COMPARE: A Study to Compare the Effects of Coreg CR and Coreg IR on Heart Function in Subjects With Stable Chronic Heart Failure

• Sponsor: CTI-1, LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00323037
• Collaborator: CTI Clinical Trial and Consulting Services (Other), GlaxoSmithKline (Industry)
• Enrollment: 318
• Locations: 75
• Arms: 2
• Duration (Months): 27
• Patients Per Site: 4.2
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if Coreg CR is as effective as Coreg IR in improving heart function in subjects with stable chronic heart failure.

Condition or Disease	Intervention/Treatment	Phase
Congestive Heart Failure	Drug: carvedilol controlled release; Drug: carvedilol immediate release	Phase 3

Detailed Description

Results of clinical trials have shown beta-blockers improve symptoms and left ventricular function, reduce hospitalizations and death in heart failure, and prolong survival [MERIT-HF, CIBIS-II, Packer, 1996]. Clinical guidelines mandate use of beta-blockers in treatment of subjects with heart failure.

Carvedilol (Coreg IR) is a multiple action adrenergic receptor blocker with alpha 1, beta 1 and beta 2 receptor blockade properties. The beta-adrenergic properties are non-selective for beta 1 and beta 2 adrenergic receptors. Coreg IR, administered twice daily, is marketed in the United States for long term treatment of mild-moderate hypertension, mild to severe heart failure and subjects surviving an acute myocardial infarction with left ventricular dysfunction with or without symptomatic heart failure.

Coreg IR significantly reduces all cause mortality and the need for cardiovascular hospitalization [Packer, 1996a; Packer, 1996b; Colucci, 1996; Cohn, 1997; Olsen, 1995; Sharpe 1997]. The effect of Coreg is dose dependent [Bristow, 1996]. In subjects treated long term after an acute myocardial infarction (MI) complicated by left ventricular systolic dysfunction, Coreg IR reduced the frequency of all-cause and cardiovascular mortality, and recurrent non-fatal MIs. These beneficial effects are additional to those of evidence-based treatments for acute MI, including ACE inhibitors [Dargie, 2001].

Left Ventricular End Systolic Volume Index (LVESVI) is an important measure of ventricular function and remodeling in the evaluation of heart failure. In controlled clinical trials, Coreg IR, administered twice daily, has reduced LVESVI in subjects with ischemic heart failure. An echocardiography substudy of the Australia-New Zealand Trial [Doughty, 1997], evaluated left ventricular remodeling in 123 subjects with ischemic heart failure with an LVEF < 45 randomized to carvedilol or placebo. The LVESVI was reduced by 6.2 + 1.6 ml/m2 after 6 months and 8.7 + 2.6 ml/m2 after 12 months of carvedilol therapy compared to the placebo treated subjects. Metra et al [Metra, 2000] observed the favorable effects of carvedilol compared with metoprolol on LVEF, LV stroke volume, and pulmonary artery pressure despite similar effects on cardiovascular outcome. Both groups also showed significant decreases in LV systolic volume. Doughty et al [Doughty, 2004] observed the favorable effects of carvedilol on LV remodeling, with improved LV end-systolic volume and ejection fraction, after 6 months of treatment.

Carvedilol phosphate CR (Coreg CR) is an approved, modified release, once-daily formulation of carvedilol that is hoped to provide an advance in patient care through improved compliance with prescribed dose.

The clinical experience with various formulations of Coreg CR is limited to eight single dose studies in healthy subjects and one repeated dose study in subjects with hypertension. In total 230, adult subjects have received at least one dose of Coreg IR or one of several CR formulations across nine studies. The subjects ranged in age from 18 to 63 years; 62% were male and 69% were white. The various formulations of Coreg CR capsules were safe and well tolerated in single dose pharmacokinetic studies in doses ranging from 6.25 to 60 mg in healthy subjects. The most common adverse events were headache, dizziness and orthostatic hypotension and are all known adverse events following administration of Coreg IR [GSK Study 386, 388, 399, 400, 402, 907].

This study will be the first controlled clinical study investigating the efficacy of treatment with Coreg CR formulation [Coreg CR filled with 7.5 mg of carvedilol phosphate immediate release (IRp) microparticles, 22.5 mg of carvedilol phosphate Micropump IIa MR microparticles, and 30 mg of carvedilol phosphate Micropump IIc MR microparticles] compared to Coreg IR evaluating LVESVI in subjects with stable chronic heart failure.

