1.0               INTRODUCTION

1.1                 Background Information and Rationale

This study aims to identify NSTEMI patients with total and non-total occlusion and correlate their ECG, Echocardiogram, Angiographic parameters and their clinical outcomes.  The patients who have an acute chest pain and cardiomyocyte necrosis as evidenced by troponin elevation are labelled as NSTEMI. These individuals may present with ongoing ischemia, electrical or hemodynamic instability and require angiography and appropriate revascularization at the earliest. The clinical presentation depends on the severity of coronary stenosis and the degree of thrombus. TIMI risk score is easy to use in day to day clinical practice and can be accessed at www.timi.org. A low TIMI score indicates intermediate or high risk.

1.2                 Rationale

1.3                 Potential Benefits

As this is an observational study, there is no direct benefit from this study for the patient. However all patients enrolled in this study will be followed up until the completion of this study. Furthermore, this study will be of help to the community by contributing to medical research.

2.0               OBJECTIVES

2.1                        Primary Objective

To assess the Electro and Echocardiogram, angiographic parameters, In hospital and one year  clinical outcomes of patients with occlusive NSTEMI Versus Non occlusive NSTEMI. 

2.2                      Secondary Objective

The secondary objective of this study is to evaluate the time delays, blood parameters, cardiac  biomarkers and adverse events in both the group.

3.0               ENDPOINTS

3.1                 Primary Endpoint

      MACE

     Left Ventricular Ejection Fraction (LVEF)

3.2       Secondary Endpoint

Death

Stroke

     Readmission

     48 hours Troponin

     Reinfarction

     Target Lesion Failure (TLF)

     Bleeding

4.0               STUDY POPULATION

In this study, approximately 1,000 patients multicentre of either sex, aged 18 and above years with acute NSTEMI.

4.1 Subject selection

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

4.1                  Inclusion Criteria

All patients presenting with angina or ECG features and raised Troponin levels suggestive of NSTEMI are included.

4.2                 Exclusion Criteria

Patients presenting with diagnosis other than NSTEMI.

5.0               STUDY DESIGN           

This study will be a prospective, observational study conducted upto 10 centers in patients with NSTEMI of total occlusion and Non total occlusion. Patient’s demographic, clinical, electrocardiographic parameters are noted on admission. All patients included in the study undergo immediate transthoracic echocardiographic examination at emergency department. Timing of intervention and 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-fatal MI, target vessel revascularization and death) are noted during hospital stay and 1 year follow up.

5.1.     Study Procedures

5.1.1         Screening /Baseline

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

Patients in the age group of 18 and above will be provided with the IEC/IRB approved written informed consent document. Informed Consent Document should be signed by the patient / LAR before baseline or screening procedures

The following parameters will be collected:

1.   A list of presenting complaints

2.   Demographic details: The demographic details of the patient such as age (in years), height (in centimeters), weight (in kilograms), and gender (male or female) will be collected.

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

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

5.   Electrocardiogram (ECG)

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

7.      To enable quick assessment and uniform reporting following echocardiogram 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 ventricular endocardial wall thickness (None/Thin/Mild/Moderate/Severe)

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

12.  Right ventricular ejection fraction - TAPSE

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

14.  Possible coronary artery disease territory – Left anterior descending artery (LAD), Left circumflex 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 blood sugar, Lipid profile, Blood urea, serum creatinine,  Sodium, Potassium

17.  Cardiac markers including Creatine Phosphokinase 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 following enrollment

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

5.1.3              1 year  from the day of enrollment

The following information will be collected during 1 year from the day of enrollment if available or the patients will be contacted telephonically to assess their health status:

·                     MACE

·                     DEATH

·                     LV function

·                     Target Lesion Revascularization (TLR)

6.0                SAFETY

The investigator will assess and record any adverse event, reportable events in detail including the date of onset, event diagnosis (if known) or sign/symptom, severity, time course, duration and outcome, relationship of the adverse event to the treatment/procedure and any action(s) taken. 

6.1                 Definitions

An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product .This includes the following:

§ Any clinically significant worsening of a pre-existing condition.

§ Any reoccurrence of a pre-existing condition.

