For Residents and Nurses CLEAR III Trial Inservice For Residents and Nurses July, 2011

Insert local call numbers here PI: SC: Study Pager - (410) 283-8342 www.cleariii.com

Agenda History And Background General Design Of Protocol Surgical Matters Catheter Management Aspiration & Flush CT-Based Dosing Decision Making ICP Control During Dosing

the Question … Does catheter based IVH reduction alter functional outcomes in IVH survivors? The basic question is: Does catheter based IVH reduction alter functional outcomes in IVH survivors?

What We Thought Then and Now new TREATMENT knowledge 1999 “Time is of the essence” Dose 3-10mg No Dual Cath. indications Placement away from clot No rules to end dose 2010 Stabilizing probably makes rt-PA clot lysis Rx safer Dose 0.3 to 1mg Dual Cath. for big clots 2nd Cath. in clot is good 3rd & 4th, mass effect, 80% We have changed the way we think. Where we once rushed to begin dosing (with a 24-hour window), we now know that waiting probably makes the treatment safer. Where we once thought high dose levels should be important, dose-response studies taught us that doses as low as 0.3 to 1 mg are adequate, as long as test article reaches its target. Where we once rejected placement of dual catheters outright, we are witnessing that dual catheters may be useful for targeting large clots in outer regions, and that while the first catheter placement away from the clot benefits CSF drainage and ICP control, a 2nd catheter targeting the clot is of benefit without additional risk. In 1999, we were dosing until the EVD was removed, once up to 23 days. Now we know to stop when the 3rd and 4th are open to CSF flow and mass effect is treated, and for those big clots in the outer regions where a second catheter is placed, that dosing benefit continues until 80% is cleared or 12 doses total is given.

What we have learned from the Safety Trial n=48 CLEAR IVH Dose Finding Results n = 16 Clear IVH Part B n=36 A few more points about what we have learned from our 1st 100 patients in our previous trials.

Dose Finding Safety Results Doses below 6 mg/day have less bleeding 6mg n=26 23% 3mg n=36 8% 2mg n=8 0% 0.3mg n=8 0% Placebo n=22 5% Here are the exact rebleeding rates for each of the dosing groups as well as 5% for the placebo group.

CLEAR Patient Baseline Scan (t = 0) Post-treatment Scan (t = 76 hours) So here we have a case example of a typical clear patient at baseline compared to post-treatment at 76 hours. We ended CLEAR Safety, CLEAR A and CLEAR B with a good safety profile and a detectable regional dose-response……

NINDS asked: “Does this therapy improve outcome?” We can only answer this question with 500 subjects; thus, we have a Phase III Trial. NINDS asked: “Does this therapy improve outcome?” We can only answer this question with 500 subjects; thus, we have a Phase III Trial. CLEAR III focuses on outcome.

CLEAR III Hypothesis: EVD + rt-PA treatment increases percent of mRS 0-3 compared to EVD + placebo So this is the definitive Phase III trial we are doing today. And the hypothesis is: does EVD+rt-PA treatment increase the percent of mRS 0-3 patients at 180 days compared to EVD alone? www.cleariii.com

CLEAR Phase III Sample size = 500 50+ sites with neurosurgical & stroke expertise Double-blinded, Placebo-controlled, randomized trial Power assumption: 15% shift mRS 0-3 < 30 cc ICH IVH obstruction of 3rd &/or 4th In general, CLEAR III Will have a sample size = 500 We have chosen 50+ sites with neurosurgical & stroke expertise…the best in the field It is a double-blinded, Placebo-controlled, randomized trial Its power assumption is: the treatment group will have a 15% shift mRS 0-3 compared to control It is a trial of small ICH and large IVH: patient eligibility is limited to those with less than 30 cc ICH IVH obstruction of 3rd &/or 4th is required for eligibility

