Welcome to our MISTIE III Safety Forum September 12, 2016

Transcription

1 Welcome to our MISTIE III Safety Forum September 12, 2016 Agenda: Update from our Surgical Centers: Where we stand surgically Mario Zuccarello, MD, University of Cincinnati Revisiting the Importance of Etiology Screening Mario Zuccarello, MD, University of Cincinnati Protocol Deviations in MISTIE III Sarah Lenington, Emissary International

2 Welcome to our MISTIE III Safety Forum September 12, 2016 Agenda: Update from our Surgical Centers: Where we stand surgically Mario Zuccarello, MD, University of Cincinnati Revisiting the Importance of Etiology Screening Mario Zuccarello, MD, University of Cincinnati Protocol Deviations in MISTIE III Sarah Lenington, Emissary International

3 Surgical Summary to date

4 Surgical Summary to Date Patients Total 359 Surgical 177 (172 underwent surgery) Surgeon Status at time of surgery Pre-qualified 91 Qualified with probation 39 Fully qualified 42 Catheter Tract/ ICH/IVH Bleeds Symptomatic 7* Asymptomatic 91* * bleeds in surgical cases, only ICH/IVH expansion or CTH during active phase

5 Note: volume calculations do not include patients who had crani after catheter placement (pts included in placement analysis, not volume analysis) Surgical Summary to Date Cont d Catheter Category Trajectory A Trajectory B Trajectory C 177 SURGICAL CASES (172 underwent surgery) GOOD INITIAL 55 (70.1% of 82) 12 (35.3% of 34) 40 (71.4% of 56) 51 SUBOPTIMAL INITIAL 14 POOR INITIAL 42 CATHETERS REPOSITIONED AFTER DOSING OR REPLACED % Evacuated Absolute reduction (ml) % subjects reaching <15ml 23 (28.0% of 82) (16 dosed; 1 replaced and dosed; 1 replaced & reached endpoint) 4 (4.9% of 82) (3 replaced and dosed, 1 replaced and removed) 12 (1 replaced d/t dislodging by pt) 15 (44.1% of 34) (5 dosed; 4 replaced & dosed; 1 replaced & reached endpoint) 7 (20.6% of 34)* (5 replaced & dosed) 20 (includes 6 repositioned after dosing, 1 inadvertent pullback, 2 replaced after dosing d/t dislodging, and 1 replaced during dosing) 13 (23.2% of 56) (10 dosed) 3 (5.4% of 56) (2 replaced & dosed, 1 replaced and removed) 10 (includes 1 new catheter placed during dosing to better target remaining clot) Surgical cases that didn t go to surgery 5 (1 pt herniated overnight before surgery, taken for crani; 1 pt improved overnight so surgeon didn t take to surgery, 1 prematurely randomized, ICH <30; 1 AVM found prior to surgery; 1 pt withdrew consent before surgery) *One case, the site exhausted their resources and did not attempt to retarget the clot. One case, site did not obtain permission from family for second procedure to retarget clot.

6 Surgical Summary to Date- Cont d Good Suboptimal Poor % Evacuated Absolute reduction (ml) % subjects reaching <15ml Prequalified (n=92) 57 (62.0% of 92) 25 (27.2% of 92) 10 (10.9% of 92) Note: volume calculations do not include patients who had crani after catheter placement (pts included in placement analysis, not volume analysis) Qualified w/ probation (n=39) Fully qualified (n=41) 22 (56.4% of 39) 28 (68.3% of 41) 16 (41.0% of 39) 11 (26.8% of 41) 1(2.6% of 39) 2 (4.9% of 41) Note: 5 cases did not go to surgery so not counted here

7 Welcome to our MISTIE III Safety Forum September 12, 2016 Agenda: Update from our Surgical Centers: Where we stand surgically Mario Zuccarello, MD, University of Cincinnati Revisiting the Importance of Etiology Screening Mario Zuccarello, MD, University of Cincinnati Protocol Deviations in MISTIE III Sarah Lenington, Emissary International

8 Etiology Screening You will not see if you don t look

9 Etiology of ICH M3 is not designed to test the safety of thrombolysis in the setting of bleed from vascular or neoplastic lesion. Primary Vascular lesions can occur in elderly and hypertensive patients! Etiology screen is required in M3. Cases with ICH from aneurysm, vascular malformation, tumor, moyamoya are excluded from M3 Help us not miss ANY case where thrombolysis might be unsafe Etiology screen for M3 is a higher threshold than in clinical practice (where early versus late diagnosis of etiology might not change outcome) You (we) won t be blamed for screening, but you (we) might regret short cuts

10 Vascular Lesions and Etiology of ICH/SAH, as Learned in CLEAR III High prevalence in younger patients (up to 50% of cases < 50 years of age) May be present at any age Distribution of blood and other features on diagnostic CT may suggest, but not totally establish/exclude May include cerebrovascular malformations, aneurysms, arterial dissection, venous occlusive disease, and other vasculopathies

11 Lesions Delineated on CTA Aneurysms (>2-3mm) Cerebrovascular malformations (AVM, maybe cavernous) Occlusive arterial lesions (Moyamoya, sickle cell arteriopathy) Dilated veins (fistulae)

12 What About Spot Sign on CTA? Risk factor of ICH expansion, most commonly seen on early CTA (prior to ICH stabilization) Not a contraindication for M3, as long as the required 6 hour stabilization is demonstrated Keep a closer eye on stability!

