CLEAR-III CT Radiology Course

CLEAR-III CT Radiology Course
CLEAR III Meeting - Thurs Morning (2) Sept 29 - Oct 1, 2010 CLEAR-III CT Radiology Course Hemorrhage Surveillance & Protocol Decision Making Using CT Baltimore, MD

CLEAR III Meeting - Thurs Morning (2)
Sept 29 - Oct 1, 2010 Objectives Imaging studies by protocol CT based protocol decisions Taking Stability Measurements Example Subjects Checking for recurrent hemorrhage Checking for stability This module will cover the following objectives: Imaging studies by Protocol - We will take a closer look at the protocol specifically addressing the schedule of scans, and how this schedule can change depending on what you find. CT based protocol decisions – The most important aspect of this module is making protocol decisions based on the findings on each daily CT scan. Specifically, CT scans are assessed each day to decide whether to stop or continue with test article administration. Stability Measurements– We will discuss the ABC/2 method for measuring ICH volume and how to measure the blood in the most involved lateral ventricle to assess IVH stability. The GRAEB score is another useful tool to assess IVH stability but is covered in a separate training module on Emissary College. Example Subjects– Finally, we will take a close look at two example subjects demonstrating instances of instability and how to use our measurement tools to asses this. Baltimore, MD

CLEAR III Clinical Protocol
CLEAR III Meeting - Thurs Morning (2) Sept 29 - Oct 1, 2010 CLEAR III Clinical Protocol Stopping early 80% removal ICH Cath. Tract IVH Need for 2nd Cath. 6 hr CT Based Decision Making Dx CT  ICH/IVH Stability Determination Consent & Enrollment EVD Test Article q8hr Dosing CT scan EVD Day 1 2 3 4 5 24hrs post last dose 6 7 72hrs post 30 = Diagnostic = Stability = Daily PI Review * Investigator may modify CT timing based on expected endpoint 365 Using the CLEAR III clinical protocol timeline, I want to draw your attention to the protocol-required CT scans. The red triangle represents the diagnostic CT and is first scan acquired that shows evidence of ICH/IVH. For transfer patients, this CT is usually taken at an outside facility. We require that you request and upload this, even if it is from at a different institution. The diagnostic CT represents a very important time point and it is essential that we use that first CT indicating the presence of a hemorrhagic stroke. Once the ICH/IVH has been identified, if indicated, an extraventricular drain will be placed. This is a requirement for subject eligibility in the CLEAR III trial. After the EVD has been placed, another CT scan must be acquired at least six hours later. This CT, represented by the green triangle, is necessary to check for any new bleeding, or changes in the clot(s) since the Diagnostic CT and EVD placement. The most important places to check for changes in are in the ICH, IVH, and catheter tract. These three areas should be checked on all scans, not just to determine initial stability but also for ongoing stability monitoring. Once you have established that all three of these sites are stable the subject can be considered eligible. Keep in mind that if a subject is not initially stable, additional scans can be done every 6 hours until the patient meets stability requirements up until the 72 hour window from the diagnostic scan has closed. The last scan taken before enrollment is considered to be the baseline stability scan. Once the patient is randomized into CLEAR III, a CT scan is required on days 1-5, and 24 and 72 hours post last dose. If the patient receives all 12 doses, 72 hours post last dose will fall on day 7. However, if you reach a treatment endpoint after only a few doses, the 24 and 72 hour post last dose time points may fall within days 1-5, and therefore no other CTs are required until the follow-up. Another special consideration pertains to the day 1 CT. Since day 1 is the date of randomization, if a stability CT is taken on the same day that the patient is randomized, an additional day 1 CT is not necessary. If, however, you confirm stability but then randomize the following morning, it is required to get another CT on that date of randomization before test article administration. Finally, a CT scan is required at the day 30 and day 365 follow-up visits. Baltimore, MD

