FAQs

Payments and Milestones

ESETT Database/WebDCU

Study Records/Data Capture, Analysis, and Publication

Ancillary Study – (Specimen Draw/Processing/Shipping)

EFIC-CC/PD

IRB

Study Drug

Site Training and Readiness

Screening – Inclusion/Exclusion

Randomization/Blinding/Unblinding

Obtaining Informed Consent

Study Survey

End of Study and Co-Enrollment

DSMB


Payments and Milestones

Q.  What is the per subject payment?

A.  Per patient payment is: $7500.00 inclusive of F&A.  Meanwhile start-up milestone payments are viewable in the Milestone document in the ESETT toolbox: www.esett.org.

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ESETT Database/WebDCU

Q: How do I add a NEW team member to the database?
A: All study team members will need to be added to the ESETT database and then added eDOA.

  • Click on [Study Team Member Request] under the [User Management] tab
  • On the right hand top corner of screen, click on [Add New]
  • This opens a new Study Team Member Request record – complete fields 1 through 8 and Save record.

 

Q: How do I set up a team member’s user permissions to access WebDCU (eg. Study Coordinator, Site Pharmacist permissions)?

A: To request user permissions in WebDCU, please go to ESETT >> [User Management] >> [User Permission Request].  In that table you’ll see a list of all your site personnel.  Click on the blue number next to the name of the person you wish to request permissions for, then click “Edit Record.” You can then add rows to request their permissions.  Please note that  “WebDCU User” is required for all users. Once permissions have been requested and the DOA log submitted and approved, SDMC will approve the permissions and they will receive an email with account login and password.

NOTE:   Study team members will need to have an account set up using the [Study Team Member Request] table before user permissions can be requested.

Site pharmacists' access to Drug Tracking module in WebDCU: The User Permission Request for pharmacists would be “site pharmacist”.  Please request this permission using [user permission request] table so pharmacists are able to access WebDCU to acknowledge receipt of study drug.

 
Q: How do I modify a team member’s role and/or responsibilities? 
A: First, add an end date for the team member’s whose role and/or responsibilities are being modified; then, add a new entry for the same team member with updated details for role/responsibilities and submit the eDOA for CCC review and approval.  Discuss with site manager if the 1572 (and/or IRB Application) needs to be updated as well.

 

Q: I have a new team member on my study team.  What are the steps to upload regulatory document for this new team member? 
A: Follow the steps below:

  • Add the new team member to the Database using the Study Team Member Request entry (See new FAQs on adding a new study team member to database)
  • Then add the team member to the eDOA log with start date, study role, and responsibilities.
  • Submit eDOA log for CCC review and approval.
  • After eDOA is approved by CCC, upload regulatory documents for new team member.
  • Discuss with site manager and update 1572 if needed; upload updated 1572.

NOTE: It is the site’s responsibility to ensure that all new team members are added to the IRB application and approval is obtained before the study team member performs study related tasks.  Upload IRB approvals as IRB Study Communication.

 

Q: How can I submit site (or people) regulatory documents?     
A: Follow the steps below.

  • From the main menu page, click on [Regulatory Document] and then [Site (or People) Reg Doc Submission] table.
  • To upload a new document, click on the Green Arrow for the document that you want to upload
  • If there are any existing documents available for selection, they will be listed.
  • If there are no existing document available, or none that you would like to select, click on the ‘upload new file’ link, browse for the document, and then click upload.
  • Enter the required information, and then click ‘Save Record.’

Tip:  User ManagementàSite Reg Doc Status table:  This will display a table view of the documents required at your site as well as the submission status of each document.

 

Q: I have a 1572 completed for my site.  Do I need a Delegation of Authority (DOA) log as well?  What is eDoA?

A: All sites need a DOA log and completed 1572.  For ESETT, in WebDCU, the DOA is entered electronically and is called eDOA.

Upload the completed and signed 1572 for your site as “FDA Form 1572 – Statement of Investigator.”

 

Q:  Where can I find the electronic Delegation of Authority (eDOA) log and how do I complete the entry? 
A:

  • Login into WebDCU-ESETT,
  • Click on the [User Management] tab
  • Click on [DOA submission]
  • Click on the blue # (number) link to the left to edit the eDOA
  • Lastly, click [Edit Record] on the top right hand corner of the page. 
  • Add the team members to the eDOA list (They need be added to the study team member request table first, see Q on “How to add NEW team member to the database?”)
  • Add responsibilities for each team member.
  • Click [Submit] for the entry to be sent to the site manager for review and approval.

 

Q: How do I remove a team member's permissions from WebDCU? 
AA team member’s user account access is not updated once an end date is added to the eDOA log. User permissions also need to be updated.

Remove all user groups in the [user permission request] table for the departed team member. Please refer to the steps below.

  • Click on the [User Management] tab, and then [User Permission Request] .
  • On the list record page, click on the blue number link to the left of the study team member name you are looking for.
  • Click on [Edit Record] in the top right hand corner of the screen.  Remove all user group permissions in Question 5. When done, click [Save Record].
  • SDMC Data manager will review and approve the request.

 

Q: How can a team member stop receiving WebDCU’s automated regulatory document emails? 
A: Follow the steps below.

  • Contact the coordinator in charge of adding people/submitting reg docs (usually the primary study coordinator) and request that your permissions be updated.
  • Coordinator in charge, click on [user permission request] tab.
  • Click edit record, and remove the user group [Submit Regulatory Document].
  • Data manager at SDMC will approve the entry.

 

Q: What is required to be uploaded in the “Full Study IRB Application Submission (Protocol V1)” record in WebDCU?

A: This entry is for the full study IRB submission after Community Consultation (CC)and Public Disclosure (PD) activities have been completed, and should include: Results from local CC and PD activities submitted to your IRB; any contingencies from your IRB and responses provided by the investigator; and all formal correspondence from and to your IRB.   Combine all documents in a single PDF and upload.   Please refer to the Regulatory Parameters Document for further details and instructions.

