Ignite Creation Date:
2025-12-25 @ 12:07 AM
Ignite Modification Date:
2025-12-25 @ 10:06 PM
Study NCT ID:
NCT00354458
Status:
COMPLETED
Last Update Posted:
2009-10-09
First Post:
2006-07-18
Is NOT Gene Therapy:
False
Has Adverse Events:
False
Brief Title:
PROTECT-2: A Study of the Selective A1 Adenosine Receptor Antagonist KW-3902 for Patients Hospitalized With Acute HF and Volume Overload to Assess Treatment Effect on Congestion and Renal Function
Sponsor:
Organization:
Raw JSON
{'hasResults': False, 'derivedSection': {'miscInfoModule': {'versionHolder': '2025-12-24', 'removedCountries': ['Belgium', 'Czechia', 'Denmark', 'Finland', 'France', 'Germany', 'Hungary', 'Israel', 'Italy', 'Netherlands', 'Poland', 'Russia', 'Sweden', 'United Kingdom', 'United States']}, 'conditionBrowseModule': {'meshes': [{'id': 'D006333', 'term': 'Heart Failure'}, {'id': 'D051437', 'term': 'Renal Insufficiency'}], 'ancestors': [{'id': 'D006331', 'term': 'Heart Diseases'}, {'id': 'D002318', 'term': 'Cardiovascular Diseases'}, {'id': 'D007674', 'term': 'Kidney Diseases'}, {'id': 'D014570', 'term': 'Urologic Diseases'}, {'id': 'D052776', 'term': 'Female Urogenital Diseases'}, {'id': 'D005261', 'term': 'Female Urogenital Diseases and Pregnancy Complications'}, {'id': 'D000091642', 'term': 'Urogenital Diseases'}, {'id': 'D052801', 'term': 'Male Urogenital Diseases'}]}, 'interventionBrowseModule': {'meshes': [{'id': 'C073525', 'term': 'rolofylline'}]}}, 'protocolSection': {'designModule': {'phases': ['PHASE3'], 'studyType': 'INTERVENTIONAL', 'designInfo': {'allocation': 'RANDOMIZED', 'maskingInfo': {'masking': 'QUADRUPLE', 'whoMasked': ['PARTICIPANT', 'CARE_PROVIDER', 'INVESTIGATOR', 'OUTCOMES_ASSESSOR']}, 'primaryPurpose': 'TREATMENT', 'interventionModel': 'PARALLEL'}, 'enrollmentInfo': {'type': 'ACTUAL', 'count': 1102}}, 'statusModule': {'overallStatus': 'COMPLETED', 'startDateStruct': {'date': '2006-10'}, 'expandedAccessInfo': {'hasExpandedAccess': False}, 'statusVerifiedDate': '2009-10', 'completionDateStruct': {'date': '2009-07', 'type': 'ACTUAL'}, 'lastUpdateSubmitDate': '2009-10-08', 'studyFirstSubmitDate': '2006-07-18', 'studyFirstSubmitQcDate': '2006-07-18', 'lastUpdatePostDateStruct': {'date': '2009-10-09', 'type': 'ESTIMATED'}, 'studyFirstPostDateStruct': {'date': '2006-07-20', 'type': 'ESTIMATED'}, 'primaryCompletionDateStruct': {'date': '2009-07', 'type': 'ACTUAL'}}, 'outcomesModule': {'primaryOutcomes': [{'measure': 'effect on heart failure signs and symptoms', 'timeFrame': '3 Days'}, {'measure': 'effect on renal function', 'timeFrame': '3 Days'}], 'secondaryOutcomes': [{'measure': 'safety', 'timeFrame': '3 Days'}, {'measure': 'within trial medical costs compared to placebo', 'timeFrame': '3 Days'}]}, 'oversightModule': {'oversightHasDmc': True}, 'conditionsModule': {'keywords': ['heart failure', 'diuretic', 'renal impairment', 'renal function'], 'conditions': ['Heart Failure, Congestive']}, 'referencesModule': {'references': [{'pmid': '29748350', 'type': 'DERIVED', 'citation': "Metra M, Cotter G, Senger S, Edwards C, Cleland JG, Ponikowski P, Cursack GC, Milo O, Teerlink JR, Givertz MM, O'Connor CM, Dittrich HC, Bloomfield DM, Voors AA, Davison BA. Prognostic Significance of Creatinine Increases During an Acute Heart Failure Admission in Patients With and Without Residual Congestion: A Post Hoc Analysis of the PROTECT Data. Circ Heart Fail. 2018 May;11(5):e004644. doi: 10.1161/CIRCHEARTFAILURE.117.004644."}, {'pmid': '28069685', 'type': 'DERIVED', 'citation': "Streng KW, Ter Maaten JM, Cleland JG, O'Connor CM, Davison BA, Metra M, Givertz MM, Teerlink JR, Ponikowski P, Bloomfield DM, Dittrich HC, Hillege HL, van Veldhuisen DJ, Voors AA, van der Meer P. Associations of Body Mass Index With Laboratory and Biomarkers in Patients With Acute Heart Failure. Circ Heart Fail. 2017 Jan;10(1):e003350. doi: 10.1161/CIRCHEARTFAILURE.116.003350."