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Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function (TOPCAT)

Primary Purpose

Cardiovascular Diseases, Heart Diseases, Heart Failure, Congestive

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Spironolactone

Placebo

About this trial

This is an interventional treatment trial for Cardiovascular Diseases focused on measuring Heart Failure, Diastolic Heart Failure, Preserved Ejection Fraction

Eligibility Criteria

50 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

INCLUSION CRITERIA: Heart failure as defined by at least one of symptom (paroxysmal nocturnal dyspnea; orthopnea; or dyspnea on mild or moderate exertion) at the time of screening and at least one sign (any rales post cough; jugular venous pressure(JVP) greater than or equal to 10cm of water(H2O); lower extremity edema; or chest x-ray demonstrating pleural effusion, pulmonary congestion, or cardiomegaly) within 12 months prior to study entry: left ventricular ejection fraction greater than or equal to 45% (per local reading); the ejection fraction must have been obtained within 6 months prior to randomization and after any MI or other event that would affect ejection fraction Controlled systolic blood pressure(BP), defined as a target systolic BP less than 140 mm Hg; participants with BP up to and including 160 mm Hg are eligible for enrollment if they are on three or more medications to control BP Serum potassium less than 5.0 mmol/L prior to randomization At least one hospital admission for which heart failure was a major component of the hospitalization some time within the 12 months prior to study entry OR brain natriuretic peptide (BNP) greater than or equal to 100pg/ml or N-terminal pro-BNP greater than or equal to 360pg/ml within the 60 days prior to study entry Women of child-bearing potential must have a negative serum/urine pregnancy test within 72 hours prior to randomization, must not be lactating, and must agree to use an effective method of contraception during the entire course of study participation Willing to comply with scheduled visits Informed consent form signed by the subject prior to participation in the trial EXCLUSION CRITERIA: Severe systemic illness with an expected life expectancy of less than 3 years Chronic pulmonary disease requiring home O2, oral steroid therapy, or hospitalization for exacerbation within 12 months of study entry, or significant chronic pulmonary disease in the opinion of the investigator Known infiltrative or hypertrophic obstructive cardiomyopathy or known pericardial constriction Primary hemodynamically significant uncorrected valvular heart disease, obstructive or regurgitant, or any valvular disease expected to lead to surgery during the trial Atrial fibrillation with a resting heart rate greater than 90 bpm MI in the past 90 days Coronary artery bypass graft surgery in the past 90 days Percutaneous coronary intervention in the past 30 days Heart transplant recipient Currently implanted left ventricular assist device Stroke in past 90 days Systolic BP (SBP) greater than 160 mm Hg Known orthostatic hypotension Gastrointestinal disorder that could interfere with study drug absorption Use of any aldosterone antagonist or potassium sparing medication in the last 14 days or any known condition that would require the use of an aldosterone antagonist during study participation; Known intolerance to aldosterone antagonists Current lithium use Current participation (including prior 30 days) in any other therapeutic trial Any condition that, in the opinion of the investigator, may prevent the participant from adhering to the trial protocol History of hyperkalemia (serum potassium greater than or equal to 5.5mmol/L) in the past 6 months or serum potassium greater than or equal to 5.0mmol/L within the past 2 weeks Severe renal dysfunction, defined as an estimated glomerular filtration rate(GFR) less than 30ml/min. Participants with serum creatinine greater than or equal to 2.5mg/dl are also excluded even if their GFR is greater than or equal to 30ml/min Known chronic hepatic disease, defined as aspartate aminotransferase(AST) and alanine aminotransferase(ALT) levels greater than 3.0 times the upper limit of normal as read at the local lab.