Making Protocol Decisions Based on CT

Outdated Clinical Definition of Rebleeding
CLEAR III Meeting - Thurs Morning (2) Sept 29 - Oct 1, 2010 Outdated Clinical Definition of Rebleeding “Rebleed” A patient with a known hemorrhage deteriorates and has a CT scan. The scan shows more blood. ** This is the old, "clinical” definition pre Novo 7 trial In order to have a clear understanding of what constitutes instability we must have a clear definition of what we’re calling a rebleed, or a recurrent bleed. The “old”, or pre-Novo 7, definition of a rebleed involves a second CT that shows more blood than a previous CT. We make the point that with only 2 CTs it is not possible to determine whether a patient ever stopped bleeding in the first place. This could be a case in which the patient was continuing to bleed from the initial injury. Baltimore, MD

CLEAR III Trial: Definition of Recurrent Hemorrhage
CLEAR III Meeting - Thurs Morning (2) Sept 29 - Oct 1, 2010 CLEAR III Trial: Definition of Recurrent Hemorrhage Stability of ICH, IVH, and catheter tract is determined. Requires comparing CTdiag and CTstability On a 3rd Scan, any new or enlarged ICH, IVH or catheter tract bleed is a recurrent hemorrhage. With our definition of what we are considering a recurrent bleed, we want to stress the point that a patient must be stable to be enrollable in the trial. Again, to prove stability we must have two scans separated by at least 6 hours that show no increase in blood in the three most important sites – those sites being the ICH, the IVH, and surrounding the catheter within tissue. After stability is confirmed, if you then observe increased blood on another scan at any point during treatment, you can confidently say that this is in fact a bleeding event as opposed to continued ongoing bleeding from the initial injury. Baltimore, MD

Primary IVH: Cessation of bleeding may be hard to define
CLEAR III Meeting - Thurs Morning (2) Sept 29 - Oct 1, 2010 Primary IVH: Cessation of bleeding may be hard to define Q: “Is IVH without ICH a predisposing condition to ongoing bleeding?” A: Possibly … Why might this be? no back pressure to bleeding 1˚ IVH may continue to enlarge longer than ICH (i.e. 12 vs. 3 hours), ref Brott & Broderick. There are additional stability concerns in patients with primary IVH. We have found that primary IVH could be a predisposing condition to ongoing or recurrent bleeding. One hypothesis for why this may be is that since the clot is is bleeding directly in the ventricle there is less “back pressure” against the bleed, allowing it to flow more freely than if it was displacing tissue to enlarge. There is evidence in previously studies by Brott & Broderick that primary IVHs continue to enlarge longer than ICHs. Baltimore, MD

Sept 29 - Oct 1, 2010 Recurrent Hemorrhage Here we have our first look at a recurrent hemorrhage. We can identify that this patient has a right putaminal ICH with IVH extension. We find that there is bilateral intraventricular blood collecting at the posterior portion of each lateral ventricle, as well as catheter tract hemorrhage that is only barely apparent on the left-hand slices, but becomes prominent on the day 5 scan on the right. Day 4 Day 5 Baltimore, MD

Sept 29 - Oct 1, 2010 Catheter Tract Hemorrhage Example Petechial < 5 mm Confluent without local mass effect <5 mm Confluent with local mass effect >5 mm Day 7 post IVC insertion Day 8 post IVC insertion Day 13 post IVC insertion We will look at a different subject to examine catheter tract hemorrhage. Here we have a closer look at an example of worsening catheter tract hemorrhage. One the left, we can just see the beginnings of a bleed around the distal portion of the part of the catheter visible in the given slice. This image was taken 7 days after the initial catheter insertion. On the next day, day 8, we see that we might have slightly more collection, and eventually by day 13 we see that we have a catheter tract hemorrhage that is greater than 5 mm in its greatest diameter with local mass effect. Baltimore, MD

