Protocol summary
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Study aim
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To compare the Efficacy and Safety of Altelyse (bio-similar Alteplase) versus the brand Actilyse in Acute MI patients with ST elevation
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Design
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This is a randomized, double-blind , parallel groups, multi center, non-inferiority and phase III clinical trial sudy.
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Settings and conduct
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Study will be conducted in five hospitals in Tehran. They are Taleghani, Shohadaye-Tajrish, Loghman, Labafi-Nejad, and Fayazbakhsh hospitals.
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Participants/Inclusion and exclusion criteria
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Patients aged 18 years or older who have had an acute myocardial infarction with ST segment elevation and who either do not have access to Primary Percutaneous Cardiac Intervention (PPCI) or will take more than two hours to receive PPCI treatment, will be potentially eligible for this study. Patient should sign nformed consent form and should not have any contraindication for thrombolytic therapy.
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Intervention groups
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There are two intervention groups in this study. All patients in both groups will receive usual treatments including Aspirin, ADP antagonist, and anti-coagulant therapies. In group 1 thrombolytic therapy patients will receive thrombolytic therapy using Altelyse ( Alteplase made by Arena Hayat Danesh Co) and in group 2 patients will receive Actilyse (Alteplase made by boehringer-ingelheim). Thrombolytic therapy will be delivered by accelerated delivery including one bolus injection plus infusion over the next 1.5 hours.
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Main outcome variables
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Primary outcome in this study is ST resolution (STR) in 90 minutes. Secondary outcomes include complete or partial resolution of ST segment STR in 90 minutes, ST resolution in 180 minutes, all cause mortality in 30 days, cardiovascular mortality in 30 days, all cause in-hospital mortality, Ventricular Ejection Fraction (EF), bleeding following thrombolytic treatment, allergic drug reaction, and Major Adverse Cardiac Events (MACE)
General information
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Reason for update
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clinical trial site update and patient recruitment update
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Acronym
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ARENA
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IRCT registration information
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IRCT registration number:
IRCT20190729044366N1
Registration date:
2019-08-25, 1398/06/03
Registration timing:
prospective
Last update:
2021-10-03, 1400/07/11
Update count:
2
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Registration date
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2019-08-25, 1398/06/03
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Registrant information
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Recruitment status
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Recruitment complete
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Funding source
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Expected recruitment start date
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2021-06-22, 1400/04/01
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Expected recruitment end date
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2022-07-21, 1401/04/30
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Actual recruitment start date
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empty
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Actual recruitment end date
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empty
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Trial completion date
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empty
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Scientific title
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A randomized, double-blind , parallel groups, multi center, non-inferiority and phase III clinical trial to compare the Efficacy and Safety of Altelyse (bio-similar Alteplase) versus the brand Actilyse in Acute MI patients with ST elevation
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Public title
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Comparing the safety and efficacy of Altelyse with Actilyse in acute myocardial infarction
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Purpose
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Treatment
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Inclusion/Exclusion criteria
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Inclusion criteria:
Chest pain compatible with ischemic heart disease for more than 20 minutes
Start of symptoms of Acute Myocardial Infarction (Peak of chest pain) 12 hours (Maximum) before thrombolytic treatment
Signs of Acute Myocardial Infarction in Electrocardiogram: ST elevation of 0.1 mili-volt or more in two adjacent leads other than v2 and v3; ST elevation of 0.25 mili-volt or more in v2 and v3 leads in men younger than 40 years; ST elevation of 0.2 mili-volt or more in v2 and v3 leads in men older than 40 years; ST elevation of 0.15 mili-volt or more in v2 and v3 leads in women irrespective of their age.
Lack of access to cath lab to do PPI, Primary Per-cutaneous Coronary Intervention or expecting a delay more than 2 hours between between first medical contact and performance of first balloon dilatation excluding the time takes from first medical contact till the start of thrombolytic therapy.
