Occlusive NSTEMI Multicenter registry

1.0INTRODUCTION1.1****BackgroundInformation and RationaleThis study aims to identify NSTEMI patients withtotal and non-total occlusion and correlate their ECG, Echocardiogram,Angiographic parameters and their clinical outcomes.  The patients who have an acute chest pain andcardiomyocyte necrosis as evidenced by troponin elevation are labelled asNSTEMI. These individuals may present with ongoing ischemia, electrical orhemodynamic instability and require angiography and appropriate revascularizationat the earliest. The clinical presentation depends on the severity of coronarystenosis and the degree of thrombus. TIMI risk score is easy to use in day today clinical practice and can be accessed at www.timi.org. A low TIMI scoreindicates intermediate or high risk.

1.2Rationale1.3****PotentialBenefitsAs this is an observational study,there is no direct benefit from this study for the patient. However allpatients enrolled in this study will be followed up until the completion ofthis study. Furthermore, this study will be of help to the community bycontributing to medical research.

2.0OBJECTIVES2.1****Primary ObjectiveTo assess the Electro andEchocardiogram, angiographic parameters, In hospital and one year  clinical outcomes of patients with occlusiveNSTEMI Versus Non occlusive NSTEMI.

2.2****SecondaryObjectiveThe secondary objective of this study is to evaluate the time delays,blood parameters, cardiac  biomarkers andadverse events in both the group. 3.0ENDPOINTS3.1****PrimaryEndpoint MACE

Left Ventricular Ejection Fraction (LVEF)

 3.2       SecondaryEndpoint

Death

Stroke

Readmission

48 hours Troponin

Reinfarction

Target Lesion Failure (TLF)

Bleeding

4.0****STUDY POPULATIONIn this study, approximately 1,000 patients multicentre of eithersex, aged 18 and above years with acuteNSTEMI.

 4.1Subject selection

Subject selection will be done under the supervision ofthe investigator at each site, following approval of the study protocol by theEthics committee and CTRI Registration. Signed informed consent must beobtained from the patient/ LAR, following which the patient will be screenedand eligible patients will be enrolled into the study. Approximately 1,000patients multicentric diagnosed with NSTEMI.

4.1****Inclusion CriteriaAll patients presenting with angina or ECG features andraised Troponin levels suggestive of NSTEMI are included. 4.2****ExclusionCriteriaPatients presentingwith diagnosis other than NSTEMI.

5.0****STUDY DESIGNThis studywill be a prospective, observational study conducted upto 10 centers inpatients with NSTEMI of total occlusion and Non total occlusion. Patient’sdemographic, clinical, electrocardiographic parameters are noted on admission. Allpatients included in the study undergo immediate transthoracicechocardiographic examination at emergency department. Timing of interventionand mode of revascularization are left to the treating physician’s discretion.The timing of revascularization and angiographic details are noted.  Patients major cardiovascular events (non-fatalMI, target vessel revascularization and death) are noted during hospital stayand 1 year follow up.

 5.1.     Study Procedures

5.1.1Screening/Baseline

The available data pertaining to screening/baseline will be captured in the spreadsheet.

Patients in the age group of 18 andabove will be provided with the IEC/IRB approved written informed consentdocument. Informed Consent Document should be signed by the patient / LARbefore baseline or screening procedures

 Thefollowing parameters will be collected:

1.   A list of presenting complaints

2.   Demographic details: Thedemographic details of the patient such as age (in years), height (incentimeters), weight (in kilograms), and gender (male or female) will becollected.

3.   Family history, Medical historyand Medication history of the patients will be collected

4.    Details pertaining to  duration of chest pain, , vital signs (Heartrate, Blood pressure), Killip class

5.   Electrocardiogram (ECG)

6.     Echocardiogram done in standard parasternal view and apical viewswere assessed for cardiac dimension, endocardial wall thickness, Left VentricularEjection Fraction (LVEF), Tricuspid annular plane systolic excursion (TAPSE), Regionalwall motion abnormality (RWMA) and ACS complications. Images are acquired andstored in Digital Imaging and Communications in Medicine (DICOM) format.

7.     To enable quick assessment and uniform reporting followingechocardiogram values are assessed and entered on this format.

