FAQs

Consent/Assent

Exclusion Criteria

FWA

Paramedics/Enrollment

Pregnancy

Risks

Study Box/Recordings

Study Medications

Other


 

Consent/Assent

Q: If a patient does not consent to continue in the trial, does HIPAA prevent the FDA from collecting data or viewing PHI to fulfill it’s regulatory mission?
A: The HIPAA privacy rule specifically allows PHI required by the FDA to fulfill its mission to be collected even without authorization.  [From OCR Guidance Explaining Significant Aspects of the Privacy Rule - DISCLOSURES FOR PUBLIC HEALTH ACTIVITIES, page 28. See also 45 CFR 164.512(b)(1)(i) and (iii)]

Protocol Reference: Section 4.6.1, p.32

 

Q: Can the IRB waive the requirement for assent?

A: Yes. Assent can be waived for some or all subjects in a study when at least one of the following three criteria are met:

1. Research offers a potential benefit unavailable outside of the context of the research.

2. Some or all of the eligible children are incapable of assent.

3. The study is of minimal risk and all of the following are met:

   a. Subjects' rights and welfare are not adversely affected.

   b. The research could not otherwise be done.

   c. When appropriate, the subjects will be provided pertinent information.  

 

Q: What if the parent and child disagree in the child's participation of the research study?

A: "If a child is capable of assent and the IRB requires that assent be sought, it must be obtained before the child can participate in the research activity. Thus if the child dissents from participating in research, even if his or her parents or guardian have granted permission, the child's decision prevails." DHHS OHRP.

Further, if the parent says NO and the child says YES, the child cannot participate.  In other words, the dissenter wins.

 

Q: Will the paramedics be obtaining consent from the patient's family members? What do paramedics say to family members watching or asking about enrollment?
A: An overwhelming priority is that this trial NOT interfere with or delay the treatment of patients with status epilepticus. If it were possible/safe to get a form of meaningful consent or refusal from family members we would do that instead of Exception From Informed Consent (EFIC), and if that were possible EFIC would not be permissible. Thus, for this trial there will NOT be an attempt to obtain any form of consent prior to enrollment. 

It is simply not safe for the patient to remain seizing during an informed consent conversation. Rapid treatment of a patient with status epilepticus is potentially life saving. In this study, paramedics must not delay treatment to provide family members an opportunity to learn about or engage in a meaningful process to provide or decline informed consent. Paramedics may use a very short prepared script (see below) that lets a family know in general terms what is happening if this does not delay treatment, but this should never be construed as a meaningful informed consent process. The one exception would be in the event that a parent has, perhaps through a prior community consultation or public disclosure process, already been engaged in a meaningful informative consent process and explicitly tells the paramedics that they are aware of this trial and would prefer routine care, then the subject would not be enrolled and would be given routine care.

As a part of the RAMPART materials there is a short script that paramedics can use while administering medications IF doing so will not delay care, especially if family members are asking what is happening, but it explicitly should NOT be used to solicit any kind of assent or refusal. While this language is not a mandate for any site, an example of such language is offered:
“Your (child/loved one) is having a seizure that does not seem to be stopping on its own. Seizures like this can be very dangerous and we are giving a benzodiazepine medicine to try to stop the seizure right now. We are giving a shot in the muscle and an injection directly into a vein and will then take (him/her) to the emergency department at ______ hospital right away. We are participating in a project looking at ways of giving antiseizure medicines. More information about this project is available in the ER.”

Protocol Reference: Section 5.1.5-5.1.6
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Exclusion Criteria

Q: Table 3 of the protocol says that treatment for hypoglycemia is an exclusion criteria for RAMPART, but does not specify a specific cutoff. The accompanying text mentions a cutoff of 60mg/dL. What if a paramedic treats a patient for hypoglycemia as the cause of seizure without using a glucometer (i.e., using only clinical judgement or a qualitative colormetric strip) or our local EMS protocol uses a slightly different cutoff for treating hypoglycemia?
A: As described in Table 3, the rationale is to exclude patients suspected and treated for hypoglycemia as the cause of their seizure. The cutoff of 60mg/dL is listed only as guidance in the supporting text, because it is the most common value used and because most EMS systems carry quantitative glucometers. As a clarification, however, the intent and interpretation of the protocol should be that patients suspected and treated for hypoglycemia as the cause of seizure, however that is determined in your system, require different therapy than that being tested in this trial. Such patients should be treated for hypoglycemia as per your local EMS protocol rather than enrolled in RAMPART.
Protocol Reference: Refer to Exclusion Criteria in Section 4.2.2, Table 3, p.24

 

Q: Does the diazepam autoinjector administration prior to EMS arrival disqualify the patient from enrolling in RAMPART?

A: There is a trial taking place that is testing the diazepam autoinjector. If the patient is participating in this trial, they would be excluded from RAMPART. If the patient is NOT taking part in this trial, they can be included in RAMPART.

 

Q: Does benzodiazepine administration (rectal diazepam, rectal ativan) prior to EMS arrival disqualify patients?

A: We considered this carefully early in the development of the protocol and gave it several hearings.  We asked two questions: is there a safety problem? and is there a study problem?   

The answer is that prior treatment with a benzodiazepine, such as DiaStat or rectal ativan, (but continued seizures on EMS arrival) is NOT an exclusion.  These patients can be enrolled in the study.  We made this decision after determining that existing EMS protocols and expert opinion do not currently alter the use of benzodiazepines in clinical practice in patients previously treated with DiaStat or rectal ativan.  That is to say, if you develop status epilepticus, are given for example, rectal diazepam, and continue to seize, paramedics do not (and should not) refrain from following their existing seizure protocols to give further diazepam or midazolam, nor do they routinely reduce the dose of subsequent treatments as compared to those given to patients not previously given DiaStat.  Despite potentially increased risk of sedation, not giving a seizing patient further benzo anti-convulsants after rectal diazepam, for example, would be more of a safety problem than providing it.  If they need further benzodiazepines, there is no increased risk in getting them within the study than rather than outside the study.  Indeed, the generalizability of the trial is enhanced by including this significant population. 

There is no negative affect on the study from including these patients as well.  Since analysis will be by intention to treat, prior benzodiazepine use will not be biased toward either treatment group.  In patients with SE and >5 min of seizures, rectal diazepam, for example, appears to be only marginally more effective than placebo, so it is not expected to cause a ceiling effect, or have much affect if there is an aberrant baseline imbalance.
Protocol Reference: Refer to Exclusion Criteria in Section 4.2.2, Table 3, p.24

 

Q: Do you enroll a patient with a tether?

A: No. Patients with tethers are excluded from RAMPART.

 

Q: Can you enroll a patient with an already established IV in place?

A: Our intention is to not enroll patients who have an already established and functional IV in place prior to paramedic arrival.

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FWA

Q: Why do I need to consider an FWA?

A: The Federalwide Assurance (FWA) is how institutions attest that they will comply with federal rules governing the conduct of clinical trials.  It is important that we promise that research conducted in the ambulance is still governed by these rules that protect human subjects.  Research in the ambulance still has to play by the rules.  We all agree with that, so the question is just how does that get documented?  We are not worried about the EMS not having an FWA.  We are concerned about an EMS system that does not want an FWA because they do not want to attest that they will conduct research by the rules.

 

Q: Do all the EMS units need to have an FWA?

A: All EMS units must be covered under an FWA.  EMS systems can obtain their own FWA’s designating another institution's IRB to be the IRB of record.  Obtaining a new FWA for this purpose may seem daunting, but I am told that it is really a very easy process.  This is the preferred strategy.  If the EMS system operates under an existing medical center FWA, this arrangement should be explicitly documented, usually within the medical center’s FWA.

