Eligibility (NEW 11-10-20)
Protocol (NEW 11-10-20)
Q: Do I submit my site’s application to Advarra?
A: No. Sites do NOT submit applications directly to Advarra. The Siren CCC will submit site applications to Advarra once the site has completed the “Initial Site Submission” in WebDCU under ICECAP – Central IRB. Sites should be submitting requests to their local IRBs to cede to Advarra. The ceding request to the local IRB and the ceding acknowledgement from the local IRB both need to be uploaded and accepted to WebDCU prior to site applications being submitted. Sites should also be working on uploading e-DOAs and other regulatory documents into WebDCU.
Q: What is required to submit in WebDCU for the central IRB?
A: Sites must complete 3 tables in WebDCU.
- Start with the Site Overview table. Go to [SIREN] Icon in WebDCU – click on [Central IRB] – click on [Site Overview] to complete the table.
- (If the table is already completed for your site, please review and email the site manager to verify that it correct).
- Next, complete the Site Regulatory Inspection History table as needed; go to the [SIREN] icon in WebDCU – click on [Central IRB] – click on [Site Regulatory Inspection History].
- You must complete a new record for each regulatory inspection for the Investigator or your research location(s) that have occurred in the last 5 years. If there are no inspections, you will need to attest that the site nor the investigator has had any reportable audits in the past 5 years.
- Lastly, complete the Initial Site Submission table; go to the [HOBIT] icon in WebDCU – click on [Central IRB] – click on [Initial Site Submission] to complete.
- Please ensure that you have uploaded ALL of the regulatory and people documents to WebDCU BEFORE completing this table.
Q: Can patients with subarachnoid hemorrhage be enrolled in ICECAP? (NEW 11-10-20)
A: A relatively small number of patients resuscitated from out-of-hospital cardiac arrest will have sub-arachnoid hemorrhage subsequently identified on CT scan. These small subset is further divided into smaller subsets including either patients with typically large SAH in whom an aneurysmal rupture is the cause of cardiac arrest, and patients with typically small traumatic SAH from collapsing and falling and hitting their head after the cardiac arrest. ICECAP does not require that a head CT be performed and interpreted prior to enrollment to determine eligibility, so SAH is not an explicit exclusion criterion for the trial. Let us consider 3 scenarios:
1. Therefore, patients without a head CT done prior to enrollment, can be enrolled if they meet all eligibility criteria, even though a small number of these may subsequently be found to have an SAH.
2. If a head CT is performed prior to enrollment and it shows an aneurysmal SAH, cooling to 33 degrees is not clinically indicated, and SAH will confound outcome determination, so such a patient would not be enrolled in the study.
3. If a head CT is performed prior to enrollment and it shows a small traumatic SAH, the clinical judgement at some sites would also be to not cool, in which case the patient should not be enrolled. If the clinical judgement at a site is that the small traumatic SAH is not clinically important and not a contraindication to cooling, the patient could still be enrolled.
As always, when in doubt, please do not hesitate to call the PI hotline to discuss the particulars of the patient in front of you.
Q: Please provide additional clarification or guidance on the exclusion of “Pre-existing neurological disability or condition that confounds outcome determination".
A: The exclusion for “pre-existing neurological disability or condition that confounds outcome determination” is intended to exclude those whose primary study outcome would still be poor even if they were completely restored to their baseline. It is deliberately flexible because of the variety of particular baseline circumstances sites may encounter. Clinical judgement is required. Generally speaking, we would intend to enroll patients who lived independently and were able to perform ADL’s prior to their arrest. Some disability pre-arrest is acceptable, if it would not be expected to confound the outcome determination much. We would intend to exclude those patients who, prior to their arrest, required skilled nursing care, were non-communicative, and did not perform ADL’s. There is, of course, a grey zone in between. An older patient in sub-acute rehab after a hip replacement, unable to perform some ADL’s but without neurological deficits would be ok, but a patient in assisted-living whose dementia makes them unable to perform any ADL’s without assistance should probably be excluded even if able to communicate and ambulate. Never a problem to err on the side of exclusion on this one.
Q: Are patients who are placed acutely on ECMO for cardiac arrest (ECPR) eligible?
A: No, we would consider this population excluded for hemodynamic instability. See MOP section 3.1.
Q: What if the patient worsens hemodynamically during the study intervention and requires mechanical support for blood pressure support? What devices are allowed? If the patient requires ECMO, does that invalidate the patient from study?
A: After enrollment, patients should still receive all indicated care. The trial does not restrict use of any mechanical support. Ideally, targeted temperature management should be continued if clinically safe to do so. Subjects are maintained in the study on an intention to treat basis regardless of what happens clinically after enrollment. See MOP section 3.1.
A: No, OHCA is usually too vague an event in those with LVADs anyway, and we would consider the need for a VAD to indicate hemodynamic instability even if pre-existing.
A: No. (at least not patients who really require this mechanical support, VAD’s are more concerning than IABPs) See MOP section 3.1.
A: The protocol was written with the expectation that subjects will be cooled to under 34 degrees within 4 hours with the help of definitive temperature control devices such that there is overlap of the four hour time-to-target window, and the 6 hour window between initiation of the definitive temperature control device and enrollment. However this is not explicitly required, and there is some potential flexibility for an eligible patient to be cooled with non-definitive means within 4 hours of the 911 call, and have definitive cooling started shortly afterward. There are explicit and implicit limitations on use of this loophole. First, the inclusion criteria still require that the patient be “cooled” to <34 degrees, so this is not met by a patient with environmental hypothermia who is spontaneously <34 degrees without any active cooling. Patients are not eligible if they arrive with a temperature <34 degrees and do not receive any cooling measures within 4 hours. Second, after cooling the patient to less than 34 degrees, the temperature has to remain under 34 degrees. Patients with a transient dip below 34 within 4 hours, or who start below 34 degrees, but who then rewarm to > 34 degrees without cooling or despite cooling after 4 hours are not eligible. Third, if the definitive temperature control device is not started within 4 hours of the 911 call, the delay to starting should be reasonably short. Maintaining hypothermia for an extended time with non-definitive cooling techniques is not good practice in clinical care, and is not consistent with the spirit of the trial.
