Emissary College

Knowledge is the key to a successful clinical trial!

 

MISTIE-III Protocol Course

 

Course Summary

COURSE SUMMARY

This course discusses the MISTIE-III protocol.

Time required: 1 hour.

 

INTRODUCTION

This presentation will give you a detailed overview of the protocol requirements and a foundation on which to build a successful MISTIE III experience with your first enrollment. The presentation includes accompanying slides that can be used for a review or in-service. After completing the course, be sure to take the quiz and save the PDF-format certificate to your local computer for subsequent uploading to the Electronic Trial Master File (eTMF).

 

PROTOCOL OVERVIEW

This is the MISTIE III study protocol at a glance (click to enlarge). Subjects randomized to either group will follow the same general pathway with surgical subjects usually receiving the MIS procedure on day 1 followed by rt-PA administrations on days 1-4. This schedule can vary if there is a delay due to stability protocols or OR scheduling. All subjects will undergo stability CT protocols prior to randomization, standard medical management, daily CTs, lab assessments and neurochecks throughout the acute period of the protocol, which is defined as days 1-6. All subjects, regardless of treatment assignment will be followed up through Day 365.

The full Schedule of Events from the protocol is below (click to enlarge). The remainder of this course module will describe each of these columns and rows.

 

REGISTRATION AND SCREENING

Screening

Early notification is important! Educating emergency department staff and residents will establish a notification network and assist in early identification of potential subjects. Practice a neurosurgical patient flow pathway to identify possibly barriers to recruitment and protocol logistics. This will prepare everyone to be ready when that first subject arrives. All subjects with ICH presenting to your site should be screened for enrollment into the trial.

Registration is the start of the screening process and begins when the study team is notified of a potentially eligible subject. All screening evaluations for eligibility should be done during the screening period but must be completed PRIOR to randomization.

Diagnostic CT

The Diagnostic CT is the first CT done that diagnoses the ICH. The date and time of this CT scan is time 0 for the 72 hour window for the initiation of surgery and the 76 hour window for administration of the first dose. The protocol will be amended to allow for a 6-hour stabilization period after surgery extending the window for the first dose to 79 hours after diagnostic CT. The diagnostic CT scan must be done within 24 hours of symptom onset. An unknown time of onset is exclusionary. 

The diagnostic CT can be done with or without contrast. The scan will be reviewed to determine the size of the ICH, and to assess if there is infratentorial involvement, and to rule out suspicion of underlying pathology. The ICH as measured by ABC/2 on this scan must be ≥ 30 cc for the patient to be eligible. Presence of infratentorial bleeding excludes the patient from randomization. This includes thalamic bleeds with apparent midbrain extension with third nerve palsy or dilated and non-reactive pupils. Other (supranuclear) gaze abnormalities are not exclusions. Patients with a posterior fossa ICH or cerebellar hematomas are not eligible to participate in this trial.

If this CT scan was done at an outside hospital ED where the patient first presented, you will need to obtain a copy of the DICOM images for upload to the electronic data capture (EDC) system. (Please see the Radiology module for more information related to uploading images.) Typically the CT is repeated upon presentation to the enrolling center from the outside hospital ED. This repeated scan is considered a stability CT and does not replace the need to obtain the outside hospital scan.

Blood Pressure Control

The patient's blood pressure must be stable to be eligible for randomization. Blood pressure stability is defined as SBP < 180 mmHg sustained over a minimum of 6 hours prior to and closest to randomization. Aggressive blood pressure management to maintain SBP < 180 mmHg will be required throughout the first 6 days of the ICU stay to reduce the risk of bleeding events with the long-term control goal of MAP < 100 or 140/80 mmHg. Transition to long-acting, oral medication(s) should occur as soon as blood pressure control is achieved to initiate long-term control and to minimize the chance of rebound hypertension.

Pregnancy Test

Female patients of childbearing ability (defined as of childbearing age and not surgically sterilized) must have a negative urine or serum pregnancy test to be eligible. If this test is not done per standard medical care at your institution, obtain informed consent prior to ordering the test.

Women who are enrolled and become pregnant during the follow-up period will be followed through the month 12 (Day 365) visit to document clinical and functional outcome but no CT scans will be done.

Toxicology Screen

The toxicology screen is done to document any chemical substances in the blood, namely cocaine and barbiturates, which may have contributed to the onset of the hemorrhagic stroke. This screen should be done as close to the time of presentation as possible so the test is not capturing substances given to the patient as treatment.

