Safety, Tolerability and Pharmacokinetics of NYX-783 and Oxycodone DDI Study

Clinical Evaluation of NMDA Modulator NYX-783 for OUD: Randomized, Double-blind, Placebo-Controlled Study to Assess Safety, Tolerability, and Pharmacokinetics of NYX-783 in Combination with Oxycodone (Study 1)

This study proposes to examine the safety, tolerability, and pharmacokinetics (PK) of NYX-783 50 mg and 150 mg versus Placebo (PBO) in combination with acute Oxycodone 15 mg and 30 mg in an inpatient randomized, cross-over study in non-treatment seeking non-dependent, opioid experienced individuals with current recreational use.

Study Overview

• Status: Completed
• Conditions: Opioid Use Disorder
• Intervention / Treatment: Drug: Placebo; Drug: Oxycodone; Drug: NYX-783

Detailed Description

Outcomes will be cardiovascular (ECG monitoring, heart rate, blood pressure), respiratory, Clinical Opioid Withdrawal Scale (COWS), treatment emergent adverse events (TEAEs), and PK of NYX-783 levels in combination with Oxycodone. Secondary outcomes will be drug effects, subjective opiate withdrawal scale (SOWS), Drug Effects Questionnaire (DEQ), pupillary diameter, the Opioid Symptom Checklist (OSC), craving, stress and pain, and study drug levels during NYX-783 and Oxycodone combination challenge sessions.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Cmhc/Cnru
    • New Haven, Connecticut, United States, 06519
      • The Yale Stress Center: Yale University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Voluntary, written, informed consent.
• full scale and verbal IQs > 80 (Shipley Institute of Living IQ Screening Test).
• Non-treatment seeking, non-dependent, opioid-experienced participants with low, opioid use via smoking or oral pills routes and with no need for medical detoxification from opiates and without past 12-month history of overdoses or medical detoxification for opioid withdrawal.
• Participants must agree to use dual contraceptive methods during the study and refrain from donating sperm or ova during study or for 28 days after final dose of drug for ova and for 90 days after final dose of drug for sperm. Dual contraceptive methods include the use of a barrier contraceptive (i.e., condoms) in addition to another effective method that can prevent pregnancy (i.e., oral or parenteral contraceptives, intrauterine devices, spermicide, etc.).
• Ability to understand and comply with study requirements and restrictions and provide a secondary contact if they cannot be reached.

Exclusion Criteria:

• Meet current DSM-5 criteria of moderate to severe Substance Use Disorder (SUD) on either sedative, hypnotics, cocaine, methamphetamine, opiates or alcohol.
• Daily heroin, fentanyl use requiring opiate detoxification and treatment.
• Regular daily prescribed use of anticonvulsants, sedatives/hypnotics, other antihypertensives, anti-arrhythmics, antiretroviral medications, naltrexone, antabuse, grapefruit juice and St. John's wort products, glucocorticoids, stimulants (amphetamine like compounds), CNS active medications (other than stabilized use of antidepressants and anti-anxiety medications), metformin, or other medications such as benzodiazepines and sedating antidepressants that in the opinion of the investigators interfere with the study.
• Women who are pregnant or nursing (as assessed by pregnancy tests during initial intake and upon CNRU admissions).
• HIV seropositivity, hepatitis or other acute ongoing infectious disease considered clinically significant by the investigator.
• Traumatic brain injury with loss of consciousness.
• Individuals with current or past history of seizure disorders.
• Current or recent diagnosis within past 6-months of Major Depressive Disorder (MDD), bipolar disorder, schizophrenia, and schizoaffective disorder.
• History of a neurodegenerative or neuro-inflammatory disorder including Huntington's, Parkinson's, Alzheimer's disease, or multiple sclerosis.
• Known familial history or known presence of long QT syndrome, or a known history of past or current clinically significant arrhythmias or ischemic heart disease.
• History of gastrointestinal disease or surgery (except simply appendectomy or hernia repair), leading to impaired drug absorption.
• Uncorrected hypothyroidism or hyperthyroidism. Participants with compensated hypothyroidism with normal thyroid-stimulating hormone levels may be enrolled.
• Sensitivity, allergy, or intolerance to N-methyl-D-aspartate receptor (NMDAR) ligands including ketamine, dextromethorphan, memantine, methadone, dextropropoxyphene, or ketobemidone and magnesium. Use of NMDAR-binding drugs within 60 days prior to dosing or during the study.
• Received an investigational product or device within 30 days of dosing (or 5 half-lives whichever is longer).
• Previously received NYX-783.
• Screening QT interval corrected for heart rate (HR) by Fridericia's formula (QTcF) > 450 (males) or 470 (females) milliseconds (msec) or an ECG that is not suitable for QT measurements (e.g., poorly defined termination of T-wave in the investigator's opinion.
• Heart rate ≤45 or >90 bpm at screening
• Creatinine clearance <60ml/min at screening or history of renal disease as assessed by Investigator.
• Uncontrolled Type I or Type II diabetes or uncontrolled hypertension characterized by fasting blood glucose > 126 mg/dl or postprandial blood glucose > 200 mg/dl, resting systolic blood pressure >160 mm Hg or resting diastolic >100 mm Hg, or clinically significant hypotension in the judgement of the Investigator as characterized by resting systolic blood pressure <90 mm Hg or resting diastolic blood pressure <60 mm Hg.