Catheter Tract Hemorrhage Stabilization Algorithm
CLEAR III Meeting - Thurs Morning (2) Sept 29 - Oct 1, 2010 < 5 ml, or < 5 mm in largest diameter > 5 ml, or > 5 mm in largest diameter, with or without local mass effect Is there a new catheter hemorrhage? No Continue Treatment on Regular Schedule Yes What kind of Hemorrhage Hold next dose and obtain a CT scan 12 hours after previous scan. Discontinue Injections and get another CT 12 hours later Continue Regular Dosing and CT Schedule Here is a an algorithm that steps through the logic of the decision making when faced with a catheter tract hemorrhage. The threshold for significance in a catheter tract hemorrhage is either 5ml, or 5mm when measuring the largest diameter of the bleed. If a catheter tract hemorrhage is less than 5ml or 5mm, you can continue with the regular dosing an CT schedule, but just remember to check carefully on the following CT scans to ensure it has not enlarged over this threshold. If the catheter tract hemorrhage is greater than 5ml or 5mm, then hold the next dose and obtain a CT scan 12 hours later to check stability of the catheter tract hemorrhage. It is essential that you not administer test article to a patient with an actively bleeding catheter tract hemorrhage. If upon review of the CT scan 12 hours later, the catheter tract hemorrhage has not enlarged by 5ml or 5mm, you can continue treatment. If it still appears to be enlarging, continue with CTs 12 hours apart until you are confident that it stable. Did the hemorrhage enlarge on the follow-up scan? Baltimore, MD

Sept 29 - Oct 1, 2010 When to hold drug? Answer : Evidence of Recurrent Bleeding Catheter tract expands by > 5 ml, or > 5 mm linear diameter ICH expands by 5 ml IVH diameter expands by 2 mm in multiple locations This slide lists the instances in which you should stop giving drug and re-confirm stability before continuing. In a few slides I will discuss in detail the methods used for measuring recurrent bleeding. Baltimore, MD

Sept 29 - Oct 1, 2010 When to Stop Drug? Answer : Treatment Success Endpoints Clearance of the IIIrd and IVth ventricles 80 % clot reduction Relief of mass effect Finally, upon review of each CT you should also be asking yourself if the patient has reached a treatment endpoint. In CLEAR III there are 3 treatment success endpoints: clearance of the 3rd and 4th ventricles, 80% clot reduction, and relief of mass effect. Any one or combination of these events is an indication of treatment success and the decision to stop test article should be discussed. Baltimore, MD

Clearance of IIIrd & IVth
CLEAR III Meeting - Thurs Morning (2) Sept 29 - Oct 1, 2010 Clearance of IIIrd & IVth This slide shows an example of clearance of the 3rd and 4th ventricles. You can see the on the left pre-dosing images that both the 3rd and 4th ventricles are obstructed due to blood, while on the post-treatment scan both are open with no blood present. Pre-dosing Post Treatment Baltimore, MD

Relief of Lateral Shift
CLEAR III Meeting - Thurs Morning (2) Sept 29 - Oct 1, 2010 Relief of Lateral Shift Here you see an example of relief of lateral shift. On the left pre-dosing, the left lateral ventricle is filled with blood causing it to cross over the midline and compress the right lateral ventricle. Post-treatment you see the left and right lateral ventricles contain no blood and are back to their normal anatomic orientation with the septum pellucidum separating them along the midline. Pre-dosing Post-treatment Baltimore, MD

Methods for Assessing Hemorrhage Change
CLEAR III Meeting - Thurs Morning (2) Sept 29 - Oct 1, 2010 Methods for Assessing Hemorrhage Change ABC/2 (ICH) Ventricular Clot Measurements (IVH) Modified GRAEB Score (IVH) Since we emphasize the importance of comparing CT scans each day during treatment to check for recurrent hemorrhage, I am now going to cover 3 quick and easy methods that will help you make these comparisons. Baltimore, MD