If a toxicology screen is not done as part of standard medical care at your institution, obtain informed consent prior to ordering the screen.

NOTE: The results of the tox screen are for data collection purposes only and do not determine the patient's eligibility for the study.

Laboratory Assessments

In addition to the tox screen and pregnancy test (if applicable), platelet count and INR will need to be ordered or reviewed if already done to determine eligibility. The INR must be ≤ 1.4 to be eligible and must remain at this level during dosing.

Additionally, as a potential treatment response covariate, a lab assessment of plasma plasminogen activity and fibrinogen will be collected either at screening or otherwise immediately prior to randomization following informed consent. Results of these lab assessments are not used to determine eligibility.

The results of daily white blood cell count, hematocrit, platelet count, aPTT, and INR will be reviewed and documented in the EDC.

Concomitant Treatments

All concomitant medications administered that are inclusive of the drug classes of interest and procedures performed during the period following randomization through day 6 will be documented in the medical record and in the EDC. Drug classes of interest include but are not limited to: anti-hypertensives, sedatives, hypnotics, hematologic modifiers, antiplatlet and anticoagulant medications, antibiotics and any other medication used to treat a neurological adverse event or any serious adverse event. Medications used to treat a neurological adverse event or any serious adverse event will be recorded in the EDC through day 365.

NIH Stroke Scale (NIHSS)

After informed consent is obtained, a certified examiner should complete an NIHSS to determine eligibility. NIHSS score must be ≥6 (or a GCS ≤14) for the patient to be eligible (including distal arm scoring). The NIHSS must be done at or as close to the time of presentation for screening and then repeated at the time of enrollment to confirm eligibility.

Barthel Index (BI)

A historical Barthel Index score should be obtained as part of the screening procedures through patient observation, medical chart review, and interview with the subject, subject's family/friends, treating physicians and nurses. This historical score does not determine eligibility and is based on the patient's level of functioning prior to the onset of symptoms and will be used in a comparison with scores obtained at 1, 3, 6, 9, and 12 months.

Modified Rankin Scale (mRS)

A historical modified Rankin Scale score should be obtained as part of the screening procedures through patient observation, medical chart review, and interview with the subject, subject's family/friends, treating physicians and nurses. The patient must have a mRS score of 0 or 1 to be eligible for the study. This historical score is based on the patient's level of functioning prior to the onset of symptoms and will be used in a comparison with scores obtained at 1, 3, 6, 9, and 12 months.

Post Consent Screening

As mentioned previously informed consent should be obtained prior to ordering any procedures that are not considered standard of care at your institution. We've already discussed the procedures listed on the left. 

During the screening process and after consent, the patient's medical and treatment history must be documented to rule out exclusion criteria (such as serious concurrent illness, clotting disorders, known risk for embolization, etc). 

An MRI/MRA will be done to rule out underlying cerebrovascular or brain pathology and to assess edema and cerebral ischemia. If the time window is short or if MR is contraindicated, a CTA should be done at the time of the stability CT and then an MRI done if possible before the first dose of rt-PA for patients randomized to surgical management or an equivalent time on day 1 for patients randomized to medical management. MRI sequences should include T1, T2, DWI, and GRE. In addition, CT angiogram or routine angiogram with evaluation for "spot sign" is encouraged and considered standard of care to complete the evaluation for aneurysm, AVM, or other malformations.

Inclusion Criteria

Most of the screening procedures we just discussed are used to determine if the patient fulfills the inclusion and exclusion criteria.

Patients must satisfy the following inclusion criteria to be eligible:

Patients must have had a spontaneous supratentorial ICH ≥30 mL as determined by the ABC/2 method and diagnosed using radiographic imaging (CT, CTA, etc), known as the diagnostic CT. The patient must be a GCS of ≤14 or have an NIHSS of ≥6.

Stability of the ICH clot is determined by repeat CT 6 or more hours after diagnostic CT. The clot size must not be larger than the most previous clot size by >5 mL as determined using the ABC/2 method. If the clot has grown by more than 5 mL, stability CT scans can be repeated every 12 or more hours until stability is achieved or until the randomization window closes.

Symptom onset must have occurred within 24 hours prior to the diagnostic CT. An unknown time of onset is exclusionary. When determining symptom onset time, do not simply rely on a note in the medical record. Interview all available family, friends, and medical staff to determine an accurate timeline of events prior to hospital presentation. The time of ICH symptom onset is time-zero for the 24-hours-prior-to-diagnostic CT window. If a patient awoke with symptoms after going to bed, the time of onset would be the time last seen without symptoms. 

