Subject Follow-up (New 10-5-20)
Q: Is the local study team blinded to treatment? If not, does this introduce bias?
A: The treatment team is not blinded to the study treatment; however, the subject is. Outcome assessments will also be blinded to study group allotment.
Q: Will we have the ability to unblind patients and providers if patients are hospitalized for their illness?
A: Patients would potentially be eligible for inpatient trials that are ongoing, but whether they received convalescent plasma or placebo would potentially alter enrollment.
The medical providers are unblinded, and the medical record should indicate what intervention was delivered. The goal is to have the patient remain blinded in order that they report their symptoms without bias. However, all providers can learn what intervention was delivered. We specifically wish to preserve the freedom of subjects to enroll in interventional trials if they are admitted to the hospital, because these may offer the best access to treatments.
Q: Is the dose (250 mL) too small for a large patient?
A: The dose of plasma for this trial is 200 ml with a titer of at least 1:160 of neutralizing antibodies. It is unknown what is the effective dose for plasma. Because side-effects (volume) may increase with more units, we selected one unit as the dose. One unit has been used in several of the inpatient studies to date.
Q: Can we accept a positive COVID-19 test from another facility?
Q: If the patient is slated for discharge from the ED and is consented for enrollment, can the patient be moved to a different (research) location for infusion of CP?
A: This would be a reasonable practice. The goal is that CP should be administered BEFORE a patient leaves the medical campus.
Q: If a patient is discharged before their result in the ED, could they be called back for enrollment?
A: The patient should receive the intervention on the day of the ED visit. It would be reasonable for the patient to go to an area to wait (e.g. observation area) or to an adjacent testing area (e.g. a COVID clinic or infusion site nearby the ED). However, we have not planned for a patient to go home and then return at this time.
Q: If we do not have a rapid test at our site can we d/c and call them back?
A: As we start this trial, we will focus on recruiting in situations where a rapid test result is available. A test from another site or a test obtained PRIOR to presenting in the ED could be used to qualify as a subject.
Q: Is there a minimum # of subjects required/hoped for from each site?
A: 3-4 subjects/month
Q: Rather than the 6-month enrollment period in the protocol, is enrollment expected to end in September?
A: End of September is optimistic. Bottom line is we need to get to 600 subjects and because it is a pandemic, we need answers asap. If we can be done by the end of September, that would be awesome!
Q: If the patient stays in the ED (e.g., observation unit) solely for receipt of CP, it will be challenging to make a case for being SOC. Would the study budget cover the time/facility cost?
A: The cost of extra survive or time should be budgeted from the per-subject payments for enrolled subjects. These were considered in setting the payments to sites for enrollment.
Q: Is there a draft or final budget available (Startup and capitation)? Will participant remuneration (e.g., for follow-up research visits) be provided in the budget?
A: That was budgeted in the site per patient reimbursement amount.
Q: Will there be a separate reimbursement for ABO? This is not standard of care.
A: The cost of blood typing should be budgeted from the per-subject payments for enrolled subjects. These were considered in setting the payments to sites for enrollment.
Q: Where are the contracts held?
A: All contracts are at the University of Michigan Grants Office and your site will be notified when they are released.
Q: Will informed Consent be available in Spanish? Other languages?
A: We will have a Spanish informed consent document. For other foreign languages, we will have IRB approved Short Forms.
Q: Are patients enrolled via LAR consent for this study? (New 7-28-20)
A: Subjects must consent for themselves. It is intentional to enroll patients who also can report their own symptoms during the remote follow-up.
Q: The training states the clinical staff should either take a picture of the infusion bag or save the bag for research staff. Is this only to ensure the info on the bag is captured? As standard process, we enter the plasma information in the electronic record.
A: We need to know the product code and donor identification number for the CP unit that each subject receives. This will help us match analysis done on CP (e.g. antibody levels) to the right subject who received that unit. Saving the bag or taking the picture will allow the study team to have the information they need to enter into the study database.
Q: What is the IND number for this trial? (New 7-28-20)
A: IND# 20722 - Dr. Kevin Schulman (Stanford University) holds the IND.
Q: Will SIREN of the IND holder be applying for CMS approval for the use of the device/method for patients? (New 7-28-20)
Q: Why wasn't plasma used as the placebo since plasma alone might modulate coagulopathy, and would also allow better investigator blinding?
A: This was discussed at length with both the PRC and the DSMB. The final decision was to use the saline control.
