This study is titled, "A Phase II Single-Center, Randomized, Double-Blind Study in Subjects with a History of Opioid Abuse to Evaluate the Dose-Response for Flushing and Safety and Tolerability of Varying Doses of Niacin in Combination with 40mg of an Opioid vs. 40mg of an Opioid Alone."   The study objectives were 1) to determine the dose response for niacin-induced flushing in male and female healthy, adult volunteers with a history of opioid abuse when niacin is administered in combination with 40 mg oxycodone HCl;  2) to evaluate the safety and tolerability of niacin–induced flushing following varying niacin doses in combination with 40 mg oxycodone HCl in subjects with a history of opioid abuse; 3) to confirm the appropriate strength of niacin to use in an Aversion® Technology formulation of oxycodone HCl; 4) to determine whether the flushing induced by niacin is of sufficient intensity to deter abuse in a population of subjects with a history of opioid abuse; and 5) to evaluate the effect of food on niacin-induced flushing when niacin is administered in combination with 40 mg oxycodone HCl.  

This study was a single-center, double-blind, randomized, placebo-controlled, five-period crossover study conducted on an inpatient basis with 5 cohorts of 5 subjects each.  Twenty-five subjects (three female and twenty-two male) were admitted for the study.  One male subject completed the first drug condition but thereafter withdrew from the study stating personal reasons unrelated to the study.  Twenty-four subjects received a single dose of study drug every 48 hours for 9 days.  Each subject was randomized to a dosing sequence that included doses of niacin (0, 240, 480, and 600 mg) administered in combination with 40 mg oxycodone HCl while the subjects were fasted on Days 1, 3, 5, and 7.  On Day 9, a dose of 600 mg niacin in combination with 40 mg oxycodone HCl was administered following a standardized high-fat breakfast.  Each dosing day, vital sign measures and subjective and behavioral effects were assessed before dosing and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 12 hours after dosing.  Vital signs included systolic and diastolic blood pressure, heart rate, oral temperature and respiratory rate.  Subjective changes were measured by subject response to a Drug Rating Questionnaire (DRQS).  As an additional measure of subjective effects, subjects completed a 40 item short form of an Addiction Research Center Inventory (ARCI) that yielded three sub-scale scores – a euphoria scale, a dysphoria scale and a sedation scale.  After completion of the study, subjects responded to a Treatment Enjoyment Assessment Questionnaire to select which of the treatments they would take again.  Prior to initiating the study, the hypothesis was that the addition of niacin to oxycodone would produce effects that are disliked by subjects with a history of opioid abuse.  The maximum scale response to the question “Do you dislike the drug effect you are feeling now?” (i.e. the "Disliking Score"), was designated as the primary efficacy variable.  Statistical analysis (maximum dislike response in comparison to 0 mg niacin) was conducted for DRQS, ARCI scales and vital signs.  Study results were as follows: 

(1)  In the fasting state, all three doses of niacin [240mg, 480mg and 600mg] in combination with oxycodone 40 mg produced significant (p ≤ .05) disliking scores compared to oxycodone   40 mg alone.  The linear regression across niacin dose was not significant.  No other subjective measure was significantly affected by the niacin addition to oxycodone.

(2)  The high fat meal eliminated the niacin effect on oxycodone 40 mg.  The high fat meal also delayed the time to oxycodone peak blood levels.

(3)  The addition of niacin to oxycodone alters the subjective response to oxycodone as indicated by the significant responses on the disliking scale.  This observation in conjunction with the results from the Treatment Enjoyment Questionnaire indicates that the addition of niacin reduces the attractiveness of oxycodone to opiate abusers.

(4)  There were no serious adverse events.  Niacin produced a dose related attenuation of pupillary constriction, diastolic blood pressure increase and probably systolic blood pressure increase produced by oxycodone.  The alterations by niacin on the vital sign responses to oxycodone 40 mg were minimal, were seen primarily with the 600 mg niacin dose and were not clinically significant. 

The principal study investigator’s overall conclusion was that the results of this pharmacodynamic study [Study AP-ADF-102] support the hypothesis that the addition of niacin to oxycodone in a minimal ratio of 30 mg niacin to 5 mg oxycodone is aversive when compared to oxycodone alone.  The addition of niacin does not alter the safety profile of oxycodone alone. The Company intends to included the data and results from StudyAP-ADF-102 in its 505(b)(2) NDA submission to the FDA for Acurox™ Tablets.