 

    Q: What is required to be uploaded in the “IRB Approval (Protocol V1)” record in WebDCU?

      A: This entry is for the final IRB approval letter that allows your Hub/Spoke/enrolling site to randomize and enroll subjects. Upload the letter of approval in full as a pdf.  This letter should reference IRB acknowledgment of the results of EFIC activities and approval to begin enrolling subjects.  Please refer to the Regulatory Parameters Document for further details and instructions.

       

        Q: What is required to be uploaded in the “IRB Approved Informed Consent Form (Protocol V1)” record in WebDCU?

          A: This entry is for the final IRB approved Informed Consent Form (ICF) that was approved along with the full study IRB Approval (protocol V1) letter, and will be used to consent subjects for continued participation at your site.  Please refer to the Regulatory Parameters Document for further details and instructions.

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          Study Records/Data Capture, Analysis, and Publication

          Q.  How long do you anticipate needing for data analysis and publication?

          A.  The study anticipates data analysis and publication to take an additional 2 years after enrollment is completed.  Enrollment is planned for 4 years.

           

          Q.  Is your plan to destroy participant identifiers at the earliest opportunity consistent with the conduct of the research?

          A.  Study records will be kept for as long as necessary for purposes of the research study.  During that time they will be kept confidential to the extent permitted by law (as described in detail in the template consent form).  Enrollment is planned for 4 years. The study anticipates data analysis and publication to take an additional 2 years after enrollment is completed.

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          Ancillary Study – (Specimen Draw/Processing/Shipping)

          Q.  What will happen to the portion of the collected specimens that are leftover at the end of the study? How/Where will they be stored? Will they be used for any future research?

          A.  The specimen collected for ESETT will be used only for testing as described in the protocol.  All specimen leftover at the end of the study will be destroyed and will NOT be used for any future research.

           

          Q.  What is the timing of the blood draw?  Can subjects be consented/assented before the blood draw?

          A.  The blood will be drawn before a patient could be consented/assented.

           

          Q.  What does “blood may be drawn” mean?

          A.  The blood draw was included in the protocol so that it can be incorporated into EFIC community consultation and public disclosure materials.  It will only be done if additional funding is obtained to run the tests.  The ESETT leadership did not want sites to have to go back and do any more community consultation and public disclosure to add the blood draw if this part of the study ends up being funded after CC and PD starts.  They included language now in anticipation that it may be done.

           

          Q.  If blinded how does the PI know what lab to draw to check level?

          A.  The blood sample will be analyzed centrally so the blinded PI/study coordinator would not need to know what the subject received.  They would just need to make sure that the blood sample was obtained, processed, and shipped to the central lab.  

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          EFIC-CC/PD

          Q.  Where can I find the EFIC CC/PD materials?

          A.  The EFIC materials are located within the ESETT toolbox under EFIC.

           

          Q.  Has the FDA weighed in on whether they are accepting of the EFIC?

          A.  The FDA does not have any concerns with the ESETT trial being conducted under EFIC.  If your site IRB would like to understand how ESETT meets the EFIC regulations, the rationale, directly from the IND, are detailed in the EFIC Plan Proposal in the ESETT toolbox.

           

          Q.  Is there a Website for EFIC Proposal?

          A.  The EFIC proposal is meant to serve as a guide for CC and PD activities.  Some of our sites have created local websites but some have not. Your marketing department may be able to assist you with developing one locally.  In the past we have also assisted with local website development. 

           

          Q.  Do you have a radio template?

          A.  We do not have a radio template, but you are welcome to create one for local use.   We would be happy to help you with the process.

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          IRB

          Q.  What might an IRB need to understand about anticipated and potentially unavoidable eligibility deviations that will occur in ESETT?

          A.  ESETT enrolls subjects in a hyper-acute phase of emergency care using eligibility criteria that involve the clinical judgment of the treating team.  As such, it is anticipated that some eligibility deviations may be unavoidable.  These include patients that are thought to be having generalized convulsive status epilepticus (GCSE) and are treated for such in the emergency setting, but who are subsequently determined to be having psychogenic non-epileptic seizures (PNES).  In prior trials of emergency treatment of status epilepticus, patients with PNES and other mimics were subsequently diagnosed in up to 7% of enrollments, required an average of 1.5 days in the ICU to be properly diagnosed, and had better clinical outcomes than patients with GCSE.  In the analysis of ESETT, enrollments with PNES are included in the primary intention-to-treat analysis, but are identified as eligibility deviations so that they can be properly excluded in the secondary per-protocol analysis.  In addition to being unavoidable, the ESETT leadership feels that such eligibility deviations do not represent a change in the level of risk to these patients or others, and therefore that such eligibility deviations may or may not be reportable events to the local IRB.  Sites should check their local reporting guidance or confer with their IRB to determine their local reporting requirements related to such eligibility deviations.  Other examples of anticipated and similarly unavoidable eligibility deviations that do not effect level of risk, may include those in which doses of benzodiazepines are mistakenly thought to have been sufficient but turn out to be slightly lower, earlier or later than required by the inclusion criteria, perhaps based on verbal communication of dosing by Emergency Medical Services prior to enrollment that does not reflect what is subsequently reported dosing on a run sheet or related to other clinical judgments.    

           

          Q.  Can you explain how the risk is justified by the anticipated benefit to the subjects?

          A.  In this comparative effectiveness study the treatments and the medical risks are the same in study participants and others treated for status epilepticus who are not participating in the trial.  As the trial progresses participants may directly benefit medically because response adaptive randomization increases the likelihood of allocation to treatment with an increased probability of having the best efficacy.  Participants may also benefit from the added attention of being followed by the study team.  The minor potential research risks related to randomization and confidentiality are justified by the potential medical benefit and by participants being able to contribute to identifying the most effective treatments for themselves and others suffering from status epilepticus in the future, since patients with epilepsy are at risk for further episodes over the rest of their lives.  