 

Q: My EMS system is already covered under my institution’s FWA, what do I need to do?

A: If your EMS system is a legal entity owned, administered and operated by the larger institution holding the FWA, then you are covered and no further documentation is required (other than a memo to us verifying this situation).  This is, however, very unusual.  Your EMS system can also be considered an “agent” of the institution, when engaged in research, for purposes of the FWA.  This is more common.  This arrangement would not have to be designated in the FWA, but written documentation of the arrangement from both parties must be maintained (and submitted to WebDCU).

 

Q: My EMS is not covered under any FWA right now, what do I do?

A: More than one approach is possible. 

We feel that the clearest way for the EMS system to attest that, within its scope of activity, it will comply with Federal requirements on the conduct of research, is for the EMS system to obtain its own FWA.  This is a straightforward electronic application.  Since EMS systems are unlikely to ever have their own IRB, the FWA obtained by an EMS system will have to include an agreement to use an institution’s IRB or an independent IRB.   

Alternatively, your EMS system can become an agent of your institution, when engaged in research, for purposes of the FWA.

 

Q: How often does my institution or my EMS agency need to renew the FWA?

A: Every 3 years.

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Paramedics and Enrollment

Q: Are there caps on enrollment?

A: No

 

Q: Do we need to have paramedics call in prior to enrollment?  

A: This question may be paraphrased as, "is the paramedic assessment good enough?"  First, paramedics are actually never independent practitioners (unlike, NP's).  Whether interacting with patients, getting routine care or investigational drugs, the medical care provided is, at least technically, always ordered by and carried out at the direction of a physician.  So EMS  Medical command can be on-line or off-line.  In the former, medics call in, tell a command physician about the patient, and get orders for care.  This was very common in the early days of EMS.  Perhaps you'll recall the TV show Emergency with LA paramedics Johnny Gage and Roy Desoto in the 1970's.  This is how they operated.  Nowadays most systems use predominantly off-line medical command in which the EMS medical director provides standing orders for medical care provided by medics in the form of protocols.  Most care is provided without ever calling in for command, but the standing protocols might call for the medics to call in for certain orders, such as letting patients refuse transport, termination of resuscitation efforts, repeated doses of some drugs like narcotics, or things like that.  In summary, paramedics (like nurses) do not decide on treatments or order medications, they just decide which protocol to follow and implement the standing orders.

With that as a background, lets take the question "is the quality of paramedic assessment adequate?"  I think the question is already answered by how EMS routinely operates in your area.  Do paramedics have off-line medical command in the form of protocols that allow them to treat seizing patients with benzodiazepines, or do they have to call in to give such care in routine practice?  If the routine practice is to give benzodiazepines on standing orders, then there has already been a determination that the medics are "good enough" in assessing seizures to justify the risk benefit of giving benzodiazepines.  The risk benefit of treatment with benzodiazepines in routine practice is essentially the same as the risk benefit of benzodiazepines in this trial.  If medics currently have to call in to give benzodiazepines in your system (unusual, but could be), then I would have them call in before treating in the trial too.

Will there be some mistakes?  Absolutely (and either way).  I am sure that we will enroll psuedoseizures.  This happened in the VA Cooperative seizure study.  They showed that benzodiazepines work for this, too.  In short, a reasonable risk of mistakes is inherent and does not pose a major safety hazard or a major scientific hazard.  This is real world.  It is a good thing.

Protocol Reference: Section 2.6, p.19

 

Q: Are the paramedics acting as investigators?
A: No, but with some accommodation.  The paramedic is just carrying out the protocol ordered by the medical command physician.  By analogy, when we enroll other patients in other trials in the emergency department, we obtain the study drug from the investigational pharmacy, write an order for it to be given, and give it to our regular ED nurses to hang and infuse.  This does not make the regular ED nurses investigators.  The paramedic is not doing any unique research functions, like obtaining informed consent or collecting special data, that would be different from what they are trained to do in routine care.  They are just doing what they would always do, assessing a patient, determining which of their standing orders to follow, and providing medications and support. 

That being said, we understand that this is not cut-and-dry, and that there is a grey zone here.  This standing order, being research, is a little different than most of their standing orders.  They know this and we know it.  Paramedics need to have special training for this protocol.  We think it is important that this include much of the CITI human subjects protection curriculum, which we will provide in a somewhat abbreviated form (less than 4 hours).  Thus, even though the paramedics should not be listed as investigators on a 1572 or IRB application, and thus are not required to have HSP training, they will get it, and we will certify that as part of their protocol training. 

In terms of precedents, no one, as far as we can tell, has made every paramedic in a system an investigator in prior studies.  Not in the ROC, PAD, FastMag, RESQ, Polyheme, or DCL-Hgb EFIC studies.  In some of these studies (e.g., FastMag) the paramedics call in before enrollment, and in others (e.g., RESQ) they do not.  So, calling in can go either way, but either way they are not listed investigators.

 

Q: Who initiates the protocol when there is more than one paramedic involved in treating the patient?  Does it have to be a consensus, or is any paramedic able to initiate the protocol, or it the senior paramedic required to make the decision?

A: Different EMS systems operate in different manners.  In some systems, a typical response may include a team with one paramedic and one basic EMT.  In others there may be two paramedics and a paramedic supervisor.  Different systems also employ different team decision making and organizational "cockpit management" strategies.  Because of this variability, the protocol does not dictate a specific procedure for how paramedic partners determine eligibility.  It is anticipated that eligibility for enrollment will be determined using the same cooperative decision-making strategy used routinely by paramedics in that system in providing standard clinical care and in making other critical emergency treatment decisions.  More detailed procedures may be implemented by individual Hub-Spoke complexes at the EMS system level if necessary.

 

Q: Is it okay for paramedics to load subjects in the ambulance and provide treatment en route to the hospital, rather than providing care at the scene prior to transport?

A: Yes. The decision whether to provide care at the scene or en route should be made per local protocols in the same manner this decision would be made if the patient was not enrolled in RAMPART.

 

Q: Sometimes, when we "load and go" and the transport times are short, paramedics will not be able to start IV access prior to arriving at the ED. Is that a problem?

A: Not a problem. It is expected and understood that it may not be possible for some patients in the IV group to have an IV started for any number of reasons, including short transport times. Difficulty and time required to start an IV is intended to be a factor in this trial. Short transport times will bias all groups against seizure termination at the time of ED arrival. The primary analysis is based on intention to treat (defined as IM injection in thigh). All we ask is that paramedics try just as hard to start an IV in study patients as they do in their routine practice.

 

Q: Is it okay for the paramedics to defer IV treatment or delay IV treatment in a RAMPART subject, in a manner that they would not have in other patients, because the patient was already given an IM injection?

A: No. Paramedics should NOT defer or delay IV treatment because an IM injection was already given. Paramedics should try just as hard to start an IV in study patients as they do in their routine practice.

 

Q: If the transport time is really short, can paramedics still give study medication after bringing the patient into the ED?

A: No. Paramedics should NOT give more study medications AFTER arrival in the ED.

 

Q: Do you enroll a patient with a tether?

A: No. Patients with tethers are excluded from RAMPART.

 

Q: Can you enroll a hemicorpectomy patient?

A: Yes. The study medication can be given in the arm for these patients.

 

Q: Can you enroll a patient with an already established IV in place?

A: Our intention is to not enroll patients who have an already established and functional IV in place prior to paramedic arrival.

