Indian Trial of Tranexamic Acid in Spontaneous Intracerebral Haemorrhage

Indian Council of Medical Research, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Postgraduate Institute of Medical Education and Research, Chandigarh, St. Stephen's Hospital, Delhi, All India Institute of Medical Sciences, New Delhi, Amrita Institute of Medical Sciences & Research Center, Kasturba Medical College Manipal, India, Institute of Neurosciences Kolkata, Bangur Institute of Neurosciences Kolkata, India, Guwahati Neurological Research Center, Guwahati, India, Baptist Christian Hospital, Tezpur, India, National Institute of Mental Health and Neuro Sciences, India, Jawaharlal Institute of Postgraduate Medical Education & Research, Christian Medical College, Vellore, India, CARE Hospitals Hyderabad, India, Lalitha Super Specialities Hospital Guntur, India, Dr. Ramesh Cardiac and Multispeciality Hospital Guntur, India, Government General Hospital Guntur, India, Fortis Escorts Hospital Jaipur, India, Institute of Medical Sciences of the Banaras Hindu University (BHU),India, Atal Institute of Medical Super Specilities, (AIMSS) Chamiana, Shimla, All India Institute of Medical Sciences, Bhubaneswar, KLEs Dr. Prabhakar Kore Hospital & Medical Research Centre Balgaum, India, Guru Gobind Singh Medical College & Hospital, PBM Hospital Bikaner, India, Shree Krishna Hospital Pramukhswami Medical College Anand, India, Apollo Excelcare Hospitals Guwahati, India, Manipal Hospital Bangalore, India, Artemis Hospital Gurgaon, India, Dr. Kamakshi Memorial Hospital Chennai, India, Bharati Vidyapeeth DTU Medical College Pune, India, Aster MIMS Hospital Calicut, India, Holy Spirit Hospital Mumbai, India, Sparsh Superspeciality Hospital Bangalore, India, All India Institute of Medical Sciences, Bilaspur, India, King George's Medical University, Assam Medical College, KG Hospital and Post Graduate Medical Institute Coimbatore, India, Tirunelveli Medical College, Tirunelveli, India, Santokba Durlabhji Memorial Hospital, Tezpur Medical College and Hospital, Assam, India, Baby Memorial Hospital Calicut, India, Institute of Human Behaviour and Allied Sciences Delhi, India, The Calcutta Medical Research Institute, Fortis Hospital Mulund Mumbai, India, Government Medical College Trivandrum, India, Ruby Hall Clinic, Pune, India, Manipal Hospital Goa, India

This multicenter, pragmatic randomized, open-label clinical trial aims to assess whether Tranexamic Acid improves outcomes in adult patients with spontaneous intracerebral haemorrhage. The participants presenting within 4.5 hours of the onset of symptoms of stroke with intracerebral haemorrhage confirmed on Computed Tomography (CT Scan) will be randomized into two groups in a 1:1 ratio using a central online randomization. The treatment arm will consist of giving intravenously 2 grams of Tranexamic Acid in 100 ml 0.9% sodium chloride administered over 45 minutes. Control arm patients will receive standard of care treatment as per the institutional protocol. In both arms, intensive systolic blood pressure reduction to less than 140 mmHg will be done using antihypertensive medications, which has to be achieved within one hour and will be maintained over next seven days. The choice of antihypertensive drug will depend on the clinician's preference. Both groups will have a repeat CT scan after 24 hours to check for any increase in the haematoma volume. Any deterioration in the neurological status will warrant urgent brain imaging. On day 7, the patient will be assessed for their NIHSS score and mRS score. On day 90, quality of life and the functional outcome will be assessed.