          NOTE:  We believe the study risk level should be classified as “minor increase over minimal risk”, and “with the prospect of direct benefit”.

           

          Q.  Can you justify that the relation of anticipated benefit to risk is at least as favorable to subjects as that presented by available alternative approaches?

          A.  In this trial patients are randomized to one of the three treatments that are already commonly used in the standard emergency treatment of status epilepticus, so the anticipated benefit to risk relationship is at least as favorable as in standard treatment alternatives.   As the trial progresses, the anticipated benefit to risk relationship may become more favorable to participants because of response adaptive randomization.

           

          Q.  Is there an option to opt out of the pediatric portion for any spoke?

          A.  Not all sites will enroll both adults and pediatric patients.  If there is a specific reason why a site would like to opt out of pediatric enrollments, the ESETT team would be willing to speak with them about any concerns, etc.  Please feel free to reach out to us.

           

          Q.  Will any of the participants enrolled be in foster care or Wards of the state?

          A.  The trial will not exclude participants for this reason, unless they are considered prisoners.  Prisoners are excluded from studies  performed under exception from informed consent (EFIC).  However, it may be possible that local policies or State laws differ.   We would suggest checking with your institution/IRB regarding this.

           

          Q.  While the ICF describes the administration of the study drug that has already occurred, and focuses on obtaining consent for the post-treatment access to medical records and the like, the ICF lists the Potential Risks/Discomforts (side effects) of the three study drugs. Those statements did not seem to align with the side effects listed in the package insert for each drug. For example, the FOS (Dilantin) insert refers to acute hepatic failure, the LEV (Keppra) insert refers to suicidal thoughts and behavior and the VAL (Depakote) insert has a boxed warning regarding hepatic failure, life threatening pancreatitis and tremor, blurry vision and vomiting. Can you please clarify?

          A.  The risks of adverse events on the package inserts refer to the chronic use of the drugs as labeled, rather than to the use of the drugs in a single dose to treat status epilepticus (SE), which remains an off label use for VPA and LEV, and for FOS in children.  We have used expert opinion, pharmacologic mechanism, and clinical experience to provide a more concise and understandable presentation of risk that is more relevant to the context of single dose administration in critically ill patients with SE.  Given that this consent form is for permission to continue in the study after the medications have already been given, we feel it may be more important to make this section as understandable as possible, rather than encyclopedic.

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          Study Drug

          Q: Who is the contact for questions on study drug?

          A: For questions regarding study drug shipment and tracking, documenting drug receipt in WebDCU, or other study drug-related questions, contact the ESETT site manager at the NETT-CCC, Erin – ezajaros@umich.edu 734-232-2137.

           

          Q: How is excess study drug handled?

          A: Excess study drug can be discarded on site.  It does not need to be saved for monitor verification nor returned.  After the ten minute infusion, the study drug vial and the infusion line should be disconnected from the patient and set aside.  When the study team arrives, they will need to confirm the study drug number printed on the label of the vial, and then the vial and the line can be appropriately disposed of.

           

          Q.  If a patient is already taking Depakote, and especially if their levels are high, would a 20mg/kg IV bolus dose place them at excess risk of dose-dependent thrombocytopenia?

          A.  Platelet reduction is not a significant concern with a single dose. Effects on platelets are transient. We do not feel that this will place them at excess risk for thrombocytopenia. There is a medical safety officer and a DSMB for this study that will be able to identify this should it occur. But not felt to be an issue with single dose. 

           

          Q.  If a patient is on lamotrigine and they could be randomized to receive (VPA) Depakote, is being on lamotrigine going to disqualify them from the study?

          A.  No. The data on the interaction between LTG and VPA are for chronic dosing.  Not for a single dose. So, while if on LTG and randomized to VPA, this is a very legitimate concern in both children and adults, we would likely not then continue treating with VPA without dose adjustments. --  bottom line. LTG is NOT an exclusion. 

           

          Q.  Is there any contraindication to using fosphenytoin in children diagnosed with Dravet Syndrome?

          A.  No. Fosphenytoin and other sodium channel blockers not used in chronic therapy of myoclonic epilepsies including Dravet can make them worse, however, the exacerbation relates to absence and myoclonic seizures. Fosphenytoin is still  the mainstay of treating convulsive status that does not respond to benzos independent of the syndrome. There is no contraindication using it for convulsive status except in those known to be allergic.

           

          Q.  When calculating the cumulative adequate dose to determine eligibility, how are doses of PR diazepam and trans-mucosal midazolam considered? What about other routes of administration for other benzodiazepines?

          A.  For the purposes of determining eligibility for this trial, PR diazepam doses are considered the same as IV diazepam dosing.  For the purposes of determining eligibility for this trial, trans-mucosal midazolam (including both intra-nasal, IN, and per-buccal, PB, routes of administration) is considered the same as IM midazolam dosing.  For all drugs, the intra-osseous route of administration is considered the same as IV. Although IM lorazepam is used for sedation and other uses, the drug is too slowly absorbed to treat status epilepticus. IM lorazepam doses are NOT considered part of the cumulative adequate benzodiazepine dose for determining eligibility for the trial.

           

          Q.  Is there an investigator brochure? Is there a Master Study Drug file?

          A.  The package inserts found at the link below can be used.  As we have to assure the FDA that the study drug is pharmacologically equivalent to the labeled commercial products, the inserts are appropriately informative, however they should be accompanied by a caveat that we are not using the commercial products.   The study drugs will be will be produced at the central pharmacy, a GMP facility at University of California, Davis.

          Click here to access the drug information.

          There is no appropriate master drug file to which to refer.