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Pregnancy

Q: What happens if an enrolled patient is pregnant?
A: We will NOT remove a patient from the study if we find out she is pregnant after the study medication is administered.  However, if the patient is known or thought to be pregnant before the study medication is administered she will not be enrolled in the study.

Q: What is the potential risk to the fetus in the event that a woman who is pregnant is enrolled into the study?

A: Benzodiazepines, including lorazepam and midazolam, are frequently prescribed during pregnancy to treat anxiety or panic disorder.  They are also commonly used to treat status epilepticus, and for procedural sedation.  Despite common clinical use, there are theoretical fetal risks from this class of medication that will be discussed in detail below. 

Most importantly, because benzodiazepines are currently routinely given to treat prehospital status epilepticus in pregnant patients, there are no incremental fetal risks from participation in this trial.  All EMS protocols that we have reviewed dictate the use of a benzodiazepine for the emergency treatment of prehospital status epilepticus without the exclusion of pregnant patients.  This is because the maternal and fetal risks of continued seizures are known and are substantial.  They are felt to far outweigh any theoretical risks of teratogenicity.  Within the class of benzodiazepines, there are no known agent-specific effects among the different drugs used to treat status epilepticus.

Although there are no incremental fetal risks from participation in this trial, and the fetal risks of continued status epilepticus outweigh the fetal risks of treatment, there are insufficient data to prove that there is not a small absolute risk from the use of benzodiazepines during pregnancy.  This risk is reviewed in the monograph “Update: Benzodiazepines in Pregnancy” Volume 7(4) by Kelly Ormond, MS, CGC and Eugene Pergament, MD, PhD, published by the Illinois Teratogen Information Service (http://www.fetal-exposure.org/BENZOUPDATE.html).  They summarized the risk as follows “Use of benzodiazepines, specifically diazepam, was previously thought to be associated with an increased frequency of cleft lip and/or palate; this finding has not been supported by the majority of recent studies. Although the balance of evidence from human studies of the benzodiazepines (chiefly, diazepam) does not show first trimester usage to be teratogenic, animal studies have shown an increase in abnormal behavioral patterns after in utero exposures at levels comparable to the usual human doses.  At this point, there is still no conclusive data regarding the possible behavioral teratogenicity of benzodiazepine use during pregnancy.”

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Risks

Q: What are the potential risks to subjects?

A: This study enrolls subjects with status epilepticus which is a life-threatening medical emergency. The risk of morbidity or mortality to these subjects from their underlying condition is substantial, but incremental risk from participation in this study is expected to be minimal or only slightly greater than minimal. Both treatment groups in this study are treated with a benzodiazepine that is commonly used to treat seizures, either IV lorazepam or IM midazolam. Both the risk of treatment failure and the risk of an adverse effect of treatment are thought to be similar for these two treatments. The risks associated with both study treatments are also thought to be similar to or lower than those associated with other forms of commonly used treatments like PR or IV diazepam.

Serious medical risks are expected to be the same in subjects in the trial as in patients given standard therapy outside of the trial. Risks of participating include the possibility that there will be an unanticipated difference between groups in the rate of expected adverse events related to status epilepticus, including:
1. Respiratory depression requiring endotracheal intubation (infrequent*)
2. Recurrent seizure activity requiring further treatment (rare to likely*)
3. Hypotension requiring a vasopressor (rare*)

Although also unanticipated, less serious medical risks include the possibility that there will be a difference between the two groups in the rate of other expected adverse events, including:
1. Pain, discomfort, bleeding, or infectious complications at the IM injection site (rare*)
2. Pain, discomfort, bleeding, or infectious complications at the IV infusion site (rare*)

*Please refer to the categories below for incidence rates:

 "Common" (i.e., approximate incidence > 25%)

 "Likely" (i.e., approximate incidence of 10-25%) 

"Infrequent" (i.e., approximate incidence of 1-10%)

"Rare" (i.e., approximate incidence < 1%)

Other medical risks include the possibility that there will be a difference between the two groups in the rate of unexpected adverse events.

Subjects in this trial will all get an intramuscular injection, which patients not in the trial may or may not have been given in standard therapy. Subjects will all be unconscious during the injection and so should have no associated pain.

The medications used in this trial are not labeled for use in pregnancy, but are not known to have any reproductive risks. Both lorazepam and midazolam are frequently prescribed in pregnancy as elective treatments for other conditions, and both are used to treat seizures during pregnancy. Please see section 37.1.1 of this IRB application for more discussion of reproductive risks, and for the justification of excluding patients known to be pregnant.

Non-medical risk of participating in this trial includes breach of confidentiality. Clinical sites along with the NETT CCC will do their best to keep all medical information that is collected confidential. Prehospital data from the study box (including the audio recordings, temperature, and sensor data for time of arrival) will be abstracted centrally at the NETT CCC and entered into the electronic CRF (e-CRF) in WebDCU. Data obtained from the study box audio recordings is limited to the time stamp at which the predetermined events are announced. Those moments of audio recording and their time stamp will be clipped centrally and maintained as source documentation. No other data are abstracted from the voice recordings. All other portions of the audio recordings will be deleted. Hubs will not access any of the audio recordings or other study box data in order to protect privacy for patients and medics during treatment and transport. This process is in place to ensure the privacy and protection of medics in the field and their patients.

RAMPART uses only the e-CRF found in WebDCU. Printable paper worksheets of the e-CRF for RAMPART are available for use only when direct data entry is not possible. It is neither expected nor desirable for sites to maintain paper CRF worksheets. If paper worksheets must be used, they must be maintained in the subjects' study binder. Information stored on the computer will be kept in password protected files that are maintained on password protected servers.

No data containing Protected Health Information (PHI) will be stored at the University of Michigan.

Protocol Reference: Section 5.1.4, p.36
MOP Reference: RAMPART Intro. Video, Q20, p.158; Lorazepam Warnings, p.170

 

Q: What is the potential risk to the fetus in the event that a woman who is pregnant is enrolled into the study?

A: Benzodiazepines, including lorazepam and midazolam, are frequently prescribed during pregnancy to treat anxiety or panic disorder.  They are also commonly used to treat status epilepticus, and for procedural sedation.  Despite common clinical use, there are theoretical fetal risks from this class of medication that will be discussed in detail below. 

Most importantly, because benzodiazepines are currently routinely given to treat prehospital status epilepticus in pregnant patients, there are no incremental fetal risks from participation in this trial.  All EMS protocols that we have reviewed dictate the use of a benzodiazepine for the emergency treatment of prehospital status epilepticus without the exclusion of pregnant patients.  This is because the maternal and fetal risks of continued seizures are known and are substantial.  They are felt to far outweigh any theoretical risks of teratogenicity.  Within the class of benzodiazepines, there are no known agent-specific effects among the different drugs used to treat status epilepticus.

Although there are no incremental fetal risks from participation in this trial, and the fetal risks of continued status epilepticus outweigh the fetal risks of treatment, there are insufficient data to prove that there is not a small absolute risk from the use of benzodiazepines during pregnancy.  This risk is reviewed in the monograph “Update: Benzodiazepines in Pregnancy” Volume 7(4) by Kelly Ormond, MS, CGC and Eugene Pergament, MD, PhD, published by the Illinois Teratogen Information Service (http://www.fetal-exposure.org/BENZOUPDATE.html).  They summarized the risk as follows “Use of benzodiazepines, specifically diazepam, was previously thought to be associated with an increased frequency of cleft lip and/or palate; this finding has not been supported by the majority of recent studies. Although the balance of evidence from human studies of the benzodiazepines (chiefly, diazepam) does not show first trimester usage to be teratogenic, animal studies have shown an increase in abnormal behavioral patterns after in utero exposures at levels comparable to the usual human doses.  At this point, there is still no conclusive data regarding the possible behavioral teratogenicity of benzodiazepine use during pregnancy.”