Q: Why did you get an IDE if you are not testing the safety and efficacy of an investigational device?
A: It is easy to misunderstand the purpose of ICECAP because of the IDE involved. The use of hypothermia is standard care in this trial, and neither the induction of hypothermia nor the devices used are the intervention being tested. Indeed induction of hypothermia with a definitive temperature control device has to have already occurred as part of standard care before a patient can even be enrolled in this trial. The intervention in the trial is only duration of hypothermia. We worked with FDA to determine whether or not to do an IDE, since the trial tests duration but does not test a device, and does not specify a device to be used. Because FDA regulated devices are used, and FDA is interested in using the trial for purposes of regulatory science, we collaboratively decided to get the IDE. Application of the devices is not experimental. The devices are investigational in the trial, but only in regard to being used for varying durations of cooling.
Q: Will the sponsor be submitting the ICECAP study to CMS for Medicare Coverage approval?
A: No. We are not seeking Medicare coverage approval from CMS for ICECAP because there are no protocol required billable devices or services to ask CMS to cover. There is an IDE because FDA regulated devices are being used, but the trial is not designed to test the efficacy or safety of an investigational device. The trial tests the effect of duration on outcome regardless of the device used.
- The cost of the devices is not a covered research expense because induction of hypothermia with a definitive temperature control device has to have already occurred as part of standard care before a patient can even be enrolled in this trial. CMS research coverage approval is only applicable to cost incurring after and because of enrollment in the trial. It does not apply to cost incurred prior to a trial. Duration of use is not a billable device cost, and does not involve a coverage request.
- Also, there are no routine care costs attributable to participation in the trial for which CMS coverage is requested related to this IDE study. ICECAP’s billing calendar is simple at all sites. The protocol only calls for the collection of labs, imaging, and testing that have been done for clinical purposes. No labs, imaging, or testing are required or performed for research purposes.
In summary, the devices are being used inside and outside the study and no study procedures are billed to clinical insurance.
Q: Does being on multiple pressors count as hemodynamic instability? (NEW 11-10-20)
A: Patients that remain hypotensive with a systolic blood pressure <80 mmHg despite vasopressors are considered hemodynamically unstable and should not be enrolled, but the use of multiple vasopressors does not, in itself, exclude a patient for hemodynamic instability. Determination of hemodynamic instability should involve the clinical judgement of the enrolling physician and be guided by the rationale and examples provided in the study materials. Please refer to section 4 of the study protocol and section 3.1 of the MoP for more detail.
Q: Does the clinical team have discretion to rewarm the patient earlier than the allocated duration of cooling, change the target temperature, or rewarm the patient more rapidly if clinically necessary?
A: Managing physicians can and should use their discretion to depart from the trial protocol if necessary to safely and effectively care for patients. However, the protocol is designed such that such departures are not anticipated. Even if clinically indicated, departures from the trial protocol, especially with regard to the timing and duration of rewarming, are to be reported as study protocol deviations. It is appropriate for study teams to talk to (and listen to) their clinical teams to understand why any departures were felt to be needed, and to provide education and feedback to try to avoid departures from the protocol that may not actually be clinically necessary.
Some specific ostensible reasons for departing from the protocol are worthy of discussion. (1) Caution is indicated in early rewarming because of hemodynamic instability, as cooling is rarely the cause of hemodynamic compromise, and rewarming rarely resolves these issues. Furthermore rewarming can trigger shivering or rebound hyperthermia that can actually exacerbate instability. Cooling routinely causes substantial bradycardia which does get better with rewarming, but such bradycardia is rarely a source of instability. (2) It is not typically necessary to avoid or reverse cooling because of risk of bleeding. Clinical trial data from the TTM study shows no difference in bleeding complications in those cooled to 33 versus 36 degrees after cardiac arrest, and thromboelastography data from the POLAR trial demonstrated similar normal coagulation parameters in hypothermic and normothermic subjects. (3) Rapid rewarming to accelerate declaration of death is generally unsafe, because it may accelerate cerebral edema and worsen neurological prognosis if the rewarmed patient does not turn out to meet brain death criteria.
Q: Why do we have to continuously monitor core body temperature from two body locations?
A: Continuously measuring core body temperature from two body locations is a best practice that is part of the Clinical Standardization Guidelines, but it is not required by the protocol. Two sites makes it easier to detect problems when a temperature probe fails or migrates from its proper position, which improves safety. Two sites can improve the quality of the source documentation by increasing the likelihood that continuous measurements are captured by both the cooling console and the bedside monitor, especially if the latter directly ports to the electronic health record.
Q: Is the SIREN e.consent platform part 11 compliant?
A: Yes. SIREN uses the University of Michigan implementation of the REDCap platform to obtain electronic consent and (in some SIREN studies) participant contact information in a process that is 21 CFR Part 11 compliant. Part 11 compliance requires information technology that is capable of supporting compliant processes, and specific operating procedures that use the IT appropriately. Documentation from the University of Michigan Health Information Technology and Services (HITS) of the physical and network information technology security that supports Part 11 compliance in this implementation is available here. Documentation that the SIREN processes are Part 11 compliant is found in the SIREN Network e.consent SOP.