When screening you should always assume the subject will be randomized to surgery so that everything is in place should this occur. OR and neurosurgical staff should be available to initiate the MIS procedure within 12 to 72 hours of the diagnostic CT. Pharmacy should also be available to prepare the first dose to be given within 76 hours of the diagnostic CT. (The protocol will be amended to allow for a 6-hour stabilization period after surgery extending the window for the first dose to 79 hours after diagnostic CT). Delays for post-surgical stabilization of catheter tract bleeding or because of unanticipated surgical delay are acceptable with an approved waiver from the coordinating center.

As discussed earlier the SBP must be maintained below 180 mmHg for the six hours closest to the time of randomization, the historical modified Rankin scale score must be 0 or 1, and the subject must be between the ages of 18 and 80, inclusive.

Exclusion Criteria

To be eligible, patients must not have any of the following:

Infratentorial hemorrhage or bleeding below the tentorium will exclude a patient. Patients with thalamic bleeds with apparent midbrain extension with third nerve palsy or dilated and non-reactive pupils are excluded. Other, such as supranuclear, gaze abnormalities are not exclusions. Patients with a posterior fossa ICH or cerebellar hematomas are not eligible.

Irreversible impaired brain stem function indicated by bilateral fixed, dilated pupils and extensor motor posturing with a GCS of ≤4 is exclusionary. 

If IVH is present, the patient must not require placement of an extraventricular drain to treat the IVH. Placement of an EVD for treatment of high ICP does not exclude a potential patient.

The MRI/MRA done prior to randomization must not show a ruptured aneurysm, arteriovenous malformation, vascular anomaly, or Moyamoya disease. Also, patients with unstable mass or evolving intracranial compartment syndrome on imaging are excluded.

Patients with a known clotting disorder or any irreversible coagulopathy are excluded. Specifically, patients with a platelet count of <100,000, an INR >1.4, or an elevated prothrombin time or activated partial thromboplastin time are excluded unless the abnormal lab can be reversed and sustained. 

Subjects requiring long-term anti-coagulation are excluded. Reversal of anti-coagulation is permitted for medically stable patients who can realistically tolerate the short term risk of reversal. The patient must not require Coumadin (anticoagulation) during the first 30 days, and normalized coagulation parameters must be demonstrated, monitored closely, and maintained during the period of brain instrumentation.

The patient must have a sustained INR ≤1.4 using short- and long-acting procoagulants [such as but not limited to Novoseven, FFP, and/or vitamin K].

If a patient was taking Dabigatran prior to symptom onset, then the patient is excluded due to the difficulty of effectively reversing the effects of this medication.

The patient must not have active internal bleeding involving the retroperitoenal sites or the gastrointestinal, genitourinary, or respiratory tracts. Active superficial or surface bleeding, observed mainly at vascular puncture and access sites or site of a recent surgical intervention is exclusionary.

As discussed earlier, pre-menopausal female patients without a documented history of surgical sterilization must have a negative positive urine or serum pregnancy test.

The patient must not have a known allergy or sensitivity to rt-PA, cannot have previously participated in MISTIE III, and cannot be planning or enroll in another interventional medical investigation or clinical trial through day 30. Patients in observational, natural history, and/or epidemiological studies not involving an intervention are eligible.

Subjects who are not expected to survive to the day 365 visit due to co-morbidities and/or are DNR/DNI status prior to randomization are excluded.

The patient must not have any concurrent serious illness that would interfere with the safety assessments including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, immunologic, and hematologic disease. 

Patients with a mechanical heart valve are excluded due to the need for anti-coagulation.

Patients must not have a known risk for embolization, including history of left heart thrombus, mitral valve stenosis with atrial fibrillation, acute pericarditis, or subacute bacterial endocarditis.

The investigator can exclude a patient for any other condition he or she believes would pose a significant hazard to the patient if the investigational therapy were initiated.

The investigator can exclude a patient for known alcohol or drug use or dependence that would interfere with adherence to study required follow-up visits.

The investigator can exclude a patient if he or she feels that the subject is unstable and would require surgical intervention rather than support care plus or minus MIS + rt-PA.

Lastly and obviously, if the patient or the legal guardian or representative are unable or unwilling to give written informed consent, then the patient is not eligible.