Measure ICH Volume: ABC/2 Method
CLEAR III Meeting - Thurs Morning (2) Sept 29 - Oct 1, 2010 A Measure ICH Volume: ABC/2 Method Choose the slice for the A and B measurements. Measure the longest diameter possible. This is your A measurement. Measure the longest remaining diameter that is perpendicular to your A measurement line. This is your B measurement. Beginning at the base slice, count the number of slices in which the ICH is visible. Multiply this number by the slice thickness in centimeters. This is your C measurement. Multiply A x B x C, and then divide the product by 2. This is your ICH volume in mL (cc). A’ The ABC/2 method is used to estimate ICH volume. This is helpful when you are presented with a large ICH and need to determine if it is under 30cc, making the patient eligible for CLEAR III. It is also a useful tool to assess ICH stability from one scan to another. The first step is to select the axial slice in the series showing the largest region of ICH. The longest possible diameter on this slice will be your A measurement. On the same slice as the A measurement, measure the longest diameter perpendicular to the A measurement in cm to serve as the B mesurement. Both of these should be recorded in cm to give you a final volume in cc. The last step is to measure C. This can be done by counting the number of slices showing the ICH and multiplying that by the slice thickness in cm. The slice number (green circle on slide) and thickness (red circle on slide) can be found on the image. *If the CT has variable slice thickness (ex. starts at 2.5mm and changes to 5mm in higher slices), you can calculate C by subtracting the lowest axial table position showing the ICH from the highest showing the ICH. Table position is also present on the image. Finally, multiply A x B x C and divide by 2. Entering the A, B, and C measurements in the CT eCRF on the Vision database, will automatically calculated the volume for you, so no math necessary! Baltimore, MD

Measure IVH: Lateral Ventricle Clot Measures
Measure width of clot in most involved ventricle at anterior, middle, and posterior regions on a single CT slice Keep measurement location consistent across daily CT scans to make comparisons Increase in 2 or more locations by ≥ 2mm is significant and stability should be re-confirmed before continuing rt-PA. Stability of the IVH is a little more difficult to measure. We suggest taking measurements of the anterior, middle, and posterior portions of the IVH in the most involved lateral ventricle to assess this. The most important thing with these measurements is to keep your measurement location as consistent as possible from scan to scan. We want to emphasize also that this is a measurement of the BLOOD in the ventricle, not the entire ventricle width. We are assessing stability of the clot so it is important to remember this rule.

Diagnostic CT Stability CT
Here you see an example of these measurements on a diagnostic and stability CT from the same patient. In this example, the measurements are used to assess stability of the IVH before randomizing the patient. Make in effort to make these cross-sectional measurements in as similar locations as possible on each CT. The screen shot underneath each CT is taken directly from the eCRF. There is a place for you to record the slice number where the measurements were done and the measurement of the clot in each region in mm.

Sept 29 - Oct 1, 2010 Timeline Example Subject 1 We are now going to look at two example subjects and apply everything we just learned. This is a timeline from the first subject. You can see that they rebleed after one dose of study drug, and then died shortly after. Baltimore, MD

Sept 29 - Oct 1, 2010 Ex. Subject 1 Pre-rebleed Here we have the first scan from this patient, prior to the rebleed. You can see blood filling the left lateral ventricle, as well as an ICH in the caudothalamic groove on the left side. There is a very small amount of blood in the right lateral ventricle and no blood apparent around the catheter. Baltimore, MD

Ex. Subject 1 CLEAR III Meeting - Thurs Morning (2) Sept 29 - Oct 1, 2010 04/29/2001 04/30/2001 We always suggest that you compare consecutive CTs side by side. When doing so for this example, can you identify regions where there is new blood in the images on the right (after) compared to those on the left (before)? before after Baltimore, MD