           

          Q.  What are the dimensions of the randomization kit boxes?

          A.  The ESETT leadership team plans to reuse the RAMPART study boxes for ESETT.  The interior dimensions (L,W,D) of these boxes are: 8-7/16 x 4-7/16 x 2-1/4.  The exterior dimensions (L,W,D) of these boxes are: 9-3/8 x 5-9/16 x 2-5/8.

           

          Q.  Will the sponsor provide the diluents?

          A.  The study drug will be produced at a central pharmacy and shipped to each site, so the site IDS will not have to dilute.

           

          Q.  All study drug vials are blinded and due to treatment urgency.  How will the study team prepare kits?

          A.  The “use next” boxes will be prepared at the site, either by the study team or the pharmacy, which will be determined locally.  Please reference Sections 7.5 and 7.6 of the protocol for specific details on study drug and study drug packaging.

           

          Q.  What is the stability of each study drug after it is diluted?

          A.  Diluted formulations are expected to remain stable for months when stored at 4-8 degrees C.

           

          Q.  Can you please provide additional references to support the adult dosing (4.5 grams) of levetiracetam? The guidelines quoted (Brophy 2012) indicate adult dosing for levetiracetam in adults is 1-3 grams.

          A.  The choice of dose for levetiracetam in ESETT differs from that on the label because the dosing on the label does not reflect the use of the drug to treat status epilepticus (SE), which remains an off-label indication.  SE requires more rapid treatment and is thought to be effective if high levels of the drug can be obtained as early as possible.  The dose is based on expert opinion, evolving clinical practice using this drug to treat SE, and convincing human safety data with these higher doses and rapid infusions.  Ramael and colleagues performed a phase I, randomized, single-blind placebo-controlled study to evaluate the safety and tolerability of LEV administered intravenously at higher doses and/or at a faster infusion rate than proposed on the label, exploring doses up to 4g  (Ramael S, Daoust A, Otoul C, Toublanc N, Troenaru M, Lu ZS, et al. Levetiracetam intravenous infusion: a randomized, placebo-controlled safety and pharmacokinetic study. Epilepsia (2006) 47:1128–3510).  Subsequently, Wheless et al evaluated the safety of a rapid loading dose of IV LEV in a prospective, open-label, single-center study of 45 study patients, aged 4–32 years of up to 60 mg/kg given as a single loading dose as a 6-min infusion (Wheless JW, Clarke D, Hovinga CA, Ellis M, Durmeier M, McGregor A, et al. Rapid infusion of a loading dose of intravenous levetiracetam with minimal dilution: a safety study. J Child Neurol (2009) 24:946–5110).

          Although Depakote is used clinically, the IRB asks for acknowledgement/support in its use in a research study under EFIC.  The reason for this is that there is concern from the IRB regarding the teratogenic effects of Depakote (given potential of an unknown pregnant female being enrolled and no time for pregnancy test) with no prospective informed consent.

          None of the concerns about safety of valproate (VPA) in pregnant women refer to the use of a single dose in critically ill patients with SE.  Rather these concerns are based entirely on data from children born to mothers taking long durations of high doses of VPA during pregnancy, whom have a tendency toward subtle but measurable and potentially important differences in some measures of cognitive performance in childhood.  These risks are known to be dose dependent and are not detectable in children of pregnant patients taking daily lower doses in pregnancy.  There is no evidence that a single dose of VPA given during pregnancy can cause birth defects, and no guideline prohibiting this use.  Relative to the risk to both mother and pregnancy associated with SE, the risk of a single dose of VPA to the pregnancy is acceptable and extremely low (Bromley R, Weston J, Adab N, Greenhalgh J, Sanniti A, McKay AJ, Tudur Smith C, Marson AG. Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child.  Cochrane Database Syst Rev. 2014;10:CD010236).

           

          Q.  How long can study drug be out of refrigeration?  What temperature logs are required for the refrigerator in which the study drugs are kept and what is required when there are excursions?

          A. As noted in the Site Study Drug Procedures document (a link to which is found in section 6 of the MoP), the study drugs are not sensitive to minor temperature excursions.  The last paragraph of the section of that procedures document entitled “Use Next Box Preparation and Use” explains that temperature logging and handling of minor excursions are handled per routine clinical standards at the site.  It is understood that refrigerators in clinical dispensing systems will have more frequent minor excursions than refrigerators in the IDS, and should not be held to the same criteria as research pharmacy refrigerators.  Only excursions thought to be clinically significant by the site need be reported as unexpected problems.  Study drug generally need only be removed and destroyed in the very uncommon event that all the other clinical contents of the refrigerator are to be destroyed as well (i.e. extended power failure). 

          It will also be common for the Use Next box to be removed from refrigeration and brought to the bedside while determination of potential eligibility is being evaluated.  Often, a potential subject will not be eligible, and the intact Use Next box can be returned to refrigerated storage.  Similarly, a Use Next box will periodically need to be removed from storage to permit recharging of the Protocol Assist Device tethered to the box.  In any of these cases, the Use Next box should be returned to refrigeration as early as is convenient, but it is permitted to remove the Use Next box for periods of up to 12 hours and then return to refrigeration without concern.

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          Site Training and Readiness

          Q.  What enrollment requirements will have to be met by the ED staff (NETT trainings, etc.)? Would every ED MD have to be trained with documentation uploaded into WebDCU?

          A.  ED staff will need to be trained, initially and ongoing throughout the trial.  However, they will not be considered study team personnel, and thus, will not need to be added to WebDCU, nor have any documents uploaded.

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          Screening – Inclusion/exclusion

          Q: Does trans-mucosal midazolam count toward the adequate dosing for eligibility?

          A: For purposes of the trial eligibility, trans-mucosal midazolam (intranasal or buccal) can be considered as equivalent to intramuscular midazolam toward a cumulative adequate benzodiazepine dose.

