A Trial Using Double-Bolus THR-100 Versus Streptokinase

STUDY SUMMARY/PROTOCOL OUTLINE

Protocol Number: BBIL/STA/O5/2007 Protocol Name: A PROSPECTIVE PHASE III PARALLEL, RANDOMISED CONTROLLED TRIAL USING DOUBLE-BOLUS THR-100 (RECOMBINANT STAPHYLOKINASE) Vs STREPTOKINASE IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION

Drug under Study: THR-100 (Recombinant Staphylokinase)

Intended Indication: Acute Myocardial Infarction

Study Design: Randomized, Parallel Group, Multicenter and Active-Comparator Trial.

Patient Population: Patients aged 30 to ≤ 75 years presenting with acute myocardial infarction within 12 hours of onset of symptoms presumed secondary to an acute myocardial infarction.

Number of Patients: 120 subjects are to be recruited into the trial, with patients randomized in a 1:1 allocation ratio to THR-100 and Streptokinase over three centers. This sample size of 120 subjects provides power of 0.90 with a significance level of 0.05 to yield a statistically significant early patency difference.

Primary Objectives: To demonstrate efficacy of THR100 as compared with streptokinase by assessment of 12-lead Electrocardiogram, specific cardiac Enzymes levels, pain relief and TIMI-90. (Non-Inferiority study) Secondary Objectives: To evaluate the safety profile of recombinant SAK in comparison with Streptokinase.

Dose Levels: Dose levels (all administered intravenously). THR-100: 15 mg double-bolus (15mg/15ml), separated by 30 minutes (total 30 mg) Streptokinase: Standard regimen (1.5 million IU) is made up in 150 ml of physiological saline or glucose solution and administered intravenously over a period of 60 minutes.

Study Parameters: Primary endpoint:

• 12-lead Electrocardiogram, ≥50% resolution of ST segment in single ECG lead of maximum deviation present at 90 minutes and 24 hours after start of thrombolytic therapy.
• Changes in cardiac Enzyme levels of CK-MB and Cardiac Troponin I or T at 6 hrs, 8 hrs, 12-16 hrs and 24 hours after start of thrombolytic therapy.
• Significant Relief of pain (a 3 point reduction on a 0-5 subjective scale) at end of 2 and 12 hrs after start of thrombolytic therapy. (0-No pain, 1-Slight pain, 2-Mild pain, 3-Moderate pain, 4- Severe pain, 5-Very severe pain).
• Assessment of culprit coronary vessel patency (TIMI- grade 3) at 90 minutes. (TIMI- Thrombolysis in myocardial infarction). Angiography shall be performed only in patients who fulfil the following guidelines

• No WPW or LBBB or IV-conduction block or Pacemaker rhythm. 2. ≥0.2 mV ST elevation in ≥2 leads V1-V6 and ≥0.3 mV ST elevation in ≥1 lead V1-V6 3. Sum of ST elevation in V1-V6 plus Sum of ST depression in II, III, aVF ≥0.8 mV (OR)

• No WPW or LBBB or IV-conduction block or Pacemaker rhythm.
• ≥0.1 mV ST elevation in ≥2 leads II, III,aVF and ≥0.2 mV ST elevation in ≥1 lead II, III, aVF 5). Sum of ST elevation in I-III, aVF plus Sum of ST depression in V1-V4 ≥0.6 mV.

Secondary endpoints:

Assessment of net clinical benefit, defined as reduced mortality, non-fatal stroke, clinically-evident intracranial hemorrhage, or recurrent myocardial infarction at thirty (30) days.

Assessment of the rates of the following in-hospital events as defined in Appendix 1:

• Heart failure,
• In-hospital death,
• Recurrent myocardial infarction,
• Refractory ischemia,
• need for urgent revascularization,
• Major complications (such as cardiogenic shock, major arrhythmias, pericarditis, tamponade, acute hemodynamically severe mitral regurgitation, acute ventricular septal defect),

Safety considerations:

• Stroke,
• Intracranial hemorrhage (see stroke),
• Major bleeding (other than intracranial hemorrhage),
• Bleeding other than major,
• Serious and non-serious adverse events (see Section 14),
• Allergic reactions,
• Laboratory data. Other angiographic end point CTFC (Corrected TIMI Frame Count), if Angiography performed.

Inclusion criteria

• Male or female patients aged 30 to < 75 years inclusive.
• Patients presenting within 12 hours with symptoms presumed secondary to an acute myocardial infarction lasting at least 20 minutes and accompanied by ECG evidence of > 1mm of ST elevation in 2 or more limb leads or > 2mm in 2 or more contiguous precordial leads or suspected new left bundle branch block will be eligible.
• Patients must be in the hospital or the emergency department and able to receive the study medication within 12 hours of onset of symptoms.
• Females of child-bearing age, not using a generally accepted method of contraception must have a negative urine pregnancy test.
• Written informed consent should be sought from the patient prior to inclusion in the study. If unable to do so, informed verbal consent will be obtained. If neither is possible, a legally acceptable representative (relative) should provide written consent.
• NB Verbal or written consent should be followed by written informed consent from the patient at the earliest subsequent opportunity.

Exclusion criteria

• Previous administration of staphylokinase.
• Active bleeding or known hemorrhagic diathesis.
• Any history of stroke, transient ischemic attack, dementia, or structural CNS damage e.g. neoplasm, aneurysm, AV malformation.
• Major surgery or trauma within the past 3 months.
• Significant hypertension i.e. SBP 180 mm Hg and/or DBP 110 mm Hg at any time from admission to randomization.
• Current treatment with vitamin K antagonists resulting with an INR > 1.5.
• Anticipated difficulty with vascular access.
• Prolonged (>10 min) cardiopulmonary resuscitation or cardiogenic shock.
• Patients who have participated in an investigational drug study within the past 30 days.
• Pregnancy or lactation, parturition within the previous 30 days.
• Any serious concomitant systemic or life limiting disorder that would be incompatible with the trial
• Patients known to have a history of or life limiting malignant disease or HIV.
• Significant hepatic or renal dysfunction or any other condition which, in the opinion of the Investigator, makes the patient unsuitable for study entry.
• Previous participation in this trial