Alabama Breastfeeding Committee

American Academy of Pediatrics
Screening and Randomization
Follow-up Visits
Biospecimens
Medication and Drug Dispensing
CHAP Inpatient Drug Dispensing
General Questions
Regulatory

American Academy of Pediatrics

• ABM Model Breastfeeding Policy
  ABM Model Breastfeeding

Screening and Randomization

• 1. How will subjects be recruited?
  Most sites intend to identify and recruit participants from their Obstetric prenatal clinics.
• 2. How are subjects screened for eligibility?
  Via medical record chart review, interview, and blood pressure measurement.
• 3. When screening subjects with a history of HTN and after chart review it is discovered the subject is >22.6 wks. Do these subjects go on the screening log?
  Yes.
• 4. When is the HP01 screening form initiated?
  At the time of initial screening.
• 5. Who gets a HP01 filled-out?
  All patients who are screened with a history of CHTN or suspected new onset CHTN.
• 6. In cases of re-screening, do we initiate a new HP01 at every screen?
  No, patients will keep their initial PID1 which is assigned by the eDES once the HP01 is entered. For patients who are being re-screened, “SAVE” the HP01, DO NOT LOCK the form until the patient is randomized or deemed permanently ineligible.
• 7. When/how do I assign a PID1?

  Once subjects have been screened and you have begun an HP01 you can data enter the following into eDES: NEW SUBJECT- write down PID1. Enter as much primary information as possible, then SAVE but not LOCK until either:

