Fibrinogen Replacement to Prevent Intracranial Haemorrhage in Ischemic Stroke Patients After Thrombolysis (FibER) (FibER)

November 2, 2022 updated by: Azienda Usl di Bologna

Fibrinogen Replacement to Prevent Intracranial Haemorrhage in Ischemic Stroke Patients After Thrombolysis: a Pilot Probe Randomized Controlled Trial (FibER)

Fibrinogen replacement could prevent haemorrhagic complications in ischemic stroke patients with secondary post-rtPA hypofibrinogenemia

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Intravenous recombinant tissue plasminogen activator (rtPA) is the first recommended reperfusion therapy for acute ischemic stroke, as well as endovascular treatment in case of large vessel occlusion, but it increases the risk of ICH.

The pathophysiological mechanisms of ICH after i.v. thrombolysis in ischemic stroke is complex: hyperglycemia, early ischemic changes on neuroimaging, clinical stroke severity assessed by the National Institutes of Health Stroke Scale score (NIHSS) on admission, advanced age and high blood pressure are known risk factors for hemorrhagic cerebral transformations. The risk of bleeding is likely mediated by coagulopathy, reperfusion injury, and breakdown of blood-brain barrier.

The rtPA binds the plasminogen within the clot, converting it to plasmin, a proteolytic enzyme capable to dissolve the clot. However plasmin activity is not specific for clot-associated fibrin, but also breaks down other circulating proteins, including fibrinogen. An early fibrinogen degradation coagulopathy can occur after i.v. thrombolysis, that could be implicated in bleeding complications.

In 2002, it was shown how high levels of fibrin and fibrinogen degradation factors at 2 hours after rtPA could be a risk factor for early ICH.

Few years ago, the investigators published a work demonstrating that an early decrease in fibrinogen levels is a risk factor for ICH within the first 24 hours and 7 days after rtPA therapy in ischemic stroke patients. In this experience, the investigators collected data about ischemic stroke patients that experienced a severe hypofibrinogenemia after 2 hours from iv rtPA. All patient were treated with fibrinogen replacement, fibrinogen infusion was well tolerated, without any thrombotic complication, and the infusion of fibrinogen did not reduce the rate of recanalization and, therefore, did not negatively affect the chances of reopening the occluded vessel. These data agree with another study showing that prominent fibrinogen turnover after thrombolysis is a relevant cause of major bleeding complications, and specifically that a decrease >200 mg/dL in the fibrinogen level 6 hours after thrombolysis emerges as a significant and independent predictor for bleeding risk. Morover, other authors confirmed that the decrease of fibrinogen level less than 2 g/L in the first 2 hours after thrombolysis multiplies the odds of early parenchymal hematoma (PH) by a factor of 12.82 . Similarly, a large study about symptomatic intracerebral haemorrhage (sICH) showed that severe hypofibrinogenemia (<150 mg/dL) was associated with ICH expansion.

The correction of the coagulopathy after rtPA remained the mainstay of treatment for sICH after

thrombolysis, but no specific agent has been shown to be most effective. Data from other disease states, however, raise the possibility that certain agents not routinely used, may be effective. As regard, in the consensus statement of 2017, American Heart Association Stroke (AHA) Council investigated possible treatments for sICH after rtPA in ischemic stroke patients, evaluating the role of cryoprecipitate, prothrombin complex concentrate, fresh frozen plasma, antifibrinolytic agents, platelets, Factor VI and vit. K. In particular, infusion of cryoprecipitate was suggested because it contains fibrinogen, that corrects dysfibrinogenemia. In particular, if sICH is diagnosed, physicians were recommended to consider immediately sending a blood sample for fibrinogen level and empirically transfusing with 10 U cryoprecipitate and anticipate giving more cryoprecipitate as needed to achieve a fibrinogen level of >150 mg/dL.

Indeed, several studies in other different medical fields, suggested fibrinogen supplementation with anti- haemorrhagic purposes in patients with severe haemorrhages and related fibrinogen deficiency, following trauma and surgery.

The investigators had previously analysed the trend of fibrinogen decrease after i.v. rtPA in 56 ischemic patients taking fibrinogen dosage at 2, 6, 12 and 24 hours from rtPA infusion: fibrinogen level drops within the first 2 hours and then slowly increases in the following 24 hours, still being lower than basal fibrinogen value. Dividing patients in two subgroups according to pre-rtPA fibrinogen level, a higher baseline fibrinogen resulted in higher risk of deep decrease in fibrinogen value. Medical literature about the rate of thrombotic complication after fibrinogen concentrate administration in stroke patients is relatively lacking. However, experiences in cardiac surgery showed that administration of fibrinogen concentrate was not associated with an increased risk of mortality and thromboembolic events, and a recent Cochrane review on fibrinogen concentrate in bleeding patients, did not show any adverse events such as thrombotic episodes following the use of fibrinogen concentrate.