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Study Box/Recordings

Q: What is the process for protecting or destroying the voice recorder recordings?

A: Sound recordings can be problematic because they may contain more information than is required for this study.  Recordings will be sent to the CCC where they will be abstracted centrally by a research assistant blinded to the EMS system involved.  Abstracted data will be limited to measures asked for in the CRF.  To protect paramedic privacy, the sound files should never be kept at the Hub complex.  The sound files are not kept in the CRF or any other networked computer environment either.  The sound files are stored to removable media and secured immediately after abstracting.  They will be destroyed at the earliest opportunity allowed by GCP.  There is some controversy regarding the relevant requirements (what kind of document are these sound recordings?).  The safest interpretation we have been given is to consider them as original source documents and should be saved as such.  We will continue to pursue this issue and if we can ever get a definitive binding interpretation that they do not need to be treated as such, these sound files will be destroyed right after abstraction.

MOP Reference: Section 14.5, p.54

 

Q: How are the study drug bundles and study boxes being distributed?

A: Study Drug Bundles

  • Study drug bundles will be distributed to all Hub-designated pharmacies from the RAMPART Central Pharmacy.
  • The study drug bundles will be packaged with both medications in both adult and child dosing.
  • They will be shipped in refrigerated packaging. 
  • Hub-designated pharmacies will be responsible for receiving, storing, and releasing the study drug bundles, and completing tracking information in WebDCU™. 
  • Upon arrival at the Hub-designated pharmacies, the study drug bundles will need to be refrigerated until they are secured in the study box and distributed to EMS providers.

All study drugs will need to be used within or destroyed after 60 days from the date the drug bundles are removed from refrigeration, secured in the study box and distributed to this EMS provider.  Expirations dates will be tracked in WebDCU™.

  • Study boxes will be distributed to the Hubs (a location specified by the Hub) separately from the study drug kits.
  • Study boxes do not need to be refrigerated.  The study drug bundles, which do need to be refrigerated, do not need to be placed in the study box until it is reset and distributed. 
  • WebDCU™ will track all study drugs and will indicate which study drug bundles should go into which study box. 
  • The study drug bundles will need to be placed in the study box, which will then be secured and locked immediately prior to distribution to the EMS provider.
  • Once the study box has been closed and secured, it cannot be opened again without the box being activated.  A regimented process outlining exactly how the box needs to be prepared and activated will be distributed to all sites.

MOP Reference: Section 6, p.30-32

 

Q: What data will be collected from the audio recording and how will it be extracted?

A: We are sensitive to the concerns that the voice recorder used to identify key time marks in this study may incidentally create a privacy issue for patients and medics during treatment and transport. In response to these concerns we have created protocols and procedures that protect privacy while ensuring that we remain compliant with Good Clinical Practice (GCP) standards.

When a subject is enrolled in the RAMPART study, medics provide verbal statements on the voice recorder at the time of IM treatment, at the time an IV is established, at the time of intravenous treatment, at any time convulsions are observed to stop or resume, at the time of any rescue treatments, and at ED arrival. These recorded statements are automatically time stamped by the study box's internal clock.

The used study box is collected by the local study team in the ED and the EMS unit is restocked with a new study box. Digital audio and data files from the memory card in the study box are uploaded directly from the card to a secured central server at the NETT Clinical Coordinating Center at the University of Michigan (NETT-CCC), and the card is physically shipped directly to the NETT-CCC. These files are never copied, stored, or opened at the local site. These raw data are not available to local study personnel or EMS agencies.

At the NETT-CCC only authorized personnel will have access to the audio files. Authorized study team personnel will abstract the time point data from the file and enter those times in the study database in a timely manner. No portion of the audio will ever go in the study database. Once the audio file is abstracted, the backup copy from the secure server is destroyed. GCP requires that all source materials be archived, so the momentary fragments of audio containing the relevant study time marks (e.g., the clip "IM med given") will be extracted, encrypted, and saved offline in locked storage. Other than those few seconds of audio that we are required to save, all other audio will be immediately destroyed. By deleting everything but the required momentary fragments, we ensure that the full audio recorded in the field is never available to anyone for any purpose.

This process is in place to ensure the privacy and protection of medics in the field and their patients.

MOP Reference: Section 14.3, p.54; Section 14.4, p.54

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Study Medications

Q: If the patient stops seizing after the IM dose, but before the IV dose is given, do you give the IV dose anyway?

A: NO. Only give study medications to patients who are convulsing. DO NOT give study medications to patients who are not convulsing at any point.
 

Q: If the patient stops seizing after the IM dose, but before the IV dose is given, and then starts seizing again and never regained lucidity are they treated with rescue drug or the IV study drug?

A: If a determination has been made of sustained cessation of convulsive seizures, and the patient begins to seize again, rescue medication should be used. Once a determination has been made that the seizure has stopped, the study medication should NOT be given.

 

Q: What if paramedics are unable to start an IV?

A: That is ok.  Paramedics should approach IV starts in the same manner they do in routine clinical practice.  This allows the use of intraosseous access, which for purposes of this trial is considered equivalent to IV access.  This is an intention to treat analysis, so patients randomized to IV are analyzed that way, even if they never get the IV.  Some will never get the IV but will stop seizing anyway and be scored as wins even though they didn’t get medicine.  Others will get a non-IV rescue drug per local protocol and will be scored a loss, even though they never got the IV medication.  This appropriately reflects, within the analysis, a key potential limitation of IV therapy in clinical practice.

Protocol Reference: Section 4.3.4, p.28

 

Q: What is the placebo used in the study and how should it be described?

A: The placebo used in the IM injection is balanced saline and the placebo in the IV injection is balanced saline-heparin IV flush solution.  In preparing study materials for a lay audience we feel that the most accurate and easiest to understand descriptions of these are "a substance containing no medication" or "an inactive solution" or simply "placebo".

 

Q: Is there an FDA advisory about using lorazepam in children?

A: No, there is no FDA advisory on using lorazepam in children, but in 2006 the FDA approved a change in the label for Ativan requested by Baxter.  This label change added wording to the PRECAUTIONS section noting that "gasping syndrome" has been associated with the administration of other intravenous solutions containing benzyl alcohol to neonates and that this is also a preservative used in IV lorazepam solutions.  It goes on to note that normal therapeutic doses of lorazepam contain very small amounts of this compound, but that premature or low-birth-weight infants, or patients getting supratherapeutic doses "may be more susceptible." This should not be a problem for children of the size eligible for enrollment in RAMPART, or for the doses given in this study.

 

Q: Can intraosseous (IO) vascular access be used when intravenous access cannot be obtained in RAMPART?

A: Yes. We recognize that over the last 20 years it has been a common practice in EMS systems and in Emergency Departments to allow placement of IO needles to obtain vascular access and deliver intravenous medications in emergency situations when peripheral IV access cannot be obtained (1). As such, in this trial the intravenous study medication (lorazepam or placebo) can be delivered through an intraosseous access when the routine clinical protocols of the participating EMS system allow use of IO access in lieu of an IV access that cannot be obtained. For the purposes of the trial, intraosseous is considered equivalent to intravenous.

The important role of prehospital use of intraosseous vascular access has been recently reemphasized by the National Association of EMS Physicians (2). The intraosseous space is directly contiguous with the vasculature and the pharmacokinetic equivalence of IO and IV routes is well established in multiple studies of central circulation time and dose equivalence (3-5). Pharmacokinetic parameters including maximum plasma concentration (Cmax), time to maximum concentration (Tmax), and area under plasma concentration-time curve (AUC), have been shown to be no different for medication given IO or IV (6). Specifically, lorazepam treatment of seizures has been shown to be equally effective with identical dosing given by IO or IV (7-8).

