Oral Tyramine Pressor Response Study of CX157 Tablets in Healthy Male Volunteers (CX157-112)
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||A Phase I, Multiple-Dose, Randomized, Double-Blind, Oral Tyramine Pressor Response Study Comparing CX157 Tablets to Placebo in Healthy Male Volunteers|
- Systolic Blood Pressure (SBP) [ Time Frame: 4 hours post dose on study Days 10, 11, 12 ] [ Designated as safety issue: Yes ]SBP was measured every 5 minutes for the first two hours and every 15 minutes for the next two hours post tyramine ingestion on study Days 10 (20 mg tyramine), 11 (40 mg tyramine), and 12 (80 mg tyramine).
- Number of subjects with adverse events as a measure of safety and tolerability of CX157. [ Time Frame: Study Days 4-12 (during the DB study drug administration) ] [ Designated as safety issue: Yes ]Adverse events were collected during the study.
- Cmax, Cmin, Tmax [ Time Frame: Study Days 6-12 ] [ Designated as safety issue: No ]The full pharmacokinetic (PK) profile was obtained after the morning dose on Day 9. In addition, trough blood samples were obtained before the morning and evening doses on study Days 6, 7, and 8; and before the morning dose on Days 10, 11 and 12.
|Study Start Date:||September 2010|
|Study Completion Date:||October 2010|
|Primary Completion Date:||October 2010 (Final data collection date for primary outcome measure)|
|Placebo Comparator: Sugar pill||
Placebo administered twice per day on study days 4-11 and in the morning of day 12.
CX157 is a reversible monoamine oxidase inhibitor (RIMA) in Phase II development for the treatment of depression.
CX157 Modified Release Tablet 125 mg administered twice per day on study days 4-11 and in the morning of study day 12.
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01633437
|United States, Florida|
|Comprehensive Phase One|
|Miramar, Florida, United States, 33025|
|Principal Investigator:||William Gerson, D.O.||Comprehensive Phase One|