Global Burden of Disease, Injury and Risk factors for hemorrhagic stroke 2010 estimated the burden of spontaneous intracranial haemorrhage (sICH) in India is profound (32 -49%) and it is associated with high mortality (up to 63 %) due to haematoma expansion which occurs in 38% of ICH within first few hours of presentation. Early administration of haemostatic drugs has been used in patients with trauma and was associated with improved outcomes. Similarly, if haemostatic drugs are administered early, which can be a simple and cost-effective intervention, may improve the functional outcomes in patients with sICH. Recently, the TICH 2 trial, which was done to see the effectiveness of the administration of tranexamic acid on hematoma expansion and functional outcomes at three months in patients who presented with sICH within 8 hours of presentation of symptoms onset, showed a decrease in haematoma expansion but no improvement in functional outcome at 90 days. Further larger randomized control trials are required to ascertain the effect of early administration of TXA in sICH. In India patients present to hospitals in the early stages that have developed symptoms after sICH and we propose to study the effect of intravenous Tranexamic Acid for hyperacute primary intracerebral haemorrhage within 4.5 hours of sICH. Trial Population: This multi-centric study will be conducted at 50 stroke centres in India associated with the INSTRuCT Network. All patients presenting with symptoms of stroke to the hospital and admitted to the stroke units will be screened for eligibility and if met, will be included in the study. The INTRINSIC trial intends to recruit 3400 patients. Trial Design: INTRINSIC Trial will be a multicenter, randomized, open-label, clinical trial. The participants will be randomized into two groups in a 1:1 ratio using a central database of INSTRuCT central online randomization. The baseline characteristics will be adjusted to stroke severity using the NIHSS score and the volume of haematoma. The treatment arm will consist of giving intravenously 2 grams of Tranexamic Acid in 100 ml sodium chloride 0.9 % administered over 45 minutes. Control arm patients will receive standard of care management as per the institutional protocol. Both groups will have a repeat CT scan after 24 hours to check for any increase in the haematoma volume. Any deterioration in the GCS will warrant urgent brain CT scans. Antihypertensive drugs used and their doses to control BP will be recorded for up to 7 days. On day 7, the patient will be assessed for their NIHSS score and mRS score. On day 90, quality of life and the functional outcome will be assessed. The need for this study: The proportion of ICH is high in India and other LMIC's, particularly in Asia. Currently, there are no effective treatments available for sICH. Moreover, Tranexamic Acid is cheap, easily available and easy to administer.

The treatment arm will consist of giving intravenously 2 grams of Tranexamic Acid in 100 ml sodium chloride 0.9 % adminsitered over 45 minutes. Intensive systolic blood pressure reduction to less than 140 mmHg will be done using antihypertensive agents (intravenous and/or oral) which is to be achieved within one hour and has to be maintained over seven days. BP monitoring is done for every 15 minutes in the first hour and thereafter every hour for the next six hours after the initiation of intensive BP control. The choice of antihypertensive will depend on the clinician's preference.

The control arm will receive a standard of care management as per the institutional practice. Intensive systolic blood pressure reduction to less than 140 mmHg will be done using antihypertensive (intravenous and/or oral) which is to be achieved within one hour and has to be maintained over seven days. BP monitoring is done for every 15 minutes in the first hour and thereafter every hour for the next six hours after the initiation of intensive BP control. The choice of antihypertensive will depend on the clinician's preference.

Injection Pause 500 mg/5 ml, Injection Cyklokapron 500 mg/5 ml, Injection Trapic 500 mg/5 ml, Injection Tramix 500 mg/5 ml

The treatment arm will consist of giving intravenously 2 grams of Tranexamic Acid in 100 ml sodium chloride 0.9 % administered over 45 minutes.

Radiological (CT scan): Change in hematoma volume from baseline to 24 hours scan, hematoma location and new infraction

Inclusion Criteria: Adult patients aged more than 18 years, presenting with non- traumatic intracerebral haemorrhage within 4.5 hours of onset of stroke symptoms Exclusion Criteria: Patients with intracerebral haemorrhage secondary to anticoagulation, thrombolysis, known underlying structural abnormality such as arteriovenous malformation, aneurysm, tumour or venous thrombosis or due to known hereditary coagulation disorders. An underlying structural abnormality does not need to be excluded before enrolment, but where known, patients should not be recruited. Known allergies to Tranexamic Acid. Premorbid modified Rankin scale score >4 at the time of enrollment. Concurrent participation in another drug or device trial. Pre stroke life expectancy <3 months (e.g. advanced metastatic cancer). Glasgow coma scale <7. ICH secondary to trauma. Women pregnant, or breastfeeding at randomization. Planned surgery for ICH within 24 hours. Concurrent or planned treatment with any other haemostatic agents. ICH volume > 60 ml as measured by the ABC/2 method on CT Scan

All information collected from medical records for the study will be stored electronically in a specifically designed database at the Christian Medical College and Hospital, Ludhiana. Participants information will be identified only by their initials and a study registration number. Any information transferred electronically will be coded to protect confidentiality. All computer records will be password protected. The study results may be presented at conferences or in scientific publications, but individual participants will not be identifiable. If needed, data will be available in future for other researchers outside the primary research group for secondary purposes, such as meta-analyses, reanalysis, or replication of results.

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