Safety, harm, and efficacy of IRRAflow® versus external ventricular drainage for intraventricular hemorrhage: A randomized clinical trial

Importance Intraventricular hemorrhage (IVH) is associated with high morbidity and mortality. A strong need exists for treatment advances. IRRAflow® was recently introduced as a method for minimally invasive, controlled, and accelerated IVH wash-out. However, no current evidence supports this technology. Here, we present the first pivotal safety/efficacy evaluation in a randomized controlled setting. Objective To evaluate the safety and efficacy of active hematoma irrigation using the IRRAflow® device compared with standard external ventricular drainage (EVD) for the IVH treatment. Design, setting, and participants This investigator-initiated, prospective multi-center, 1:1 randomized, single-blinded, clinical trial was conducted at the Aarhus University Hospital and Odense University Hospital in Denmark from January 13, 2022 to November 24, 2022. The trial was set to include 58 IVH patients with prespecified interim analysis at final endpoint collection for the first 20 patients. Interventions Patients were randomized to receive either IRRAflow® or standard EVD treatment. The IRRAflow® performs periodic active irrigation and aspiration contrary to standard passive gravity-driven EVD. Main outcomes and measures Outcomes were chosen to reflect key IRRAflow® value propositions. The primary outcome was rate of catheter occlusions. The main outcome of the prespecified interim analysis was risk of severe adverse events (SAEs). Secondary outcomes were hematoma clearance rate, shunt dependency rate, procedure time for primary catheter placement, length of intensive care unit (ICU) stay, treatment duration, functional outcome (modified Rankin Scale (mRS) and extended Glasgow Outcome Scale (eGOS)) 90 days after inclusion, adverse events (AEs) (including catheter-related infections and procedure-related complications), and overall survival. Results The study was terminated early due to a significantly increased risk of SAEs in the IRRAflow® group compared with EVD (risk difference = 0.43, 95% confidence interval (CI) (0.059;0.813), p=0.044), incidence rate ratio divided by person time = 6.0, 95%CI 1.38-26.11) p=0.012). The catheter occlusion rate was 37.5% in the IRRAflow® group versus 6.6% in the EVD group (p=0.141), which met the prespecified 0.2 alpha level. The median procedure time for primary catheter placement was 53.5 min compared with 12 min in the control group (p=0.0001). No significant difference was observed for other secondary outcomes. The majority of SAEs had a causal relationship with the intervention. Conclusion and relevance We found that the current IRRAflow® treatment is encumbered by a significantly increased number of SAEs. We recommend caution when using the device. Based on root-cause analysis, our recommendation is that a number of changes be implemented to improve the safety of the device in IVH treatment. We believe that our results are pivotal in ensuring the future safety of patients with IVH. Trial registration [ClicalTrials.gov][1] identifier: [NCT05204849][2], registered 15 December 2021, updated 24 December 2022. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT05204849 ### Funding Statement Aarhus University provided funding in the order of 1,800,000 DKK supporting the PhD study associated with the trial and a grant support was received from IRRAS, 2,857,000 m DKK in the course of the study period. The trial protocol was designed by sponsor-investigator Aarhus University Hospital. The funding bodies have peer reviewed the trial protocol but have had no role in the design of the study, in the analysis, and interpretation of data or in the writing of this manuscripts. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study abides by the ethical principles of the Declaration of Helsinki, Good Clinical Practice Guidelines, and ISO-14155 standards, with approval from the Danish Central Region Committee on Health Research Ethics Journal no. 1-10-72-34-21 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript [1]: http://ClicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05204849&atom=%2Fmedrxiv%2Fearly%2F2023%2F07%2F12%2F2023.07.08.23292286.atom