  1. patient is ready to be randomized
  2. patient is a definitive screen failure
• 7a. Additional PID1 info:
  You must data enter into eDES to receive a PID1. Remember these numbers are assigned consecutively and not in batches so it is important to track if there are more than one CRC screening at different sites!
• 8. What if it is not SOC for a site to perform a routine ultrasound prior to 18 weeks gestation. Will the CHAP study cover the cost of earlier ultrasounds in order to screen patients for eligibility?
  No, the CHAP study will not cover the cost of ultrasounds. Patients who do not have ultrasounds prior to 18 weeks gestation will be excluded from the study.
• 9. In the event where the earliest U/S is not available but there is specific documentation in the medical records that state LMP, date of U/S with an exact gest age (wks & days) and that it is based on CRL. Is this documentation OK?
  Yes but must be exact documentation of gest age (wks & days not just wks). The bedside US is ok to use for the pregnancy dating. However, please note that Table 1 in the MOO reflects ACOG criteria and all 4 measurements (BPD, HC, AC, FL) give a more valid estimate.
• 10. What if the U/S is a bedside U/S rather than a formal U/S?
  The bedside US is OK to use for the pregnancy dating.
• 11. Can patients be randomized and not be present?
  No. Patients have to be randomized in person.
• 12. If the research nurse fills out the Inclusion/exclusion form and patient is to be randomized, does the form need a physician signature prior to randomization or can the forms be batched and signed?
  The forms can be batched per institutions protocol/policy.
• 13. Once subjects are randomized, will there be a need to use a specific bottle code/number for the initial and subsequent dispensing, or will bottles be dispensed randomly out of the stock?
  You may pull any bottle from the shelf for dispensing to the patient. Dispensed bottles will be reported by Bottle ID on the HP04 Study Drug Dispensing Log, where it will be connected with the Patient ID, date of dispensing, etc.
• 14. If participants do not agree to allow their samples to be kept and used for future research on the treatment of hypertension in pregnancy, DO NOT collect their samples and will they still be eligible for participation in the trial?
  Yes, only collect samples if participants agree to allow their samples to stored and used for future research. This refers to both maternal and cord blood samples.
• 15. Is UAB creating patient brochures/flyers to give to potential participants? Is UAB creating a study subject identification card with pertinent information?
  UAB has created a CHAP study brochure that will be shared with the consortium.
• 16. How is substance abuse determined? This is an exclusion criterion.
  If a woman reports using drugs at the time of screening, she will be excluded. If current substance use is marked in her medical chart, she will be excluded. (smoking, alcohol, marijuana, methadone ok)
• 17. Are patients who are currently using marijuana on a regular basis excluded?
  Patients on marijuana will be included in the trial if they are deemed or found to be compliant with clinical care and doesn’t appear to be a ‘flight risk’. Patients such as these will be included on an individual basis.
• 18. Patients currently on Methadone are they included or excluded? Does it depend on how long they have been on methadone? For instance what if they are going through methadone conversion in pregnancy?
  Patients on methadone will be included in the trial if they are deemed or found to be compliant with clinical care and doesn’t appear to be a ‘flight risk’. Patients such as these will be included on an individual basis.
• 19. What is the ‘Red Zone’ BP for exclusion without obtaining a pragmatic blood pressure?
  Patients with documented SBP ≥ 160 or DBP ≥ 110 on several occasions and the provider determines that the patient has severe hypertension should be excluded.
• 20. For patients whose BP remain below study threshold (e.g. those with BP < 140/90 without treatment or non-compliant on monotherapy), how are they followed?
  >A form HP01 will be started and finalized during subsequent visits when the BP reaches the inclusion threshold or when they are excluded after 19.6 weeks GA (patients who have not been diagnosed with mild hypertension) or 22.6 weeks GA without reaching the threshold.
• 21. Are any research procedures performed at enrollment visit besides blood pressure and review of PHI? Is collection of urine results, BMI, etc., from the medical record info? If these are research procedures, then why they aren’t in the protocol or consent form?
  At enrollment visit (after passing the screening criteria) the participants will be randomized and will then be provided education as to their group assignment, i.e. medication regimen vs no medication, the medical records will be abstracted for items on the CRF. They will have the first sample of blood collected for storage (if they consent for future storage and future use of their samples)
• 22. On the HP02 question 13, is there nowhere to put LMP? What is meant by EDD confirmed by US?
  Since for this study, EDD has to be confirmed by US, this question is verifying that an US was used to confirm the EDD.
• 23. Can we use the MFMU calculator (ACOG )? I know you cannot tell us to use it as it is not yours, but it is so much easier than trying to calculate on our own.
  This is clearly up to you. We are not telling sites if they can or can’t use it, this decision is site specific (it clearly works great!)
• 24. 2 BPs at least 4 hrs apart. Is there a date timeline for this? For instance, 2 BPs of 140/90: #1 BP 6/2014 (>1 yr prior to pregnancy) #2 10/2015. Can the 1st BP be used even though that BP was >1 yr ago?
  Must be 4 hrs apart within in the last year for newly diagnosed CHTN.
• 25. Should everyone with asthma be started on Nifedipine ER instead of Labetalol?
  No, only moderate to severe asthma, those with current symptoms (wheezing) or who have symptoms at least weekly.
• 26. For subjects with CHTN Dx. not currently on meds:
  Need to have a qualifying blood pressure on the day of randomization SBP 140-159 and/or DBP 90-104.
• 27. For consented subjects that we are currently following with BP measurements. We will continue to follow up to 22.6 wks?
  Yes
• 28. If the subject has one pragmatic BP that is above the qualifying BP criteria does that exclude the subject?
  No, as long as the AVERAGE of the two pragmatic BPs are in the qualifying BP range
• 29. In the event where a subject consents and has qualifying pragmatic BPs but is not willing to be randomized that day, can you randomize her the next day instead?
  The qualifying pragmatic BPs MUST be done on the same day as the randomization
• 30. If a patient, with a history of CHTN or new/unknown CHTN is on an anti-hypertensive medication for reasons other than hypertension such as maternal tachycardia, migraines, etc., is this considered being treated?
  No, the patient is considered untreated and screening/randomization protocol procedures for this group should be followed

Follow-up Visits (HP03)