           

          Q. Is a patient who is hypotensive prior to enrollment eligible for enrollment?  Should they be enrolled with a slower rate of infusion?

          A. Hypotension is not a specific exclusion criterion.  However, if one of the study drugs is deemed contraindicated for a particular patient by clinical team then that patient is not eligible and should not be enrolled, based upon the exclusion criterion “Known allergy or other known contraindication to FOS, PHT, LEV, or VPA”. So, if the clinical team feels, for example, that FOS would be specifically contraindicated because of pre-existing hypotension, then the patient should not be enrolled. Reduction in the rate of infusion is indicated for medication-induced hypotension, not hypotension in general. Do not initiate treatment at a reduced rate of infusion.

           

          Q. Is a patient who gets some form of advanced airway, but is not endotracheally intubated, excluded from enrollment in ESETT?

          A. Patients that are endotracheally intubated are not enrolled in ESETT because intubation and mechanical ventilation typically require the use of induction and sedation agents with confounding anticonvulsant properties, and because there is no benefit to 2nd line anticonvulsants over 3rd line anticonvulsants in those already intubated.  Patients treated transiently only with a supraglottic airway may still be eligible.  Those treated with supraglottic devices such as an oropharyngeal airway, nasopharyngeal airway, laryngeal mask airway (LMA), SALT, i-gel, King, Combitube, or similar, but who have these devices removed without subsequent transition to an endotracheal tube, and who are not treated with excluded induction agents, are still eligible for the study.  Obviously those requiring surgical airways are endotracheally intubated and are not eligible. 

           

          Q.  Does having a chronic tracheostomy exclude an otherwise eligible patient from enrollment in ESETT? 

          A.  Usually not, but sometimes yes.  The relevant exclusion criteria is related to endotracheal intubation.  The question is whether a chronic trach is like an endotracheal tube for purposes of eligibility.  In the protocol, Section 4.2 Table 2, provides the rationale for excluding intubation, which is “Prevents evaluation of patient for responsiveness.”  We interpret the chronic trach as an exclusion, akin to endotracheal intubation, when the same rationale applies.  A trach is an exclusion when it indicates the same kind of unresponsiveness that is usually indicated by endotracheal intubation.  That is, a patient who has a trach because they are chronically comatose or persistently vegetative are those that will not wake up even when they return to baseline after a seizure.  In such patients the trach indicates inability to evaluate responsiveness just like an ET tube and they are excluded by the ET tube criterion.  Most often, however, patients with chronic trach’s are not persistently unresponsive at baseline.  A patient with a chronic trach who is normally awake at baseline would not be an excluded by this criterion. 

           

          Q. Please provide rationale for not specifically excluding patient’s with Dravet syndrome and other disorders that preclude them from receiving certain antiepileptics.

          A. Valproate and leviteracetam are often used in children with Dravet, even chronically.  While sodium channel blockers such as phenytoin are not used in Dravet cases for chronic therapy, phenytoin or fosphenytoin continue to be the first line therapy for convulsive status for children with Dravet.   The same is true of other disorders such as Lennox-Gastaut syndrome, where we avoid phenytoin as chronic therapy but use it as first line for convulsive SE.   The treatment of convulsive SE in these syndromes is identical to treatment of SE for other children . A benzo followed by one of the ESETT agents.

          In general, the evidence about not using certain drugs for some syndromes, which is largely anecdotal, pertains to chronic usage and does not apply to single doses in context of abortive therapy.   While we do not use phenytoin or carbamazepine in children with Dravet for chronic dosing, there is no evidence that treatment of convulsive SE should be different.    Please note that while Dravet children frequently have status, they represent a tiny fraction of children over age 2 who present with SE.

          The protocol for convulsive SE is the same for these syndromes as for other children with SE.  In addition, there is no data to suggest that treatment of convulsive SE, unlike chronic therapy, is syndrome specific.

           

          Q.  Can you confirm that pediatric patients do not have to be admitted?  A lot of our status patients are transferred out after stabilized, but never within first hour.

          A.  Patients on ESETT do not have to be admitted.  Sites may follow standard process after stabilization, including transfer.  NOTE: Patients could be followed if transferred to a ESETT participating hospital.

           

          Q. When referring to "generalized convulsive seizure" as a requirement for enrollment, is this inclusive of seizures other than GTC seizures?

          A.  The inclusion criteria are intended to include those whose clinical syndrome is Generalized Convulsive Status Epilepticus (GCSE).  It is not intended to define a narrow or specific semiology.  So, for example, there is no reason to exclude a patient with GCSE whose presentation evolves to hemiclonic convulsion, but we would not include a conscious and alert patient with isolated focal seizures.

           

          Q.  Consider a patient who gets a dose of benzodiazepines and stops convulsing, then 35 minutes later convulses again and is given an additional dose of benzodiazepines. The cumulative benzodiazepine dose is adequate, but the patient is still convulsing 5 minutes after the second dose. Is this patient eligible?

          A.  Yes.

           

          Q.  Are patients on daily levetiracetam, phenytoin, or valproic acid excluded if they took their med that day?

          A.  No.  Patients are excluded if they were given levetiracetam, phenytoin, or valproic acid as emergency treatment for the current episode of SE.  Patients are not excluded because they take one of these medications orally as daily anticonvulsive therapy.   

           

          Q.  Does the exclusion criterion ‘metabolic disease’ refer to patients with diabetes?

          A.  No.  “Metabolic disease” does not refer to either diabetes nor to the so-called pre-diabetic “metabolic syndrome”.  Rather, the term “metabolic disease” is an exclusion based upon a warning on the FDA label for VPA referring to certain rare inborn errors of metabolism in children less than 2 years old.  

