A Study in Opioid-Experienced, Non-Dependent Recreational Drug Users to Determine the Abuse Potential and Safety of CL-108 Tablets Administered Via the Oral Route

Charleston Laboratories, Inc40 enrolled

Overview

The purpose of this study is to assess the abuse potential of CL-108 tablets, including the abuse deterrent effects of promethazine, following oral administration, relative to hydrocodone/acetaminophen (APAP) tablets and placebo in non-dependent, recreational opioid users; to assess the cognitive and behavioral effects of CL-108 tablets following oral administration relative to hydrocodone/APAP tablets and placebo in non-dependent, recreational opioid users; and to assess the safety of orally administered CL-108 tablets relative to hydrocodone/APAP tablets and placebo in non-dependent, recreational opioid users.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

DOUBLE

Enrollment

Conditions

Pain Nausea Vomiting

Interventions

CL-108DRUG

7.5 mg/325 mg/12.5 mg tablet

M366DRUG

7.5 mg/325 mg tablet

PlaceboDRUG

Eligibility

Sex: ALLMin age: 18 YearsMax age: 55 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * BMI within 18.0 to 33.0 kg/m2, inclusive (minimum weight of 50.0 kg at Screening) * Healthy, as determined by no clinically significant medical history, physical examination findings, 12-lead ECG findings, vital signs measurements, and laboratory results at screening, as judged by the investigator * Current opioid users who had used oral opioids for recreational (non-therapeutic) purposes, at least 10 times in the past year Exclusion Criteria: * Drug or alcohol dependence within the last 12 months (except nicotine) * Subjects who had ever been in treatment for substance use disorders (except smoking cessation * History of presence of any clinically significant cardiac, neurologic, pulmonary, psychiatric, endocrine, hematologic, hepatic, immunologic, metabolic, urologic, dermatologic, renal, or other major disease at screening, which in the opinion of the investigator, would have jeopardized the safety of the subject or the validity of the study results * History or presence of hypotension, judged to be clinically significant based on investigator judgement

Outcomes

Primary Outcomes

Subjective Effects: Maximum Effect (Emax) and Minimum Effect (Emin) of High Visual Analog Scale (VAS) in Dose Selection Phase

High VAS measures the positive effects experienced by the participant on a 100 mm unipolar VAS, where responses are unidirectional and range from a response of 'none' (0 mm = 'definitely not') to 'extremely' (100 mm = 'definitely so'). For VAS assessment, pre-dose (baseline) value was subtracted from each post-dose value prior to calculation of the pharmacodynamic (PD) parameter. Emax is the largest effect score and Emin is the smallest effect score between 0 to 24 hours post-dose.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours (post-dose)

Subjective Effects: Emax of Any Effects VAS in Dose Selection Phase

Any drug effects VAS measures other subjective effects experienced by the participant on a 100 mm unipolar VAS, where responses are unidirectional and range from a response of 'none' (0 mm = 'definitely not') to 'extremely' (100 mm = 'definitely so'). Emax is the largest effect score between 0 (pre-dose) to 24 hours post-dose.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours (post-dose)

Emax of Drug Liking VAS in Treatment Phase

Drug liking VAS is the measure of balance of effects that assesses the degree that a participant likes a drug effect at the time the question is being asked (that is, at the moment). It is scored using a 100 millimeter (mm) bipolar (VAS) anchored in the center with a neutral anchor of 'neither like nor dislike' (score of 50 mm), on the left with 'strong disliking' (score of 0 mm) and on the right with 'strong liking' (score of 100 mm). Emax is the largest effect score between 0.5 to 24 hours post-dose.

Time frame: 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8 and 24 hours

Secondary Outcomes

Number of Adverse Events in Dose Selection Phase

AE=Adverse Event. SAE=Serious adverse event. TEAE=Treatment-emergent adverse event.

Time frame: Up to visit 3 (Follow up)

Data from ClinicalTrials.gov

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Balance of Effects: Emin of Drug Liking VAS in Treatment Phase

Drug liking VAS is the measure of balance of effects that assesses the degree that a participant likes a drug effect at the time the question is being asked (that is, at the moment). It is scored using a 100 millimeter (mm) bipolar (VAS) anchored in the center with a neutral anchor of 'neither like nor dislike' (score of 50 mm), on the left with 'strong disliking' (score of 0 mm) and on the right with 'strong liking' (score of 100 mm). Emin is the smallest effect score between 0.5 to 8 hours post-dose.

Time frame: 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours

Balance of Effects: Time-averaged Area Under the Effect Curve (TA_AUE) of Drug Liking VAS in Treatment Phase

TA\_AUE is AUE0-8hr divided by time from dosing to the actual time of the 8-hour post-dose assessment using the trapezoidal rule.

Time frame: 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours

Balance of Effects: Emax and Emin of Overall Drug Liking VAS in Treatment Phase

Overall drug liking VAS is the measure of balance of effects that assesses the participant's global perception of drug liking (that is, effects over the whole course of the drug experience including any carryover effects). A 100 mm bipolar VAS is used to assess response based on a score ranging from 0 mm to 100 mm (0 mm = 'strong disliking', 50 mm = 'neither like nor dislike', and 100 mm = 'strong liking'). Emax is the largest effect score and Emin is the smallest effect score between 0 to 8 hours post-dose.