}, {'pmid': '27658757', 'type': 'DERIVED', 'citation': "Matsue Y, van der Meer P, Damman K, Metra M, O'Connor CM, Ponikowski P, Teerlink JR, Cotter G, Davison B, Cleland JG, Givertz MM, Bloomfield DM, Dittrich HC, Gansevoort RT, Bakker SJ, van der Harst P, Hillege HL, van Veldhuisen DJ, Voors AA. Blood urea nitrogen-to-creatinine ratio in the general population and in patients with acute heart failure. Heart. 2017 Mar;103(6):407-413. doi: 10.1136/heartjnl-2016-310112. Epub 2016 Sep 22."}, {'pmid': '27507112', 'type': 'DERIVED', 'citation': "Ter Maaten JM, Damman K, Hanberg JS, Givertz MM, Metra M, O'Connor CM, Teerlink JR, Ponikowski P, Cotter G, Davison B, Cleland JG, Bloomfield DM, Hillege HL, van Veldhuisen DJ, Voors AA, Testani JM. Hypochloremia, Diuretic Resistance, and Outcome in Patients With Acute Heart Failure. Circ Heart Fail. 2016 Aug;9(8):e003109. doi: 10.1161/CIRCHEARTFAILURE.116.003109."}, {'pmid': '27448534', 'type': 'DERIVED', 'citation': "Tromp J, Meyer S, Mentz RJ, O'Connor CM, Metra M, Dittrich HC, Ponikowski P, Teerlink JR, Cotter G, Davison B, Cleland JG, Givertz MM, Bloomfield DM, van Veldhuisen DJ, Hillege HL, Voors AA, van der Meer P. Acute heart failure in the young: Clinical characteristics and biomarker profiles. Int J Cardiol. 2016 Oct 15;221:1067-72. doi: 10.1016/j.ijcard.2016.06.339. Epub 2016 Jul 5."}, {'pmid': '27266853', 'type': 'DERIVED', 'citation': "Ter Maaten JM, Valente MA, Damman K, Cleland JG, Givertz MM, Metra M, O'Connor CM, Teerlink JR, Ponikowski P, Bloomfield DM, Cotter G, Davison B, Subacius H, van Veldhuisen DJ, van der Meer P, Hillege HL, Gheorghiade M, Voors AA. Combining Diuretic Response and Hemoconcentration to Predict Rehospitalization After Admission for Acute Heart Failure. Circ Heart Fail. 2016 Jun;9(6):e002845. doi: 10.1161/CIRCHEARTFAILURE.115.002845."}, {'pmid': '24281137', 'type': 'DERIVED', 'citation': "Givertz MM, Postmus D, Hillege HL, Mansoor GA, Massie BM, Davison BA, Ponikowski P, Metra M, Teerlink JR, Cleland JG, Dittrich HC, O'Connor CM, Cotter G, Voors AA. Renal function trajectories and clinical outcomes in acute heart failure. Circ Heart Fail. 2014 Jan;7(1):59-67. doi: 10.1161/CIRCHEARTFAILURE.113.000556. Epub 2013 Nov 26."}, {'pmid': '24281134', 'type': 'DERIVED', 'citation': "Cleland JG, Chiswell K, Teerlink JR, Stevens S, Fiuzat M, Givertz MM, Davison BA, Mansoor GA, Ponikowski P, Voors AA, Cotter G, Metra M, Massie BM, O'Connor CM. Predictors of postdischarge outcomes from information acquired shortly after admission for acute heart failure: a report from the Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) Study. Circ Heart Fail. 2014 Jan;7(1):76-87. doi: 10.1161/CIRCHEARTFAILURE.113.000284. Epub 2013 Nov 26."}, {'pmid': '22339573', 'type': 'DERIVED', 'citation': "Teerlink JR, Iragui VJ, Mohr JP, Carson PE, Hauptman PJ, Lovett DH, Miller AB, Pina IL, Thomson S, Varosy PD, Zile MR, Cleland JG, Givertz MM, Metra M, Ponikowski P, Voors AA, Davison BA, Cotter G, Wolko D, Delucca P, Salerno CM, Mansoor GA, Dittrich H, O'Connor CM, Massie BM. The safety of an adenosine A(1)-receptor antagonist, rolofylline, in patients with acute heart failure and renal impairment: findings from PROTECT. Drug Saf. 2012 Mar 1;35(3):233-44. doi: 10.2165/11594680-000000000-00000."}, {'pmid': '21900185', 'type': 'DERIVED', 'citation': "O'Connor CM, Fiuzat M, Lombardi C, Fujita K, Jia G, Davison BA, Cleland J, Bloomfield D, Dittrich HC, Delucca P, Givertz MM, Mansoor G, Ponikowski P, Teerlink JR, Voors AA, Massie BM, Cotter G, Metra M. Impact of serial troponin release on outcomes in patients with acute heart failure: analysis from the PROTECT pilot study. Circ Heart Fail. 2011 Nov;4(6):724-32. doi: 10.1161/CIRCHEARTFAILURE.111.961581. Epub 2011 Sep 6."