IVH Study

If you cannot find the answer to your question(s) below, please e-mail your question(s) to Nicole McBee at nmcbee@jhmi.edu.

Why do we have an upper age limit of 75 years?
This is an arbitrary age limit chosen to help limit age-related variables among the treatment arms, which may independently affect clot resolution rate and/or outcome.
Daily CT scans are not done as standard of care for this indication. Could we do them every other day instead?
We accounted for standard of practice scans, which are done every other day, in writing the protocol. Therefore, study funds are provided to pay for the following scans: 24 hours post diagnostic CT, days 3, 5, 7, and 30. It is important to note that the rate of clot resolution is our primary outcome measure and daily scans are necessary to accurately to calculate this rate.
If residents, nurse practitioners, or designated others administer the drug, do they have to be listed on the FDA form 1572?
No. An investigator listed on the 1572 or the 1572 investigator's designee can perform IVC injections.
Can study drug administration be stopped when clot resolution has been achieved according to CT even though the IVC is still in place?
Yes. The primary outcome measure is rate of clot resolution not length of external ventricular drainage duration. Once there is CT evidence of third and fourth ventricle clearing (i.e. CSF flow is restored), rt-PA administrations should be stopped.
If the patient is taken for surgery, are they immediately out of the study? If not, how long after surgery could they resume study drug administration?
Yes the patient may go to surgery. Of course this would have to be prominently noted in the data collection forms. It is assumed that the surgery will likely be for intraparenchymal clot evacuation and not for ventricular clot evacuation. The surgeon should note whether the ventricle was entered during the surgery. Resumption of the study drug administration would be up to the surgeon, we would offer no sooner than 12 hours. Any break in the drug administration schedule will be documented on the CRF study medication form.
Are the IVC weaning guidelines in the protocol to be followed per protocol or are individual centers permitted to use their own methods?
The guidelines in the protocol are guidelines only. The neurosurgeon/neurointensivist is free to follow standard practice at each individual study center. During the initial site visit we will document what type of method each center uses.
The sample consent form reads "We shall try to reduce the risk of infection by giving you an intravenous antibiotic…" Are you doing this as a standard practice already? If so, what are you using and how?
Use of prophylactic antibiotics is at the discretion of each study center's PI. It is assumed that a standard protocol is in place for all patients within a given center. If your center does not advocate prophylactic use of antibiotics, you should delete this sentence from the consent form.
Does the t-PA fall out of solution?
No, t-PA should stay in solution if dissolved in sterile water or further diluted with normal saline.
When should the stability CT be performed?
The stability CT should be performed no sooner than 6 hours after IVC placement to confirm correct IVC placement and verify clot stability.
What is the reason for the 30cc cutoff?
We would like to minimize the effect of other variables (i.e. ICH size) on the adverse outcomes in our study population. This will give us the most potential for clinical benefit.
If a patient has 2 focal areas of intraparenchymal bleeding, how is the intraparenchymal clot size determined using the ABC method?
Both areas should be measured separately and then their total area added together. If this total area is less than 30 cc and all other inclusion/exclusion criteria are satisfied, the patient is eligible for the study.
What is the INR cut-point for the coumadin exclusion criteria?
Normal INR at baseline. Normal is 1.0 + 0.2.
How long should be the interval between an old IVC and a new IVC before study drug administrations can continue?
A major consideration is the degree of ICP elevation. If the ICP is high and requires drainage this may determine how long before the catheter can be discontinued. A second consideration is whether the prior treatment with rt-PA increases the risk of hemorrhage from catheter insertion. We have no evidence of this in humans at this time. Analysis of the current trial data may reveal further information later after completion. Thus we have no human data to define safe practices here other than bleeding has not been a problem in our test population where therapy was started within approximately 6 to 12 hours after IVC placement.

It is worth noting that one of our participating study centers (Cincinnati, Dr. Mario Zuccarello) has developed an animal model of catheter placement. In their model, the time period from 1 to 3 hours after catheter placement should not be used for drug administration because increased peri-catheter bleeding occurs.