Time frame: 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours

Balance of Effects: Emax and Emin of Take Drug Again VAS in Treatment Phase

Take drug again VAS is the measure of balance of effects. It is a subjective assessment of the degree to which a participant would desire to take the drug again if given the opportunity. It is presented on a 100 mm bipolar VAS with score ranging from 0 mm to 100 mm (0 mm = 'definitely not', 50 mm = 'do not care', and 100 mm = 'definitely so'). Emax is the largest effect score and Emin is the smallest effect score between 0 to 8 hours post-dose.

Time frame: 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours

Positive Effects: Emax of High VAS in Treatment Phase

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours (post-dose)

Positive Effects: TA_AUE of High VAS in Treatment Phase

TA\_AUE is AUE0-8hr divided by time from dosing to the actual time of the 8-hour post-dose assessment using the trapezoidal rule.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours (post-dose)

Positive Effects: Emax of Good Effects VAS in Treatment Phase

Good drug effects VAS measures the positive effects experienced by the participant on a 100 mm unipolar VAS, where responses are unidirectional and range from a response of 'none' (0 mm = 'definitely not') to 'extremely' (100 mm = 'definitely so'). Emax is the largest effect score between 0.5 to 8 hours post-dose.

Time frame: 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours

Positive Effects: TA_AUE of Good Effects VAS in Treatment Phase

TA\_AUE is AUE0-8hr divided by time from dosing to the actual time of the 8-hour post-dose assessment using the trapezoidal rule.

Time frame: 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours

Negative Effects: Emax of Bad Effects VAS in Treatment Phase

Bad effects VAS measures the negative effects experienced by the participant on a 100 mm unipolar VAS, where responses are unidirectional and range from a response of 'none' (0 mm = 'definitely not') to 'extremely' (100 mm = 'definitely so'). Emax is the largest effect score between 0.5 to 8 hrs.

Time frame: 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours

Negative Effects: TA_AUE of Bad Effects VAS in Treatment Phase

TA\_AUE is AUE0-8hr divided by time from dosing to the actual time of the 8-hour post-dose assessment using the trapezoidal rule.

Time frame: 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours

Sedative and Other Effects: Emin of Alertness/Drowsiness VAS in Treatment Phase

Alertness/Drowsiness VAS measures the sedative effects. It is scored using a 100 mm bipolar VAS anchored in the center with a neutral anchor of 'neither drowsy nor alert' (score of 50 mm), on the left with 'very drowsy' (score of 0 mm) and on the right with 'very alert' (score of 100 mm). Alertness/Drowsiness VAS was calculated by subtracting pre-dose (baseline) value from each post-dose value. Emin is the smallest effect score between 0 to 8 hours post-dose.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours (post-dose)

Sedative and Other Effects: TA_AUE of Alertness/Drowsiness VAS in Treatment Phase

Alertness/Drowsiness VAS measures the sedative effects. It is scored using a 100 mm bipolar VAS anchored in the center with a neutral anchor of 'neither drowsy nor alert' (score of 50 mm), on the left with 'very drowsy' (score of 0 mm) and on the right with 'very alert' (score of 100 mm). Alertness/Drowsiness VAS was calculated by subtracting pre-dose (baseline) value from each post-dose value. TA\_AUE is AUE0-8hr divided by time from dosing to the actual time of the 8-hour post-dose assessment using trapezoidal rule.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours (post-dose)

Sedative and Other Effects: Emax of Any Effects VAS in Treatment Phase

Time frame: 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours

Sedative and Other Effects: TA_AUE of Any Effects VAS in Treatment Phase

TA\_AUE is AUE0-8hr divided by time from dosing to the actual time of the 8-hour post-dose assessment using the trapezoidal rule.

Time frame: 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours

Objective Measures: Change From Baseline in Choice Reaction Time (CRT) in Treatment Phase

CRT is a computerized 5-choice reaction time test in which the subject must press and hold down a touchscreen button at the bottom of the screen. A yellow spot appeared inside one of 5 yellow circles at the top of the screen. Subjects were to respond to the spot as quickly as they could by letting go of the button and touching the circle where the yellow spot appeared. This was repeated for 30 trials. Lower scores indicate better performance.

Time frame: 0 (Baseline, pre-dose), 1, 2, 4, 8 and 24 hours (post-dose)

Change From Baseline in Number of Errors (Any Errors) in CRT Test in Treatment Phase

Time frame: 0 (Baseline, pre-dose), 1, 2, 4, 8 and 24 hours (post-dose)

Pupillometry: Maximum Pupil Constriction (MPC)

Pupillometry assessments measured change in pupil size (miosis) as an indicator of opioid pharmacological properties. Pupil diameter was measured using electronic pupillometer. Measurements were collected under mesopic lighting conditions. For each subject, every effort was made to use the same eye for all assessments throughout the study. MPC is calculated as smallest observed pupil diameter - baseline pupil diameter.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours (post-dose)

Pupillometry: TA_AUE of MPC in Treatment Phase

TA\_AUE is AUE0-8hr divided by time from dosing to the actual time of the 8-hour post-dose assessment using the trapezoidal rule.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours (post-dose)