Sept 29 - Oct 1, 2010 Post-rebleed 04/30/2001 Category: recurrent IVH + new cath. tract The first thing that is noticeable about this scan is the presence of catheter tract bleed not previously noted. Also, we can see that the right lateral ventricle is now full of blood, whereas previous it was not. Both of these are circled in red. The lessons to learn form this example are that a catheter tract can bleed and extend into the ventricles and that bleeding into the ventricles does not always lead to distention of the ventricles. This patient was a perfect example of this in that the right ventricle actually appeared more distended with CSF pre-rebleed than it did after once filled with blood. Baltimore, MD

Sept 29 - Oct 1, 2010 Example Subject 2 Here is our third and final patient example. Baltimore, MD

Timeline Sept 29 - Oct 1, 2010 The second example subject shows the importance of confirming clot stability before randomization. The vertical line on this graph represents randomization, and each point on the lines represents a different CT scan. You can see that this patient had 4 scans before being enrolled in CLEAR III. This was necessary because both the IVH and ICH significantly increased between the diagnostic and the first stability CT scan. After confirming stability of the IVH and ICH, the IVH clotted and needed to be replaced. In doing this, a small catheter tract hemorrhage developed, so stability of that had to be confirmed as well before randomizing. Baltimore, MD

Sept 29 - Oct 1, 2010 Ex. Subject 2 Diagnostic CT May 25th at 12:19 Purpose: Identify patient as CLEAR III candidate This is the diagnostic CT for example subject 2. The purpose of this scan was to diagnose the hemorrhagic stroke and identify the patient as a potential candidate for CLEAR III. Baltimore, MD

Sept 29 - Oct 1, 2010 Ex. Subject 2 Stability CT #1 May 25th at 21:31 (IVC #1 placed 5/25/10 at 14:45) Purpose: Check placement of IVC (SOC) Here is the first scan taken after the diagnostic CT and about 6 hours after an IVC was placed. You can see the IVC terminating in the right lateral ventricle. On this scan we need to check for stability of the IVH, ICH, and catheter tract. The good news here is there is no catheter tract hemorrhage present. However, just by eye-balling the IVH and ICH, it looks to be enlarged, but lets take some measurements to be sure. Baltimore, MD

Ex. Subject 2 Sept 29 - Oct 1, 2010 Here we have the two scans side by side. The red lines show the measurements of the clot in the right lateral ventricle and ABC/2 for the ICH. In this example, due to mass effect from the ICH, it was not possible to measure a middle portion in the right lateral ventricle. If this is the case, you will indicate “0” as the clot diameter for the middle portion on the eCRF, and compare the two measurements that you are able to take. These measurements show that on the second CT, both the anterior and posterior portions of the IVH in the right lateral ventricle increased by more than 2mm. In addition, using the ABC/2 method it is apparent that the ICH increased by much more than 5cc. This indicates that the patient has not stopped bleeding and it is necessary to get another CT at least 12 hours to confirm stability before enrolling. Diagnostic (5/25/10 12:19) Anterior: 16.59mm Posterior: 17.93mm ICH ABC/2: 9.49cc Stability CT #1 (5/25/10 21:31) Anterior: 18.94mm Posterior: 26.23mm ICH ABC/2: 32.10cc Baltimore, MD

Sept 29 - Oct 1, 2010 Ex. Subject 2 Stability CT #2 May 26th at 09:44 Purpose: Confirm stability IVH ICH Catheter Tract This is the second stability CT taken 12 hours after the first one, to check for stability of the IVH and ICH. Even though there was no catheter tract hemorrhage on the previous scan, we want to check the catheter tract to be sure nothing new has developed. Baltimore, MD

Ex. Subject 2 Sept 29 - Oct 1, 2010 After completing the measurements and comparing to the previous CT, we can confirm that the hemorrhage is now stable in all locations. Normally, at this point you would be ready to randomize. However, in this case the catheter became obstructed due to blood and new one needed to be placed. Stability CT #1 (5/25/10 21:31) Anterior: 18.94mm Posterior: 26.23mm ICH ABC/2: 32.10cc Stability CT #2 (5/26/10 09:44) Anterior: 17.00mm Posterior: 23.22mm ICH ABC/2: 29.46cc Baltimore, MD

