Frequently Asked Questions
Q: What is the necessary level of drug accountability for the trial?
A: It is up to each site’s pharmacist to keep adequate accounting of study drug use for the trial. The pharmacist may use his/her own template log/sheet for drug accountability.
Q: May a legally authorized representative sign the consent form when the subject lacks the necessary mental capacity?
A: The determination of who is an acceptable legally authorized representative is established by each site’s Internal Review Board and the Board’s definition of who may provide medical consent.
Q: A subject arrives at the ED with BP at 200 and starts to receive BP reducing agents other than nicardipine. How and when may the subject be enrolled in the trial?
A: If the patient ONLY took oral agents before arrival, this does not change the qualifying parameters for trial inclusion. SBP must still be above 180 to qualify for the trial at the time of randomization. While study staff should account for the earlier dose of oral BP medication -when prescribing other agents and titrating nicardipine – these oral agents do not otherwise disqualify the subject from trial participation.
If other agents were given in the hospital, these are captured on the Concomitant Medications CRF. If these agents are IV antihypertensives, then (1) the qualifying SBP becomes 140 mmHg at the time of randomization, and (2) only if there is at least one qualifying SBP over 180 mmHg since the time of symptom onset. Sometimes this will occur in the pre-hospital setting so the ambulance records should be checked and retained in order to capture this information.
During the 24-hour study period, there is a place for secondary agents to be recorded on Form 05 (far right column), and any details or events that affected the nicardipine titration in particular should be recorded in the General Comments section.
Medical staff need to be aware of the known reaction that may occur if a patient receives a beta-blocker, nicardipine, and fentanyl (often given if a subject is intubated or in terrible pain) within a short time span. In this case, a marked, sudden and otherwise unanticipated drop in blood pressure may occur.
Q: Since DABIGATRAN is an exclusion criteria for the trial, should all other oral anticoagulants be considered exclusionary?
A: Follow the same time standard that is in place for DABIGATRAN for other oral anticoagulants in the same category.
Since additional medications in the “NOAC” (New Oral Anti-Coagulant) category are now entering the market with increasing use, patients with intracranial hemorrhage who are found to be taking these medications should be excluded from participation in the ATACH-II trial using the same 48-hours-since- last-dose exclusion policy because adequate testing to measure active drug level is still not available and neither are reliable reversal agents. These medications include: rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Savaysa, Lixiani) (approved in Japan; US NDA submitted Jan. 9, 2014) in addition to dabigatran (Pradaxa; Prazaxa in Japan).
Q: What is the difference between a recurrent stroke and a stroke in progression?
A: A recurrent stroke is a new neurological deficit consistent with the definitions for ischemic or hemorrhagic stroke – occurring after a period of unequivocal neurological stability or improvement lasting for at least 24 hours – and not attributable to edema, mass effect, or brain shift syndrome. Recurrent stroke is a new stroke within the same vascular distribution or same area of the brain. In practical usage, they are almost synonymous.
Petty GW, Brown RD J, Whisnant JP, et. al. Ischemic stroke subtypes : a population-based study of functional outcome, survival, and recurrence. Stroke. 2000;31:1062-1068.
Stroke in progression is any sustained deterioration in neurological deficits including conscious level, arm, leg or eye movement deficits, and/or worsening in speech deficits, between consecutive neurological assessments is rated as “progressive stroke” within the first 24 hours after initial symptom onset.
Birschel P, Ellul J, Barer D. Progressing stroke: towards an internationally agreed definition. Cerebrovasc Dis 2004;17:242-252
Q: How should I document a delay in the start of nicardipine?
A: A delay in the start of nicardipine from randomization should be explained in the study record and recorded in the General Comments section of Form 05, Study Drug Infusion and 24-hour Monitoring CRF. The time recorded as T0 should always be the randomization time regardless of when nicardipine was started.
A blood pressure reading does not need to occur at exactly T0 but rather each reading represents the beginning or end of a range. Overall the frequency should meet the parameters for both recording and titrating (safely). Sometimes it is not medically feasible to capture every requested reading on the Form 05. In these cases, a brief explanation is requested for convenience in data interpretation.
If the nicardipine start time does not occur within the allowable time window of 4.5 hours then a protocol violation has occurred and must be filed accordingly with an appropriate explanation.