8.     Left ventricular end diastolic and systolic dimension(Normal/Dilated)

9.     Right ventricular size (Normal/Dilated)

10.  Left ventricularendocardial wall thickness (None/Thin/Mild/Moderate/Severe)

11.  Left ventricularejection fraction (simpson/eyeball assessment) - Normal/Mild/Moderate/Severe

12.  Right ventricularejection fraction - TAPSE

13.  Regional wall motionabnormality (16 segments) – Present/Absent; If present- number of segments out of 16

14.  Possible coronaryartery disease territory – Left anterior descending artery (LAD), Leftcircumflex artery (LCX), Right coronary artery (RCA)

15.  Complications of ACS-Mitral Regurgitation (MR) with severity, Ventricular septal rupture (VSR),pericardial effusion (PE)

16.  Complete Haemogram, Random bloodsugar, Lipid profile, Blood urea, serum creatinine,  Sodium, Potassium

17.  Cardiac markers including CreatinePhosphokinase test (CPK), CK-MB fraction and the 0hr,1hr and 48 hrs Troponin levels

18.  Adverse events

19.  Duration of hospital stay

 5.1.2                         Other data to be collected followingenrollment

The data pertaining to the tests/procedures performed, AE, SAE and concomitant medication administered duringthe hospitalization for all the patients enrolled will be collected and enteredin spreadsheets.

 5.1.3             1 year from the day of enrollment

The followinginformation will be collected during 1 year from the day of enrollment ifavailable or the patients will be contacted telephonically to assesstheir health status:

 Â·                    MACE

·                    DEATH

·                    LVfunction

·                    TargetLesion Revascularization (TLR)

6.0 SAFETY The investigator willassess and record any adverse event, reportable events in detail including thedate of onset, event diagnosis (if known) or sign/symptom, severity, timecourse, duration and outcome, relationship of the adverse event to the treatment/procedureand any action(s) taken.

6.1****DefinitionsAn adverse event (AE) is any untowardmedical occurrence in a patient or clinical investigation subject administereda pharmaceutical product and which does not necessarily have a causalrelationship with this treatment.  An AEcan therefore be any unfavorable and unintended sign (including an abnormallaboratory finding), symptom, or disease temporally associated with the use ofa medicinal product, whether or not related to the medicinal product .This includesthe following:

 Â§Anyclinically significant worsening of a pre-existing condition.

§Anyreoccurrence of a pre-existing condition.

 A pre-existingcondition is a clinical condition (including the condition being treated) thatis diagnosed before the subject signs the informed consent form and that isdocumented as part of the subject’s medical history.

 An AE is consideredto be treatment emergent if

 (1) It was notpresent when the active phase of the study began and is not a chronic conditionthat is part of the subject’s medical history

(2) It was present atthe start of the active phase of the study or as part of the subject’s medicalhistory, but the severity or frequency increased during the active phase.

SeriousAdverse Event****s

 Serious adverse eventslike Death, Life-threatening condition and persistent or significant disabilityor incapacity will be reported to the ethics committee and all participatinginvestigators.

 Deathof Subject: Anevent that results in the death of a subject.

**Life-Threatening:**An event that,in the opinion of the investigator, would have resulted in immediate fatalityif medical intervention had not been taken. This does not include an event that would have been fatal if it hadoccurred in a more severe form.

Persistentor Significant Disability / Incapacity: An event that results in a condition thatsubstantially interferes with the activities of daily living of a study subject.Disability is not intended to include experiences of relatively minor medicalsignificance such as headache, nausea, vomiting, diarrhea, influenza, andaccidental trauma (e.g.,sprained ankle).

 Submission of reportsregarding AE and SAE will be as per the Ethics Committee requirements.

 Significant expectedAdverse Eventsmay involve:

·              Intracranialhaemorrhage or significant bleeding

·              Recurrentmyocardial infarction

·              Death

·              Restenosis

 All AEs will beentered onspreadsheets.

 Thefollowing AE information must be included (when applicable):

 The specificcondition or event; whether the condition was pre-existing (i.e. an acutecondition present at the start of the study or history of a chronic condition)and, if so, whether it has worsened (e.g. in severity and/or frequency); thedates and times of occurrence; severity; action taken; and outcome. Laboratoryabnormalities found to be of clinical significance may be reported as AEs.

 The details of AEsand SAEs should be collected from the time of obtaining the informed consent.SAEs that are not treatment/ procedure related may nevertheless be consideredby the participating investigators or the medical monitor (or designee) to berelated to the conduct of the clinical study, i.e. to a patient’s participationin the study.

Thecausal relationship of AEs to the study drug will be rated as follows:

1.     Related– Events that are procedure related example: stent thrombosis

2.     Unrelated- Events that are not procedure related example: fracture of leg due toaccidental fall

7.0STATISTICALCONSIDERATIONS7.1****Study Hypothesis            The aim is to evaluate theclinical and angiographic outcomes of patients with occlusive Non-ST elevationmyocardial infarction (NSTEMI) as compared to Non-occlusive NSTEMI undergoingpercutaneous coronary intervention (PCI)

7.2****SampleSizeA sample size of 1,000 patientsmulticentric is considered sufficient to provide the basis for future pivotalstudy.