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 1.0 mg Test Article q8hr Dosing CT scan EVD Day 1 2 3 4 5 6 7 30 = Diagnostic = Stability = Daily PI Review * Investigator may modify CT timing based on expected endpoint 365 Following the current CLEAR III protocol, A subject presents with symptoms that indicate a CT scan. The first scan acquired that shows evidence of ICH/IVH is your Diagnostic CT scan. Once the ICH/IVH has been identified, it is standard practice according to current guidelines to place an extraventricular drain. 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 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 enrollable. Keep in mind that if a subject is not initially stable, additional scans can be done every 12 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 Stability Scan. Once stability is confirmed the patient should be consented. If enrolled, the patient is randomized to either drug or placebo q8hr. The overall dose/scan sequence is shown in the brown box below. Reading from left to right we see that we have the initial diagnostic scan, which leads to the EVD placement. After 6 hours, a stability scan is taken, and if stable the subject receives 3 intrathecal injections over the first 24 hours. At the start of day 2 a CT scan is taken to again assess stability and also the check if any study endpoints have been met; we’ll talk more about endpoints in the coming slides. Assuming the patient is stable and no endpoints have been met the patient will receive an additional 3 doses on day 2. This process is repeated out through day 4, with an additional CT scan taken on day 5. Note, while injections may be suspended or discontinued during the process, all CTs scans are required through day 5, with additional follow up scans at day 7 and day 30.

Important Exclusion Criteria CLEAR III Thursday Morning Handouts 8/13/2009 Important Exclusion Criteria Untreated ruptured cerebral aneurysm Ruptured intracranial AVM Treated aneurysm or AVM within 90 days Tumor Choroid plexus vascular malformation Moyamoya disease Other: arterial dissection, venous occlusive disease, other vasculopathies The first six exclusions center on concurrent medical conditions. We do not want to enroll patients who have an: Untreated ruptured cerebral aneurysm A ruptured intracranial AVM A treated aneurysm or AVM within the last 90 days Any brain tumor Any choroid plexus vascular malformation, or Moyamoya disease

Vascular Lesions & ICH/IVH May cause ICH/IVH at any age High prevalence in younger patients (up to 50% of cases < 50 years of age) Distribution of blood and other features on diagnostic CT may not establish/exclude satisfactorily in preparation for rt-PA

Keeping CLEAR III Safe Not designed to test safety/effectiveness of thrombolysis in the presence of cerebrovascular lesions Exclude cerebrovascular lesions Looking for exclusions is REQUIRED.

Rule Out Vasculopathies! CTA is advised in EVERY case Except renal failure OR severe allergy MRI/MRA is advised if CTA not done Tumor, ischemia or cavernous angioma is suspected Any particular question remains after CTA

The Gold Standard Catheter angiogram is advised if there is a question on CTA or MRI/MRA Consider catheter angiogram in every young patient < 50 years of age

Catheter management

Eligibility: EVD Passes EVD placed using < 2 complete passes Includes “soft passes” using the original trajectory If > 2 passes, must wait 24o for stability No significant bleeding < 5 mm or 5 cc An EVD placed using less than 2 complete passes This does include “soft passes” using the original trajectory If greater than 2 passes, wait 24o and repeat stability scan

Sometimes dosing has to be held.

Clogged Catheters rt-PA for EVD is not SOC Not FDA-approved indication Intraventricular rt-PA is being tested in this trial rtPA is the experimental test article It cannot be used off-protocol in an enrolled or to-be-enrolled, eligible subject

During screening If catheter clogs and the patient is in screening for the study, the patient cannot receive t-PA Normal saline flush is acceptable Use of t-PA during screening excludes patient from participation

During dosing – rt-PA on board If catheter clogs and needs replacement: Try to wait 24 hours (unless medically necessary)

Sometimes dosing has to be held.

Aspiration & Flush

3-way connector IVC to drainage system

CSF Aspiration Try to remove 5-10mL taking more than you need to replace creates a net reduction of CSF volume that may help with maintaining ICP control during one-hour closure. Larger aspirations allow for full flushes which may produce a wider distribution of test article in the ventricular system.

Test Article Injection Always use the port closest to the head When you cannot inject 4mL flush, inject 3mL, etc. A minimum of 2mL is required to disperse into the periclot region

Saline Flush 4mL selected to balance test article distribution ICP control.

CSF Laboratory Testing Once per day x 6 days Choose a daytime dosing time Use the isovolumetric CSF aspirated Glucose & Protein WBC & RBC count Local lab; no special supplies provided

CT-Based DOSING DECISION Making

PI Decision Responsibility Personally attend to decision relating to stability, catheter placements, and dosing decisions. Team work is critical, but all decisions ultimately rest with the PI.