Sites / Locations

University of Alabama at Birmingham
Cardiovascular Consultants, Ltd.
Carl T. Hayden VA Medical Center
Central Arkansas Veterans Healthcare System
Heart Clinic Arkansas
Cynthia Thaik
Fresno VA Medical Center
Clinica Medica San Miguel
CAPRI
VA Medical Center West Los Angeles
Mehrdad Kevin Ariani, MD, Inc.
UC Davis Medical Center
Central Coast Cardiology
Naval Medical Center San Diego
Olive View - UCLA Medial Center
University of Colorado Health Sciences Center
Cardio-Vascular Institute
University of Connecticut Health Center
Howard University Hospital
Washington Hospital Center
Washington DC VA Hospital
Daytona Heart Group
M & O Clinical Research, LLC
Florida Heart Center
University of Florida
Mayo Clinic Florida
Brevard Cardiovascular Research Associates, Inc
Tallahassee Research Institute
Emory University at Grady Health System
Morehouse School of Medicine
Northside Cardiology Center
InnovaMed Alliance
Rush University Medical Center
University of Illinois at Chicago Medical Center
Northwestern University
Cardiovascular Research Foundation
Heart, Lung and Vascular Institute
HeartCare Midwest
The Care Group, LLC
Cardiovascular Research of Northwest Indiana, LLC
University of Iowa Hospitals and Clinics
Baptist Healthcare System, Inc. d/b/a Baptist Hospital East
Leonard J. Chabert Medical Center
Ochsner Clinic Foundation
Northeast Cardiology
University of Maryland Medical Center
Sinai Hospital of Baltimore
Kaiser Permanente
Northwest Hospital
Delmarva Heart Research Foundation
Associates in Cardiology, PA
Brigham and Women's Hospital
Boston University Medical Center
Caritas St. Elizabeth's Medical Center
Merrimack Valley Cardiology Associates
Compass Medical East Bridgewater
Pentucket Medical Associates
Charles River Medical Associates
Hawthorn Medical Associates
Baystate Medical Center
Umass Memorial Medical Center
Veterans Affairs Ann Arbor Health Care System
Oakwood Hospital and Medical Center
Detroit VA Medical Center
Henry Ford Hospital
William Beaumont Health Center
Minneapolis VA Medical Center
Heartland Regional Medical Clinic
Glacier View Cardiology
Bryan LGH Heart Institute
The Creighton Cardiac Center
Deborah Heart and Lung Center
Cardiovascular Associates of the Delaware Valley
Cardiovascular Associates of the Delaware Valley
NJ Heart
St. Joseph's Regional Medical Center
The Valley Hospital
Electrophysiology Research Foundation
Community Medical Center
New Jersey Cardiology Associates
Bronx-Lebanon Hospital Center
New York Methodist Hospital
Research Foundation State University of New York at Buffalo
Buffalo Heart Group, LLC
Jamaica Hospital Medical Center
Mid Valley Cardiology
Winthrop Cardiology Associates
Soundshore Medical Center of Westchester
NYU School of Medicine
St. Lukes Roosevelt
Northport VA Medical Center
University of Rochester Medical Center
Lewin, Fagen, and Lown, MD, PC
SUNY Upstate Medical Center
Syracuse VA Medical Center
Northeast Medical Center
Durham VA Medical Center
Wake Forest University Health Sciences
The Lindner Clinical Trial Center
University of Cincinnati
University Hospitals of Cleveland/Case Western Reserve University
MetroHealth Medical Center
Ohio State University Hospital East
VAMC Dayton
CCHS Clinical Research Office/Marymount Hospital
CCHS Clinical Research Office/ Hillcrest Hospital
COR Clinical Research
Oklahoma City VA Medical Center
Oklahoma Foundation for Cardiovascular Research
Oklahoma Heart Institute
St. Charles Health System
Providence Heart and Vascular Institute
Capital Area Research
Geisinger Medical Center
Medicor Associates, Inc
The Milton S. Hershey Medical Center
Lancaster Heart and Stroke Foundation
Drexel University College of Medicine
University of Pennsylvania
Thomas Jefferson University Hospital- Dept. of Family and Community Health
Thomas Jefferson University
Temple University Hospital
Eastwick Primary Care
Pittsburgh VA Healthcare System
The Reading Hospital and Medical Center
Memorial Hospital Rhode Island
VAMC - Charleston, SC
Black Hills VA Health Care System
The Stern Cardiovascular Center
Memphis VA Medical Center
Memphis Heart Clinic
University of Tennessee Health Science Center
Vanderbilt Heart and Vascular Institute
DCT - APHC, LLC dba Discovery Clinical Trials
Dallas VA Medical Center
Cardiovascular Research Institute of Dallas
U.T. Southwestern Medical Center
Michael E. DeBakey VA Medical Cntr.
The Methodist Hospital Research Institute
Wilford Hall Medical Center
Texas Tech University Health Sciences Center
Cardiology Clinic of San Antonio
Tyler Cardiovascular Consultants
LDS Hospital
University of Utah
Cardiovascular Associates Ltd.
Sentara Cardiovascular Research Institute
Evergreen Healthcare
Providence St. Peter Hospital
Sound Health Research
University of Washington
