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OPTIMAS: OPtimal TIMing of Anticoagulation After Acute Ischaemic Stroke : a Randomised Controlled Trial (OPTIMAS)

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ClinicalTrials.gov Identifier: NCT03759938
Recruitment Status : Recruiting
First Posted : November 30, 2018
Last Update Posted : November 9, 2020
Sponsor:
Information provided by (Responsible Party):
University College, London

Brief Summary:
OPTIMAS is a large, prospective, partially blinded randomised controlled trial of early (within ≤4 days [96hrs]) or standard (between day 7 and day 14 after stroke onset) initiation of anticoagulation after stroke in patients with atrial fibrillation (AF), using any licensed dose of a direct oral anticoagulant (DOAC). The trial will use a non-inferiority gatekeeper approach to test for non-inferiority of early anticoagulation followed by a test for superiority, if non-inferiority is established.

Condition or disease Intervention/treatment Phase
Stroke, Acute Atrial Fibrillation Drug: Direct oral anticoagulant (DOAC) Not Applicable

Detailed Description:

Current guidelines do not provide clear recommendations on the timing of OAC after acute AF-related stroke. Current United Kingdom (UK) guidelines for anticoagulation state that "delay for an arbitrary 2-week period is recommended" for "disabling" stroke and that anticoagulation can be started "no later than 14 days" for other strokes, at the prescriber's discretion.

OPTIMAS will investigate whether early initiation of DOAC treatment, within 4 days (96hrs) of onset, in patients with acute ischaemic stroke and AF is as effective as, or better than, standard initiation of DOAC treatment, no sooner than day 7 (>144hrs) and no later than day 14 (<336hrs) after onset, in preventing recurrent ischaemic stroke, systemic embolism and symptomatic intracranial haemorrhage (sICH)? Participants will be randomised 1:1 to the intervention or control. The exact timing of initiating treatment within each group is at the discretion of the treating clinician.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 3478 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Patients will be randomised in a 1:1 ratio to intervention or control arms of the study. Participants and their physicians will not be blinded to study arm allocation.The exact timing of anticoagulation within the period specified for the allocated study arm is at the discretion of the treating physician, as is the choice of DOAC. Apart from the timing of DOAC initiation, the DOAC should be prescribed in accordance with usual clinical practice
Masking: Single (Outcomes Assessor)
Masking Description:

The Event Adjudication Committee is a study group (of at least three members) responsible for the review of clinical events to ensure consistent, standardized, objective and unbiased results throughout all participating sites and minimise the likelihood of discrepant interpretations.

This group consists of a panel of experts who have the relevant therapeutic area expertise, are experienced in clinical trials, and have been trained on the specific study protocol.

The Event Adjudication Committee will centrally review events reported using all available clinical and imaging data and evaluate efficacy and/ or safety endpoints in a blinded and unbiased manner on a regular basis to ensure accurate, consistent and standardized assessments of important study events such as recurrent symptomatic ischaemic stroke, systemic embolism and death.

Primary Purpose: Treatment
Official Title: OPtimal TIMing of Anticoagulation After Acute Ischaemic Stroke: a Randomised Controlled Trial
Actual Study Start Date : June 18, 2019
Estimated Primary Completion Date : September 30, 2022
Estimated Study Completion Date : September 30, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Early initiation of DOAC
Early initiation of any direct oral anticoagulant (DOAC) at a dose licensed for stroke prevention in AF, within four days (96hrs) of onset of acute ischaemic stroke
Drug: Direct oral anticoagulant (DOAC)
Any of the DOACs listed above may be used for treatment in either study arm. The DOAC will be supplied from normal hospital stock, using local hospital prescriptions.
Other Name: dabigatran, apixaban, edoxaban, rivaroxaban

Active Comparator: Standard Initiation of DOAC
Standard initiation of any DOAC at a dose licensed for stroke prevention in AF, no sooner than day 7 and no later than day 14 after the onset of acute ischaemic stroke (i.e. between 144hrs and 336hrs from onset).
Drug: Direct oral anticoagulant (DOAC)
Any of the DOACs listed above may be used for treatment in either study arm. The DOAC will be supplied from normal hospital stock, using local hospital prescriptions.
Other Name: dabigatran, apixaban, edoxaban, rivaroxaban




Primary Outcome Measures :
  1. Composite outcome of the combined incidence of:recurrent symptomatic ischaemic stroke,symptomatic intracranial haemorrhage and systemic embolism [ Time Frame: At 90 days from randomisation ]
    OPTIMAS will investigate whether early initiation of DOAC treatment in patients with acute ischaemic stroke and atrial fibrillation is as effective as, or better than, standard initiation of DOAC treatment in preventing recurrent ischaemic stroke, systemic embolism and sICH.