 

ACUTE TREATMENT

Randomization

Patients who meet all of the inclusion and exclusion criteria using the screening procedures we've just discussed and who provide informed consent will be randomized to receive either conventional medical management or MIS plus rt-PA. 

Patients will be randomized using a covariate-adaptive design, which is discussed in detail in the Randomization Training Module. The screening and randomization process is the same for all patients and making the adaptive randomization process transparent.

Randomization should occur as close as possible to the time that all eligibility criteria are met. If randomization is postponed to accommodate scheduling, then a CT scan should be repeated to confirm stability of the ICH and blood pressure stability should be confirmed prior to initiating the surgical procedure if randomized to the MIS plus rt-PA intervention. The surgical intervention should be initiated as close to randomization as possible.

Post-Randomization/Pre-Surgery

The screening lab assessments, documentation of concomitant medications/treatments, NIHSS, historical Barthel Index, and historical modified Rankin Scale should have already occurred during screening. If not, then these should occur prior to the subject receiving any study interventions.

Day 1 (Day of Randomization)

Now that the subject is eligible and randomized they have entered the acute treatment period defined as the 6 days post randomization. Day 1 is always defined as the date of randomization to allow for comparison between the two groups.

Medical Management

Subjects in both groups will be treated medically using standard ICU protocols that are found in Appendix 3 of the protocol. This includes but is not limited to the following guidelines:

  • Placement of an ICP monitor is recommended for subjects demonstrating obtundation, which we define as GCS ≤8 on a minimum of two observations over 8 hours. 
  • ICP monitor would ideally be placed prior to rt-PA administrations or at least three hours after dosing. 
  • A new CT scan must be obtained after ICP monitor placement to assess stability of the current hemorrhage and to monitor for any new bleeding. 
  • ICP should be monitored every 4 hours with routine zeroing and recalibration of the system. 
  • The goals of ICP management are to sustain intracranial pressure below 20 mmHg and to improve the patient's level of consciousness.

Neurological status will be assessed every 4 hours using GCS scoring. A neurological deterioration or neuroworsening will be defined as any GCS decrease of >2 points on the motor scale sustained for eight hours without sedation. Daily attempts to discontinue sedation will be made. A daily neurologic exam is recommended to be coordinated with this attempted sedation withdrawal.

Cardiovascular management will be directed towards the goal of maintaining blood pressure ≤160/90 during active treatment in the first week with a goal of reaching and sustaining blood pressure of 140/80 as rapidly as clinically possible. Utilizing long acting oral and supplementary IV medications to achieve this goal is encouraged.

Respiratory care will be directed at promoting adequate oxygenation without airway compromise, with full pulmonary inflation, and with oxygenation ≥90% on room air or supplemental O2 by face mask of 28% or less.

Nutritional support will consist of optimal calories, defined as ≥30 kcal/kg an d1.5 gm protein/kg. Feeding will be achieved by the least invasive means necessary, but with the goal of reaching full nutritional support by no later than day 7 of illness.

Deep venous thrombophlebitis and pulmonary embolus prophylaxis will be undertaken on the day of admission with the use of sequential compression devices. For patients at high risk of thromboembolism, low dose subcutaneous heparin can be initiated 72 hours after termination of intracerebral rt-PA therapy for those subjects randomized to surgical management. In the interest of patient safety, therapy may be initiated sooner than 72 hours after last dose of rt-PA at the discretion of the site PI but this will be documented as a protocol variation.

Withdrawal of care discussions of prognosis and decisions to continue or limit, or to withdraw, life-sustaining interventions will be conducted according to each institution's policies for end-of-life decision-making, as well as their institutional codes of medical ethics. The study assumes any such discussion will reflect the patient's wishes and the known facts regarding prognosis. Where the PI is not the managing physician, it is assumed that those individuals will confer prior to presentation of the consensus prognosis and planned course of treatment. In some situations, the investigator may choose to select a colleague to serve in the clinician role or request a review by the hospital's ethics committee or other knowledgeable expert.

MIS Procedure

There is a separate training module to be completed by the neurosurgeon as part of the credentialing process. Please see that module for an in depth overview of the actual procedure.