• 1. What if patients are seen by a MFM physician practice for randomization and BP (Chap) management only but is also being seen by a general OB physician also for routine prenatal care (urine dips, routine labs, antenatal testing, etc.), which visit will be documented on the HP03 “Prenatal Clinic Study Visit Form?”
  A HP03 CRF will be completed for both visits. For data not collected (missing data) at a particular visit, answer that question on the form as instructed for “missing data”.
• 2. What is the outer most window for a postpartum visit?
  12 weeks is the outermost window for the postpartum follow up visit. The target is 6 weeks PP with an acceptable range of 4 to 12 weeks.
• 3. If a subject switched to another medication by a treating MD, then does she continue in the study?
  We hope that the sites will be able to convince any treating MD to follow the treatment algorithm suggested by the study. However, if she is switched she will continue in the study, and the protocol deviation will be reported. If yes, then how does this affect analyses? The study is an intent to treat analysis. The protocol provides scenarios to change or add medication.
• 4. What’s involved in the 5-year follow-up? Do subjects get paid for this visit?
  The 5-year follow-up is a separate planned grant application. At this point, we intend to try to simply maintain contact with the participants so that if a 5-year grant is funded, we will be better able to find the original participants. They will likely get paid, but it is dependent on a successful new grant application.
• 5. Do you have a copy of the follow-up questionnaire to be used?
  It wasn’t included with the protocol. No materials for the planned follow-up study have been developed.
• 6. Is there a questionnaire (or CRF) for questions to be asked at 3-month follow-up?
  There is a CRF (HP07) for the 3 month visit and the procedures are in the protocol.
• 7. What is the max for Nifedipine?
  Increase nifedipine by 30 mg daily (increase by 30 mg each visit as indicated) to a max of 120 mg (or 60 mg BID)
• 8. What is meant by splitting to TID before increasing the Labetalol
  To be clear, you increase the labetalol to its max of 2400 mg before you add the nifedipine (unless there is another reason to start the nifedipine earlier). Also, the medical provider will be involved and will help make these decisions. It might help you to think of it in total mg per day. The start dose of labetalol is 400 mg (1 tablet BID). If her pressure is up, but not very much, you have the option of only adding 1 200 mg tablet and change the frequency to TID which gives a total dose of 600mg. If it’s still up the next time, you could change her to 2 tablets BID, which is a total dose of 800 mg. But it would have been equally fine to do option B at the first BP elevation. Split dosing labetalol, for optimal BP goal, you can give BID or TID dosing (rather than 400 mg BID (800 mg daily), give 300 mg TID (900 mg daily) or give 200 mg TID (600 mg daily). Make the decision based on patient’s tolerance of med and where her BP is. Place a medication label on the bottle that accurately describes the dosage.
• 9. What is split dosing nifedipine?
  Starting dose of nifedipine is 30 mg qd. Split dosing giving 30 mg BID rather than 60 mg qd (make changes at subsequent visits). Place a medication label on the bottle that accurately describes the dosage.
• 10. Do participants need pragmatic BP measurements in order to adjust her medication dose?
  Yes, the patient must have the pragmatic BP.

Biospecimens

• 1. What will be collected from maternal and cord blood samples?
  Maternal blood samples are as follows: Randomization – EDTA (whole blood, plasma), SST (serum) and PAXgene tube (RNA). Midtrimester – EDTA (whole blood, plasma), SST (serum) and PAXgene tube (RNA). Delivery – EDTA (whole blood, plasma), SST (serum)
  Cord blood samples are as follows: EDTA (whole blood, plasma), SST (serum)
  *See manual for complete biospecimen collection and processing instructions.
• 2. If participants do not agree to allow their samples to be kept and used for future research on the treatment of hypertension in pregnancy, DO NOT collect their samples and they will still be eligible for participation in the trial?
  Yes, only collect samples if participants agree to allow their samples to be stored and used for future research. This refers to both maternal and cord blood samples.
• 3. How long can samples wait/sit before processing takes place?
  Ideally, samples should be processed within 1-2 hrs. of collection. However, if no research staff is available for processing, samples can be refrigerated at 2-8 C until a trained staff person is available. It is anticipated that 2-3 days will be the longest period of time without coverage. This process will be monitored and changes will be made as indicated.
• 4. What if a site only have a -20°C freezer, how long can samples remain there before being transferred to a -80°C freezer?
  It is anticipated that samples will be transferred within a 2-3 day period. This process will be monitored and changes made as indicated.
• 5. Please describe whether any PHI or what information will be sent to UAB along with the specimens for storage.
  Storage of specimens at UAB: at this time, basic information will be sent along with specimens such as study#, date/time collection, specimen type.
• 6. Is there is a specific type or brand of Cryovial for CHAPs that is required?
  No, there isn’t a specific brand or type, and the thread type doesn’t matter either.

Medication/Drug Dispensing

• 1. When is a HP04 log initiated?
  Each month the previous month’s HP04 is locked and a new HP04 log started. A log/month will capture
  data for multiple patients for multiple visits.
• 2. What date should be used for the start date on the HP04 form?
  It’s ideal for the log date to be the first day of the month OR the first date of the month that study drug is dispensed. There are form rules that prevent the log start date from being after the dispensing dates. The dates within the log should be entered in chronological order, as dispensed.
• 3. Is the HP04 filled out every time patient comes in? What am I putting on the HP04 at each visit?

  Each time study drug is dispensed, the bottle ID is logged on the current month’s HP04 Study Drug Dispensing Log. This may or may not occur at every single patient visit; it just depends on each patient case. You would click the button “add study drug” (which would actually make more sense if it said “dispense study drug” or “add dispensing record” or something like that) and then enter the PIDs for the patient, the Bottle ID, date, etc. You would just save the log, continuing to enter records at patient visits, saving the log, etc. until the end of the month. Then you would lock the old month’s HP04 and start a new one.