Signed informed consent
Age of 18 years or more
Exclusion criteria:
Presence of left bundle block in electrocardiogram
Presence of accompanying severe diseases such as renal failure (GFR<30); hepatic failure; POrtal hypertension; Hepatitis; Thrombocytopaenia; Known pancreatitis (information gathered from first clinical examination upon arrival because of cheat pain
Cardiogenic shock (Systolic pressure less than 90 mm Hg)
Killip class III & IV
Any history of intracranial bleeding or stroke with unknown origin irrespective of the time of occurrence
Ischemic stroke
Known central nervous system lesions, neoplasms (primary or metastatic), arteriovenous malformations
Aortic dissection
Active bleeding or known bleeding disorder (excluding menses)
Major trauma to Head and Neck in the last 3 months
Intracranial or spinal surgery in the last 2 months
Other major trauma or surgery within the preceding month
Gastrointestinal bleeding within the preceding month
Sever uncontrolled hypertension (Resistant to emergency treatment)
Non-compressible punctures in the past 24 hours (e.g. liver biopsy, lumbar puncture)
History of poorly controlled chronic hypertension
Hypertension at the time of eligibility assessment: Systolic BP >180 mm Hg or diastolic BP > 110 mm Hg
Transient ischemic attack in the preceding 6 months
Dementia
Pregnancy or within 1 week postpartum
Internal bleeding within the last 2-4 weeks
Active peptic ulcer
Infectious endocarditis
Cardiopulmonary resuscitation that has caused injury to the chest or lasted more than 10 minutes
Patients who receive anticoagulant therapy such as warfarin
Advanced liver disease
Known intracranial lesions other than those listed as absolute contraindications for thrombolytic therapy
Diabetic Hemorrhagic Retinopathy or other hemorrhagic ophthalmic conditions
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Age
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From 18 years old
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Gender
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Both
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Phase
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3
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Groups that have been masked
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- Participant
- Care provider
- Investigator
- Outcome assessor
- Data and Safety Monitoring Board
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Sample size
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Target sample size:
150
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Randomization (investigator's opinion)
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Randomized
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Randomization description
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We used block randomization stratified by hospitals using variable block size of 4 and 6. A separate chain of randomization sequence will be developed for each hospital. Excel software and rand() function will be used to create the random sequences. Concealment will be carried out and a random code will be assigned to every patient according to the randomization sequence. The codes will be put in sealed envelops and the envelops will be numbered incrementally from 1 according to the randomization sequence. For each eligible patient enrolled to the study an envelop will be opened according to the sequential number. Patients will receive the intervention assigned to them based on the code inside the envelop.
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Blinding (investigator's opinion)
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Double blinded
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Blinding description
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In this study we used secondary packaging of Actilyse and Altlelyse to achieve blinding. The packages will be labelled using the concealment codes. Once the randomization is done, and the thrombolytic treatment package for the patient is known, a separate nurse not in the study team, will be given the responsibility to open the package and prepare the thrombolytic injection. It will then be given to the research team for use.
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Placebo
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Not used
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Assignment
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Parallel
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Other design features
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Acronym ARENA stands for Assessing Re-perfusion Efficacy in Nationally manufactured thrombolytic, Altelyse in AMI
Ethics committees
1
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Ethics committee
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Approval date
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2019-07-21, 1398/04/30
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Ethics committee reference number
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IR.SBMU.REC.1398.025
Health conditions studied
1
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Description of health condition studied
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Acute Myocardial Infarction with ST elevation
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ICD-10 code
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I21.3
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ICD-10 code description
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ST elevation (STEMI) myocardial infarction of unspecified site
Primary outcomes
1
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Description
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Percentage of ST resolution (STR) at 90 minutes
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Timepoint
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90 minutes after start of thrombolytic therapy
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Method of measurement
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To estimate percentage of ST resolution at 90 minutes, we will measure the height of ST elevation at 20 milisecond after J point in those leads that have shown elevation of ST in a 12 lead standard ECG at time points 0 and 90. Sum of ST elevations in all 12 leads at 90 minutes will be deducted from the sum of ST elevations at time 0 to work out the total ST resolution (STR) at 90 minutes. We will then calculate the percentage of ST resolution by dividing total STR at 90 minutes to the sum of ST elevations at time 0. In a second measurement approach, percentage of patients who have had more than 50% resolution in their ECG lead with highest ST elevation will be calculated.
Secondary outcomes
1
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Description
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Complete or partial resolution of ST segment (STR) in 90 minutes
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Timepoint
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90 Minutes after thrombolytic therapy
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Method of measurement
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Complete resolution is defined as 70% resolution in sum of ST elevations and partial resolution is defined as 30 to 70% resolution in sum of ST elevations. Method of calculation of STR is the same as the primary outcome.
2
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Description
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Percentage of ST resolution (STR) at 180 minutes
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Timepoint
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180 Minutes after thrombolytic therapy
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Method of measurement
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To estimate percentage of ST resolution at 180 minutes, we will measure the height of ST elevation at 20 milisecond after J point in those leads that have shown elevation of ST in a 12 lead standard ECG at time points 0 and 180. Sum of ST elevations in all 12 leads at 180 minutes will be deducted from the sum of ST elevations at time 0 to work out the total ST resolution (STR) at 180 minutes. We will then calculate the percentage of ST resolution by dividing total STR at 180 minutes to the sum of ST elevations at time 0.
3
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Description
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All cause mortality in 30 days
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Timepoint
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30 days after intervention
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Method of measurement
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All deaths irrespective of the cause of death in the first 30 days following thrombolytic therapy starting from the First Medical Contact (FMC) will be counted
4
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Description
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Cardiovascular mortality in 30 days
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Timepoint
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30 days after intervention
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Method of measurement
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All cardiovascular deaths in the first 30 days following thrombolytic therapy starting from the First Medical Contact (FMC) will be counted
5
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Description
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In-hospital mortality due to any cause
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Timepoint
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Up until discharge from hospital
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Method of measurement
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All deaths irrespective of their cause up until discharge from hospital will be counted
6
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Description
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Ventricular Ejection Fraction
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Timepoint
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2 to 5 days following thrombolytic therapy
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Method of measurement
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Echocardiography
7
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Description
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Bleeding
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Timepoint
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After thrombolytic therapy
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Method of measurement
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All episodes of major and minor bleeding following thrombolytic therapy will be recorded and categorized in three groups according to GUSTO 5 criteria. Severe or life threatening bleeding: Intracranial bleeding and any other bleeding that cause severe haemodynamic instability for the patient. Moderate bleeding: patient will need blood transfusion. Mild bleeding: all other bleeding
8
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Description
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Allergic drug reaction
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Timepoint
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After thrombolytic therapy
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Method of measurement
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Allergic skin reactions at the injection site and systemic reactions including anaphylactic shock, Angioedema, Urticaria, and drop in systolic blood pressure to 90 mmHg or lower, will be identified and recorded.
