ACTIVE Study - Use of ACTIVE Fluid Exchange to Treat Intraventricular Hemorrhage

Use of ACTIVE Fluid Exchange to Treat Intraventricular Hemorrhage

Randomised controlled trial evaluating active irrigation using IRRAflow device in patients with intraventricular hemorrhages (IVH). Patients will be randomized in a 1:1 fashion to IRRAflow active irrigation and aspiration compared to standard passive external ventricular drainage.

The investigators hypothesize that active irrigation using the IRRAflow system will reduce the occlusion rates of the ventricular drain. Further, reduce the rate of catheter related infection and reduce time needed for clearance of blood from the intraventricular space compared with passive drainage alone. Further more, reduce treatment time, patient length of stay, and overall treatment cost when compared with passive drainage.

Study Overview

• Status: Recruiting
• Conditions: Intraventricular Hemorrhage
• Intervention / Treatment: Device: IRRAflow; Procedure: Standard ventriculostomy

Detailed Description

Intraventricular extension of hemorrhage (IVH) is a particularly poor prognostic sign, with expected mortality between 50% and 80%. IVH is a significant and independent contributor to morbidity and mortality, yet therapy directed at ameliorating intraventricular clot has been limited. Conventional therapy centers on managing hypertension and intracranial pressure while correcting coagulopathy and avoiding complications such as rebleeding and hydrocephalus. Surgical therapy alone has not changed the natural history of the disease significantly. Although ventriculostomy appears to be effective in controlling ICP, this technique does little to reduce morbidity and does not address the inflammatory process. The severity of communicating hydrocephalus appears to be related to IVH volume and the duration of exposure of CSF to clotted blood.

Management of hemorrhagic patients is typically orchestrated by neurosurgeons and neuro-intensivists. Comprehensive care should include surveillance and monitoring of intracranial pressure (ICP), Cerebral Perfusion Pressure (CPP), and hemodynamic function. Furthermore, prevention of infection, complications of immobility through positioning and mobilization within physiological tolerance play an important role in optimizing outcomes after intracerebral hemorrhage (ICH).

There are multiple approaches to facilitating Cerebrospinal Fluid (CSF) drainage and intracranial pressure (ICP) monitoring. Routinely, ICP is measured by use of devices inserted into the brain parenchyma or cerebral ventricles. A Ventricular Catheter (VC) inserted into the lateral ventricle allows for drainage of CSF to help reduce ICP.

The IRRAflow system performs active, controlled fluid exchange, based on the notion that it is faster to wash out IVH, compared to gravity drainage alone. IRRAflow combines periodic, controlled irrigation and aspiration of the catheter probe with neutral physiological fluids. The continuous perfusion cleans the entire inner catheter probe's surface while the fluid movement helps to disrupt potential clot or bacteria colony formation on the catheter probe's intracranial external surface, thereby eliminating the underlying reasons for the problems associated with passive drainage: blockage and infection. Furthermore, IRRAflow perfusion is combined with continuous ICP monitoring that includes safety alarms. Contrary, with passive drainage, such as today's standard of care, the external ventricular drain (EVD), is inherently inefficient because of its inability to overcome blood clot adhesion. As a result, EVD's generally need a lot of treatment time for the evacuation of a clinically significant blood volume and often leave enough volume of residual blood to create secondary adverse effects, like hydrocephalus. IRRAflow was designed to increase drainage efficiency by means of gradual and continuous dilution of the pathological intracranial fluids through irrigating the catheter with physiological fluids as well as the continuous pressure fluctuations inside the pathological collection, which are created by the appropriate irrigation patterns. By design, the IRRAflow catheter probe is irrigated regularly in a way that maintains its patency. Catheter blockages are theoretically very unlikely since any material build-up at the catheter's tip is washed away during the next irrigation phase, which will occur in, at most, a couple of minutes. Additionally, the volume and flow rate of each irrigation is such that the length of the IRRAflow catheter probe's outer surface is washed by backflow, thus arguably reducing the chance for bacterial colonisation (Data on File at IRRAS). As for safety, IRRAflow automatically, reliably, and continuously monitors ICP and alerts hospital personnel with visual and sound alarms immediately when the patient's ICP is out of the pressure range set by the treating neurosurgeon, which eliminates any delay in detecting under or over drainage and any treatment's compromise.