Sept 29 - Oct 1, 2010 Ex. Subject 2 Stability CT #3 May 26th at 17:32 (IVC #2 placed 5/26/10 at 11:19) Purpose: Confirm Stability after new IVC placement The clogged catheter was removed and a new one was inserted around 11am on the 26th. A second stability CT was done 6 hours later to check this new placement. This stability CT shows this new IVC terminating again in the right lateral ventricle. The other remarkable thing about this scan is the presence of a catheter tract hemorrhage. Baltimore, MD

Sept 29 - Oct 1, 2010 Repeat CT >12hrs Later to Confirm Stability Comparing the third stability CT showing the new IVC placement to the one before, the ICH and IVH remain stable. However, the new catheter tract hemorrhage is greater than 5mm in diameter and requires and additional stability CT at least 12 hours later. Stability CT #3 (5/26/10 17:32) Anterior: 17.42mm Posterior: 24.92mm ICH ABC/2: 23.92cc Catheter Tract: 13.30mm Stability CT #2 (5/26/10 09:44) Anterior: 17.00mm Posterior: 23.22mm ICH ABC/2: 29.46cc Baltimore, MD

Sept 29 - Oct 1, 2010 Ex. Subject 2 Stability CT #4 May 27th at 05:30 Purpose: Confirm Catheter Tract Stability The final stability CT was done on the 27th at 5:30 in the morning, which is 12 hours after the one showing the new catheter tract hemorrhage. The purpose of this scan is to confirm stability of the catheter tract hemorrhage but it is important to measure the IVH and ICH again to make sure the bleed remained stable in those locations as well. Baltimore, MD

Sept 29 - Oct 1, 2010 Repeat CT >12hrs Later to Confirm Stability At least, on stability CT #4, we can confirm that the IVH and ICH remain stable, as well as the catheter tract hemorrhage. And now this patient is ready to be enrolled in CLEAR III! Stability CT #3 (5/26/10 17:32) Anterior: 17.42mm Posterior: 24.92mm ICH ABC/2: 23.92cc Catheter Tract: 13.30mm Stability CT #4 (5/27/10 05:30) Anterior: 17.16mm Posterior: 25.53mm ICH ABC/2: 26.92cc Catheter Tract: 12.28mm Baltimore, MD

Sept 29 - Oct 1, 2010 Lesson Measure the ventricle diameter accurately in 3 locations to check of IVH stability. Use ABC/2 to check ICH stability. Check for catheter tract hemorrhage with insertion and manipulation of all catheters. If any of these locations show increased bleeding, wait and get another CT before randomizing the patient. * Do not enroll an unstable patient Don’t give up! Most of your cases will not require such a long stability period. However, this case shows how important it is to not give up and follow that potential patient all the way though the end of the screening window. When doing this, remember to measure the ventricle diameter accurately in up to 3 locations and measure the ICH using the ABC/2 method. Even if the ICH and IVH appear stable, always check the catheter tract as well, especially after manipulation or replacement of a catheter. Baltimore, MD

Sept 29 - Oct 1, 2010 What to take home? Always compare two CT’s. Look for signs of NEW or EXPANDING: ICH, IVH, Catheter tract blood. When comparing new to old scan always ask can we stop drug now? i.e. Is the 3rd and 4th open? Is the lateral shift gone? Has 80% reduction been achieved? (Therefore, I can consider stopping drug now.) The important take home messages from the radiology training module are as follows: Always compare two CTs, looking for signs of NEW or EXPANDING ICH, IVH, catheter tract blood. We must be confident that the patient has stopped bleeding before randomization and administration of test article to ensure the safety of the subject. During the acute treatment phase, always ask yourself if you can stop drug based on the findings in the most recent CT. (i.e. Is the 3rd and 4th open? Is the lateral shift gone? Has 80% of the clot been reduced?) Baltimore, MD

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