Study Design

• Study Type: Interventional
• Actual Enrollment: 318 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter,Randomized, Double Blind, Double Dummy, Parallel Group Study to Compare Effects of Coreg CR and Coreg IR on Left Ventricular End Systolic Volume Index in Subjects With Stable Chronic Heart Failure
• Study Start Date: Mar 1, 2006
• Actual Primary Completion Date: Apr 1, 2008
• Actual Study Completion Date: Jun 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1	Drug: carvedilol immediate release; Carvedilol immediate release (3.125, 6.25, 12.5 or 25 mg) and placebo, taken PO, twice-daily.; Other Names: Coreg Coreg IR
Active Comparator: 2	Drug: carvedilol controlled release; Carvedilol controlled release (10, 20, 40 or 80 mg) and placebo taken in the morning. Two placebos taken in the evening. A total of 4 pills will be taken PO daily.; Other Names: Coreg CR

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Left Ventricular End Systolic Volume Index (LVESVI) Characterized by 2-D Echocardiography [24 weeks after entry into the maintenance period]

   Maintenance Visit 3 minus Baseline. Maintenance Visit 3 occurred 24 weeks after entry into the maintenance period. The maintenance period started after completion of a titration period of variable duration.

Secondary Outcome Measures

1. Change From Baseline in Left Ventricular Ejection Fraction [24 weeks after entry into the maintenance period]

2. Change From Baseline in Left Ventricular Remodeling (IVST, PWT, LVM, ESV, EDV, EDVI, ESD, EDD, Deceleration Time, and E:A Ratio) [24 weeks after entry into the maintenance period]

3. Change From Baseline in BNP Levels [24 weeks after entry into the maintenance period]

4. Incidence of Hospitalizations From Exacerbation of Heart Failure [Up to 32 weeks (titration and maintenance phases)]

5. Hospitalizations From All Causes [Up to 32 weeks (titration and maintenance phases)]

6. Drug Dose Tolerability [Up to 32 weeks (titration and maintenance phases)]

7. Safety and Tolerability of Coreg CR [24 weeks after entry into the maintenance phase (after unblinding)]

8. Drug Compliance [Up to 32 weeks (titration and maintenance phases)]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or non-pregnant female

• At least 18 years of age at the time informed consent is signed

• Stable, chronic, mild to severe heart failure as defined as subjects with symptoms of heart failure who do not require IV diuretics, inotropes, or vasodilators or those that require support with a left ventricular assist device

• Angiotensin converting enzyme inhibitors or angiotensin receptor blockers should be prescribed to all patients with HF due to LV systolic dysfunction with reduced LVEF unless contraindicated or intolerant to use

• At screening, subject has an LVEF < 40 as measured by 2-D echocardiography

• Willing to provide written informed consent

Exclusion Criteria:

• On beta-blocker therapy for greater than 42 days prior to consent

• Acute ischemic coronary event or coronary revascularization (PTCA, CABG, thrombolysis) within 1 week of screening echocardiography

• Scheduled or expected to be scheduled coronary revascularization within 4 weeks

• Unstable angina (angina characterized by sudden changes in the severity or length of angina attacks or a decrease in level of exertion that precipitates an episode

• Uncorrected primary obstructive or severe regurgitant valvular disease, nondilated (restrictive) or hypertrophic cardiomyopathies

• Uncontrolled ventricular arrhythmias (symptomatic or sustained ventricular arrhythmias not controlled with antiarrhythmic therapy or an implantable defibrillator)

• Current treatment of calcium channel blockers except for long acting dihydropyridines

• Current treatment on any Class I or III antiarrhythmic, except amiodarone

• History of sick sinus syndrome unless a pacemaker is in place

• Second or third degree heart block unless a pacemaker is in place

• Current clinical evidence of obstructive pulmonary disease (e.g., asthma or bronchitis) requiring inhaled or oral bronchodilator or steroid therapy; or having a history of bronchospastic disease not undergoing active therapy in whom, in the investigator's opinion, treatment with study medication could provoke bronchospasm

• Expected biventricular pacemaker placement within 8 months of enrollment

• Resting systolic blood pressure <90 mmHg (based on the average of 3 readings

• Resting heart rate <50 beats per minute (bpm) (based on the average of 3 readings)

• Current decompensated heart failure

• Elevated liver enzymes (i.e., ALT or AST levels greater than 3 times upper limit of normal)

• History of drug sensitivity or allergic reaction to alpha or beta-blockers

• Contraindication or intolerance to beta-blockers

• Pregnant or lactating women and women planning to become pregnant. NOTE: Female subjects must be post-menopausal (i.e., no menstrual period for a minimum of 6 months prior to screening), surgically sterilized, using a double barrier method contraceptive, or using Depo-Provera or implanted contraceptives for at least one month prior to screening and agree to continue to use the same contraceptive method throughout the study.