Secondary Outcome Measures :
  1. All-cause mortality [ Time Frame: At 90 days from randomisation ]
    All cause mortality reported in both arms

  2. Incidence of vascular death [ Time Frame: At 90 days from randomisation ]
    Any incidence of vascular death reported in both arms

  3. Incidence of recurrent ischaemic stroke [ Time Frame: At 90 days from randomisation ]
    Any incidence of recurrent ischaemic stroke reported in both arms

  4. Incidence of systemic embolism [ Time Frame: At 90 days from randomisation ]
    Any incidence of incidence of systemic embolism reported in both arms

  5. Incidence of venous thromboembolism (deep vein thrombosis [DVT], pulmonary embolism [PE], cerebral venous thrombosis [CVT]) [ Time Frame: At 90 days from randomisation ]
    Any of Incidence of venous thromboembolism (deep vein thrombosis [DVT], pulmonary embolism [PE], cerebral venous thrombosis [CVT]) reported in both arms

  6. Functional status assessed by the modified Rankin scale (mRS) in both arms [ Time Frame: At 90 days from randomisation ]
    The Modified Rankin Scale measures the degree of disability and dependence following a stroke. The scale consists of 7 category descriptions, where 0 means no symptoms, 1 means no significant disability, 2 means slight disability, 3 means moderate disability, 4 means moderately severe disability, 5 means severe disability and 6 means death. The assessment is carried out by asking the participant or their carer about their activities of daily living.

  7. Cognitive ability assessed by the Montreal Cognitive Assessment (MoCA) questionnaire in both arms [ Time Frame: At 90 days from randomisation ]
    The Montreal Cognitive Assessment is a questionnaire widely used as a screening assessment for detecting cognitive impairment. It assesses different cognitive domains: attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. An abbreviated version of the MoCA assessing attention, verbal learning, memory, executive functions/language and orientation can be performed over the phone. MoCA scores range between 0 and 30. A score of 26 or over is considered to be normal. In a study and people with mild cognitive impairment (MCI) scored an average of 22.1.

  8. Quality of life at 90 days assessed by EuroQol 5 Dimensions 5 level questionnaire [EQ-5D-5L] in both arms [ Time Frame: At 90 days from randomisation ]
    The EQ-5D-5L includes 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The EQ VAS records the respondent's self-rated health on a vertical, visual analogue scale where the endpoints are labelled 'Best imaginable health state' and 'Worst imaginable health state'. In instances in which the participant struggles with giving answers on their own, the participant's next-of-kin or a friend who knows the participant well will be asked to complete the EQ-5D-5L proxy version. The proxy is asked to rate how they think the participant would rate their own health-related quality of life, if the participant were able to communicate it. In case a proxy is not available, the research team member who was looking after the participant will complete it on their behalf.

  9. Patient reported outcomes assessed by the Patient-Reported Outcomes Measurement Information System Global Health questionnaire (PROMIS-10) in both arms. [ Time Frame: At 90 days from randomisation ]
    The PROMIS Global-10 short form consists of 10 items that assess general domains of health and functioning including overall physical health, mental health, social health, pain, fatigue, and overall perceived quality of life. The scoring system of the PROMIS Global-10 allows each of the individual items to be examined separately to provide specific information about perceptions of physical function, pain, fatigue, emotional distress, social health and general perceptions of health where 0 means never experienced this problem or symptoms and 1 means always. The higher score for each response indicate better health.

  10. Ongoing anticoagulation [ Time Frame: At 90 days from randomisation ]
    Ongoing anticoagulation will be assessed based on patient self-reporting and follow up patient medical records if necessary in both arms

  11. Time to first incidence of primary outcome component (recurrent ischaemic stroke, systemic embolism, or sICH) [ Time Frame: At 90 days from randomisation ]
    Time to first incidence of primary outcome component (recurrent ischaemic stroke, systemic embolism, or sICH) reported in both arms

  12. Length of hospital stay for stroke-related care [ Time Frame: At 90 days from randomisation ]
    Length of hospital stay for stroke-related care in both arms

  13. Health and social care resource use [ Time Frame: At 90 days from randomisation ]
    Health and social care resources (assessed by a study specific questionnaire) in both arms

  14. Incidence of symptomatic intracranial haemorrhage (sICH) [ Time Frame: At 90 days from randomisation ]
    Incidence of symptomatic intracranial haemorrhage (sICH) classified according to site intracerebral haemorrhage (within the brain parenchyma); subdural haemorrhage; extradural haemorrhage; subarachnoid haemorrhage; and haemorrhagic transformation of a brain infarct, in both arms

