This current phase 2 and feasibility study evaluates the IRRAflow system. A closed system VC with active irrigation and aspiration in comparison to standard passive external ventricular drainage (Fig. 1). We hypothesize that closed system active irrigation will be safe use and will reduce the occlusion- and infections rates, increase clearance rate and clot removal. This manuscript is based on protocol version 4.0 dated 16th of January 2022
The study is an investigator initiated, prospective multi center, 1:1 randomized, comparative phase 2 trial evaluating the efficacy and safety of active irrigation external ventricular drainage (INTERVENTION - IRRAflow) compared to passive external ventricular drainage (CONTROL - EVD) (fig. 2). The investigators are unblinded for the treatment, but there is blinding concerning evaluations of endpoints where possible.
The trial will enroll an expected sample size of 58 patients (sample size calculation see “sample size and statistical considerations”). The enrollment period is estimated to be 24 months from the date of first patient enrolled. Patients will be followed for 3 months with expected trial termination after 27 months from initiation.
The IRRAflow device
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 minimizing the problems associated with passive drainage: blockage and infection. IRRAflow perfusion is combined with continuous ICP monitoring that includes safety alarms.
Primary endpoint
- Catheter occlusion evaluated by hours to first observed occlusion from VC placement
Secondary endpoints
- Clearance of ventricular blood measured by absolute volume of blood in ml on head CT scans
- Rate of catheter-related infection.
- Length of ICU stay
- Rate of shunt dependency
- Functional Status – Extended Glascow outcome scale (eGOS) and modified Rankin scale (mRS) at inclusion, discharge to rehabilitation and 90 days.
- Mortality rates at 30 days and 90 days
Exploratory endpoints
- Duration of ventricular drainage (EVD and IRRAflow) in days
- Procedure complications
- Device related complications
- Procedure time
- Rate of revision procedures of the ventricular catheter
- Rate of occurrence of repeated hemorrhagic events
- Number of flushes required
- Total cost of procedure
Trial overview
The patient population for this study will be comprised of up to 58 patients with diagnosis of primary intraventricular hemorrhage or secondary IVH from SAH or ICH with intraventricular breakthrough.
Ethics
Patient selection criteria are established according to clinical, radiologic, and neurologic components. Patients who meet all the Inclusion Criteria and none of the Exclusion Criteria will be eligible for study participation. Candidates for enrolment in the trial will typically be severely disabled by the acute neurological injury occurring due to hemorrhagic stroke. Patients will be in a state of coma or medically sedated and often intubated leaving them physically and/or mentally incapacitated, legally incompetent, and unable to make a proper conscious decision about trial participation and therefore also unable to provide informed consent at the appropriate time of enrollment and guidelines on “acute study” conduct will be followed. The trial investigators will subsequently obtain a written informed consent from the patient or a relative to the patient upon first possible notice in accordance with §§3-5 in the Danish Law on Health Research Ethics.
Inclusion Criteria
- Age >18 years of age
- Intraventricular hemorrhage documented on head CT or MRI scan. The scan must be no older than 24 hours.
- Intraventricular hemorrhage Graeb Score ≥3 points (7).
- Need of cerebrospinal fluid drainage (<24 hours) deemed by treating physician
- Deterioration of consciousness or under 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).
- Indication for active treatment evaluated by the treating physicians
- Use of validated anti-conception for fertile female participants in concordance with guidelines provided by the Danish Health and Medicines Authority or a negative urine HCG test.
Exclusion Criteria
- Patient with fixed and dilated pupils
- Pregnant or nursing women (fertile female participants are required to take a validated pregnancy test for evaluation of pregnancy)
The randomization procedure
Patients eligible for inclusion following above mentioned criteria will be randomized in a 1:1 fashion for EVD or IRRAflow. The randomization procedure is performed using the RedCAP randomization module. Randomization will be carried out upon arrival to the operation room and informed consent will be obtained at the first possible occasion after VC placement (Fig 3).
Ventricular catheter placement
VC placement is a standard neurosurgical procedure, and all patients will receive catheters placed according to the standard procedure for EVD placement in both groups. The procedure is performed neuronavigational guided to ensure correct placement and safety for the patient. The catheter is placed in the lateral ventricle containing the least blood and always intended to be placed in CSF outside of the hematoma. The IRRAflow catheter will be placed by reverse tunneling (Fig. 4a, b, c), whereas the standard EVD will be placed on a bolt.
Device training
All investigators, co-investigators and study personnel will undergo standardized training in study conduct and procedures, including the use and operation of the IRRAflow device, prior to study participation. IRRAflow training and certification will be conducted by a qualified IRRAS Associate or designee.
Follow up assessments
After placement of the VC, the patients in the two arms will receive the same treatment and monitoring. They will be admitted to the intensive care unit and later transfer to the stationary neurosurgical department before discharge to a rehabilitation facility. Patients will be followed closely regarding the primary, secondary and exploratory endpoints. During the admission period, the patients will be followed with a CT scan at day 0, day 2, day 4, day 6 and day 8 to evaluate the size of the hematoma using CT volumetrics.