  One other thing of note, just for reference:
  When entering the Medication Bottle ID under #4, a “label” containing the name of the study drug that matches the Bottle ID will appear just below the field. You should use your mouse to click on that label. This will populate the med name under #5.

  

• 4. Will the investigational drug service be used to dispense the study drugs?
  Drugs will be dispensed to the sites using a central Drug Distribution Center. Sites can dispense the medication directly from their prenatal clinics or their research pharmacy. It is required that drugs are kept in a secure storage area.
• 5. Are there any requirements that we use our local investigational pharmacy?
  No, there are no requirements that you use your local investigational pharmacy.
• 6. Who are the co-investigators?
  They are whoever the PI at your site designates as co-investigators. Unless you need to list all of the collaborating sites, we interpret CO-PI as a local determination.
• 7. Is Labetalol given in a tablet or capsule form?
  Labetalol is a scored 200mg tablet.
• 8. Is Nifedipine ER given in a tablet or capsule form?
  Nifedipine ER is a tablet. It is not scored.
• 9. When the patient returns for a visit and has tablets remaining from the previous visit, are these tablets re-dispensed or returned to the coordinator?
  The patient is to continue to use what is in the bottle until fully consumed (a new sealed bottle will be dispensed if it is thought that supply will not last until the next visit, however, the patient will be instructed to complete the current bottle first). The only reasons that a patient may return the bottle include expired or the patient does not tolerate the medication and is being switched to something else. No additional supply will be dispensed if the study coordinator and patient determine that there is enough left until the next visit.
• 10. What if a patient reports loosing or damaging a bottle, do we count what should have been left in that bottle?
  No, pill counts cannot be patient reported. If a patient looses/damages a bottle, dispense a new bottle. If on RTC she reports finding the old bottle and brings it in with her, she may continue to use it if it has not expired.
• 11. If a participant in the treatment group is admitted to the hospital, how would we dispense the study drug to them?
  Removing them from the site’s inventory through the eDES Study Drug Inventory Management page. In the same way sites would handle damaged or expired inventory, they would “remove” these bottles from inventory by changing the bottle status to “Inpatient Use”.

CHAP Inpatient Drug Dispensing

• Sites are encouraged to conserve study medication when possible, while complying with local hospital and pharmacy policy. The following general guidance is provided:
  Use patient’s prescribed bottle if available and if hospital policy permits.
  If a patient’s prescribed bottle is not available or if hospital policy does not permit its use for whatever reason, there are two options:

  1. The site may pull a bottle of CHAP study drug from inventory for dispensing during the inpatient stay. This bottle should be identified within the pharmacy and set aside for general, CHAP inpatient use and the study drug dispensed across CHAP patients as needed. Use of the bottle should be documented via the eDES Study Drug Inventory Management page, changing the status of the bottle from “1=Ready to dispense” to “6=Inpatient Use”.
  2. The site may use internal pharmacy supply but it is not covered by the study.

General Questions

• 1. How long will UAB keep the data collected?
  UAB will keep the data as long as analyses are ongoing: a minimum of 5 years post study closure but as long as analyses are being conducted and IRB approval is maintained. As well, the data will be made publicly available according to NIH guidelines after the study is over.
• 2. Will the results be shared with patients?
  Study results will be accessible to participants through ClinicalTrials.gov. Results will also be shared with the PIs and unless otherwise instructed, say by the DSMB, results may be shared by PIs with their patients. The DSMB may create a notification plan for patient debriefing.
• 3. Will the Clinical Trial Research Center be used? If not, where will study visits occur?
  It is not mandatory to use the CTRC. Most sites will see the participants during a routine prenatal exam.
• 4. How much will subjects get paid?
  The draft consent lists $100 total ($30 + $30 + $40). This is a local decision. We are dispensing $100 at UAB but this is not mandated across the consortium.
• 5. Is there a Manual of Operations?
  There is a Manual of Operations
• 6. It is our understanding that if a site does not routinely send placentas to pathology for patients with CHTN, it is not an expectation that they send it and pay for it with study funds.
  Sites are encouraged to send the placentas for the clinical indication of chronic hypertension in pregnancy if at all possible (many are able to do so even though they would not otherwise necessarily send for the indication).

Regulatory

• 1. Since sites will have clinical access to a patient’s medical record in either the MFM offices or the outpatient clinic, will there need to be a waiver granted by the IRB to review charts of patients from any other areas of the hospital (such as another outpatient clinic where you’re not an employee, etc.)?
  This is a local item/decision.
• 2. Is it mandatory for sites to use IRB share?
  It’s not required for sites to use IRB share.

For any other questions, please contact us at chap@uabmc.edu