 7.3****AnalysisPopulationsNo of patients enrolled for 1year in both arms together. Estimated around 1000 patients

7.4****Demographicand Baseline characteristics Patient’s demographic, clinical;electro cardiographic and echocardiographic parameters are noted on admission.Timing of intervention and mode of revascularization are left to the treating physician’sdiscretion. The timing of revascularization and angiographic details are noted.Patients major cardiovascular events (non-fatal MI, target vesselrevascularization and death) are noted during hospital stay and 1 year followup. The patient’s inclusion to the Per-Protocol and Safety Population will alsobe summarized. All demographic data will be listed.

7.5****Safety Review Safety analysis willbe performed on the Safety population. Safety and tolerability will be assessedin terms of adverse events, laboratory data, vital sign data, which will becollected for all patients. Appropriate summaries of these data will bepresented. Concomitant medications will be tabulated by patient with drugcategory and preferred term.

Continuous variableswill be summarized using descriptive statistics and the categorical data willbe presented as numbers with percentages. The time-delays are presented asmedians with 25th and 75th percentiles. Appropriate test will be used forcomparison of categorical and continuous variables.

7.6****FinalAnalysis PlanDetailedmethodology for summary and statistical analyses of the data collected in this

observational study will be documented.

 8.0       SourceDocuments and Access to Source Data/Documents

All source documents will bestored in their respective sites.  Accessto source data if necessary at the time of data analysis or any queryclarification it can be done by the respective sites.

 8.1****Source Documents and SpreadsheetsCompletionOriginalsource document data will be entered and the same will be complete inSpreadsheets.

8.1.1     Source Documents

 Source documents aredefined as original documents, data and records.  This may include hospital records, clinical charts,laboratory data, and recorded data from automated instruments and/orx-rays.  Data collected during this studymust be recorded on the spreadsheets.

 Theinvestigator(s)/institution(s) will permit study-related monitoring, audits,IEC/IRB review, and regulatory inspection(s), providing direct access to sourcedata documents.

 Data will be collected from thepatients’ file regarding all the tests and procedures that were performed to assesstheir condition.

8.0

8.1

8.1.1

8.1.2****Accessto Source Data/Documents Asrequired by the ICH GCP guidelines and regulatory authorities the investigatorwill allow direct access to all pertinent medical records in order to allow forthe verification of data gathered in the spreadsheets and for the review of thedata collection process. The records, including source documentation, must alsobe available for inspection by relevant regulatory health authorities.

8.1.3****SpreadsheetSpreadsheet (Excel) must becompleted for each subject screened/enrolled in this study.  The spreadsheet data for this study will be collectedand same will be validated for the study-specific.

 The investigator/hospital staffwill document subject data in his/her own subject files.  These subject files will serve as source datafor the study.  All data required by thisprotocol will be recorded by investigative site personnel in the spreadsheet.  All data entered into the spreadsheet will besupported by source documentation. Vital status and clinical outcome will bedetermined for all patients and reported on appropriate entry.

 The investigator or an authorizedmember of the investigator’s site will make any necessary corrections to the spreadsheetbefore sending it to The Madras Medical Mission.

9.0****QualityControl and Quality Assurance By signing thisprotocol, the investigator agrees to be responsible for ensuring that a qualitycontrol and quality assurance systems with written standard operatingprocedures (SOP) will be in place to ensure that the study will be conductedand data will be generated, documented, and reported in compliance with theprotocol, accepted standards of Good Clinical Practice, and all applicable locallaws, rules and regulations relating to the conduct of the clinical study.

10.0****Ethical Conduct of the Study This study will beconducted in accordance with the ethical principles that have their origin inthe current Declaration of Helsinki with ethics approval and will be consistentwith ICH GCP and applicable regulatory requirements. The study will be registeredunder CTRI. The study will be conducted in compliance with the protocol.

 The rights, safetyand well-being of the study subjects are the most important considerations andshould prevail over interests of society and science.

 GCP requires that theclinical protocol, any protocol amendments, the informed consent and all otherforms of subject information related to the study (e.g., advertisements used torecruit subjects) and any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the ethical,scientific and medical appropriateness of the study before it isconducted.  IEC/IRB approval of theprotocol, informed consent and subject information and/or advertising, asrelevant, will be obtained prior to the start of the study.

Any amendments to theprotocol will require IEC/IRB approval prior to implementation of any changesmade to the study design.  Theinvestigator will be required to submit, maintain and archive study essentialdocuments for 5 years.

 10.1****InformedConsent  Obtaining consent isthe responsibility of the Investigator. Prior to the beginning of the study,the Investigator must have the IEC/ IRB written approval of the written informedconsent form and any other information to be provided to the patients.

 The investigator mustprovide the subject or legally acceptable representative (if applicable) with acopy of the consent form and written information about the study in thelanguage in which the subject is most proficient. The language must benon-technical and easily understood by the subject.

