The major objective of this award is to fund early phase pre-clinical work and initial clinical research in support of a planned future P01 application using an epicatechin based intervention in human subjects. A research plan has been developed whose ultimate goal is the granting of an Investigational New Drug (IND) approval by the Federal Drug Administration (FDA). An IND approval would allow the implementation of clinical studies using (+/-)-epicatechin (i.e., epicatechin racemate). The plan is structured around 6 major goals (aims) as follows:
Aim 1. Complete a pre-IND consultation package to be submitted to the FDA. Participating scientists will prepare a pre-IND application package for consultation with the FDA to ascertain the information and data required for a future IND submission and approval.
Aim 2. Pursue pharmacokinetic (PK) studies in rodents and/or dogs using (+/-)-epicatechin. Future dose optimization studies in humans may require initial studies in animals to identify a dose range deemed likely to be effective for the racemic epicatechin mixture.
Aim 3. Employ outside contracting services to pursue toxicology studies in rodents and/or dogs using (+/-)-epicatechin. A 28-day toxicology study in rodents and/or dogs will be implemented to evaluate the safety of (+/-)-epicatechin, data that may be essential for its subsequent use in humans.
Aim 4. Based upon the above collected information and results, submit an IND application to the FDA in pursuit of phase I studies. The research team will collect all relevant information and results for the submission of an IND application to the FDA to implement phase I studies in humans.
Aim 5. Phase I studies: Perform single and multi-dose PK and pharmacodynamic (PD) analysis of (+/-)-epicatechin in human subjects to determine a safe dosing range. For one day studies, human subjects will be given (+/-)-epicatechin (one of up to six incremental doses) and blood sampled serially. For 7 day studies, repeated daily dosing with (+/-)-epicatechin will take place and blood also sampled serially. Primary outcomes will be safety measures (e.g., electrocardiogram, blood pressure, clinical chemistry) and concentrations of epicatechin in blood and urine. Secondary outcomes will be lipids, glucose and insulin concentrations, and markers of systemic inflammation.
Aim 5 includes contingency plans (sub aims A and B) in case animal studies are not required by the FDA.
Aim 5 A will use blood samples collected to ascertain macrophage polarity and regulation of cytokine secretion.
Aim 5 B will use serum samples collected to perform metabolomics profiling and test for evidence of altered mitochondrial function.
Aim 6. Based upon all of the above collected information and Phase I results (Aim 5), submit an IND application to the FDA in pursuit of long-term clinical studies in humans. The proposed plan will ultimately allow the research team to gather critical pre-clinical and clinical information deemed likely to be required by the FDA in granting approval for longer-term studies in human subjects using the epicatechin racemate.