Only neurosurgeons credentialed by the Surgical Center may perform the MIS procedure. The neurosurgeon will review a 3D reconstruction of the ICH on the CT scan to determine the burr hold location, catheter trajectory, and hematoma target to be used. The images will be uploaded for Surgical Center review. See the Radiology training module for more details regarding review of this scan and uploading of DICOM images. Surgical center personnel will review the 3D images in real-time (within 3 hours of data submission) and confirm the selected burr hole location and trajectory or to recommend a different location and/or trajectory. The site neurosurgeon has the option to either proceed with the proposed surgical plan or to follow the Surgical Center recommended plan.

Antibiotic therapy should be administered pre-operatively (hospital protocol or 1 to 2G Ancef IV, dose is subject-weight dependent), then repeated every 8 hours until the catheter is removed (hospital protocol or Ancef IV 1G every 8 hours). If the subject has a known or suspected penicillin drug allergy, then antibiotic coverage will be administered pre-operatively and continued with each institution's non-penicillin drug of choice until the catheter is removed.

The procedure will be performed in either the operating room, in a procedural CT or MRI scanner, or in the ICU using image guidance. A post-catheter placement CT should be done after the MIS procedure is complete and the catheter is secured to measure clot size reduction as compared to the volume measured on the stability CT scan. These images will be uploaded to the EDC for Surgical Center review and approval prior to rt-PA administration. 

After placement of the catheter a six-hour post-surgical stabilization period is required prior to the first injection of rt-PA. The current protocol states that this is a 3-hour stabilization period but effective immediately and to further enhance patient safety, this period is now 6 hours. This change will be reflected in the next version of the protocol. Keep the drainage system to drainage for three hours post catheter placement prior to first dose of rt-PA. This time is mandated to reduce the possibility of secondary hemorrhage.

Catheter adjustments/replacement prior to dosing require a repeat stability CT, review by the Surgical Center and 6-hour stabilization period. Catheter adjustments/replacement during dosing must be done ≥24 hours after the most recent dose and all stability protocols and Surgical Center review repeated as if this were the original catheter placement. 

Review of Systems Post Surgery

The neurological status of the subject will be assessed three or more hours after the MIS procedure to document clinical worsening or improvement.

Dosing

There is an entire separate training module to be completed by the neurosurgeon, neurocritical care physician, and their trained designee(s) as part of the dosing credentialing process. Please see that module for an in depth overview of the dosing procedure.

Who

  • A neurosurgeon or neurocritical care physician or their trained designee will perform rt-PA injections under standard sterile technique. Viewing the Coordinating Center video demonstration of catheter injection protocol is mandatory before credentialing a center's physicians and coordinators. 

What

  • Randomized subjects will receive injections of 1.0 mg/1.0 mL of rt-PA followed by 3.0 mL of flush via the catheter every 8 hrs for up to 9 doses. 

Where:

  • Injections will be done bedside.
  • Daily, before dosing, the investigator will be required to view the most recent CT scan, confirming that the catheter tip is placed in an appropriate location within the clot. This requirement will help restrict the delivery of test article to clot that can be lysed.

When

  • The first dose will occur no sooner than 6 hours after catheter placement and no later than 79 hours after the diagnostic CT scan and only after confirming appropriate catheter placement and clot stability by head CT. 

 How

  • All manipulations of the system will be performed using sterile technique. There is a demonstrated low incidence of infection associated with this procedure. 
  • Intracranial pressure (if monitored) and blood pressure will be monitored before, during, and after each injection. After injection, the catheter will be closed for 1 hour to prevent drainage of the drug away from the clot and to allow adequate time for drug-clot interaction. The catheter will be reopened within that initial hour only if medically necessary. Medically refractory ICP will be treated by a standardized regimen of hyperventilation, osmotic therapy, diuresis, and pharmacological sedation before opening the catheter prematurely. After 1 hour of closure, the catheter will be opened with an appropriate drainage gradient. After the last dose the catheter will be closed for one hour and then reopened to drain for 24 hours to allow for complete removal of test article. 
  • Each dose administration should be documented in the Medical Administration Record of the medical record as source documentation. A progress note should also be written in the medical record as source documentation to record the date and time of each dose, the amount of drug administered, the amount of flush administered, the time the catheter was closed and reopened, the ICP (if monitored), SBP, and DBP prior to the dose and prior to reopening the catheter, and the name and title of the person who administered the dose. 

Dosing Eligibility

A CT scan is required daily on days 1 through 4. During dosing, all patients must receive a minimum of one scan per day, preferably in the morning, but at least after every three doses are administered. This CT scan will assist with monitoring for clot lysis and asymptomatic bleeding. The CT should be reviewed for clot stability and clot resolution to decide if further dosing should continue. 