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

An AE is considered to be treatment emergent if

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

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

Serious Adverse Events

Serious adverse events like Death, Life-threatening condition and persistent or significant disability or incapacity will be reported to the ethics committee and all participating investigators.

Death of Subject: An event that results in the death of a subject.

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

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

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

Significant expected Adverse Events may involve:

·               Intracranial haemorrhage or significant bleeding

·               Recurrent myocardial infarction

·               Death

·               Restenosis

All AEs will be entered on spreadsheets.    

The following AE information must be included (when applicable):

The specific condition or event; whether the condition was pre-existing (i.e. an acute condition 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); the dates and times of occurrence; severity; action taken; and outcome. Laboratory abnormalities found to be of clinical significance may be reported as AEs.

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

The causal 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 to accidental fall

7.0               STATISTICAL CONSIDERATIONS

7.1                  Study Hypothesis

The aim is to evaluate the clinical and angiographic outcomes of patients with occlusive Non-ST elevation myocardial infarction (NSTEMI) as compared to Non-occlusive NSTEMI undergoing percutaneous coronary intervention (PCI)      

7.2                    Sample Size

A sample size of 1,000 patients multicentric is considered sufficient to provide the basis for future pivotal study.

7.3                                Analysis Populations

No of patients enrolled for 1 year in both arms together. Estimated around 1000 patients

7.4                                Demographic and 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’s discretion. The timing of revascularization and angiographic details are noted. Patients major cardiovascular events (non-fatal MI, target vessel revascularization and death) are noted during hospital stay and 1 year follow up. The patient’s inclusion to the Per-Protocol and Safety Population will also be summarized. All demographic data will be listed.

7.5                        Safety Review

Safety analysis will be performed on the Safety population. Safety and tolerability will be assessed in terms of adverse events, laboratory data, vital sign data, which will be collected for all patients. Appropriate summaries of these data will be presented. Concomitant medications will be tabulated by patient with drug category and preferred term.

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

7.6                 Final Analysis Plan

    Detailed methodology for summary and statistical analyses of the data collected in this   

    observational study will be documented.

8.0       Source Documents and Access to Source Data/Documents

All source documents will be stored in their respective sites.  Access to source data if necessary at the time of data analysis or any query clarification it can be done by the respective sites.

8.1        Source Documents and Spreadsheets Completion

Original source document data will be entered and the same will be complete in Spreadsheets. 

8.1.1     Source Documents

Source documents are defined as original documents, data and records.  This may include hospital records, clinical charts, laboratory data, and recorded data from automated instruments and/or x-rays.  Data collected during this study must be recorded on the spreadsheets.

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

Data will be collected from the patients’ file regarding all the tests and procedures that were performed to assess their condition.

8.0         

8.1         

8.1.1         

8.1.2        Access to Source Data/Documents

As required by the ICH GCP guidelines and regulatory authorities the investigator will allow direct access to all pertinent medical records in order to allow for the verification of data gathered in the spreadsheets and for the review of the data collection process. The records, including source documentation, must also be available for inspection by relevant regulatory health authorities.

8.1.3           Spreadsheet

Spreadsheet (Excel) must be completed for each subject screened/enrolled in this study.  The spreadsheet data for this study will be collected and same will be validated for the study-specific.

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

The investigator or an authorized member of the investigator’s site will make any necessary corrections to the spreadsheet before sending it to The Madras Medical Mission. 

9.0                 Quality Control and Quality Assurance

By signing this protocol, the investigator agrees to be responsible for ensuring that a quality control and quality assurance systems with written standard operating procedures (SOP) will be in place to ensure that the study will be conducted and data will be generated, documented, and reported in compliance with the protocol, accepted standards of Good Clinical Practice, and all applicable local laws, rules and regulations relating to the conduct of the clinical study.

10.0          Ethical Conduct of the Study

This study will be conducted in accordance with the ethical principles that have their origin in the current Declaration of Helsinki with ethics approval and will be consistent with ICH GCP and applicable regulatory requirements. The study will be registered under CTRI. The study will be conducted in compliance with the protocol.

