
stomach discomfort	4/415 (1%)		4/212 (1.9%)
vomiting	8/415 (1.9%)		1/212 (0.5%)
General disorders
edema peripheral	6/415 (1.4%)		3/212 (1.4%)
influenza like illness	4/415 (1%)		0/212 (0%)
Infections and infestations
bronchitis	12/415 (2.9%)		2/212 (0.9%)
gastroenteritis	4/415 (1%)		0/212 (0%)
gastroenteritis viral	2/415 (0.5%)		3/212 (1.4%)
influenza	8/415 (1.9%)		1/212 (0.5%)
nasopharyngitis	13/415 (3.1%)		6/212 (2.8%)
sinusits	9/415 (2.2%)		3/212 (1.4%)
upper respiratory tract infection	16/415 (3.9%)		11/212 (5.2%)
urinary tract infection	3/415 (0.7%)		3/212 (1.4%)
Investigations
blood creatinine increased	4/415 (1%)		0/212 (0%)
Musculoskeletal and connective tissue disorders
arthralgia	2/415 (0.5%)		3/212 (1.4%)
back pain	10/415 (2.4%)		3/212 (1.4%)
muscle spasms	4/415 (1%)		0/212 (0%)
musculoskeletal pain	5/415 (1.2%)		3/212 (1.4%)
pain in extremity	7/415 (1.7%)		1/212 (0.5%)
Nervous system disorders
headache	11/415 (2.7%)		8/212 (3.8%)
Psychiatric disorders
depression	4/415 (1%)		2/212 (0.9%)
insomnia	4/415 (1%)		4/212 (1.9%)
Respiratory, thoracic and mediastinal disorders
asthma	5/415 (1.2%)		0/212 (0%)
cough	7/415 (1.7%)		1/212 (0.5%)
dyspnea	1/415 (0.2%)		3/212 (1.4%)
pharyngolaryngeal pain	8/415 (1.9%)		2/212 (0.9%)
sinus congestion	3/415 (0.7%)		3/212 (1.4%)
Skin and subcutaneous tissue disorders
rash	3/415 (0.7%)		3/212 (1.4%)
Vascular disorders
hypertension	11/415 (2.7%)		4/212 (1.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.