           

          Q.  Whom are the patients that are intended to be excluded by the ‘metabolic disease’ criteria?

          A.  Investigators may use their clinical judgment in interpreting this exclusion based upon the FDA warning on the label for VPA referring to congenital but unspecified conditions occurring mostly in children less than two.  All children under age 2 are already excluded from ESETT.  It is thought that the warning refers only to the inborn errors related to the six urea cycle disorders (deficiencies of NAGS, N-acetylglutamate synthase deficiency, ASL, arginosuccinate lyase, CPS1, carbamyl phosphate synthetase, AS, argininosuccinic acid, OTC, ornithine carbamoyltransferase, and citrullinemia).  It may also be appropriate to exclude those with known mitochondrial DNA polymerase-gamma (POLG) gene mutations (e.g., Alpers Huttenlocher Syndrome), tyrosinemia, porphyria, MELAS and Gaucher disease.  This exclusion only applies to those with known and already established diagnoses.  It is neither necessary nor feasible to test for these conditions prior to treatment in patients presenting with convulsive status epilepticus.  These suggestions supersede a misleading list of examples of congenital conditions mentioned in a previous version of an FAQ.  

           

          Q. An IRB requested that “known or suspected overdose/poisoning be included as an exclusion criteria since all three of the study drugs would be contraindicated in that scenario.”  The site study team opined that the exclusion for “other known contraindication to FOS, PHT, LEV or VPA” covers this situation.  The IRB responded that this should be added as a local exclusion, especially for our adult population, as this is often a factor in adult seizure patients.  They thought it should be more directly addressed for each screening/enrollment rather than “other known contraindication”.

          A. The ESETT study team does not object to the site adding this as a local exclusion.  We agree with the site study team that this exclusion is adequately covered by the “other known contraindications” exclusion criterion.  We agree with the IRB that in many cases seizures known to be caused by identified drug overdoses require specific antidotes in preference to second line anticonvulsants and should not be enrolled, however, such cases are rare.  In the prior NETT and PECARN status epilepticus emergency treatment trials, known drug overdoses other than alcohol were identified in less ½ of one percent of enrollments.  Most of these responded to benzodiazepines and do not reflect subjects that would be eligible for ESETT anyway.     

           

          Q.  How is the word “known” to be interpreted in the ESETT eligibility criteria?

          A.  Five of the ESETT exclusion criteria include “known” as a qualifier on the item described.  We recognize that this term is ambiguous and therefore offer the following clarification.  The term “known” is ambiguous in this context because it is does not indicate to whom the information is known, or when it was known.  In these eligibility criteria “known” is intended to indicate information already possessed by the clinical team or the study team at the time of enrollment.  Criteria qualified with “known” are not violated by a subsequent discovery, after enrollment, of a new or existing diagnosis or condition of which the clinical or study team was not aware at enrollment. 

          For example, a patient in SE should not be enrolled if she is obviously gravid on exam or if someone accompanying the patient at presentation provides a history that the patient is pregnant, because known pregnancy is an exclusion criterion.  If a patient in SE is enrolled, however, and during the subsequent portion of the ED visit or hospitalization is found by history or laboratory evaluation to be pregnant, this would not be considered an eligibility violation.  It does not matter whether or not the pregnancy was known to the patient or others; it is not a violation if it was not information readily available to the treating team at enrollment. 

          Contrast the use of “known” as it relates to pregnancy in the prior example with another exclusion that is not qualified by the word “known”.  Consider a subject enrolled after being transferred for SE from another institution.  The patient was enrolled because the treatment team was told that the patient had only received benzodiazepines at the referring ED.  Review of medical records faxed over from the referring ED after the enrollment indicate that the patient had also already been treated with LEV prior to transfer.  Although understandable and potentially unavoidable, this is an eligibility violation even though it was unknown at the time of enrollment.  This is because the exclusion is “treatment with a second line anticonvulsant for this episode of SE” rather than “known treatment with….” 

          We acknowledge the potential subtlety of this distinction, and are happy to work through specific situations with sites as they arise.  Note that the goal of this distinction is derived from the rational for the exclusion criteria in Table 2 of the study protocol (section 4.2), and how the collection of eligibility data is intended to be used.  Interpretation does not consider real or perceived leniency or fairness related to the enrolling teams.

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          Randomization/Maintaining Blind/Unblinding

          Q.  Is there a cut off where the CRC should no longer push the “start button” on the protocol assist device? Ex. If they miss the infusion by 2 minutes, should you still press the “Start Protocol” button or let it go? 

          A. We are not specifying a cut off, but in general, the protocol assist device should not be used to time the infusion or record assessments if the start button is not pressed at the time that the infusion is actually started.  The only reason to hit the start button late if overlooked at the start of infusion is if it is anticipated that there will be a desire to use the protocol assist device to unblind after 60 minutes. 

           

          Q.  Is there a fixed number of pediatric patients that must be randomized prior to RAR in the peds population?

          A.  No.  Response adaptive randomization is introduced in all strata when the trial has enrolled a total of 300 subjects across all strata.

           

          Q.  Will a study coordinator have to be present immediately after enrollment in the ED or could the data be looked up later on?

          A.  We anticipate that study team will arrive within 30 minutes of enrollment.

           

          Q.  Describe randomization scheme/assignment including ratio such as 1:1, 2:1 etc.

          A.  As described in section 10.1 of the protocol: “The randomization scheme will be equal allocation (1:1:1) for the first 300 patients. Once 300 subjects are enrolled, response-adaptive randomization (RAR) will be utilized with the goal of maximizing the likelihood of identifying the most effective treatment arm (Connor 2013). The target allocation ratio will be updated every 100 patients. We will use a “Step Forward” centralized randomization procedure developed for emergency treatment trials. (Zhao 2010) Randomization will be stratified by age.”