}, {'pmid': '21545947', 'type': 'DERIVED', 'citation': "Voors AA, Dittrich HC, Massie BM, DeLucca P, Mansoor GA, Metra M, Cotter G, Weatherley BD, Ponikowski P, Teerlink JR, Cleland JG, O'Connor CM, Givertz MM. Effects of the adenosine A1 receptor antagonist rolofylline on renal function in patients with acute heart failure and renal dysfunction: results from PROTECT (Placebo-Controlled Randomized Study of the Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). J Am Coll Cardiol. 2011 May 10;57(19):1899-907. doi: 10.1016/j.jacc.2010.11.057."}, {'pmid': '20925544', 'type': 'DERIVED', 'citation': "Massie BM, O'Connor CM, Metra M, Ponikowski P, Teerlink JR, Cotter G, Weatherley BD, Cleland JG, Givertz MM, Voors A, DeLucca P, Mansoor GA, Salerno CM, Bloomfield DM, Dittrich HC; PROTECT Investigators and Committees. Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. N Engl J Med. 2010 Oct 7;363(15):1419-28. doi: 10.1056/NEJMoa0912613."}, {'pmid': '18926433', 'type': 'DERIVED', 'citation': "Cotter G, Dittrich HC, Weatherley BD, Bloomfield DM, O'Connor CM, Metra M, Massie BM; Protect Steering Committee, Investigators, and Coordinators. The PROTECT pilot study: a randomized, placebo-controlled, dose-finding study of the adenosine A1 receptor antagonist rolofylline in patients with acute heart failure and renal impairment. J Card Fail. 2008 Oct;14(8):631-40. doi: 10.1016/j.cardfail.2008.08.010. Epub 2008 Sep 14."}]}, 'descriptionModule': {'briefSummary': 'The study is being conducted to examine whether KW-3902IV will result in greater improvement in signs and symptoms of heart failure, with less treatment failure than standard therapy, when it is added to IV loop diuretics in subjects with acute heart failure syndrome and renal impairment.', 'detailedDescription': "Loop diuretics are generally first line therapy in patients hospitalized with acute heart failure syndrome (AHFS). Their use far exceeds that of vasoactive agents. Tubuloglomerular feedback (TGF) is the body's compensatory response to avoid excess fluid loss, and it is activated when elevated sodium concentrations in the distal tubule are detected. TGF is proposed as a contributing factor for the observed diuretic resistance that occurs in patients with heart failure. Higher doses of diuretics are required to overcome the decreased natriuresis and reduced RBF induced by TGF. Ultimately, this action creates a vicious cycle of worsening renal function and diminished diuretic effectiveness.\n\nThe primary pharmacologic rationale for the use of KW-3902 in subjects with AHFS is its mechanism of action as an adenosine A1 receptor antagonist. TGF promotes release of adenosine, and adenosine binding to A1 receptors causes vasoconstriction of the afferent arteriole, decreased RBF, and enhanced sodium reabsorption by the proximal tubule. This action results in a decrease in GFR, diminished renal function, and sodium and water retention. Blocking adenosine A1 receptors via a selective adenosine receptor antagonist may limit sodium reabsorption by the proximal tubules without triggering TGF. It promotes vasodilation of the afferent arteriole of the glomerulus, and thus, this strategy offers the potential to overcome diuretic resistance or enhance diuretic responsiveness. It may also reduce the need for increasing diuretic doses that have been associated with worse outcomes.\n\nThe objectives of this study are to evaluate the effect of KW-3902IV in addition to intravenous (IV) loop diuretics (such as furosemide) on heart failure signs and symptoms, renal function, and safety in subjects hospitalized with AHFS, volume overload, and renal impairment, and to estimate and compare within-trial medical resource utilization and direct medical costs between patients treated with KW-3902IV versus placebo."