13 What About Spot Sign on CTA? Not all spot signs are created equal! Make sure the spot sign is not a compressed aneurysm of AVM Discuss with your neuroradiologist; SC may weigh in Err on side of safety

14 Lesions Delineated on MR (MRI, MRA, Gadolinium, Special Sequences) MR can detect many of the same lesions as CTA Lesser sensitivity than CTA for AVMs and aneurysms, unless specific MRA sequences are obtained Greater sensitivity than CTA for cavernous malformations, with GRE (or SWI/Ven Bold) sequences Tumors Typically metastatic; require Gadolineum if metastasis is suspected, as with history of systemic cancer Evidence of brain ischemia on DWI (incidental versus hemorrhagic conversion)

15 What About Hemorrhagic Angiopathy on MRI? Familial CCM Hypertensive Hemorrhagic Angiopathy Not always easy to distinguish from familial CCM (lesion distribution, age, risk factors) Typically would exclude patient from MISTIE (especially if multiple hemorrhagic lesions are seen on conventional MRI sequences) SC and Study PIs will help weigh in

16 Types of Lesions Found on Catheter Angiogram Aneurysms and AVMs too small to be seen on CTA/MRA (or to confirm CTA/MRA) Indicated up front in most younger patients, especially in absence of history of untreated hypertension, or with suspicious ICH pattern/distribution

17 Practical Take Home Message on Etiology Screening CTA or MRA in EVERY case prior to dosing, unless exceptional rationale and specific exemption by PI Do CTA with image guidance CT, unless renal failure of dye allergy MRI is required in M3 (days 1 and 7) May be substituted for CTA if done prior to dosing Angiogram is advised if there is a question on CTA or MRI (consider in every young patient <40-50 years of age)

18 Arteriovenous Malformation 1 51 year old female with suspicious CTA with asymmetric vessels and no clear nidus, so angiogram done revealing an AVM Right lenticulostriate AVM with early draining vein and intra-nidal aneurysm

19 Arteriovenous Malformation 2 26 year old, underwent MRI/MRA that did not reveal a definite lesion Catheter angiogram done in view of high likelihood of etiology in young patient Angiogram confirmed small thalamic AVM and treated with embolization.

20 Arteriovenous Malformation 3 61 year old female with no definite parenchymal bleed source (primary IVH) and abnormal CTA AGE IS NOT A GUARANTEE AGAINST VASCULAR ETIOLOGY

21 Small AVM or Atypical Aneurysm 37 year old female, during screening, site considered potential AVM despite apparent negative CTA Catheter angiogram done in view of high likelihood of etiology in young patient Catheter angiogram showed either a small AVM arising from the R anterior choroidal artery, or an atypical aneurysm Excluded from CLEAR

22 Moyamoya 1 39 year old with hx of cocaine use enrolled without a CTA or other etiologic screen* CTA done after enrollment, and dosing, demonstrated basal arterial occlusions and Moyamoya collaterals Catheter angiogram confirmed diffuse Moyamoya and associated aneurysms. Dosing was stopped in patient and being followed up closely * A protocol deviation

23 Moyamoya 2 55 year old female w/ hx of pneumonia, site did CTA Moyamoya identified on CTA

24 ACom Aneurysm 34 year old patient with ICH and IVH, some basal subarachnoid extension Confirmed ACom aneurysm by angiogram and treated with coiling

25 Mycotic Aneurysm 50 year old with subtle abnormal contrast enhancement on CTA Mycotic aneurysm confirmed on angiogram and treated with coiling

26 Incidental aneurysm-allowed to enroll 62 year old female, site did CTA Site neuroradiology found suspected unrelated/unruptured aneurysm arising from the anterior communicating artery; nothing found in region of the left thalamic/basal ganglia hematoma Not excluded from CLEAR

27 CT to Inform Etiology Screen Edema suggests underlying etiology (tumor, infarct, or new on old bleed CTA alone may not address this differential Dx MRI required prior to MISTIE/CLEAR procedure

28 Post randomization diagnosis of Moyamoya 56 y/o M with hx of noncompliant HTN Platelets 208, INR 1.1 at baseline CTA reported negative Patient randomized to medical arm

29 CTA report excerpt There is occlusion at M1 segment of right MCA with reconstitution of flow just distal to the occlusion, this may represent chronic occlusion versus less likely vasospasm. Overall the caliber of the distal anterior cerebral and middle cerebral arteries is small and irregular. It is not clear whether this is secondary to vasospasm and edema, or if it is related to contrast bolus timing.