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

GCP requires that the clinical protocol, any protocol amendments, the informed consent and all other forms of subject information related to the study (e.g., advertisements used to recruit 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 is conducted.  IEC/IRB approval of the protocol, informed consent and subject information and/or advertising, as relevant, will be obtained prior to the start of the study.

Any amendments to the protocol will require IEC/IRB approval prior to implementation of any changes made to the study design.  The investigator will be required to submit, maintain and archive study essential documents for 5 years.

10.1             Informed Consent

Obtaining consent is the responsibility of the Investigator. Prior to the beginning of the study, the Investigator must have the IEC/ IRB written approval of the written informed consent form and any other information to be provided to the patients.

The investigator must provide the subject or legally acceptable representative (if applicable) with a copy of the consent form and written information about the study in the language in which the subject is most proficient. The language must be non-technical and easily understood by the subject.

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

The subject or legally acceptable representative should receive a copy of the signed informed consent and any other written information provided to study subjects prior to subject’s participation in the trial.

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

The informed consent and any other information provided to subjects or the subject’s LAR, should be revised whenever important new information becomes available that is relevant to the subject’s consent, and should receive IRB/IEC approval/favorable opinion prior to use.

11.0          CONFIDENTIALITY

11.1              Confidentiality of data

By signing this protocol, the investigator affirms that information provided to the investigator(s) will be maintained in confidence and such information will be divulged to the IRB/IEC or other regulatory authorities, or similar or expert committee; affiliated institution; and employees only under an appropriate understanding of confidentiality with such board or committee, affiliated institution and employees. Data generated by this study will be considered confidential by the investigator, except to the extent that it is included in a publication as provided in Publications.

11.2              Confidentiality of subject records

By signing this protocol, the investigator agrees that the IRB/IEC or regulatory agency representatives may consult and/or copy study documents in order to verify data. By signing the consent form, the subject agrees to this process. If study documents will be photocopied during the process of verifying information, the subject will be identified by unique code and initials; full names will be masked prior to transmission to all the participating investigators, IRB/IEC or regulatory agency.

12.0          PREMATURE TERMINATION OR SUSPENSION OF THE TRIAL

If a trial is prematurely terminated or suspended, the investigator should promptly inform the Ethics committee of the termination or suspension and the reason (s) for the termination or suspension. The IRB/IEC should also be informed promptly and provide the reason(s) for the termination or suspension by the investigator/institution, as specified by the applicable regulatory requirement(s).

The investigator will conduct the study in compliance with the protocol and complete the study within the timeframe specified in the contract. Continuation of this study beyond this date must be mutually agreed upon in writing by all the participating investigators. 

13.0          STUDY COMPLETION AND ARCHIVAL

The investigator will conduct the study in compliance with the protocol and complete the study within the timeframe specified and agreed upon by all the participating investigators. Continuation of this study beyond this date must be mutually agreed upon in writing by all the participating investigators. The investigator will provide a final report to the IEC/IRB following conclusion of the study.

It is the responsibility of the Investigator to maintain a comprehensive and centralized filing system of all relevant documentation. The CRO will ensure that appropriate training is given to the study site personnel and any new information relevant to the performance of this study will be forwarded to the staff involved.

Copies of all pertinent records will be retained by the Investigator for at least 5 years. These records include documents pertaining to IRB/IEC, informed consent, source documents, as well as eCRFs. No documents shall be transferred from the site or destroyed without first notifying the participating investigators. If the Investigator withdraws from the study, the records shall be transferred to a mutually agreed upon designee. Notice of such transfer will be given in writing to all the participating investigators if the investigator is not able to retain the records, he/she must notify all the participating investigators to arrange alternative archiving options.

14.0          PUBLICATION POLICY

All information supplied by the investigator in connection with this study and not previously published, 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, product uses, processes, formulae, costs, financial data, marketing plans and direct selling systems, customer lists and technical and commercial information relating to customers or business projections used by the investigators in its business. Any data, inventions or discoveries collected or developed, as a result of this study is considered confidential. This confidential information shall remain the sole property of all the participating investigators, shall not be disclosed to any unauthorized person or used in any unauthorized manner without written consent of all the participating investigators and shall not be used except in the performance of the study.

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

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