           

          Q.  Is emergency unblinding available at 20 minutes if patient has failed primary outcome?

          A.  Yes.  In fact, emergency unblinding will be available at any time it is needed, even before 20 minutes. Sites access emergency unblinding by calling the national ESETT Hotline (1-855-ESETT-PI), and having the on-call PI look up the treatment assignment on the WebDCU website. Unblinding will be available through the protocol assist device after the determination of the primary outcome on the device.

          From a safety perspective, however, I would emphasize to an IRB that guideline-driven rescue therapy at 20 minutes for continuing convulsions should generally be progression to third line therapy with intubation and anesthesia OR progression to phenobarbital, rather than emergency unblinding in order to attempt rescue with another one of the two alternative study drugs.  Yes, emergency unblinding is available for the latter, guideline-deviant, option when special circumstances arise in which this might be thought best for a particular patient, but is not recommended or anticipated to be routine.

          To avoid providing an incentive to prematurely declaring treatment failure in non-intubated subjects in order to perform early emergency unblinding, it is a protocol deviation to emergency unblind before 60 minutes.  I.e., if we find that someone had a protocol deviation by unblinding at 40 minutes, they could not go back and make the deviation go away just by declaring treatment failure at 38 minutes.   This is meant to address those who are thinking things like, “I want to give her Keppra if she didn’t get it already, so I need you to unblind now.  Do whatever you have to do.”  This at least keeps such cases from contaminating the per-protocol analysis.

           

          Q.  If treatment fails and study team is blinded, how will the PI know which treatment failed and what to give next?

          A.  If the treating team needs to know what the subject received in order to know what to give next, then the treating team can find out.  There will be an option for emergency unblinding on the protocol assist device (like an iPod Touch) after 60 minutes of the start of study drug infusion.  We prefer that the study team remain blinded, but if keeping the study team blinded would cause a delay in care, then a study team member can become unblinded for the purpose of getting the study treatment assignment from WebDCU or the protocol assist device and giving it to the treating team so as not to delay care.  But the rest of the study team should remain blinded. 

           

          Q.  The study protocol in CICERO says that interim monitoring will begin once 400 of the planned 795 enrolled subjects have been treated. Is that too long to determine if one of the study drugs has statistically significant improved outcomes or raises safety issues such that it should be deleted as an option, as the protocol describes?

          A.  The DSMB will monitor safety throughout the trial, with frequent safety reports, and can stop the trial at its discretion.  Response adaptive randomization begins after a 300 participant burn-in period, and will allocate more subjects to the arms that appear more likely to be more efficacious.  These allocation vectors are adjusted with each iterative interim analysis.  Extensive clinical trial simulation was performed to optimize the design parameters (like the size of the burn in period) such that the trial has favorable operating characteristics over a wide range of possible truth scenarios.  Depending on the scenario, simulations reveal the plausible mean sample sizes needed to identify a best treatment are greater than 500 subjects.  This design process for ESETT has been reported in detail (J Clin Epidemiol. 2013 Aug;66(8 Suppl):S130-7).

           

          Q. Will it be OK to unblind the study drug sometime after the primary outcome but before hospital discharge to determine which drug might be the best to prescribe the patient after their hospital discharge?

          A. Yes. The protocol accommodates this frequent request, and we plan for this to be very easy to do.  (We note, however, that the decision about what drug to use for chronic suppression should rarely be based upon response to a single dose IV treatment used to attempt to abort status epilepticus.)  Unblinding after 60 minutes is not a protocol deviation.  Unblinding before 60 minutes, or before the primary outcome , can also occur if thought to be needed for patient safety, but is a protocol deviation.

           

          Q. In the scenario where a subject stops seizing after study drug is set up but before start of infusion, is there a length of time we will be expected to watch subject to see if they start seizing(becoming eligible again) before the clinical team begins to load them with FOS, outside of the study? Protocol here is to begin loading with FOS on these patients. How long do we tell the clinical team to wait and watch?

          A. So, that is really the scenario of the person who does have a benzo-responsive status epilepticus.  It is not the intent of this trial to ever delay suppression medications in patients successfully treated with benzo’s regardless of whether the study drug kit has been opened or not.  However, brief pauses in convulsions without waking up are common in patients with ongoing status, so some effort to make the proper diagnosis is important.  We don’t encourage waiting, but subjects who have recurrent convulsions up to 30 minutes after the last benzo dose, can still be enrolled.  

           

          Q.  An IRB requested a change to 10.2 "blinding and unblinding".   Please remove the 60 minute waiting period for unblinding. A suggested change would be "...will be performed at a treating physician's discretion," as a physician may determine that unblinding is needed sooner for the safety/treatment of the subject.

          A.  We provide the following clarification regarding emergency unblinding for the IRB.  The ESETT emergency unblinding process will reveal treatment assignment when requested for the safety or treatment of the patient even prior to 60 minutes or prior to determination of failure to respond to the study drug (the primary outcome), but such unblinding will be considered a protocol violation.  Established clinical treatment guidelines state that patients with status epilepticus that fail second line anticonvulsant therapy should be treated with third line anesthetic anticonvulsant therapy to induce coma, titrated to seizure or burst suppression.  Knowledge of study treatment assignment is therefore never anticipated to be necessary for the safety of the patient or be needed to determine the next immediate treatment, and so is not consistent with the protocol.   The process for unblinding early has been provided, however, to accommodate situations where physicians judgment varies from established guidelines or for unanticipated situations.   On the other hand, the protocol explicitly permits emergency unblinding when the team feels the information is necessary to guide subsequent suppressive therapy or future episodes of second line anticonvulsant treatment, and this information is provided when it is anticipated to be needed.

           

          Q.  What if the EMS and the treating ED physician gave a total of 8 mg Versed and decided it was time to go to giving antiepileptic, can they go ahead with the randomized kit or will these be a eligibility violation?  Some patients cannot tolerate the amounts of benzodiazepines that are being recommended before they have respiratory depression so are these truly fixed amounts that have to be given to enroll.  Would you be able to check with Dr. Kapur on this question as to won't it be up to the treating ED physician to determine that adequate amounts of benzodiazepines have been given before proceeding to the kit and that sometimes these amounts may not reach the specific minimum amounts that are stated in the study?