The catheter tract must also be reviewed on the daily CT scan to determine if there is a new onset or expansion of catheter tract hemorrhage.

 

So how do you decide if you should interrupt or stop dosing? 

  • The ICH volume is reduced to 10 to 15 ml or approximately 20% of the initial clot volume as measured on the stability CT scan.
  • If the subject receives all 9 doses, then dosing is discontinued after dose number 9 is administered. 
  • If there is symptomatic bleeding during dosing, dosing will be discontinued immediately. As a reminder, obtain an unscheduled CT scan if the subject's GCS motor scale score deteriorates by 2 or more points for 8 hours, or sooner if clinically indicated. 
  • If catheter tract bleeding occurs or expands and is more than 5 mm or 5 cc as compared to the most previous CT, the next dose is skipped and a CT scan is done 24 hours later. If the bleeding is stable, grows again by < 5 mm or 5 cc, then dosing may restart. 
  • Use clinical judgment for dosing suspension or discontinuation if there is asymptomatic expansion of the ICH clot, or IVH clot if present.  
  • Additional ICH or IVH bleeding, a disseminated systemic bleeding event, or in the opinion of the investigator any drug-associated event will be considered an endpoint for drug administration. 
  • Uncontrolled coagulopathy defined as INR >1.4
  • Document your decision to continue or stop dosing based on the criteria above. 

Days 2 and 3 (Post Randomization)

If remaining clot volume is ≤10 mL of the initial clot volume, rt-PA should not be given. The current protocol also calls for dosing discontinuation if the remaining ICH is <=20% of the initial clot volume. This dosing endpoint will be removed from the next version of the protocol. The catheter should remain in place and open to drain for a minimum of 24 hours after the last dose prior to removal.

All subjects will have CT scans on days 1 through 4 regardless of treatment assignment and regardless of when dosing is discontinued. Daily CTs are reviewed for clot and catheter tract stability during dosing. Vital signs and neurochecks are to be monitored for improvement and deterioration. Lab assessments are done daily for safety and concomitant treatments are documented.

Daily Safety Labs

Serum samples will be collected and assessed at your local clinical laboratory. The screening samples were discussed earlier. The baseline serum samples are drawn just prior to the first dose. The remaining labs are drawn daily through post-randomization day 6. Labs should be drawn more frequently using clinical judgment in situations of bleeding or infection. 

Collect daily serum samples with the am labs. This way if a sample is corrupted, (e.g., the blood sample is hemolyzed), there is time to draw a new sample.

Baseline and daily serum labs are white blood cell count, hematocrit, platelet count, INR, PT, aPTT, plasminogen, fibrinogen, and d-dimer. The daily INR must remain < 1.4 for dosing to continue. 

All lab results should be reviewed daily for safety. Unfavorable, clinically-significant laboratory findings (even those not collected for the study) should be recorded on the adverse event form if a diagnosis/etiology for the lab finding has not already been documented as an AE or Concurrent Condition. 

Record the etiology for any abnormal lab findings on the Concurrent Conditions/Procedures form.

Any missed lab assessment will be documented as a protocol deviation.

Days 4-6 (Post Randomization)

The CT on day 4 is the last day for daily CT unless dosing will continue past day 4. Additionally as mentioned earlier, the catheter is open to drain for 24 -36 hours after the last dose and then removed. 24 hours after the catheter is removed a CT scan is done to look for catheter tract and clot stability. Vital signs, neurochecks, lab assessments, and documentation of concomitant treatments continue through day 6. 

 

FOLLOW-UP

Day 7 (Post Randomization)

On day 7 an MRI is obtained to compare with the MRI done prior to first dose. The MRIs will be compared and reviewed by the Reading Center for edema and ischemia.

An NIHSS should be done by a certified examiner. This NIHSS will be compared to the NIHSS done at randomization during the final analyses.

Follow-up (Post Symptom Onset)

Again, there is an entire separate presentation on the outcomes assessments so we're not going to spend time on these during this presentation. The time points, windows, and assessments are summarized here.

Resource Utilization

Statistical analyses will compare treatment groups on length of ICU stay, length of hospital stay, and time at home (not in hospital or rehab) to determine quality of life and secondary efficacy.