Q: The study team is titrating nicardipine and the BP increases due to the subject’s headache, nausea, or vomiting. The study team thinks the BP will go down on its own once the event subsides. They wait 30 minutes before changing the titration. Is 30 minutes acceptable?
A: Yes, if it is in the best medical interest of the subject, as would be the case when doing this to avoid over-titration and a potential hypotensive state. Any changes to the titration schedule should be documented, with the reason given, in the General Comments section of Form 05. Please note, any changes to medical condition should be entered as adverse events if they were not present at baseline. If they were present at baseline, they should be noted on the medical history case report form.
Q: What is the “adequacy of care” expectation, versus specific protocol and data entry requirements for the ATACH-II trial?
A: An ICH patient should be managed in an ICU setting, where the level of staffing and attention is such that q 2 hour complete neuro checks would be standard and recorded, and an hourly GCS would be recorded. “Focal” neuro checks refer to the specific areas of most concern neurologically, which will always include level of consciousness but may also include things such as worsening of symptoms already seen, for example one-sided weakness and/or a facial droop, that are specifically related to the area of the brain affected.
These are not an added check to general standard of care and are not a study-specific requirement. Data collected from these checks is not required for the study, unless an adverse event, such as worsening of neurological status, were to occur.
Checking frequently for urine output is again not a data point requirement, but rather an aspect of adequate care for safety monitoring since reduced urine output may be an early sign of hypotension and reduced tissue perfusion.
Sufficient documentation could be within a progress note, for example, “patient monitored closely and checked frequently (approx. q 30 min.) for neurological changes and remained stable throughout the shift with urine output approx. 60 cc/hour.”
An hourly GCS is required for the 24-hour study period and is recorded on CRF form 05.
As for recording of vital signs, specifically SBP and heart rate, at least q 30 minute recording through the 24-hour study period is required, with more frequent recording during titrations and for the first hour following randomization.
Close attention to overall safety through care at the expected standard is an important criteria for site participation in ATACH-II. In general, certified stroke centers will meet this standard easily. Monitoring of subject safety as related to their participation in a clinical research trial is coverable under Medicare policies for reimbursement should this be of concern, per CMS policy in publication 100-3, section 310.1, originally effective 9/19/2000 and affirmed 7/9/2007.
Q: A subject is randomized into the trial and assigned a treatment arm but later is admitted for surgery within the first 24 hours. How should the study team move forward?
A: If a subject is admitted for surgery, the nicardipine drip will usually be discontinued and the assigned range ignored. Document the event under General Comments on Form 05 (for convenience in data interpretation, use the line number and corresponding time), and enter the increasing hematoma volume (or other condition requiring surgery) as an adverse event. Continue to follow the subject until the Day 90 visit.
Q: A subject is randomized into the trial and assigned a treatment arm but seems to be allergic to nicardipine. The study team stops titration of the study drug and relies on other BP reducing agents. How should the study team move forward?
A: Document the allergic reaction to nicardipine and change to other agents in General Comments on Form 05 so it is understood what happened when examining this data. Maintain subject in the same assigned SBP range using the other agents unless this is specifically contraindicated. Enter an adverse event for the allergic reaction to nicardipine.
Q: If the trial’s inclusion criteria states subject eligibility is 4.5 hours of symptom onset then why does the screen failure log reference 6 hours of symptom onset?
A: Within 6 hours of symptom onset is the reporting criteria for inclusion in the screening failure log. This extended time window allows the Clinical and Data Coordinating Units to assess the potential subject volume within close range of meeting our inclusion criteria of 4.5 hours.
Q: Who may fill the role of the blinded assessor and what is the blinded assessor responsible for?
A: The blinded assessor needs to be certified in the Modified Rankin Scale, and should have a medical background adequate to communicate appropriately in a medical situation and perform basic assessments. A nurse with experience in neurocritical care and clinical research is allowable if a neurologist is not available.
The blinded assessor should complete the CRFs due at 30 and 90 days, including asking about SAEs however the blinded assessor should not be accessing the subject’s medical records. The blinded assessor should refer to the scripted questions for the 30-day call, which are available under Project Documents in WebDCU.
In any situations where the assessor’s blindness seems comprised, please provide an explanation in either the General Comments section of the CRFs or in a note to file. Monitors will be checking for the assessor’s blindness when reviewing the data for each subject.