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31 2 weeks later, site did IR angiogram, definitively diagnosing the patient with Moyamoya

32 Lessons learned Site should consider possible etiology factors even when not spelled out by CTA. Basal occlusive disease should have suggested Moyamoya. SC and study leadership cannot weigh in if a study is uploaded as negative. We cannot divine that there was basal occlusive disease, nor independently read negative scans It is imperative that site PI views and clears all etiology scans

33 Importance of etiology screening 54 y/o male History included HTN, diabetes, prior smoker, BP up to 250/115 on admission CTA done, read as negative PI stated CTA suggested suspicious etiology so scheduled cath angio Found AVM, pt screen failed Risk factors alone are not enough to exclude vascular etiology Dural Arteriovenous Fistula

34 Welcome to our MISTIE III Safety Forum September 12, 2016 Agenda: Update from our Surgical Centers: Where we stand surgically Mario Zuccarello, MD, University of Cincinnati Revisiting the Importance of Etiology Screening Mario Zuccarello, MD, University of Cincinnati Protocol Deviations in MISTIE III Sarah Lenington, Emissary International

35 In the MISTIE III Study

36 Definition A deviation is any deviation from the protocol even if unavoidable or it occurred without any fault on the part of the site. Some deviations may occur for very good reasons, e.g. The protocol specifies that each patient needs an MRI at screening and on D7. However, MRI may be counter-indicated for a particular patient or a patient may not be able to tolerate the exam, so it is not done. This is not the fault of the site, but it is still a protocol deviation.

37 Reasons for Tracking Protocol Deviations According to the FDA Guidance for Good Clinical Practice The investigator, or person designated by the investigator, should document and explain any deviation from the approved protocol. It helps us plan future studies when we can see what parts of the protocol seem to pose consistent obstacles for sites. It helps us identify those protocol deviations that may have serious implications for patient safety or the validity of the study.

38 Types of Protocol Deviations Deviations can be classified as Major or Minor: Major: a deviation that may have a significant impact on the safety of the patient or the scientific validity of the study. Minor: a deviation that will NOT have a significant impact on the safety of the patient or the scientific validity of the study.

39 Major Deviations that Affect Patient Safety Not meeting I/E criteria when randomized No surgical center review Dosing without stability Not monitoring INR or platelets during dosing. Dosing when INR > 1.4 Dosing with platelets < 100,000 will be added to protocol v. 5 Less than 6 hours between doses Administering rt-pa greater than 1.0 mg/1.0 cc at any one dose Daily CT scan not done on schedule when dosing Continuing dosing after study treatment endpoint Catheter manipulation within 24 hours of dosing Administration of prohibited meds during specified time periods SAE not reported within 24 hours of knowledge of the event.

40 Major Deviations that Affect Scientific Validity Not meeting I/E criteria when randomized Insufficient flush/excessive flush Day 180 visit OOW Rankin video not done Surgery not performed in a surgical patient (family withdrew consent, emergency craniotomy needed) Uncertified personnel performing study-specific procedures Missed Day 30, Day 180 and Day 365 follow-up visits

41 Deviations in First 337 Patients* * 1.7 deviations/subject

42 Most Common Major Deviations Administration of prohibited meds (aspirin or full dose heparin) during specified time period Missed INR or PLTs during dosing SAE not reported within 24 hr

43 Most Common Minor Deviations Missed lab assessments (medical patients) Missed CTs (other than those missed during dosing) Missed MRI Catheter removed OOW Follow-up visit (other than D180) OOW Antibiotic prophylaxis not given for entire time catheter was in place No catheter tip culture Secondary Outcome assessments missed during FUV

44 How to Handle Protocol Deviations (EDC Entry)

45 How to Handle Protocol Deviations (IRB Reporting) The written procedures for this study, require that all Major deviations be reported to the IRB as soon as the deviation occurs. Minor deviations may only need to be reported in the annual report the site gives to its IRB.

46 How We Plan to Handle Protocol Deviations There are two issues of particular concern: Reporting the Major Protocol Deviations to the IRB Our monitors, Sarah and Nicki have sent sites an listing all the Major Protocol deviations that have occurred at that site. Sites that have an unusually large number of deviations (even if they are minor). This raises concern that the site may not be aware of all the details on the protocol. These sites will be contacted by their Site Manager with a CAPA plan and be required to attend a webinar on the protocol.