In a pilot experience, the investigators administrated i.v. fibrinogen in 39 patients with severe hypofibrinogenemia after 2 hours from i.v. rtPA. Fibrinogen infusion was well tolerated: no thrombotic complications occurred in 37 out of 39 patients (94.77%). Two patients developed pulmonary embolism, of which 1 was only segmental and 1 in an active cancer patient. Moreover fibrinogen replacement did not reduce the rate of recanalization, so it did not negatively affect the chances of reopening the occluded vessel.

Study Type

Interventional

Enrollment (Anticipated)

200

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Bologna, Italy
        • Recruiting
        • IRCCS Istituto delle Scienze Neurologiche di Bologna

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion criteria:

  • patients with acute ischemic stroke treated with i.v. thrombolysis (rtPA 0,9 mg/Kg, 10% in bolus and 90% in infusion in 60 minutes)
  • age >18 years
  • critical hypofibrinogenemia post-tPA, defined as a decrease of serum fibrinogen level <200 mg/dl and/or a rate decrease >50% than baseline level
  • written informed consent

Exclusion criteria:

  • contraindication to rtPA treatment;
  • patients who present symptomatic ICH during infusion of rt-PA,
  • absence of written informed consent

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: fibrinogen infusion
fibrinogen infusion (2 g) in stroke patients with secondary post-rtPA hypofibrinogenemia
Drug: fibrinogen infusion
fibrinogen infusion (2 g) in stroke patients with secondary post-rtPA hypofibrinogenemia
No Intervention: No fibrinogen infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Intracranial hemorrhage defined as parenchymal hematoma
Time Frame: 7 days after randomization
Change in combined rate of parenchymal hematomas within the infarct area (PH1, PH2) or remote from the actual infarct (rPH1, rPH2), either asymptomatic or symptomatic (according to the NINDS, ECASS and SITS classification) documented on the brain CT scan after 24 hours from rtPA infusion, or before in case of clinical worsening, and at day 7 (or at the discharge if before).
7 days after randomization

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Symptomatic intracranial hemorrhage
Time Frame: 7 days after randomization
Number of participants who develop symptomatic intracranial hemorrhage (sICH) according to NINDS, ECASS and SITS classifications.
7 days after randomization
Extracranial bleedings
Time Frame: 7 days after randomization
Number of participants who develop any extracranial bleedings.
7 days after randomization

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Serious thromboembolic adverse events
Time Frame: 7 days after randomization
Number of participants who develop serious thromboembolic adverse events, including deep vein thrombosis, pulmonary embolism, myocardial infarct, recurrence of ischemic stroke, and MACE defined as all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke.
7 days after randomization
National Institutes of Health Stroke Scale (NIHSS)
Time Frame: 7 days after randomization
Clinical outcome at 7 days defined as National Institutes of Health Stroke Scale (NIHSS) score, ranging from 0 to 42 with higher scores meaning worse outcome.
7 days after randomization
Modified Rankin Scale (mRS)
Time Frame: 3 months after randomization
Functional outcome at 3 months defined as Modified Rankin Scale (mRS) score, ranging from 0 to 6 with higher scores meaning worse outcome.
3 months after randomization
hyperfibrinolysis diagnosis
Time Frame: 7 days after randomization
To evaluate the diagnosis of hyperfibrinolysis detected with Rotation thromboelastometry (ROTEM) in the whole ischemic stroke population randomized in the RCT (200 patients)
7 days after randomization
hyperfibrinolysis diagnosis 2
Time Frame: 7 days after randomization
To correlate hyperfibrinolysis with cerebral bleeding in the whole ischemic stroke population and in each arm
7 days after randomization

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Azienda Usl di Bologna

Collaborators

Ministero della Salute, Italy

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 8, 2022

Primary Completion (Anticipated)

December 31, 2024

Study Completion (Anticipated)

December 31, 2024

Study Registration Dates

First Submitted

March 1, 2022

First Submitted That Met QC Criteria

March 28, 2022

First Posted (Actual)

March 29, 2022

Study Record Updates

Last Update Posted (Actual)

November 3, 2022

Last Update Submitted That Met QC Criteria

November 2, 2022

Last Verified

November 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 1123-2020-FARM-AUSLBO
  • 2020-005242-41 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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