CAMC Health Education and Research Institute
William S. Middleton Memorial VA Hospital
University of Wisconsin-Madison
Aspirus Heart and Vascular Institute
Instituto de Investigaciones Clinicas de Bahia Blanca
Clinica Coronel Suarez
Hospital Italiano de La Plata
Instituto de Investigaciones Clinicas de Mar Del Plata
Instituto de Investigaciones Clinicas de Quilmes
Policlinico Modelo de Cipoletti
IMAI Research
CIPREC
Instituto Cardiologico Ezpecializado S.R.L
Clinica IMA
Clinica Privada Del Prado
Instituto de Investigaciones Clinicas de Rosario
Hospital San Bernardo
Centro de Investigaciones Clinicas del Litoral SRL
Sanatorio Mayo S.A.
Centro Privado de Cardiologia
Centro Modelo de Cardiología
Instituto de Cardiologia SRL
Hospital Felicio Rocho
Santa Casa De Belo Horizonte
HMCP PUC Campinas
Irmandade da Santa Casa de Misericordia de Curitiba
Hospital das Clinicas da Universidade Federal de Goias
Instituto do Coracao de Marilia
Hospital Sao Vicente de Paulo
PROCAPE
Hospital de Clinicas de Porto Alegre
Hospital Mae De Deus
Hospital Universitario Pedro Ernesto
Santa Casa de Misericordia do Rio de Janeiro
Instituto de Molestias Cardiosvaculares
Instituto de Cardiologia de Santa Catarina
Incor Fmusp
UNIFESP/Hospital Sao Paulo
Instituto do Coracao do Triangulo Mineiro
University of Calgary
Fraser Clinical Trials Inc.
St. Boniface General Hospital
Health Science Centre
Capital District Health Authority
Dr. Saul Vizel Cardiac Research Office
Cornwall Clinical Trials
Hamilton Health Sciences - General Site
London Health Sciences Center
Ottawa Heart Institute
Dr. Gurcharan Syan (PP)
St. Michael's Hospital
Mount Sinai Hospital
CHUS - Hopital Fleurimont
Service de la Recherche
Cite de la Sante de Laval
Clinique Cardiologie Levis
Hopital Du Sacre Coeur de Montreal
Montreal Heart Institute
CHUM - Hotel Dieu
Chum Hotel Dieu
Royal Victoria Hospital
Montreal General Hospital
Centre de recherche clinique de Quebec
Centre Hosp Regional de Lanaudiere
C.S.S.S.B.
Hopital Laval
CSSS du Sud de Lanaudiere (Hopital Pierre-Le Gardeur)
Centre De Sante et De Services Sociaux De Thetford
Misericordia Hospital - Cardiac Sciences
CDRC Rive-Sud
SMBD Jewish General Hospital
Saskatchewan Heart Centre
Cardiology Clinical Trials - Surrey Memorial Hospital
Centre Hospitalier de Trois-Rivieres
L &J Clinic
Tbilisi State Medical University Clinic #1
Cardio-Reanimation Centre
Multiprofile Clinical Hospital of Tbilisi #2
Emergency Cardiology Centre
National Center of Therapy
Diagnostic Services Clinic
Clinic of Angiocardiology "ADAPTI"
Cardiology Clinic
Municipal Healthcare Institution <>
Altay State Medical University of federal agency of public health and social progress RF
Municipal Health Care Institution "City Hospital #1"
Kaliningrad Region Hospital
Kemerovo Cadiologiy Dispensary, Kemerovo Medical Academy
Nonstate Healthcare Institution
State Healthcare Institution "Region Clinical Hospital #1
National Research Center for Preventitive Medicine
Russian State Medical University, Hospital Therapy Department #1
State Education High Professional Education Russian State Medical University
Federal State Institution "Outpatient clinic #3 of President's Management Department of Russian Fede
Research Institute of Physico-Chemical Medicine Center for Atheosclerosis and Laboratory
Non State Health Care Institution Central Hospital #6 of Russian Railways JSC
Novosibirsk Municipal Clinical Emergency Hosp. # 2
Saint-Petersburg State Healthcare Institution "City Alexander's Hospital"
Saint-Petersburg State Institution of Health Protection, "City Hosptial # 15"
Chair of Nephrology and Dialysis of St Petersburg State Medical University
Public Institution of Health City Hospital # 28
Federal State Health Care Institution
Medico- Military Academy, Navy Therapy Dept
Saint-Petersburg State Health Institution "Pokrovskaya City Hospital"
Federal State Institution
State Educational Institution of High Professional Education Saratov State Medical University
Almasov research institute of Cardiology
State Institution Saint-Petersburg Dzhanelidze Scientific
Saint-Petersburg Clinical Hospital of RAMS, policlinic department
Saint-Petersburg State Health Care Institution "City Hospital of Saint George the Martyr"
Non-state Health Care Institution
City Hospital #26
City Hospital No 26
Chair and Department of Hospital Therapy
State Institition Research Institution of Cardiology of Tomsk
State Educational institution of Higher Professional Education "Volgograd State Medical University o
State Health Care Institution "Voronezh Regional Clinical Consultative & Diagnostic Centre"
City Healthcare Institution Clinical Hospital #8
Yaroslavl Regional Clinical Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Experimental