}, 'eligibilityModule': {'sex': 'ALL', 'stdAges': ['ADULT', 'OLDER_ADULT'], 'minimumAge': '18 Years', 'healthyVolunteers': False, 'eligibilityCriteria': "Inclusion Criteria:\n\n1. History of heart failure of at least 14 days duration for which diuretic therapy has been prescribed\n2. Hospitalized for acute heart failure syndrome requiring IV diuretic therapy.\n3. Impaired renal function\n\nExclusion Criteria:\n\n1. Acute contrast induced nephropathy\n2. Ongoing or planned IV therapy for heart failure with positive inotropic agents, vasopressors, vasodilators, or mechanical support with the exception of IV nitrates\n3. BNP \\<500 pg/mL or NT-pro-BNP \\<2000 pg/mL\n4. Ongoing or planned treatment with ultrafiltration, hemofiltration, or dialysis\n5. Severe pulmonary disease\n6. Significant stenotic valvular disease\n7. Heart transplant recipient or admitted for cardiac transplantation\n8. Clinical evidence of acute coronary syndrome in the 2 weeks prior to screening\n9. Heart failure due to significant arrhythmias\n10. Acute myocarditis or hypertrophic obstructive, restrictive, or constrictive cardiomyopathy.\n11. Known hepatic impairment\n12. Non-cardiac pulmonary edema, including suspected sepsis\n13. Allergy to soybean oil or eggs\n14. History of seizure\n15. Stroke within 2 years\n16. History of or current brain tumor of any etiology\n17. Brain surgery within 2 years\n18. Encephalitis/meningitis within 2 years\n19. History of penetrating head trauma\n20. Closed head injury with loss of consciousness (LOC) over 30 minutes within 2 years\n21. History of, or at risk for, alcohol withdrawal seizures\n22. Advanced Alzheimer's disease\n23. Advanced multiple sclerosis\n24. Hgb \\<8 g/dL, Hct \\<25%, or the need for a blood transfusion\n25. Previous exposure to KW-3902"}, 'identificationModule': {'nctId': 'NCT00354458', 'briefTitle': 'PROTECT-2: A Study of the Selective A1 Adenosine Receptor Antagonist KW-3902 for Patients Hospitalized With Acute HF and Volume Overload to Assess Treatment Effect on Congestion and Renal Function', 'organization': {'class': 'INDUSTRY', 'fullName': 'NovaCardia, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)'}, 'officialTitle': 'A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Effects of KW-3902 Injectable Emulsion on Heart Failure Signs and Symptoms and Renal Function in Subjects With Acute Heart Failure Syndrome and Renal Impairment Who Are Hospitalized for Volume Overload and Require Intravenous Diuretic Therapy', 'orgStudyIdInfo': {'id': 'CKI-302'}, 'secondaryIdInfos': [{'id': '2007_804'}, {'id': 'MK7418-302'}]}, 'armsInterventionsModule': {'armGroups': [{'type': 'PLACEBO_COMPARATOR', 'label': '1', 'interventionNames': ['Drug: Comparator: Placebo (unspecified)']}, {'type': 'EXPERIMENTAL', 'label': '2', 'interventionNames': ['Drug: rolofylline']}], 'interventions': [{'name': 'rolofylline', 'type': 'DRUG', 'otherNames': ['KW-3902IV', 'MK7418'], 'description': 'rolofylline 30 mg IV QD; 3 days', 'armGroupLabels': ['2']}, {'name': 'Comparator: Placebo (unspecified)', 'type': 'DRUG', 'description': 'rolofylline Pbo 30 mg IV QD; 3 days', 'armGroupLabels': ['1']}]}, 'contactsLocationsModule': {'overallOfficials': [{'name': 'Barry Massie, MD', 'role': 'STUDY_CHAIR', 'affiliation': 'University of California San Francisco, USA'}, {'name': "Christopher O'Connor, MD", 'role': 'STUDY_CHAIR', 'affiliation': 'Duke University, USA'}, {'name': 'Marco Metra, MD', 'role': 'PRINCIPAL_INVESTIGATOR', 'affiliation': 'University of Brescia, Italy'}]}, 'sponsorCollaboratorsModule': {'leadSponsor': {'name': 'NovaCardia, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)', 'class': 'INDUSTRY'}, 'collaborators': [{'name': 'Merck Sharp & Dohme LLC', 'class': 'INDUSTRY'}], 'responsibleParty': {'oldNameTitle': 'Executive Vice President, Clinical and Quantitative Sciences', 'oldOrganization': 'Merck & Co., Inc.'}}}}