 The Investigatorshould allow time sufficient for subject or subject’s (LAR) legally acceptablerepresentative to clarify the details of the study decide and then informedconsent must be signed and personally dated by the subject or the subject’slegally acceptable representative and by the person who conducted the informedconsent discussion.

 The subject orlegally acceptable representative should receive a copy of the signed informedconsent and any other written information provided to study subjects prior tosubject’s participation in the trial.

       If the subject or LARis unable to read, a reliable and impartial witness should be present duringthe entire informed consent discussion. The choice of the witness must notbreach the subject’s rights to confidentiality. A reliable independent witnessis defined as one not affiliated with the institution or engaged in theinvestigation. A family member or acquaintance is appropriate independentwitnesses.

 The informed consentand any other information provided to subjects or the subject’s LAR, should berevised whenever important new information becomes available that is relevantto the subject’s consent, and should receive IRB/IEC approval/favorable opinionprior to use.

11.0CONFIDENTIALITY11.1****Confidentiality of dataBy signing this protocol,the investigator affirms that information provided to the investigator(s) willbe maintained in confidence and such information will be divulged to theIRB/IEC or other regulatory authorities, or similar or expert committee;affiliated institution; and employees only under an appropriate understandingof confidentiality with such board or committee, affiliated institution andemployees. Data generated by this study will be considered confidential by theinvestigator, except to the extent that it is included in a publication asprovided in Publications.

11.2****Confidentiality of subjectrecordsBy signing thisprotocol, the investigator agrees that the IRB/IEC or regulatory agencyrepresentatives may consult and/or copy study documents in order to verify data.By signing the consent form, the subject agrees to this process. If studydocuments will be photocopied during the process of verifying information, thesubject will be identified by unique code and initials; full names will bemasked prior to transmission to all the participating investigators, IRB/IEC orregulatory agency.

12.0****PREMATURE TERMINATION OR SUSPENSIONOF THE TRIAL If a trial isprematurely terminated or suspended, the investigator should promptly informthe Ethics committee of the termination or suspension and the reason (s) forthe termination or suspension. The IRB/IEC should also be informed promptly andprovide the reason(s) for the termination or suspension by theinvestigator/institution, as specified by the applicable regulatory requirement(s).

 The investigator willconduct the study in compliance with the protocol and complete the study withinthe timeframe specified in the contract. Continuation of this study beyond thisdate must be mutually agreed upon in writing by all the participatinginvestigators.

  13.0****STUDY COMPLETION AND ARCHIVAL The investigator willconduct the study in compliance with the protocol and complete the study withinthe timeframe specified and agreed upon by all the participating investigators.Continuation of this study beyond this date must be mutually agreed upon inwriting by all the participating investigators. The investigator will provide afinal report to the IEC/IRB following conclusion of the study.

 It is theresponsibility of the Investigator to maintain a comprehensive and centralizedfiling system of all relevant documentation. The CRO will ensure thatappropriate training is given to the study site personnel and any newinformation relevant to the performance of this study will be forwarded to thestaff involved.

 Copies of allpertinent records will be retained by the Investigator for at least 5 years.These records include documents pertaining to IRB/IEC, informed consent, sourcedocuments, as well as eCRFs. No documents shall be transferred from the site ordestroyed without first notifying the participating investigators. If theInvestigator withdraws from the study, the records shall be transferred to amutually agreed upon designee. Notice of such transfer will be given in writingto all the participating investigators if the investigator is not able toretain the records, he/she must notify all the participating investigators toarrange alternative archiving options.

14.0****PUBLICATION POLICY All informationsupplied by the investigator in connection with this study and not previouslypublished, is considered confidential information. This information includes,but is not limited to, data, materials (i.e., the clinical protocol, CRFs),equipment, experience (whether of a scientific, technical, engineering,operational or commercial nature), designs, specifications, know-how, productuses, processes, formulae, costs, financial data, marketing plans and directselling systems, customer lists and technical and commercial informationrelating to customers or business projections used by the investigators in itsbusiness. Any data, inventions or discoveries collected or developed, as aresult of this study is considered confidential. This confidential informationshall remain the sole property of all the participating investigators, shallnot be disclosed to any unauthorized person or used in any unauthorized mannerwithout written consent of all the participating investigators and shall not beused except in the performance of the study.

 No publication ordisclosure of study results will be permitted, except under the terms andconditions of a separate, written agreement between the investigator and / orthe investigator’s institution.

 The investigator musthave the opportunity to review and approve all proposed abstracts, manuscripts,or presentations regarding this study sixty (60) days prior to submission forpublication/presentation. Any information identified by the investigator asconfidential must be deleted prior to submission.