References:

1. Salassi-Scotter M, Fiser DH. Adoption of intraosseous infusion technique for prehospital pediatric emergency care. Pediatr Emerg Care. 1990;6(4):263-5. 2. Fowler R, Gallagher JV, Isaacs SM, Ossman E, Pepe P, Wayne M. The role of intraosseous vascular access in the out-of-hospital environment (resource document to NAEMSP position statement). Prehosp Emerg Care. 2007;11(1):63-6. 3. Warren DW, Kissoon N, Mattar A, Morrissey G, Gravelle D, Rieder MJ. Pharmacokinetics from multiple intraosseous and peripheral intravenous site injections in normovolemic and hypovolemic pigs. Crit Care Med. 1994;22(5):838-43. 4. Cameron JL, Fontanarosa PB, Passalaqua AM. Acomparative study of peripheral to central circulation delivery times between intraosseous and intravenous injection using a radionuclide technique in normovolemic and hypovolemic canines. J Emerg Med. 1989;7(2):123-7. 5. Orlowski JP, Porembka DT, Gallagher JM, Lockrem JD, VanLente F. Comparison study of intraosseous, central intravenous, and peripheral intravenous injusions of emergency drugs. Am J Dis Child. 1990;144(1):112-7. 6. Von Hoff DD, Kuhn JG, Burris HA 3rd, Miller LJ. Does intraosseous equal intravenous? A pharmocokinetic study. Am J Emerg Med. 2008;26(1):31-8. 7. Pender ES, Pollack DV Jr, Woodall BN, Parks BR. Intraosseous administration of lorazepam: same-dose comparison with intravenous administration in the weanling pic. J Miss State Med Assoc. 1991;32(10):365-8. 8. Jim KF, Lathers CM, Farris VL, Pratt LF, Spivey WH. Suppression of pentylenetetrazol-elicited seizure activity by intraosseous lorazepam in pigs. Epilepsia. 1989;30(4):480-6.

Protocol Reference: Section 4.3.4, p.28

 

Q: Is it a protocol violation if the IM injection is not given in the thigh, but given in the arm?

A: Administering the IM injection in the arm, rather than in the thigh, is considered a protocol deviation. This would become a protocol violation if an SAE was involved as a result of the medication given in the arm. The IM injection should be given in the thigh as stated in the protocol.

 

Q: What is the stability of lorazepam at high temperatures?

A: We have reviewed the question of storage of lorazepam in EMS systems subject to very high summer temperatures.  This review includes what is known about temperature and EMS drug storage conditions and on the stability of lorazepam.  

The literature on the effects of storage temperatures of EMS drug supplies suggests that this issue is germane to the broad spectrum of medications used in the prehospital environment, not just lorazepam.1-3  Although uniform standards do not exist, it has been reported that awareness of the problem resulted in development of procedures to mitigate temperature extremes in their drug supply in almost every system throughout one state,4 and that many solutions are simple and inexpensive.5  However, the scope of the problem remains unclear, as does the effectiveness of existing procedures. 

Brown summarized several reports in 20041 including his own collaborative efforts with the United States Pharmacopeial Convention (USP), the American Ambulance Association, and other EMS researchers.6  This study included 5 sites over 12 months, and found the highest drug storage temperatures in Mesa, Arizona in the summer where the mean kinetic temperature (MKT) was 86 degrees F, and the peak temperature recorded in the drug bag was 114 degrees F.   

The effects of storage temperature on the stability of lorazepam and diazepam were studied by Gottwald in 1999.7  The residual potency of the drugs determined by HPLC were studied at various time intervals over many months in both an oven with a fixed temperature of 100 degrees F, and after storage on ambulances in San Francisco over the summer where peak temperatures were 100 degrees F in the drug bag.  At 60 days, diazepam stored in the ambulance had degraded about 10%, whereas lorazepam had degraded less than 1%.  In the samples kept in an oven where the MKT was 100 degrees F, the diazepam degraded 12% at 60 days, and the lorazepam degraded 21% at 60 days.  This oven test had a higher MKT than that seen even in Mesa, AZ, but in this test the temperatures were constant.  There are no direct data on lorazepam involving transient spikes to higher temperatures, but there are data showing that in epinephrine, another drug with some instability at very high temperatures, cyclical heat variations cause less degradation than constant heat.2, 8 

In summary, the pharmacological effects of EMS drug storage temperatures have not been evaluated for most drugs carried on ambulances in this country, and this question remains a subject of study.  There are better data for the stability of diazepam and lorazepam at various temperatures than there are for most drugs.  In actuality on ambulance storage conditions in a moderately hot environment with peak temperatures of 100 degrees F, lorazepam is slightly more stable than diazepam.  In a simulated extreme environment, with a 60 day mean temperature of 100 degrees F, lorazepam was slightly less stable than diazepam.  All variations are of minimal clinical significance.  Given the doses of lorazepam used in the proposed RAMPART study, i.e., 4 mg in adults, degradation of this to 3.2 mg remains solidly within the therapeutic range used to treat seizures.  Although the hottest locations participating in this trial have temperature spikes in the drug bag of up to 14 degrees higher than the constant extreme temperature tested, the mean in the hottest locations is 14 degrees cooler than the test temperature, and temperature cycling causes less degradation than constant temperatures in other heat labile drugs.   

These data suggest to us that the heat lability of lorazepam in the RAMPART study can be addressed adequately in the following manner: 

    1. Rapid replacement of lorazepam every 60 days

    2. Colorimetric indicators to show exposure to a MKT > 100 degrees in real time

    3. Continuous monitoring of drug box temperatures for analysis

    4. Ongoing quality control with random sampling of returned drug for degradation

    5. Encourage EMS system solutions to very high drug box temperatures

References: 

1. Brown LH, Krumperman K, Fullagar CJ. Out-of-hospital medication storage temperatures: a review of the literature and directions for the future. Prehosp Emerg Care 2004;8:200-6. 2. Gill MA, Kislik AZ, Gore L, Chandna A. Stability of advanced life support drugs in the field. Am J Health Syst Pharm 2004;61:597-602. 3. Helm M, Castner T, Lampl L. Environmental temperature stress on drugs in prehospital emergency medical service. Acta Anaesthesiol Scand 2003;47:425-9. 4. Mehta SH, Doran JV, Lavery RF, Allegra JR. Improvements in prehospital medication storage practices in response to research. Prehosp Emerg Care 2002;6:319-21. 5. Brown LH, Campagna JD. Medication storage in the EMS environment: understanding the science and meeting the standards. Emerg Med Serv 2005;34:71, 3-7, 90. 6. Brown LH, Bailey LC, Medwick T, Okeke C, Krumperman K, Tran CD. Medication storage on US ambulances: a prospective multi-center observational study. Pharm Forum 2003;29:540-7. 7. Gottwald MD, Akers LC, Liu PK, et al. Prehospital stability of diazepam and lorazepam. Am J Emerg Med 1999;17:333-7. 8. Church WH, Hu SS, Henry AJ. Thermal degradation of injectable epinephrine. Am J Emerg Med 1994;12:306-9.

Protocol Reference: Section 4.3.4, p.28 and 5.1.2, p.35-36

 

Q:Is midazolam contra-indicated in some HIV patients?
A: Recent guidelines regarding drug-drug interactions in patients with HIV on highly active anti-retroviral therapy have recommended that more than 40 common medications including midazolam not be prescribed to these patients.