The clinical efficacy of the IRRAflow system is currently validated to a limited extent based on case series (Evidence grade 4) with a total number of patients around 200 distributed across multiple countries including in Greece, India, Sweden, Germany, UK, USA, and Finland. The system has been used to treat subarachnoid, intraventricular, intraparenchymal, and subdural hemorrhages. The system was CE Marked in 2014 and began limited market release in Germany in 2017. It received US FDA clearance in July of 2018 and began to be used commercially based on the conclusion that the device was safe. Case report data on the 200 initial patients has been collected by the company and maintained on file. The data has shown that zero IRRAflow catheter occlusions have been experienced when the irrigation setting has been activated (unpublished). Furthermore, treatment times were much shorter and posttreatment residual blood volumes were less than expected by the treating neurosurgeons (31), (Data on File at IRRAS). To date there have not been any documented blockages or probe associated infections detected in any IRRAflow treatment.

At present time, there is no level 1 evidence for treatment efficacy. However, the treatment is new and intuitively rational, and it is applied for patients with intraventricular hemorrhage, which has an extremely high mortality and morbidity rate, for whom there are no other treatment options.

In light of the above, the current clinical ACTIVE study is being initiated to evaluate the hypothesis that active irrigation by IRRAflow® will reduce the time needed for clearance of intraventricular blood from intraventricular space compared with passive drainage. Further, active controlled irrigation can improve catheter occlusion and infection rates compared with passive drainage. This is accomplished through IRRAflow's mechanism of action, Active Fluid Exchange (continuous, intelligent irrigation combined with continuous drainage and ICP monitoring). This active fluid exchange could enable an optimal washout of the ventricles thus leading to better outcomes than traditional treatment. Clinical evidence supporting this hypothesis has already been established by Zhang et al., 2007, and the aforementioned article. The investigators aim to provide that similar results can be obtain through less invasive methods.

The investigators expect that the ACTIVE study will provide the first grade 1 evidence to date characterizing the IRRAflow IVH clearance performance, documenting device safety, and additionally provide preliminary indications of the potential correlated improvements in clinical outcome and cost-effectiveness of treatment as well as a potential reduction in post-surgical complications such as post-ictus hydrocephalus and central nervous system (CNS) infection. Endpoints and objectives are elaborated further below. If positive, the Study will provide a pivotal argument for the use of active fluid exchange in the treatment of hemorrhagic stroke with ventricular involvement, potentially changing standard practice for the better

The proposed study is a multi center prospective, controlled, randomized trial to evaluate the efficacy and safety of evacuation of intraventricular hematoma by Active external ventricular drainage (INTERVENTION - IRRAflow) compared to passive external ventricular drainage (CONTROL - EVD).

Randomization of the study will occur following enrollment upon the patient presentation to the emergency room. Upon initial diagnosis and enrollment, if it is determined that a CSF drainage is necessary, the patient will be randomized to either the IRRAflow with Active Fluid Exchange arm (intervention) or a standard practice EVD arm (control). The randomization will occur in a 1 to 1 fashion. This means, that 50% of cases will be randomized to the intervention and 50% to control. Drainage therapy with EVD or IRRAflow will commence for as long as it is deemed necessary by the treating physician. All patients enrolled in the trial will receive additional supportive and medical treatment by choice of the treating physician and in accordance with standard of care. Such treatment may include neurointensive care, neuromonitoring, and surgical or endovascular occlusion identified sources of intracranial hemorrhage, e.g. vascular anomalies, aneurisms, etc. Interventional treatment will be stopped in case of 1) patient exclusion from the trial, 2) ethical or medical safety contraindications for further interventional treatment determined by the Investigators.