• Use of an investigational drug within 30 days of enrollment

• Participation in an investigational device trial within 30 days of enrollment

• Known drug or alcohol abuse 1 year prior to enrollment

• In the opinion of the investigator the subject is known to be noncompliant with prescribed medication regimen

• Has any systemic disease, including cancer, with reduced life expectancy (<12 months)

• Has a history of psychological illness/condition that interferes with ability to understand or complete requirements of the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cardiology Associates	Mobile	Alabama	United States	36608
2	Mobile Heart Specialists	Mobile	Alabama	United States	36608
3	Mayo Clinic Arizona	Phoenix	Arizona	United States	85054
4	Scottsdale Cardiovascular Research Institute	Scottsdale	Arizona	United States	85251
5	South West Heart	Tucson	Arizona	United States	85715
6	Inland Heart Doctors Medical Group	Corona	California	United States	92879
7	Rancho Los Amigos USC	Downey	California	United States	90242
8	William Bowden, DO Private Practice	Healdsburg	California	United States	95448
9	Merced Heart Associates	Merced	California	United States	95340
10	Sutter Memorial Hospital	Sacramento	California	United States	95819
11	Southern California Cardiology Medical Group, Inc.	San Diego	California	United States	92120
12	Medvin Clinical Research	Van Nuys	California	United States	91405
13	Aurora Denver Cardiology Associates	Denver	Colorado	United States	80218
14	Medical Center of the Rockies Foundation	Loveland	Colorado	United States	80538
15	Bay Area Cardiology	Brandon	Florida	United States	33511
16	Clearwater Cardiovascular and Interventional Consultants	Clearwater	Florida	United States	33756
17	White-Wilson Medical Center, PA	Fort Walton Beach	Florida	United States	32547
18	South Florida International Cardiology Consultants, Inc.	Miami	Florida	United States	33137-3732
19	Palm Beach Cardiology	Palm Beach Gardens	Florida	United States	33410
20	Cardiac Disease Specialists, PC	Atlanta	Georgia	United States	30309
21	Harbin Clinic	Rome	Georgia	United States	30165
22	North Shore Cardiovascular Research Consortium	Bannockburn	Illinois	United States	60015
23	Saint Francis Hospital	Evanston	Illinois	United States	60202
24	Illinois Heart and Vascular	Hinsdale	Illinois	United States	60521
25	HeartCare Midwest	Peoria	Illinois	United States	61614
26	Rockford Cardiology Research Foundation	Rockford	Illinois	United States	61107
27	Prairie Cardiovascular Consultants	Springfield	Illinois	United States	62701
28	The Care Group LLC	Indianapolis	Indiana	United States	46260
29	River Cities Cardiology	Jeffersonville	Indiana	United States	47130
30	Iowa Heart Center	West Des Moines	Iowa	United States	50266
31	Mid-America Cardiology	Kansas City	Kansas	United States	66160
32	Via Christi Research, Inc.	Wichita	Kansas	United States	67214
33	Comprehensive Cardiology Associates	Florence	Kentucky	United States	41042
34	Cardiovascular Associates	Louisville	Kentucky	United States	40205
35	Louisville Cardiology Medical Group	Louisville	Kentucky	United States	40207
36	One Heart, LLC	Baltimore	Maryland	United States	21215
37	Minnesota Heart Clinic	Edina	Minnesota	United States	55435
38	Hennepin County Medical Center	Minneapolis	Minnesota	United States	55415
39	Regions Hospital Cardiology Research	Saint Paul	Minnesota	United States	55101
40	St. Paul Cardiology	Saint Paul	Minnesota	United States	55102
41	Cardiology Associates Research, LLC	Tupelo	Mississippi	United States	38801
42	Rocky Mountain Heart & Lung	Kalispell	Montana	United States	59901
43	Diagnostic and Clinical Cardiology	West Orange	New Jersey	United States	07052
44	University of New Mexico	Albuquerque	New Mexico	United States	87131-0001
45	Albany Associates in Cardiology	Albany	New York	United States	12205
46	Montefiore Medical Center	Bronx	New York	United States	10467
47	Buffalo Heart Group, LLP	Buffalo	New York	United States	14215
48	Long Island Heart Associates	Mineola	New York	United States	11501
49	New York Cardiovascular Associates	New York	New York	United States	10035
50	South Bay Cardiovascular Associates	West Islip	New York	United States	11795
51	University of North Carolina	Chapel Hill	North Carolina	United States	27599
52	LeBauer Cardiovascular Research Foundation	Greensboro	North Carolina	United States	27401
53	Wake Forest University Baptist Medical Center	Winston-Salem	North Carolina	United States	27157
54	Sterling Research Group Ltd.	Cincinnati	Ohio	United States	45219
55	The Lindner Clinical Trial Center	Cincinnati	Ohio	United States	45219
56	University Hospital	Cincinnati	Ohio	United States	45267-0542
57	Northwest Ohio Cardiology Consultants	Toledo	Ohio	United States	43615
58	Oklahoma Cardiovascular Research Group	Oklahoma City	Oklahoma	United States	73120
59	Samaritan Cardiology	Corvallis	Oregon	United States	97330
60	Blair Medical Associates	Altoona	Pennsylvania	United States	16602
61	Tri-State Medical Group	Beaver	Pennsylvania	United States	15009
62	Central Bucks Specialists	Doylestown	Pennsylvania	United States	18901
63	Cardiology Consultants of Philadelphia	Philadelphia	Pennsylvania	United States	19148
64	Mid State Medical Service	Philipsburg	Pennsylvania	United States	16866
65	Buxmont Cardiology Associates, PC	Sellersville	Pennsylvania	United States	18960
66	Rhode Island Heart Failure Center	Providence	Rhode Island	United States	02903
67	Charleston Cardiology	Charleston	South Carolina	United States	29403
68	South Carolina Heart Center	Columbia	South Carolina	United States	29204
69	Heart Specialists	Friendswood	Texas	United States	77546
70	Texas Cardiac Center	Lubbock	Texas	United States	79410
71	Intermountain Medical Center	Murray	Utah	United States	84107
72	Heart Center	Salt Lake City	Utah	United States	84124
73	Winchester Medical Center	Winchester	Virginia	United States	22601
74	Luther Midelfort Mayo Health Systems	Eau Claire	Wisconsin	United States	54702
75	Green Bay HeartCare	Green Bay	Wisconsin	United States	54303