(See http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf or http://www.hivguidelines.org).

We have carefully reviewed these guidelines, and have determined that they do not have significant implications for RAMPART. The topic, however, does warrant further discussion.

Foremost is that the guidelines specifically allow for midazolam to be used in a single dose in a monitored situation. Since subjects in RAMPART are only given a single dose of midazolam, and already warrant monitoring by virtue of presenting in status epilepticus, the study is consistent with guidelines.

Secondarily, it is worth understanding the context of the concern.  The concern is that several HAART medications are potent inducers or inhibitors of the cytochrome P4503A4 system.  Drugs such as efavirenz are inducers of CYP4503A4 and may reduce potency of dozens of medications.  Protease inhibitors such as ritonavir are inhibitors of this system and can increase the potency of the same medications.  It is important to understand that cytochrome P450 (CYP) 3A4 is not only the most abundant isoform in human liver but that it matabloizes approximately 60% of known therapeutic drugs  (Zhou S. Curr Drug Metab. 2004;5:415-42).  It is also important to understand that, at least at this point, the concerns with midazolam are theoretical.  The guidelines state, "Certain listed drugs are contraindicated based on theoretical considerations.  Actual interactions may or may not occur among patients."  There are no reported cases in the medical literature of oversedation from interactions between HAART and midazolam.  Indeed the absence of such case reports has been remarked upon (Dresser GK. Clin Pharmacokinet. 2000;38:41-57).

Thirdly, the theoretical concern itself should be mentioned because it really only applies to oral preparations of midazolam.  CYP4503A4 is prevalent in both the liver and the gut.  Drug-drug interactions involving inducers and inhibitors of this system are related almost entirely to enteric and first-pass hepatic metablolism.  Thus, the theorectival concerns with midazolam have been related mostly to its high oral bioavailability and substantial first pass effects.  The single dose interaction of intravenously administered midazolam with CYP3A4 inhibitors has been empirically shown to be much smaller than the interaction of oral midazolam with the same CYP3A4 inhibitors (Olkkola KT. Anesth Analg. 1996;82:511-16).

In summary, neither existing guidelines nor theoretical concerns should impact the use of a single dose of parenteral midazolam in RAMPART.  Given the interest of some investigators, however, we are examining the possibility of collecting further data on the use of the 30 or more known inducers or inhibitors of CYP4503A4.  It is felt that we can accurately determine these data in the context of the trial's streamlined processes, these may be added to a future revision of the study CRF.  Stay tuned.

 

Q:What is the rationale for the dosing selected, especially for children?

A: This trial compares two agents given in moderate to high doses from within the usual dose ranges defined in their respective package inserts.  Two dose tiers are used, one for smaller children, and another for adolescents and adults.  Children’s dosing is based on estimated weight from a length-based weight estimation tool, similar to the Broselow tapes commonly used in pediatric resuscitations.  The dosing in this trial is designed to achieve a therapeutic dose as rapidly as possible.  An autoinjector is used to maximize the speed and ease of intramuscular delivery in order to provide initial treatment as rapidly as possible and to reduce delay in initiating intravenous access to a nominal latency of about 20 seconds. 

An alternative strategy for the administration of benzodiazepines commonly used in the emergency department is to use multiple repeated smaller doses rather than immediate administration of the total dose likely to be required.  While this is effective in applications such as procedural sedation, it is likely to be a less safe strategy in the treatment of prehospital SE.  In patients with SE, underdosing of anticonvulsants is likely to be as, or more, risky than giving higher doses of benzodiazepines.  Fixed dosing over a range of weights was selected over calculated individual dosing to simplify treatment and to avoid the known problems with the frequent marked overdosing and underdosing reported in pediatric resuscitations.1

The dose of lorazepam proposed for adults in this trial is the initial recommended dose for treatment of status epilepticus in the package insert.  This is higher than the dose initially given during the PHTSE trial, and is more consistent with, but slightly lower than, the initial dose given in the VA Cooperative trial.  Lorazepam is not yet FDA approved in children, but is commonly used.  The doses used in this trial are within the dose range commonly required for the treatment of SE in children.

The midazolam dose given in this study is targeted at the most commonly used dose given in the studies of emergency use in pediatric SE, 0.2 mg/kg, but varies with patient weight.  Even the maximal dose given, however, is within the recommended dose range for IM midazolam in children undergoing pre-anesthetic sedation.  This range is also consistent with the range of midazolam dosing reported for the treatment of SE in a variety of settings.  Yoshikawa2 gave initial IV doses of up to 0.3 mg/kg for SE, and for refractory SE in children, Morrison3 suggests the initial optimal IV dose is 0.5 mg/kg.  Buccal and IM midazolam have been shown to have similar pharmacokinetics4-67  Several reports8-10 of IM midazolam for seizures have also targeted initial doses of 0.2 mg/kg.    and in a relatively large clinical trial of buccal midazolam, children with seizures were successfully treated with fixed dosing that varied around a target dose of 0.5 mg/kg.

Data relating dosing to respiratory depression and subsequent need for endotracheal intubation are limited, but in Chamberlain’s pilot study using IM midazolam at a target dose of 0.2 mg/kg, the two children requiring intubation for respiratory depression were those that did not stop seizing, suggesting the possibility that significant respiratory depression might actually turn out to be more common in those getting lower doses of anticonvulsants.10  Indeed this was also the experience in the PHTSE trial, where respiratory depression and intubation were more commonly related to the underlying status epilepticus than to the adverse effects of the benzodiazepines.

The strategy in this study is to rapidly give a moderate to high, and thereby more likely effective, dose of either IM midazolam or IV lorazepam right away and wait long enough for the drug to peak.  Given weight variation in the lower dose tier, the maximum initial dose given may be more than is currently used in an initial dose in some EMS11 systems.  The dose used may be considered the first two doses that would be given in a strategy of smaller repeated doses.  This is intended to optimize efficacy and decrease the risk of underdosing, which is likely more dangerous than the risks of sedation.  This front loaded strategy also more safely permits waiting 10 minutes for drug levels to peak, rather than having to re-dose while the drug levels may still be going up, a problem that can actually increase the risk of overdosing with smaller repeated doses.  The length based resuscitation tapes used in this study are unlikely to be a source of overdosing as they are quite accurate under five years of age and when they err they tend to underestimate rather than overestimate weight.

Reports of clinically significant respiratory depression with benzodiazepines given at these doses are uncommon, but respiratory depression is certainly an expected adverse event in this trial resulting from both the SE itself and from the benzodiazepines, and is likely to occur in some subjects.  Endotracheal intubation will be tracked carefully.  Furthermore, paramedics are already trained to monitor for respiratory depression in patients with SE, and paramedics have advanced airway skills allowing them to support ventilation and oxygenation to prevent morbidity in patients with clinically significant respiratory depression.