CLEAR III Thursday Morning Handouts 8/13/2009 For safety, start with a 3:1 ratio dosing-to-CT Many site dose 0600-1400-2200 Obtain CT 0400-0500 am each morning 3rd/4th clearing: May increase CT frequency as clearance increases The triangles represent CT scans. The red is the diagnostic CT scan, the green, the stability scan; and the black triangles represent the daily CT scans over 4 24-hour periods., which includes post catheter removal and then again at days 7, 30 and 365. The arrows above the horizontal bar beginning with the EVD placement represent doses. For safety, please keep at least a dosing to CT ration of 3 doses to one CT. When the third and fourth ventricles are clearing and you expect an endpoint very near, then you will want to increase the frequency of CTs perhaps, one after each dose. The 3:1 rule will definitely not apply as clearance increases.

CLEAR III Thursday Morning Handouts 8/13/2009 Following a CT scan, NO DOSE SHOULD BE ADMINISTERED until the new scan (compared to previous scan) is read for: STABILITY 3RD AND 4TH CLEARANCE OTHER STUDY ENDPOINT or AE The triangles represent CT scans. The red is the diagnostic CT scan, the green, the stability scan; and the black triangles represent the daily CT scans over 4 24-hour periods., which includes post catheter removal and then again at days 7, 30 and 365. The arrows above the horizontal bar beginning with the EVD placement represent doses. For safety, please keep at least a dosing to CT ration of 3 doses to one CT. When the third and fourth ventricles are clearing and you expect an endpoint very near, then you will want to increase the frequency of CTs perhaps, one after each dose. The 3:1 rule will definitely not apply as clearance increases.

Sometimes dosing has to be held Sometimes dosing has to be held. You are permitted to hold dose for safety reasons, CT scans, adverse events, catheter manipulations. Wait 24 hours for IVC placements or catheter bleeds > 5 cc or mm For adverse events or other safety reasons, local discretion determines the number of hours to withhold the next dose.

Test Article Stopping Rules CLEAR III Thursday Morning Handouts 8/13/2009 Test Article Stopping Rules 3rd and 4th open & mass effect is treated Subjects receives 12 doses Any event the PI believes dosing should be stopped Symptomatic/clinically significant bleeding (systemic or local) Subject/family refuses further dosing Withdrawal of care It is as important to know when to stop dosing as well as when to start it. Please stop dosing when: 1. The 3rd and 4th ventricles are open & mass effect is treated 2. The subjects receives 12 doses 3. The subject or family representative refuses further treatment 4. Should there be symptomatic or clinically significant bleeding (either systemic or local) 5. Or, you may stop for any other condition where you believe dosing should be stopped. And please stop dosing if the family decides to withdrawal care. Please note that this does not mean the subject is withdrawn from the study; it means that study dosing is stopped early and then eventually the subject is early terminated due to death.

CLEAR III Thursday Morning Handouts 8/13/2009 DVT Prophylaxis Standard of care policies govern the use of low molecular weight, fractionated and unfractionated heparins during the acute treatment follow-up periods. Heparin flushes of systemic lines are also permitted Normal saline flushes be used for IVC New to protocol v3: During dosing, study center standard of care policies may govern the use of low molecular weight, fractionated and unfractionated heparins for DVT prophylaxis during the acute treatment and follow-up periods.

ICP Control during dosing

ICP Under Control If you cannot remove 5mL CSF Clamp the IVC to accumulate CSF Retry in 1 hour Use at least 2mL of flush

If ICP is High If you cannot remove 5mL CSF Establish ICP control before dosing Instill study agent (1mL) with at least 2mL of flush

During 1-Hr Closure Use additional medical management to control/maintain ICP If ICP cannot be controlled, open the IVC at a pop off of 25mmHg

Funding Acknowledgements The Intraventricular Hemorrhage Thrombolysis Trials were supported by grants FD-R-001693 (to Drs Naff and Hanley) and FD-R 002018 (to Drs Hanley and Rhoney) from the Office of Orphan Products Development, Food and Drug Administration, funding from the American Heart Association and funding from a research grant (FD- R-001693) from the Office of Orphan Products Development. Current funding for CLEAR III is supported by grants U01NS062851 and RO1NS046309 from the National Institutes of Health/NINDS, grant 272-2007 from the Eleanor Naylor Dana Charitable Trust, the Jeffrey and Harriet Legum Endowment, and materials grants from Genentech, Inc.

Questions ?