Thus our best answer to this question is catheters should not be used for drug administration for the first six hours after placement and at least three hours should pass between the last dose of rt-PA and the next catheter placement.
The exclusion criterion for infratentorial hematoma is unclear.
The exclusion criterion has been changed to parenchymal/posterior fossa hematoma. All cerebellar hematomas are excluded.
Can we reuse a randomization number if the patient does not receive drug?
No. Once a randomization number is assigned the patient must be followed for an intention-to-treat analysis
Do we stop drug if there is an anaphylactic reaction to another drug?
No. The anaphylaxis would be recorded as a serious adverse event and study drug administrations could continue. The coordinating center should be notified by fax within 48 hours of the event.
DNR exclusion clarification.
If a patient is DNR (s)he should not be entered into the study.
Regarding the information describing the procedure for preparation and freezing of t-PA sent to each site by the Johns Hopkins Investigational Drug Service. The "special technique" described goes a step beyond the standard sterile preparation by transferring the preparation to a sterile syringe by a "sterile pharmacist" and packaging the final product in sterile packaging. Do we have to use this procedure and if so, it will increase our costs?
When the information was sent the following statement was issued: "The following procedure is outlined according to the study protocol and Johns Hopkins Hospital policies. Preparation at your institution may vary." Our intent was not to change policies and procedures at each of the individual study centers. Study centers are free to mix the t-PA as they see fit, according to their institutions standard procedures.
Can tPA solutions be filtered during administration?
According to Genentech, the use of IV filters cannot be recommended as extensive studies evaluating different filter types and pore sizes have not been conducted. Possible protein sharing may occur when a 0.22-micron polyether sulfone filter is used.
How can I re-order drug when needed?
A supply order form has been developed for this purpose. This form was sent to the sites with the drug shipment. Contact Janet Mighty at (410) 955-6337 or by email at jmighty@jhmi.edu for additional forms.
How long after the last dose can the drain be removed?
At least 4 hours. For safety reasons we need to give ample time to watch for changes in ICP and any hemorrhage extension or new hemorrhage. If the subject has tolerated 24 hours without intraventricular drainage and you have waited 4 hours from the last dose, then it should be safe to remove the drain.

The drain should never remain in the subject just for study purposes. The drain should be removed as soon as clinically indicated and should not wait until after the next scheduled dose.
Is fever related to the administration of rt-PA?
There is nothing in the published literature to link fever with the administration of rt-PA. We are tracking temperature before each dose, during each dose, and after each dose. This is a data point we will analyze once the blind is broken.
Can a patient who tests positive for cocaine be enrolled into the study?
Yes. Cocaine-related intracranial hemorrhages occur frequently and will most likely make up a substantial number of our target population. The fact that the subject's ICH was induced by cocaine will be recorded on the case report forms.
What is the definition of infection?
Culture speciation of an organism within a CSF sample from a ventricular drain in association with 1) fever and an elevated peripheral white blood cell count or 2) greater than 25% rise in CSF white blood cell count. The associated findings are required to avoid categorizing a lab or skin contaminant as an infection.
Is missing a dose a study-stop event or a protocol violation?
Missing a dose is a protocol violation but does not preclude withdrawing the subject from the trial. The date and time the dose should have been given is documented on the case report form as a missed dose. The next dose should be given as close to the original dosing schedule as possible.
How often are CT scans performed?
CT scans are performed daily while receiving rt-PA administrations (up to 8 doses for dose-finding) plus daily for 3 days after the last dose of rt-PA is administered. A CT scan is also required at the Day 30 (dose-finding and dose-escalation) and the Day 180 follow-up visit (dose-escalation only).
Is a post-ICH evacuation patient eligible for enrollment?
No. Patients who undergo ICH evacuation are already at an increased risk of rebleed so we would not want to enroll them into this study. If a rebleed were to occur, it would be impossible to determine if the event was due to the study drug/placebo or to the surgical procedure that occurred prior to enrollment.

Last updated: March 5, 2004