References: 

1. Kozer E, Seto W, Verjee Z, et al. Prospective observational study on the incidence of medication errors during simulated resuscitation in a paediatric emergency department. Bmj 2004;329:1321. 2. Yoshikawa H, Yamazaki S, Abe T, Oda Y. Midazolam as a first-line agent for status epilepticus in children. Brain Dev 2000;22:239-42. 3. Morrison G, Gibbons E, Whitehouse WP. High-dose midazolam therapy for refractory status epilepticus in children. Intensive care medicine 2006;32:2070-6. 4. Rey E, Treluyer JM, Pons G. Pharmacokinetic optimization of benzodiazepine therapy for acute seizures. Focus on delivery routes. Clinical pharmacokinetics 1999;36:409-24. 5. Schwagmeier R, Alincic S, Striebel HW. Midazolam pharmacokinetics following intravenous and buccal administration. British journal of clinical pharmacology 1998;46:203-6. 6. Kutlu NO, Dogrul M, Yakinci C, Soylu H. Buccal midazolam for treatment of prolonged seizures in children. Brain Dev 2003;25:275-8. 7. McIntyre J, Robertson S, Norris E, et al. Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomised controlled trial. Lancet 2005;366:205-10. 8. Lahat E. A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Pediatr Emerg Care 1997;13:449. 9. Shah I, Deshmukh CT. Intramuscular midazolam vs intravenous diazepam for acute seizures. Indian J Pediatr2005;72:667-70. 10. Chamberlain JM, Altieri MA, Futterman C, Young GM, Ochsenschlager DW, Waisman Y. A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Pediatr Emerg Care 1997;13:92-4. 11. Hashikawa A, Juhn Y, Homme J, Gardner B, Moore B. Does length-based resuscitation tape accurately place pediatric patients into appropriate color-coded zones? Pediatr Emerg Care 2007;23:856-61.

Protocol Reference: Section 2.4-2.7, p.16-20

 

Q: What dose do small adults get?

A: The low dose tier (purple coded) is given only to children determined by the length-based-weight-estimation tool to have an estimated weight of less than 40 kg.  This tool is only valid in children.  Estimation of weight in adults is unreliable and potentially time consuming; therefore, all adults are treated with the higher (white coded) dose tier.

Protocol Reference: Section 4.3.3, p.26-27
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Other

Q: Why is there a suggested ED and in-patient management plan?

A: The guidance is provided for those who would find it helpful.  The language repeatedly emphasizes that this is non-mandatory and that sites can use whatever treatment protocol they wish.  It is understood that most major tertiary care facilities are likely to have existing treatment plans, but that some smaller receiving hospitals may not.  This optional guidance may be helpful in those facilities.

 

Q: Will you be obtaining a Certificate of Confidentiality from the NIH?

A: Certificates of Confidentiality are issued by the NIH to protect the privacy of subjects enrolled in clinical studies.  They are used in studies where sensitive information about the subject exists only in the study’s dataset to protect investigators from being compelled to release that information under court order in civil and criminal legal actions.  Although the information collected in RAMPART could be sensitive, for example having had seizures could affect a patient’s employability, there are no sensitive data that do not also already exist in the medical record.  The information in the medical record is still accessible by court order, and is not protected by the Certificate of Confidentiality.  After discussing our trial and this issue with our General Counsel, he has determined that a Certificate of Confidentiality has no potential to provide any supplemental protection of privacy to subjects in the RAMPART trial.  Subsequently, we will not be obtaining a Certificate of Confidentiality for the RAMPART trial.

 

Q: Since the primary outcome is the Attending Emergency Physician’s clinical assessment of the presence of seizure at ED arrival, does that mean all the ED attendings need to be investigators? 
A: No, the study team responding to the emergency department will collect this piece of clinical information from the attending physician, and record it in the CRF.  There is no reason for all the ED attendings to be investigators.

Protocol Reference: Section 6.1, p. 50
 

Q: What is the time frame (# of minutes) that the ED attending must see the patient to determine whether or not the patient is still seizing when the patient arrives to the ED?

A: There is no specified time frame in which the ED attending must see the patient. The primary outcome is not the status of the patient as determined by the attending physician on arrival; it is the status of the patient on arrival as determined by the attending physician when queried by the study team using whatever information is available to that point.

It is understood, for example, that a patient treated for seizures who stops convulsing, and arrives at the ED talking and appropriate at triage may not be seen for some time. That is ok. The attending physician can determine from the triage record that if the patient was talking at arrival, then the patient wasn't seizing even if the patient was not seen by the physician at that time. Similarly, if a patient is still convulsing on arrival, the patient may be seen by a resident who treats the patient resulting in termination of the status before the attending is at the bedside. That is ok. The attending can use the resident's presentation of the case to inform the attending's determination of the patient's status on arrival.

Remember that the paramedics also verbally state their determination of status on arrival on the study box at the time of ED arrival. This is an alternative source for missing data for the primary outcome.

Protocol Reference: Section 6.1, p.50

 

Q: Do I need to offer opt-out bracelets?

A: Providing a mechanism to opt-out of a clinical trial that uses exception from informed consent (EFIC) for emergency research is not a requirement of the regulations that govern these trials.  The FDA has, however, asked for opt-out provisions to be included in some previous EFIC studies, particularly those involving new drugs not otherwise approved for use in humans.  We have not been asked by the FDA to provide an opt-out provision for RAMPART, at least not yet.  We have, nevertheless, chosen to include an opt-out provision for this trial. 

It is important to understand the limitations of the opt-out provision from an ethical standpoint, as the true value of these mechanisms are often overstated.  Opt-out is a reasonable provision to include in these trials so that certain individuals who learn about the trial and do not wish to participate have the opportunity to express that wish.  That being said, it should be understood that in most EFIC trials the eligible enrollment events are rare, and the likelihood that any particular identifiable individual ever being eligible is very small.  Even with extensive public disclosure activities, past trials have shown that the subjects enrolled rarely if ever knew about the study prior to the acute medical emergency for which they were enrolled.  Given past experiences as a guide, on a purely probabilistic grounds, the number of patients requesting the opt-out is small enough compared to the general population, that none of those who have opted out ever get screened for the study.  That is, in practical terms, there are so many people out there in the world that those who wish to opt-out never really have the opportunity to be included anyway, and those who are enrolled, are rarely the same individuals reached by public disclosure activities.  This has been the overwhelming experience in prior EFIC studies.

Our provision takes advantage of existing behaviors and resources on the part of both the patients and the paramedics.  Paramedics will look for medical alert tags on patients prior to treatment in this study, just as they would in routine emergency care.  If the words “RAMPART DECLINED” appear on the medical alert tab of a patient, then that patient will not be enrolled and will be treated by the standard emergency response for that EMS system.  This is the least stigmatizing option, since patients with epilepsy generally already wear such tags to notify rescuers of their condition.  It avoids making an individual wishing to opt out from having to wear a special study-specific identifier at all times for that purpose.  In previous trials, however, investigators have sometimes been required by their institutional review boards to provide bracelets to individuals who want to opt-out.  Because such bracelets have not been particularly effective in previous trials, and because of the potential for stigmatizing patients we do not feel this is the ideal solution for RAMPART.  That being said, we understand that some IRBs may still request or require their Hubs to provide such opt-out bracelets, and we have acquired some low-cost silicone medical alert bracelets with the words “RAMPART DECLINED” on them.  If your site is required to use bracelets, let us know and we will provide these to you. 

Because of past experiences in which bracelets have become desired as novelty items rather than as an expression of autonomy, we are also making available medical alert bracelets that simply say RAMPART, which can also be given out to people who want a bracelet but who do not want to opt out of the trial.  We feel that decision making is not really in the spirit of autonomy if it is not informed, so it is reasonable to require that individuals learn about RAMPART before being issued a free bracelet.  If you are required to give out bracelets, the following is a list of several suggestions on issuing the bracelets:

1. After a community consultation meeting, attendees may complete a "Bracelet Form" that asks for their name, address, bracelet size (youth or adult), and to check a box indicating they are opting-in or opting-out.  The form is then used to mail out bracelets, only.  It is not maintained as a record of those wishing to opt out.  