• Study Type: Interventional
• Enrollment (Anticipated): 58
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Mette Haldrup, MD; Phone Number: 22715657; Email: methalje@rm.dk
• Study Contact Backup: Name: Anders Korshøj, MD, PhD; Phone Number: 40956927; Email: Andekors@rm.dk

Study Locations

• Denmark
  • Aarhus, Denmark
    • Recruiting
    • Aarhus University Hospital
    • Contact: Mette Haldrup Jensen, MD; Phone Number: 004522715657; Email: methalje@rm.dk
    • Principal Investigator: Anders Rosendal Korshøj, MD, Phd

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥ 18 years of age
2. Intraventricular hemorrhage documented on head CT or MRI scan, no older than 24 hrs.
3. Intraventricular hemorrhage Graeb Score ≥3 points
4. Urgent need of cerebrospinal fluid drainage (<24 hours)
5. Deterioration of consciousness or medical sedation at the time of enrollment causing the patient to be mentally and/or physically incapacitated and legally incompetent in the decision of inclusion ("acute study" conduct).
6. Indication for active treatment evaluated by the treating physicians
7. Use of validated anti-conception in fertile female participants in concordance with guidelines provided by the Danish Health and Medicines Authority or a negative urine human chorion gonadotropin (HCG) test.

Exclusion Criteria:

1. Patient has fixed and dilated pupils
2. Pregnant or nursing women (fertile female participants will be required to take a validated pregnancy test for evaluation of pregnancy)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active irrigation and aspiration; Patients randomized to IRRAflow will receive a ventricular catheter with active irrigation and aspiration.	Device: IRRAflow; Ventriculostomy using IRRAflow with active irrigation and aspiration
Active Comparator: Standard passive external ventricular drainage; Patients randomized to passive external ventricular drainage will receive a standard EVD.	Procedure: Standard ventriculostomy; Standard passive external ventricular drainage

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Drain survival time	Time to first observed occlusion of the catheter	Time with ventricular catheter from placement to fist observed occlusion, an average of 11 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Catheter related infections	Rate of ventriculitis and meningitis related to the ventriculostomy	Time with ventricular catheter from placement to fist observed occlusion, an average of 11 days
Rate of shunt dependency	No. of patients with resistent need of CSF drainage receiving a ventriculo-peritoneal (VP)-shunt	During the first 90 days after intervention
Time to clearance of blood	CT volume of head CT scans	At day 0, 2, 4, 6, 8
Length of stay at the ICU	Length of stay at the ICU	Expected between 1 and 30 days
Functional outcomes - eGOS and mRS	Extended glasgow outcome scale and modified rankin scale	At inclusion, at discharge (an average of 30 days) and 90 days
Mortality rate	Evaluation of mortality rates	At 30 days and 90 days

Collaborators and Investigators

• Sponsor: University of Aarhus
• Collaborators: Aarhus University Hospital; IRRAS
• Investigators: Principal Investigator: Anders Korshøj, MD, PhD, Dept. of Neurosurgery, Aarhus University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): January 13, 2022
• Primary Completion (Anticipated): February 1, 2025
• Study Completion (Anticipated): February 1, 2025

Study Registration Dates

• First Submitted: December 15, 2021
• First Submitted That Met QC Criteria: January 10, 2022
• First Posted (Actual): January 24, 2022

Study Record Updates

• Last Update Posted (Actual): February 10, 2022
• Last Update Submitted That Met QC Criteria: January 26, 2022
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: Ventriculostomy; Intraventricular Hemorrhage; Catheter occlusions; Catheter-Related Infections; Clearance of blood; Active irrigation and aspiration; IRRAflow
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Intracranial Hemorrhages; Hemorrhage; Cerebral Hemorrhage
• Other Study ID Numbers: 47723569

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: All collected IPD
• IPD Sharing Time Frame: Protocol will be published primo 2022.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No