Oral Tyramine Pressor Response Study of CX157 Tablets in Healthy Male Volunteers

Methodology: The trial was a Phase 1, single center, DB, three-period study of cardiovascular safety following oral administration of encapsulated tyramine prior to treatment with double-blind (DB) study drug (CX157 Modified Release Tablets, 125 mg administered twice per day (BID) or matching placebo administered BID) and the administration of tyramine in yogurt along with a standard meal during the DB study treatment administration, after CX157 reached steady state. Prior to treatment with DB study treatment, baseline cardiovascular sensitivity to oral tyramine administered in a fasting state was established in 15 subjects during Period 1 Days 1-3. Following completion of Period 1, the study's 12 subjects were randomized to CX157 (10 subjects) or placebo (2 subjects) and treated for six consecutive days (Days 4-9) to reach steady state. Subjects continued their DB study treatment in Period 3 (Days 10-12); however, during this period tyramine was administered to subjects in the fed state on Day 10 (tyramine 20 mg), Day 11 (tyramine 40 mg) and Day 12 (tyramine 80 mg). The tyramine pressor dose (minimum dose of tyramine necessary to achieve endpoint) for Period 1 was established through a series of three tyramine challenges (24 hours apart) with tyramine doses based upon a predetermined paradigm. During Period 1, untreated fasting subjects received an initial tyramine challenge dose of 400 mg and were monitored for SBP endpoint changes (SBP increase of ≥30 mmHg on three consecutive occasions at least five minutes apart over a 10-minute (i.e., TYR303). If pressor endpoint was achieved, the tyramine challenge dose administered on Period 1 Day 2 was reduced to 200 mg. However, if endpoint was not achieved, the tyramine challenge dose was raised on Period 1 Day 2 to 600 mg. This dose escalation/reduction paradigm was repeated on Period 1 Day 3 based upon the results of Period 1 Day 2 in order to establish the tyramine pressor dose during that period. During Period 2 (Days 4-9) subjects were treated with CX157 or placebo twice daily to reach the steady state. On Day 8 of Period 2, single-blind yogurt without tyramine was administered with lunch to familiarize subjects and the clinic staff with the procedures for Period 3. The tyramine challenges for Period 3 Days 10 - 12 began after six consecutive days of treatment with CX157 or placebo twice daily. The tyramine doses for Period 3 were 20, 40, and 80 mg (24 hours apart). The endpoint for Period 3 was the same as described above for Period 1, reaching of the pressor endpoint (i.e., TYR303). The study planned for 12 healthy male volunteer subjects to be randomized at Period 2. Ten (10) subjects were to be randomized to CX157 MR Tablets, 125 mg and 2 to matching placebo. Approximately 15 subjects were to enter Period 1 in order to ensure randomization of 12 subjects to Period 2 of the study.