2. Alternatively, patients could be directed to your local site's website to watch the RAMPART video or read a summary about RAMPART.  Once the patient has watched the video or read the RAMPART study information she will be asked if she has any questions.  If yes, the patient will be directed to call your local site coordinator/contact person.  If no, the patient will be directed to an online Bracelet Form that asks for her name, address, bracelet size (youth or adult), and to check a box indicating she is opting-in or opting-out. 

3. Patients are welcome to call your local site's coordinator/contact person or the NETT's toll-free number, 1-866-929-NETT(6388), to receive the required information and then a bracelet.

MOP Reference: Appendix 12, p.159

 

Q: What should be included in an EMS Pharmacy Control Plan?

A: 1. The Hub-designated pharmacy receives meds from the RAMPART Central  Pharmacy. The Hub-designated pharmacy will be responsible for receiving, storing, and releasing the study drug kits, and completing tracking information in WebDCU™. Upon arrival at the Hub-designated pharmacy, the study drug bundles will need to be refrigerated until they are secured in the study box and distributed to EMS providers. All study drug bundles will need to be used within or destroyed after 60 days from the date the drug bundles are removed from refrigeration, secured in the study box and distributed to the EMS provider. Expiration dates will be tracked in WebDCU. 

2. A RAMPART Study Coordinator signs for drug received at HUB-designated pharmacy, as per the Hub-designated pharmacy's protocol, to be delivered to the EMS provider. 

3. Describe who matches the study drug bundles to the study box, and who activates the box. 

4. A RAMPART Study Coordinator delivers the study box to the EMS department and fills out the RAMPART Receipt Log - the coordinator and paramedic receiving drug must sign this form. 

5. The paramedic then completes the EMS Drug Accountability Form and places the study box within the EMS bag/box (unless state requirements specify it be locked inside the ambulance cabinet. 

6. Daily inventory at the EMS provider requires use of the EMS Drug Accountability Form and requires signatures from both the paramedic going off duty and the paramedic coming on duty. 

7. Study Box and Study Drug Bundle Replacement - Notify on-call RAMPART personnel – the study box must remain with the patient until retrieved by RAMPART study personnel.  The on-call RAMPART personnel makes arrangements for study box replacement.  Upon returning to station EMS logs the patients name and run number on the EMS Drug Accountability form.  The RAMPART Study Coordinator will collect the old EMS Drug Accountability form and begin a new one with the new study box. 

MOP Reference: Section 13.2, p.51

 

Q: Is there compensation from the sponsors for study-related injuries?
A: No. There is no compensation from the funders or sponsors for study-related injuries.

 

Q: How are source documents being handled for RAMPART?

A: RAMPART uses only the electronic CRF (e-CRF) found on WebDCU. Printable paper worksheets of the e-CRF for RAMPART are available for use only when direct data entry is not possible. It is neither expected nor desirable for sites to maintain paper CRF worksheets. If paper worksheets must be used, they must be maintained in the subjects' study binder.

For purposes of completing the e-CRF at the Hub level, source documents for RAMPART may include the medical record (including the EMS run sheet) and the e-CRF itself. The study team should complete the e-CRFs to the extent possible using the source documents available (ED and inpatient medical record, run sheet, lab results if relevant, etc.). Some data elements will not be obtained from the record, but will be obtained verbally directly by the study team from the treating medical team, or by observing or talking to the subject. These data are recorded directly on the e-CRF and the e-CRF is the source document for these data (i.e., it is the place where these data are first recorded).

We are not asking paramedics to complete any study data forms for RAMPART. Prehospital data will include those communicated verbally through the treating team and the study team, and those recorded on the routine clinical run sheet (part of the medical record). Prehospital data from the study box (including the audio recordings, temperature, and sensor data for time of arrival) will also be abstracted centrally at the NETT CCC and entered into the e-CRF in WebDCU. Data obtained from the study box audio recordings is limited to the time stamp at which the predetermined events are announced. Those moments of audio recording and their time stamp will be clipped centrally and maintained as source documentation. No other data are abstracted from the voice recordings. All other portions of the audio recordings will be deleted. Hubs will not access any of the audio recordings or other study box data in order to protect privacy for patients and medics during treatment and transport.

MOP Reference: Section 9.1, p.42

 

Q: Who should be included on RAMPART screening logs? Do I have to try to capture every patient with any kind of seizure activity?

A: Screening logs should capture all patients in your participating EMS systems treated with benzodiazepines for seizure, but not enrolled in RAMPART. You do NOT have to try to capture every patient with any kind of seizure. For example, in most EMS runs for seizure the patient's seizure is likely to have stopped prior to EMS arrival, and in those cases it is likely that EMS will not treat with benzodiazepines. Such cases do NOT need to be included in the screening log. If a patient is not enrolled in RAMPART because they are no longer seizing on EMS arrival, but EMS does give a benzodiazepine anyway for some reason, that patient would be included in the seizure log. If a patient is hypoglycemic and seizing on EMS arrival, and is treated only with D50W, they do not need to be included in the screening log. If a hypoglycemic seizing patient is treated with D50W, continues seizing and is treated with diazepam, then the patient should be included in the screening log. The intention here is threefold: (1) to provide a fairly consistent criteria for logs from site to site, (2) to allow you to use medication use logs to easily identify patients for the log, and (3) to keep data entry for these logs manageable.

 

Q: How is the primary outcome on the ED Arrival Form determined if a patient is taken to a non-participating hospital?

A: If a patient is taken to a non-participating hospital, the primary outcome on the ED Arrival Form will be determined by the data in the medical record.

When a patient arrives at a non-participating hospital, the study team would contact the patient at the earliest opportunity, obtain consent, return to the hospital with the consent, review the medical record, and complete the ED Arrival Form to the best of their ability based on the medical record data. If it is clearly documented on the medical record, they can answer the primary outcome. If it is not possible to access the medical record at the hospital, or it is not clearly documented, the study team  will leave this item on the ED Arrival Form blank. The primary outcome will then be obtained from the study box voice recording.

 

Q: How often do you need to follow-up on a RAMPART patient?

A: You only need to follow-up on RAMPART patients at 24 hours and then at end of study. Non-serious AEs are not collected after the first day. At end of study, you should gather SAEs from the record and report them. You certainly can follow-up more often and report SAEs along the way, especially if it is easier for you, but the protocol only obligates you to three data collection time points: enrollment, 24 hours, and end of study. Remember, though, if you do become aware of an SAE along the way, it has to be reported when you become aware of it; so you may only want to check at the three required time points.
 

 

Q: What part of a complicated hospital course should be reported as SAEs?

A: This is ultimately a question of clinical judgement, but there are some key points to remember to simplify when possible. First, is there a likely precipitating illness that caused the seizure for which the patient was enrolled and a bunch of other problems? The precipitating illness is, by definition, pre-existing, so clinical findings that are simply manifestations of the precipitating illness "event"/diagnosis should not be considered SAEs unless they represent a dramatic unexpected worsening of that condition. Other adverse events that are consequences of his treatment and hospitalization do need to be reported as SAEs, but clinical judgement should be used to aggregate under unifying diagnoses whenever possible. For example, I would describe an intubated ICU patient with a fever, infiltrate on chest x-ray, hypotension, and renal failure in a single SAE called "sepsis" or "SIRS" rather than in four SAEs. Although either reporting strategy could be ok, the latter is ultimately more informative, more consistent with my reading of FDA and ICH guidance, and creates less busy work. So, when you look back at SAEs at the end of study, use the retrospectroscope to find these unifying diagnoses when possible. Do not, however, lump unrelated adverse events into a single report. That is, don't name an SAE "pneumonia and DVT" or "rhabdomyolysis and subdual hematoma".
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