  15. Incidence of major extracranial bleeding [ Time Frame: At 90 days from randomisation ]
    Incidence of major extracranial bleeding reported in both arms

  16. Incidence of all major bleeding (intracranial and extracranial) [ Time Frame: At 90 days from randomisation ]
    Incidence of all major bleeding (intracranial and extracranial) reported during the study period, in both arms

  17. Incidence of clinically relevant non-major bleeding [ Time Frame: At 90 days from randomisation ]
    Incidence of clinically relevant non-major bleeding reported in both arms


Other Outcome Measures:
  1. Ongoing anticoagulation at 90 days [ Time Frame: At 90 days from randomisation ]
    Ongoing anticoagulation at 90 days assessed by patient self-reporting and/ or follow up patient medical records if necessary.

  2. Individual cognitive domain subscores [ Time Frame: At 90 days from randomisation ]
    Individual cognitive domain subscores measured using the MoCA questionnaire



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Aged 18 years or over
  2. Clinical diagnosis of acute ischaemic stroke
  3. AF, confirmed by any of:

    1. 12-lead ECG recording
    2. Inpatient ECG telemetry
    3. Other prolonged ECG monitoring technique (e.g. Holter monitor)
    4. Known diagnosis of atrial fibrillation verified by medical records (e.g. primary care records, letter from secondary care)
  4. Eligibility to commence DOAC in accordance with approved prescribing recommendations confirmed by treating physician
  5. Uncertainty on the part of the treating physician regarding early versus standard initiation of DOAC.

Exclusion Criteria:

  1. Contraindication to anticoagulation:

    1. Coagulopathy or current or recent anticoagulation with vitamin K antagonist (VKA) leading to INR ≥1.7 at randomisation.
    2. Thrombocytopenia (platelets < 75 x 10⁹/L)
    3. Other coagulopathy or bleeding tendency (based on clinical history or laboratory parameters) judged to contraindicate anticoagulation by treating clinician
  2. Contraindication to early anticoagulation

    1. Known presence of haemorrhagic transformation with parenchymal haematoma occupying >30% of the infarct volume and exerting significant mass effect (i.e. PH2) (NB: HI1, HI2 and PH1 are not considered contraindications)
    2. Presence of clinically significant intracranial haemorrhage unrelated to qualifying infarct
    3. Any other contraindication to early anticoagulation as judged by the treating clinician
  3. Contraindication to use of DOAC:

    1. Known allergy or intolerance to both Factor Xa inhibitor and direct thrombin inhibitor
    2. Definite indication for VKA treatment e.g. mechanical heart valve, valvular AF, antiphospholipid syndrome
    3. Severe renal impairment with creatinine clearance (Cockcroft & Gault formula) <15 mL/min (i.e. 14 mL/min or less)
    4. Liver function tests ALT > 2x ULN
    5. Cirrhotic patients with Child Pugh score equating to grade B or C
    6. Patient is taking medication with significant interaction with DOAC, including:

      • Azole antifungals (e.g. ketoconazole, itraconazole)
      • HIV protease inhibitors (e.g. ritonavir)
      • Strong CYP3A4 inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital or St. John's Wort)
      • Dronedarone
  4. Pregnant or breastfeeding women
  5. Presence on acute brain imaging of non-stroke pathology judged likely to explain clinical presentation (e.g. mass lesion, encephalitis)
  6. Inability for patient to be followed up within 90 days of trial entry
  7. Patient or representative refusal to consent to study procedures, including the site informing GP and healthcare professional responsible for anticoagulation care of participants
  8. Any other reason that the PI considers would make the patient unsuitable to enter OPTIMAS.

Note that current DOAC treatment is NOT an exclusion criterion, as long as the treating physician considers it appropriate to restart (or continue) according to the timings specified in the OPTIMAS trial protocol. Continuation of the DOAC would be recorded as a start time of zero hours.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03759938


Contacts
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Contact: Marisa Chau +44 20 7670 4618 ext 64618 ctu.optimas@ucl.ac.uk

Locations
Show Show 44 study locations
Sponsors and Collaborators
University College, London
Investigators
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Study Chair: David Werring, Prof UCL
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Responsible Party: University College, London
ClinicalTrials.gov Identifier: NCT03759938    
Other Study ID Numbers: 18/0316
First Posted: November 30, 2018    Key Record Dates
Last Update Posted: November 9, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University College, London:
ischaemic stroke, atrial fibrilation
Additional relevant MeSH terms:
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Stroke
Atrial Fibrillation
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Arrhythmias, Cardiac
Heart Diseases
Pathologic Processes
Rivaroxaban
Apixaban
Edoxaban
Dabigatran
Anticoagulants
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action