Arm Label

Placebo

Spironolactone

Arm Description

Placebo of spironolactone

Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.

Outcomes

Primary Outcome Measures

Composite Outcome of Cardiovascular Mortality, Aborted Cardiac Arrest, or Hospitalization for the Management of Heart Failure, Whichever Occurred First

Secondary Outcome Measures

Cardiovascular Mortality

Aborted Cardiac Arrest

First incidence of aborted cardiac arrest

Hospitalization for the Management of Heart Failure

First incidence of a hospitalization for the management of heart failure

All-cause Mortality

Composite Outcome of Cardiovascular Mortality or Cardiovascular-related Hospitalization (i.e., Hospitalization for Myocardial Infarction(MI), Stroke, or the Management of Heart Failure), Whichever Occurred First

Cardiovascular-related Hospitalization

Hospitalization for MI, stroke or the management of heart failure, whichever occurred first

Total Hospitalizations (Including Repeat Hospitalizations) for the Management of Heart Failure

Composite Outcome of Sudden Death or Aborted Cardiac Arrest, Whichever Occurred First

New Onset Diabetes Mellitus, Among Subjects Without a History of Diabetes Mellitus at Baseline.

First incidence of new onset diabetes mellitus among subjects without a history of diabetes mellitus at baseline.

Development of Atrial Fibrillation, Among Subjects Without a History of Atrial Fibrillation at Baseline.

First incidence of atrial fibrillation among subjects without a history of atrial fibrillation at baseline

Myocardial Infarction

First incidence of myocardial infarction

Stroke

First incidence of stroke

Deterioration of Renal Function

First incidence of a deterioration of renal function. The TOPCAT protocol defines deterioration of renal function as occurring if a subject has a serum creatinine value which is at least double the baseline value for that subject, and is also above the upper limit of normal (assumed to be 1.0 mg/dL for females and 1.2 mg/dL for males.)

Composite Outcome of Sudden Death, Aborted Cardiac Arrest, or Hospitalization for the Management of Ventricular Tachycardia, Whichever Occurred First

Quality of Life, as Measured by the Kansas City Cardiomyopathy Questionnaire.

Average post-baseline quality of life, taking into consideration baseline quality of life, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual. The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. The KCCQ was administered at the following study visits: baseline, month 4, month 12 and annually thereafter.

Quality of Life, as Measured by the EuroQOL Visual Analog Scale.

Average post-baseline quality of life, taking into consideration baseline quality of life, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual. The EuroQOL visual analog scale (EQ5D) is a single-item, self-administered instrument that quantifies current health status. Scores can range from 0-100, in which higher scores reflect better health status. The EQ5D was administered at the following study visits: baseline, month 4, month 12 and annually thereafter.

Quality of Life, as Measured by McMaster Overall Treatment Evaluation Questionnaire.

Average post-baseline quality of life, taking into consideration baseline quality of life and treatment group. The McMaster Overall Treatment Evaluation questionnaire is a self-administered 3-item instrument that measures a patient's perception of change in their health-related quality of life since the start of therapy. The questionnaire consists of a single question - "Since treatment started, has there been any change in your activity limitation, symptoms and/or feelings related to your heart condition?" Scores can range from -7 to +7, and higher scores reflect better health status. The questionnaire was administered at the following study visits: month 4 and month 12. Valid translations of this questionnaire were only available for subjects enrolled in the United States, Canada and Argentina.

Depression Symptoms, as Measured by Patient Health Questionnaire.

Average post-baseline depression, taking into consideration baseline depression, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual. The Patient Health Questionnaire (PHQ) is a 10-item, self-administered instrument for screening, diagnosing, monitoring and measuring the severity of depression. Scores can range from 0-27, in which lower scores reflect better mental health status. The PH-Q was administered at the following study visits: baseline, month 12 and annually thereafter. Valid translations of this questionnaire were only available for subjects enrolled in the United States and Canada.

Hospitalization for Any Reason

First incidence of a hospitalization for any reason

Potassium

Average post-baseline Potassium, taking into consideration baseline Potassium, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual.

Serum Creatinine

Average post-baseline serum creatinine, taking into consideration baseline serum creatinine, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual.

Sodium

Average post-baseline Sodium, taking into consideration baseline Sodium, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual.

Chloride

Average post-baseline Chloride, taking into consideration baseline Chloride, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual.