          A. Benzodiazepines are the most effective first line treatment for patients with status epilepticus.  Under-dosing of benzodiazepines has been shown to be the most common cause of treatment failure in clinical practice.  Since ESETT is a study of patients with status epilepticus refractory to benzodiazepines, it is important to only include patients who continue to have seizures after having received a minimum adequate dose of benzodiazepines.  To enforce this, it is essential to establish a threshold.  The thresholds selected as minimum adequate doses for benzodiazepines in this trial are actually quite low.  Best guideline-driven practice may be to give about twice the minimum doses proposed here before progressing to second line agents.  Deciding that a patient is refractory to benzodiazepines if they have only been given doses lower than the minimally adequate thresholds set here is not consistent with established treatment guidelines.  Furthermore, because lower doses of benzodiazepines do not control seizures well, and continued seizures is the most common cause of respiratory depression in patients with status epilepticus, placebos and lower doses of benzodiazepines may actually be associated with higher rates of respiratory depression.  Individual physicians should always use their judgment to determine the best treatment for the patients they treat, but those seizure patients whom they feel should not be treated with benzodiazepines, or whom they feel should only get very low doses, are not eligible for ESETT and should not be enrolled.   

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          Informed Consent Discussion

          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.  Is there any information on how long after enrollment that consent needs to be attempted? Is it like RAMPART where we’d have to respond to the hospital in the middle of the night to get consent as soon as it’s appropriate? If a patient comes in at 8pm, is it possible to attempt consent at 8am when the day research staff comes in?

          A.  As we anticipate study team arriving within 30 minutes of enrollment.   Upon arrival, the study team must assist the clinical team in evaluating the participant and capturing key outcomes.  The study team will approach the family or LAR as soon as practicable to notify about the enrollment, review the content of the consent form, answer any questions, and determine whether there is consent to continue participation. 

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          Study Survey

          Q.  What is the age range of subjects asked to complete the ESETT patient survey? Is this something we need to decide?

          A.  The NETT doesn’t require that subjects of certain ages complete the survey.  These are based on local decisions and site IRB guidelines.  The suggestion for younger participants unable to read could be that the survey questions be administered (by a member of study team) and responses recorded.

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          Withdrawal from Study

          Q.  Will LAR/family member be able to withdraw a participant within the first 60min of study enrollment?

          A.  It is unlikely to be feasible to withdraw a subject from the study within the first 60 minutes, but it is not prohibited.  The study team will typically be activated at the time of subject enrollment and will have a target response time to the emergency department of less than 30 minutes.  It is unlikely the study team will ever be present during the intervention which is a single dose of medication given over 10 minutes.  Upon arrival, the study team must assist the clinical team in evaluating the participant and capturing key outcomes.  The study team will approach the family or LAR as soon as practicable to notify about the enrollment, review the content of the consent form, answer any questions, and determine whether there is consent to continue participation.  In circumstances where the participant is withdrawn from the study, no further data will be collected after the time of withdrawal regardless of when that occurs, but it is very unlikely that this will all happen within 60 minutes.

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          End of Study and Co-enrollment

          Q.  If an EEG is not standard of care at hospital discharge, would that be a protocol deviation if not done?

          A.  No, if an EEG is not done, it would not be a protocol deviation for ESETT.

           

          Q.  At what point is participation in ESETT considered over so that a patient could be enrolled into another clinical trial?

          A.  Participation in ESETT is over when the participant reaches end of study (hospital discharge or 30 days, whichever is shorter, or death or withdrawal from the study).  However, given the early intervention and determination of the primary outcome, participants may be able to be enrolled in another study prior to completing participation in ESETT.  In particular, sites have inquired, and we have determined that ESETT subjects who later become eligible may be enrolled in the Super Refractory Status Epilepticus trial being conducted by Sage Therapeutics.  This has been discussed and agreed to by the leadership of both clinical trials.

           

          Q.  Will ESETT leadership allow co-enrollment in ESETT and observational studies?  Do you need a copy of the protocol, ICF, or any other study documents in order for ESETT leadership to approve co-enrollment in the observational study?

          A.  The ESETT leadership is open to permitting the co-enrollment of subjects into ESETT and other observational studies, but requires these studies to be reviewed and approved individually by the ESETT study leadership.  Interested parties should submit the synopsis and protocol of observational studies seeking to co-enroll ESETT participants.

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          DSMB

          Q.  How frequently does the DSMB meet and how often will reports be issued?  What data (blinded or unblinded) will the DSMB review?

          A.  The DSMB will monitor safety throughout the trial, with frequent safety reports.  The frequency of meetings will be determined by the DSMB, and this has not occurred yet.

          Open and Closed Reports will be prepared by the SDMC at pre-specified intervals at a frequency also to be determined by the DSMB.  Open reports will be distributed to the study leadership, while the Closed Reports will be distributed only to the DSMB.  Open Reports include data on recruitment and baseline characteristics, and pooled data on eligibility violations, completeness of follow-up, compliance and summary data on AEs and SAEs.  Closed Reports contain the Open Report information displayed by treatment-group code (A, B, or C) but not the name of the actual treatment.  If the DSMB wishes to completely unblind itself from the partially unblinded reports, then a sealed envelope that contains the treatment-code identification will be made available.  Closed Reports also include the interim analysis results at the pre-planned time.

          Please also reference protocol section 12.2 for specific information on the DSMB and 10.7 on interim analyses.

           

          Q.  Where can I find a list of DSMB members for ESETT?

          A.  A list of DSMB members can be located in the Toolbox under DSMB.

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