Sponsors and Collaborators

• CTI-1, LLC
• CTI Clinical Trial and Consulting Services
• GlaxoSmithKline

Investigators

• Study Chair: Barry Greenberg, MD,

Study Documents (Full-Text)

None provided.

More Information

Publications

• Bristow MR, Gilbert EM, Abraham WT, Adams KF, Fowler MB, Hershberger RE, Kubo SH, Narahara KA, Ingersoll H, Krueger S, Young S, Shusterman N. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. MOCHA Investigators. Circulation. 1996 Dec 1;94(11):2807-16.
• Cohn JN, Fowler MB, Bristow MR, Colucci WS, Gilbert EM, Kinhal V, Krueger SK, Lejemtel T, Narahara KA, Packer M, Young ST, Holcslaw TL, Lukas MA. Safety and efficacy of carvedilol in severe heart failure. The U.S. Carvedilol Heart Failure Study Group. J Card Fail. 1997 Sep;3(3):173-9.
• Colucci WS, Packer M, Bristow MR, Gilbert EM, Cohn JN, Fowler MB, Krueger SK, Hershberger R, Uretsky BF, Bowers JA, Sackner-Bernstein JD, Young ST, Holcslaw TL, Lukas MA. Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. US Carvedilol Heart Failure Study Group. Circulation. 1996 Dec 1;94(11):2800-6.
• Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet. 2001 May 5;357(9266):1385-90.
• Doughty RN, Whalley GA, Gamble G, MacMahon S, Sharpe N. Left ventricular remodeling with carvedilol in patients with congestive heart failure due to ischemic heart disease. Australia-New Zealand Heart Failure Research Collaborative Group. J Am Coll Cardiol. 1997 Apr;29(5):1060-6.
• Doughty RN, Whalley GA, Walsh HA, Gamble GD, López-Sendón J, Sharpe N; CAPRICORN Echo Substudy Investigators. Effects of carvedilol on left ventricular remodeling after acute myocardial infarction: the CAPRICORN Echo Substudy. Circulation. 2004 Jan 20;109(2):201-6. Epub 2004 Jan 5.
• Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999 Jun 12;353(9169):2001-7.
• Greenberg BH, Mehra M, Teerlink JR, Ordronneau P, McCollum D, Gilbert EM. COMPARE: comparison of the effects of carvedilol CR and carvedilol IR on left ventricular ejection fraction in patients with heart failure. Am J Cardiol. 2006 Oct 2;98(7A):53L-59L. Epub 2006 Aug 28.
• Olsen SL, Gilbert EM, Renlund DG, Taylor DO, Yanowitz FD, Bristow MR. Carvedilol improves left ventricular function and symptoms in chronic heart failure: a double-blind randomized study. J Am Coll Cardiol. 1995 May;25(6):1225-31.
• Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996 May 23;334(21):1349-55.
• Packer M, Colucci WS, Sackner-Bernstein JD, Liang CS, Goldscher DA, Freeman I, Kukin ML, Kinhal V, Udelson JE, Klapholz M, Gottlieb SS, Pearle D, Cody RJ, Gregory JJ, Kantrowitz NE, LeJemtel TH, Young ST, Lukas MA, Shusterman NH. Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure. The PRECISE Trial. Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise. Circulation. 1996 Dec 1;94(11):2793-9.
• Randomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease. Australia/New Zealand Heart Failure Research Collaborative Group. Lancet. 1997 Feb 8;349(9049):375-80.
• The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999 Jan 2;353(9146):9-13.