9
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Description
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MACE (Major Adverse Cardiac Events)
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Timepoint
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After thrombolytic therapy
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Method of measurement
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Any of the following adverse cardiac events will be counted: Death, Bleeding GUSTO type I and II, Cerebrovascular Accident (CVA)
Intervention groups
1
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Description
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Intervention group 1: This group will receive thrombolytic therapy using Altelyse ( Alteplase made by Arena Hayat Danesh Co). People weighing more than 67kg will receive 15 mg bolus, 50 mg in the first 30 minutes and 35 mg within the next 60 minutes. People weighing 67kg or less will receive 15 mg bolus, 0.75 mg/kg in the first 30 minutes and 0.5 mg/kg within the next 60 minutes. All patients in the intervention groups 1 and 2 will receive Aspirin, ADP receptor antagonists and Anticoagulant therapy. Aspirin therapy: All patients who are not on Aspirin will receive 300-325 mg Aspirin in the emergency room. ADP receptor antagonist therapy: People not on clopidogrel and 75 years old or less will receive 300 mg clopidogrel loading dose and then 75mg daily. People not on clopidogrel and older than 75 years will only receive the daily dose without the loading dose. Anticoagulant therapy: All patients will receive one bolus injection of Unfractionated heparin 60 unit per kg (maximum 4000 units) followed by 12u/kg (maximum 1000 units) per hour until PTT reaches to 1.5 to 2 times normal (50-70 seconds) and stays at that level. Beta blockers, Angiotensin Enzyme inhibitors (ACE/ARB receptor inhibitors/blockers) and Statins will be given according to the existing guidelines.
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Category
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Treatment - Drugs
2
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Description
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Intervention group 2: This group will receive thrombolytic therapy using Actilyse. People weighing more than 67kg will receive 15 mg bolus, 50 mg in the first 30 minutes and 35 mg within the next 60 minutes. People weighing 67kg or less will receive 15 mg bolus, 0.75 mg/kg in the first 30 minutes and 0.5 mg/kg within the next 60 minutes. All patients in the intervention groups 1 and 2 will receive Aspirin, ADP receptor antagonists and Anticoagulant therapy. Aspirin therapy: All patients who are not on Aspirin will receive 300-325 mg Aspirin in the emergency room. ADP receptor antagonist therapy: People not on clopidogrel and 75 years old or less will receive 300 mg clopidogrel loading dose and then 75mg daily. People not on clopidogrel and older than 75 years will only receive the daily dose without the loading dose. Anticoagulant therapy: All patients will receive one bolus injection of Unfractionated heparin 60 unit per kg (maximum 4000 units) followed by 12u/kg (maximum 1000 units) per hour until PTT reaches to 1.5 to 2 times normal (50-70 seconds) and stays at that level. Beta blockers, Angiotensin Enzyme inhibitors (ACE/ARB receptor inhibitors/blockers) and Statins will be given according to the existing guidelines.
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Category
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Treatment - Drugs
1
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Sponsor
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Grant name
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Grant code / Reference number
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Is the source of funding the same sponsor organization/entity?
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Yes
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Title of funding source
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Arena Life Science Company
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Proportion provided by this source
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100
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Public or private sector
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Private
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Domestic or foreign origin
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Domestic
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Category of foreign source of funding
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empty
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Country of origin
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Type of organization providing the funding
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Industry
Sharing plan
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Deidentified Individual Participant Data Set (IPD)
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Yes - There is a plan to make this available
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Study Protocol
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Yes - There is a plan to make this available
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Statistical Analysis Plan
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Undecided - It is not yet known if there will be a plan to make this available
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Informed Consent Form
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Yes - There is a plan to make this available
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Clinical Study Report
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Yes - There is a plan to make this available
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Analytic Code
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Undecided - It is not yet known if there will be a plan to make this available
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Data Dictionary
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Not applicable
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Title and more details about the data/document
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These includes identified individual participant data on primary and secondary outcomes, study protocol, informed consent form and clinical study report
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When the data will become available and for how long
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Data will be available one year after study completion or publication of the main results whichever comes later
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To whom data/document is available
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Data will only be available to academic researchers at the universities
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Under which criteria data/document could be used
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Data will only be shared for the purpose of meta-analysis
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From where data/document is obtainable
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You can contact Ms Hoda Shojaei at Arenalifesciences Co
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What processes are involved for a request to access data/document
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Medical Director of the Arenlifesciece co should make sure that the condition for sharing data is met and should approve it
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Comments
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none