A scheduled follow-up will be applied for all included patients including a clinical status at the time of inclusion, discharge, and 3 months post-procedure. The follow-up will include GCS and mRS at inclusion, discharge, and 3 months. Further, eGOS will be evaluated at discharge and 3 months. Rate of shunt dependency, adverse events and serious adverse events will be evaluated continuously during the inclusion period. Mortality rates will be evaluated at 30 days and 3 months.
Patient Withdrawal and Lost to Follow-Up
A patient or patients relative may elect to withdraw from this clinical study at any time. The patient or the patients relative should notify the Investigator of the request to withdraw. The Investigator should encourage patients to return for all required follow-up visits and request that they return for the withdrawal visit.
All patients who withdraw from the study will complete an end of study visit. No further visits will be required by the patient once the end of study visit is complete. A patient has the right to withdraw from the trial at any time and for any reason without prejudice to his or her future medical care by the physician or the institution. Trial withdrawal by a patient or their LAR specifically means withdrawal of consent from further participation in the trial. Patients who withdraw consent after enrollment will be evaluated to the time of withdrawal, and withdrawal of consent precludes any further trial-related treatment or data collection. LAR may also withdraw consent. At a minimum, every effort should be made to document patient outcome at the time of trial withdrawal.
All patients will be expected to continue in the trial through the final follow-up assessment except in the event of death or upon the patients or patients relative written request for early withdrawal from the clinical trial.
Sample size and statistical considerations
The sample size of the study was determined based on the primary outcome. We considered a two-sided log-rank test for comparison of the time-to-catheter occlusion between the two treatment groups. Further, we assumed equal length of follow-up together with an occlusion risk of 10% and 35% in the intervention and control group. Patient mortality was assumed to be independent of the considered time to catheter occlusion and to correspond to 30% dropout. We used a significance level of 20% due to the exploratory nature of the study. Then, for a power of 80%, Schoenfeld’s approach resulted in a required sample size of 58 (i.e., 29 subjects with drain per treatment group).
Data will be analyzed according to the intention-to-treat principle. For the primary outcome (time to catheter occlusion), time-to-event analysis will be used, in which drains are considered the basic experimental units. Times corresponding to drains without occlusion during follow-up will be considered censored. Especially, since catheter occlusion is independent of patient mortality, patient death is treated as censoring event. Time-to-occlusion will be described by Kaplan-Meier plots and investigated by Cox-regression. Estimated beneficial treatment effects with a two-sided p-value ≤ 20% will be considered an interesting finding worth further investigation.
Further outcome measures (secondary/exploratory) will be used for descriptive and exploratory purposes only; no formal statistical hypotheses will be tested.
Secondary endpoints (subject-based unless otherwise specified) will be handled as follows:
Kaplan-Meier estimates and Cox regression will be used to describe time to recurrence of hemorrhage and time to death (with a follow-up time of 3 months).
Occurrence of catheter related infections and shunt dependency will be reported as proportions, length of stay in ICU will reported as means. Clearance of ventricular blood will be described with the help of linear mixed effect models. Measures of functional status will be dichotomized and analyzed by baseline-adjusted logistic regression. All estimates will be reported together with corresponding confidence intervals (CIs).
Exploratory endpoints (mainly drain-based) will be handled as follows:
Proportions and CIs will be reported for technical success, procedure success and necessity of revision procedures. Procedure time, duration of VC in place and number of required flushes will be described by means and CIs.
Reported CIs will include a Bonferroni adjustment to maintain the family-wise coverage probability at 95%.
For early safety monitoring, an interim analysis is done when 20 subjects have been enrolled in the study (10 subjects per arm). The analyzes will be performed in an intent-to treat fashion.
Monitored safety outcomes are mortality as well as the total number of adverse and serious adverse events related to catheter treatment (infections, bleedings in relation to intervention, displacements of catheters, catheter misplacement). For p-values below 20% early stop of the study will be considered (non-binding) otherwise the study continues until the study end.
Data monitoring committee
An Independent Data Monitoring Committee (DMC) has been created with the main purpose of patient safety. The DMC will achieve this by monitoring especially adverse events and severe adverse events and further analyzing the benefit vs risk ratio of the treatment. The DMC will evaluate safety of the study after enrollment of 10 patients. The safety evaluation will be based on severe adverse events in each group. For p-values below 20% early stop of the study will be considered (non-binding). Additionally, the DMC will provide an independent scientific review of the interim analysis and recommend continuation or discontinuation of the trial. If the trial passes interim analysis, the DMC will review the final data as well. The DMC will serve in an advisory capacity to the sponsor.
Trial steering committee
The Trial Steering Committee (TSC) will consist of the sponsor-investigator and two representatives from each study site. The TSC will act in an advisory capacity to the sponsor in terms of reviewing the progress of the trial and, if necessary, recommend amendments to the protocol or trial logistics to ensure optimal trial progress. Furthermore, the recommendations provided by the DMC will be discussed and, if needed, implemented by the TSC.
Publication
All results will be published in peer-reviewed, preferably open access, international scientific journals and presented at international scientific conferences, regardless of academic conclusions. Positive, negative, and inconclusive results will be publicly available.