Estimated Glomerular Filtration Rate (GFR)

Average post-baseline GFR, taking into consideration baseline GFR, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual.

Full Information

NCT ID

NCT00094302

First Posted

October 15, 2004

Last Updated

February 11, 2015

Sponsor

Carelon Research

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

1. Study Identification

Unique Protocol Identification Number

NCT00094302

Brief Title

Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function

Acronym

TOPCAT

Official Title

Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT)

Study Type

Interventional

2. Study Status

Record Verification Date

January 2014

Overall Recruitment Status

Completed

Study Start Date

August 2006 (undefined)

Primary Completion Date

June 2013 (Actual)

Study Completion Date

June 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Carelon Research

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this study is to evaluate the effectiveness of aldosterone antagonist therapy in reducing cardiovascular mortality, aborted cardiac arrest, and heart failure hospitalization in patients who have heart failure with preserved systolic function.

Detailed Description

BACKGROUND: Heart failure (HF) is a major cause of morbidity and mortality, particularly in older people. Indeed, it is the most common discharge diagnosis in patients older than 65 years. As the United States population ages, heart failure will continue to grow as a public health concern. Therapeutic trials of heart failure have dealt almost exclusively with patients who have systolic dysfunction. However, there is now an emerging awareness that nearly half of the patients with heart failure have preserved systolic function and that the survival of these patients is adversely affected. This study is a randomized clinical trial of a novel therapeutic approach, specifically the use of spironolactone, an aldosterone antagonist, in treating these patients. While this treatment has been shown to be useful in treating heart failure with reduced systolic function, it has not been studied in patients with preserved systolic function. Patients with heart failure and preserved systolic function have a poor prognosis. The annual mortality rate is intermediate between the prognosis for those without heart failure and for those with heart failure and reduced systolic function. For instance, Family Health Study participants with heart failure and preserved systolic function had a mortality rate of 9% compared to 3% for their age- and gender-matched controls. The mortality rate was 19% in heart failure patients with reduced systolic function heart failure compared to 4% for their matched controls. As heart failure develops, neurohormones are released that initially improve cardiac output but ultimately contribute to progression of left ventricular dysfunction. The renin-angiotensin-aldosterone system is an important part of this compensatory response. Aldosterone levels may rise to 20 times normal levels in heart failure and aldosterone contributes to the development of myocardial fibrosis. Spironolactone is a potassium-sparing diuretic that acts on the distal tubule, inhibiting sodium and potassium ion exchange. There are several potential beneficial actions, including prevention of cardiac fibrosis. A recent trial evaluated spironolactone in patients with systolic dysfunction heart failure. Spironolactone treatment caused a 30% reduction in mortality compared to placebo (p< 0.001). The improvement resulted from a reduction in all cause mortality. More recently, the Eplerenone Post-Myocardial Infarction (MI) study showed that this aldosterone antagonist significantly reduces mortality despite background treatment with an angiotensin-converting enzyme (ACE) inhibitor and beta-blocker. Advantages of using spironolactone in this study are that it is commercially available, inexpensive, and no longer under patent (therefore this study will not be done by industry). Also, there is a clear physiologic rationale for its use, and the side effect profile is well understood. The study enrolled subjects who had preserved systolic function with heart failure and who met clearly defined eligibility criteria that were selected to make the results widely generalizable to clinical practice. DESIGN NARRATIVE: This is a randomized, double-blinded, placebo-controlled trial of aldosterone antagonist therapy (15 mg dose spironolactone or placebo; titrated up to 30 or 45 mg/day) in 3,445 adult patients with heart failure and preserved systolic function. Patients were recruited from August 2006 through January 2012, treated, and will be followed through June 2013. Approximately 270 clinical sites in six countries were subcontracted by the clinical trial coordinating center. Subject visits to a clinical center will occur every four or six months. Data collected include demographic and clinical data, including the results of history and physical exams, laboratory and imaging data, repository specimens for special physiology studies, and genetic studies. Additionally, data regarding quality of life and compliance with assigned treatment will also be collected and assessed.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Cardiovascular Diseases, Heart Diseases, Heart Failure, Congestive

Keywords

Heart Failure, Diastolic Heart Failure, Preserved Ejection Fraction

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

3445 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Placebo of spironolactone

Arm Title

Spironolactone

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Spironolactone

Other Intervention Name(s)

aldosterone antagonist

Intervention Description

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Placebo of spironolactone

Primary Outcome Measure Information:

Title

Composite Outcome of Cardiovascular Mortality, Aborted Cardiac Arrest, or Hospitalization for the Management of Heart Failure, Whichever Occurred First

Time Frame