Design Consultation for a Phase I/II Trial

Inflammation and Cerebral Palsy in Term Infants

The client was developing a proposal to conduct a Phase I/II trial of acute, high-dose erythropoietin in term infants with neonatal encephalopathy for the purpose of improving cognitive outcomes.

Questions and Issues

What study design would be most appropriate given a severely limited sample size? You expect about 5-7 eligible infants per year at Parnassus (and similar numbers from Seattle and Oakland Childrens). You are currently proposing to examine 3 different epo doses with 4 infants per dose-group, and an additional 6 infants in a control group. You would like to have specific advise about the expected boundaries of interpretation of safety data from a dose-escalation trial given such limited sample size.

1. What time points are appropriate for pharmacokinetic analysis, and for how many days?
2. You would like more information about the FDA drug approval process.
3. You would like more information about how to assemble a Drug Safety Monitoring Board, and how to create the appropriate protocol.
4. For the Phase II portion, you will conduct 3-month follow-up to assess outcomes such as mortality, disease-specific severity measures, and radiographs. Is this rational?

One issue we discussed is that, given prior studies of high-dose epo with pre-term infants, and prior or ongoing studies of high-dose epo in adults with stroke... how much phase I/II data is necessary before moving forward with the more relevant Phase III trial? I thought the investigator should discuss this further with Johnson & Johnson scientific personnel and with her mentors.

Suggestions

For many of the questions above, I wonder if there could be some support for the investigator through the Center for Drug Development Sciences. While this group is not formally a part of CTSI, I think that there are strong linkages with this or a similar drug development group at UCSF. I encouraged the investigator to check out their website: http://cdds.ucsf.edu and consider contacting Howard Lee (Howard.Lee@ucsf.edu) to gain more information about resources to support the development of your research proposal and the conduct of your research project.

Biostatistical consultations should also be sought.