• Responsible Party: CTI-1, LLC
• ClinicalTrials.gov Identifier: NCT00323037
• Other Study ID Numbers: 104852
• First Posted: May 9, 2006
• Last Update Posted: Feb 22, 2018
• Last Verified: Jan 1, 2018

• Keywords provided by CTI-1, LLC: heart failure
• Additional relevant MeSH terms: Heart Failure; Carvedilol

Study Results

Participant Flow

Recruitment Details	The recruitment period was from April 2006 until August 2007.

Arm/Group Title	Coreg Immediate Release	Coreg Controlled Release
Arm/Group Description
Period Title: Overall Study
STARTED	165	153
COMPLETED	132	126
NOT COMPLETED	33	27

Baseline Characteristics

Arm/Group Title	Coreg Immediate Release	Coreg Controlled Release	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	165	153	318
Age, Customized (participants) [Number]
< 65 years	117 70.9%	110 71.9%	227 71.4%
65<=Age<75	27 16.4%	21 13.7%	48 15.1%
Age>=75 years	21 12.7%	22 14.4%	43 13.5%
Sex: Female, Male (Count of Participants)
Female	52 31.5%	45 29.4%	97 30.5%
Male	113 68.5%	108 70.6%	221 69.5%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Left Ventricular End Systolic Volume Index (LVESVI) Characterized by 2-D Echocardiography
Description	Maintenance Visit 3 minus Baseline. Maintenance Visit 3 occurred 24 weeks after entry into the maintenance period. The maintenance period started after completion of a titration period of variable duration.
Time Frame	24 weeks after entry into the maintenance period

Outcome Measure Data

Analysis Population Description

Analysis was performed on the modified intent to treat population (mITT), which were those subjects with both a Baseline and an evaluable End of Study echocardiogram.

Arm/Group Title	Coreg Immediate Release	Coreg Controlled Release
Arm/Group Description
Measure Participants	128	125
Mean (Standard Deviation) [mL/m^2]	-18.34 (18.84)	-20.81 (25.43)

2. Secondary Outcome

Title	Change From Baseline in Left Ventricular Ejection Fraction
Time Frame	24 weeks after entry into the maintenance period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Change From Baseline in Left Ventricular Remodeling (IVST, PWT, LVM, ESV, EDV, EDVI, ESD, EDD, Deceleration Time, and E:A Ratio)
Time Frame	24 weeks after entry into the maintenance period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Change From Baseline in BNP Levels
Time Frame	24 weeks after entry into the maintenance period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Incidence of Hospitalizations From Exacerbation of Heart Failure
Time Frame	Up to 32 weeks (titration and maintenance phases)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Hospitalizations From All Causes
Time Frame	Up to 32 weeks (titration and maintenance phases)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Drug Dose Tolerability
Time Frame	Up to 32 weeks (titration and maintenance phases)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Safety and Tolerability of Coreg CR
Time Frame	24 weeks after entry into the maintenance phase (after unblinding)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Drug Compliance
Time Frame	Up to 32 weeks (titration and maintenance phases)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The publishing party will submit any proposed manuscript or publication to the sponsor for comment at least 60 days prior to its release. The publishing party will make every reasonable attempt to incorporate comments received from the sponsor, and will upon request remove any previously undisclosed confidential information, prior to publication or disclosure. There will be no publication or publicizing of individual site data or results prior to the multicenter publication.