Q: With the national shortage of the preferred multivitamin, can you please clarify what the acceptable ingredients, ratios, mix of vitamins will be? Is each site now left to mix their own vitamin mixture at will, so long as it has a similar color to plasma? Or are we still aiming to have each site use the same “recipe” to standardize the placebo across sites? In other words, will the trial protocol still be directing a specific "recipe" that must be utilized by sites? Or does the national shortage open up more leeway in the recipes used across sites?
A: For the MVI, we discussed with Pharmacists and we are changing the protocol to be flexible within reason: 1-5 ml of multivitamins (from any manufacturer) in 250 ml of saline. Based on what we see so far; this whole range gets about the correct color.
Q: Multivitamins come in (2) 5cc vials each, which are both mixed with IVF in clinical use. Does the study protocol wish to max the volume of multivitamin at 5cc or is 10cc sufficient to add to 250cc bag of NS? (New 7-28-20)
A: The study is not concerned with the exact concentration of the multivitamin. However, most of the product inserts we examined recommended 10cc in 500ml, which would be 5cc in 250ml. When the vials are divided, one may be yellow and the other clear. Only the yellow solution is required, because the multivitamin is intended solely to disguise the placebo for the subject.
Q: Will a blinded label be provided or does the pharmacy or blood bank need to create one? Also, are there examples of order sets already being used or created? (New 7-28-20)
A: We have prepared placebo labels that look like plasma labels (with fake numbers on them), and we will mail these to sites.
Q: We have quantitative antibody levels on all the CPP units in our blood bank. There is huge variability and we transfuse only those units with high levels (above the median based on our donor cohort). Is that practice compatible with the study? We do not have titers, and titers have no meaning unless you are using a standardized assay and no one really is doing that right now.
A: The plasma for this study will be provided by Vitalant. Vitalant will perform titers for antibodies using a standard assay in their laboratories. We have set a minimum titer in that assay for plasma to be considered usable. In this way, the plasma will be comparable across all sites.
Q: We will use low titer plasma per the study protocol, but we cannot perform such titers - the products from Vitalant would have to come labelled as such and we would need to establish computer bar code reading of all Vitalant supplied products in advance. Can you confirm this will be the case?
A: The plasma will be provided by Vitalant. For low titer Group A plasma, the plasma will have titers confirmed by Vitalant and be labeled (E codes / bar codes) consistent with this.
Q: Can you provide a few more details regarding shipping the plasma to sites? Just so we can coordinate with our hospital loading dock and shipping/receiving supervisor to ensure that we are notified when plasma arrives. Is it correct that UPS will be used to ship the plasma? Will there be package tracking numbers provided? Will a signature be required upon delivery? Will plasma be shipped and/or delievered on the weekends?
A: Vitalant is preparing detailed instructions and SOPs on the plasma shipping that they are going to share with SIREN. We will post those details as soon as they are final. It should be identical to any way that your blood bank currently receives a blood product from a national vendor or blood supplier.
Q: Is the SIREN e.consent platform part 11 compliant?
A: Yes. SIREN uses the University of Michigan implementation of the REDCap platform to obtain electronic consent and (in some SIREN studies) participant contact information in a process that is 21 CFR Part 11 compliant. Part 11 compliance requires information technology that is capable of supporting compliant processes, and specific operating procedures that use the IT appropriately. Documentation from the University of Michigan Health Information Technology and Services (HITS) of the physical and network information technology security that supports Part 11 compliance in this implementation is available here. Documentation that the SIREN processes are Part 11 compliant is found in the SIREN Network e.consent SOP.
Q: Can we screen patients on only certain times of the day and only certain days when study personnel are available?
A: Screening at certain times may be necessary based on available personnel. We would hope to avoid bias in recruitment because of this limitation, and screen failures from the entire time should still be recorded.
Q: What are the steps in obtaining the 15- and 30-day Assessments? (New 10-5-20)
Q: The protocol training stated that the subject phone calls would be completed centrally. However, the protocol states that this could be done by blinded staff at the site or the central pool. Is this a choice left to the site?
A: Follow up on days 2, 4, 6, 8, 10, 12, and 14 will be completed by the central follow-up core. They will reach out to you if they are having difficulties with contacting the subject. Make sure you tell the subject at enrollment to expect a call from the follow-up core. Your site will be responsible for completing follow-up assessments and blood draws on days 15 and 30.