This information should be updated at every follow-up visit to gain an accurate picture of the amount of time the subject spends at home, out of the hospital and rehab

Concomitant Medications

Starting at the time of symptom onset, list any medications the patient received within 7 days of symptom onset if those medications are from any of the specified drug classes on the Concomitant Medications form (see Protocol tab). 

All concomitant medications administered during active treatment (randomization through day 6) that are inclusive of the drug classes of interest will be recorded on the case report forms. This includes, but is not limited to: anti-hypertensives, sedation, blood products, antiplatelet and anticoagulant medications, antibiotics.

Document any medication used to treat a neurological adverse event or any serious adverse event through Day 365. 

Required Interventions. All subjects randomized will receive up to 9 doses of study drug. Any subjects who are randomized and receive the first dose of study drug will be followed and analyzed as intent to treat.

Prohibited Interventions

During the follow-up period (72 h post last dose of study drug through the 12 month visit), avoid enoxaparin at therapeutic doses >1.0 mg/kg sc Q12 h. Subsequently, use of enoxaparin for DVT prophylaxis in the ICU at the usual doses of 30 mg sc Q12 h or 40 mg sc QD is permitted as long as the patient has good renal function (creatinine clearance of > 30 ml/min) or does not have an unusually low body weight (< 45 kg). 

After the Day 30 follow up visit other antithrombotic and antiplatelet agents such as Coumadin (warfarin) and Dabigatran, glycoprotein IIb/IIIa inhibitors (eptifibatide/Integrilin, abciximab/Reopro, tirofiban/Aggrastat), ASA, clopidogrel/Plavix may be administered. 

The use of Urokinase, Retevase, Desmoteplase, Tenecteplase or any other thrombolytic agent administered via any brain catheter is prohibited. Clogged catheters should be treated with normal saline flushes.

Precautionary Interventions

If the catheter needs to be replaced, a stability CT scan must be performed > 6 h after all placements to confirm correct placement, clot stability, and absence of significant blood along the catheter tract. Once these are confirmed, dosing may start/restart.

If a subject experiences an asymptomatic catheter tract hemorrhage that is < 5 mm in the largest diameter, continue the dosing and CT schedule. If the catheter tract hemorrhage is > 5 mm in the largest diameter, with or without mass effect, the next scheduled dose is skipped and a repeat CT scan is done > 24 h after the previous dose. If the catheter tract hemorrhage is stable (i.e., has not further grown by > 5 mm), then dosing may restart.  

Particular caution needs to be observed with renal dialysis patients receiving rt-PA. Because this group of patients can experience wide variations in blood pressure with dialysis attendant cardiac volume changes, attention to long term and intra procedure blood pressure control is important. Similarly, attention to regional anti-coagulation management is important.

AE & SAE Reporting

Please review the Safety Reporting presentation for more information regarding adverse and serious adverse events.

Daily monitoring of all adverse events will continue until day 6. This includes monitoring of additional medications used and additional procedures and ICU care required.  Serious adverse events will be monitored throughout the initial hospitalization.  Serious adverse events and neurological adverse events only will be recorded at all subsequent follow-up visits. 

All suspected unexpected serious adverse reactions will be reported to your site for submission to your IRB. The coordinating center will prepare a safety report detailing the SUSAR. In addition, Annual safety reports will also be sent to your site for IRB submission.  

Final Visit

At the subject's final visit to occur at approximately 12 months post ictus, the following will be done: modified Rankin Scale, NIHSS, Barthel Index, extended GOS, and Stroke Impact Scale. Also at this time the subject will be asked about any new neurological adverse events or any serious adverse events that may have occurred since the nine-month telephone contact. The subject will also be specifically asked about any neurosurgical procedures. All serious and non-serious adverse events that occurred prior to the 12 month visit but remain documented as "ongoing" will be confirmed as "ongoing" or documented as "resolved" and a resolution date recorded. The examiner will document if the subject was prescribed and is compliant with any blood pressure medications at the 6 month visit and document if any of the following have occurred since the three-month telephone contact: death, new bleeding on CT, bleeding extension on CT, surgical site infection, or cerebritis. The subject will be instructed that this is the final visit.

 

Additional Resources, and Training Materials

Here is the the full set of slides for this module. Alternatively, you can download them as a PowerPoint presentation.

Name File size    
MISTIE III Protocol Training Course Slides (PowerPoint) 460.31 KB

MISTIE III Protocol 1.72 MB
 

 

 

 

 

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Brain Injury Outcomes

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