• Impaired hepatic function characterized by a previous known diagnosis of chronic liver disease and/or the presence of:

  1. direct bilirubin > 1.5x the upper limit of normal at screening
  2. alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, or gamma-glutamyl transferase (GGT) > 2x the upper limit of normal at screening.
• History of severe COVID-19 infection requiring hospitalization, treatment with oxygen or mechanical ventilation, that may interfere with study participation as assessment by the Investigator.
• Any participant with a medical history of Covid-19 infection (positive test) within the last 2 months, or current symptoms consistent with Covid-19 infection, as assessed by the Investigator.
• Donated blood during the past 8 weeks.
• Participants who do not report an increase in subjective opioid effect, as measured by the Drug Effects Questionnaire (DEQ, see below) by minimum of 10% or more to initial challenge with oxycodone in Session 1 will be excluded from the DDI phase sessions 2-7.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo + Oxycodone; Participants will receive placebo with + 15 mg oxycodone then placebo + 30 mg oxycodone in separate inpatient randomized sessions in this, cross-over study over 6 experimental sessions.	Drug: Placebo; This study proposes to examine the safety, tolerability, and pharmacokinetics (PK) of NYX-783 at 50 mg and 150 mg doses versus Placebo (PBO) in combination with acute Oxycodone 15 mg and 30 mg in an inpatient randomized, cross-over study over 6 experimental sessions.; Drug: Oxycodone; This study proposes to examine the safety, tolerability, and pharmacokinetics (PK) of NYX-783 at 50 mg and 150 mg doses versus Placebo (PBO) in combination with acute Oxycodone 15 mg and 30 mg in an inpatient randomized, cross-over study over 6 experimental sessions.
Active Comparator: NYX-783: 50 mg dose + Oxycodone; Participants will receive NYX-783 50 mg dose with + 15 mg oxycodone then NYX-783 50 mg + 30 mg oxycodone in separate inpatient randomized sessions in this, cross-over study over 6 experimental sessions.	Drug: Oxycodone; This study proposes to examine the safety, tolerability, and pharmacokinetics (PK) of NYX-783 at 50 mg and 150 mg doses versus Placebo (PBO) in combination with acute Oxycodone 15 mg and 30 mg in an inpatient randomized, cross-over study over 6 experimental sessions.; Drug: NYX-783; This study proposes to examine the safety, tolerability, and pharmacokinetics (PK) of NYX-783 at 50 mg and 150 mg doses versus Placebo (PBO) in combination with acute Oxycodone 15 mg and 30 mg in an inpatient randomized, cross-over study over 6 experimental sessions.; Other Names: ((2S, 3R)-3-hydroxy-2-((S)-5-isobutyryl-1-oxo-2,5-diazaspiro[3.4]octan-2-yl)butanamide)
Active Comparator: NYX-783: 150 mg dose + Oxycodone; Participants will receive NYX-783 150 mg dose with + 15 mg oxycodone then NYX-783 150 mg + 30 mg oxycodone in separate inpatient randomized sessions in this, cross-over study over 6 experimental sessions.	Drug: Oxycodone; This study proposes to examine the safety, tolerability, and pharmacokinetics (PK) of NYX-783 at 50 mg and 150 mg doses versus Placebo (PBO) in combination with acute Oxycodone 15 mg and 30 mg in an inpatient randomized, cross-over study over 6 experimental sessions.; Drug: NYX-783; This study proposes to examine the safety, tolerability, and pharmacokinetics (PK) of NYX-783 at 50 mg and 150 mg doses versus Placebo (PBO) in combination with acute Oxycodone 15 mg and 30 mg in an inpatient randomized, cross-over study over 6 experimental sessions.; Other Names: ((2S, 3R)-3-hydroxy-2-((S)-5-isobutyryl-1-oxo-2,5-diazaspiro[3.4]octan-2-yl)butanamide)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in respiratory rate	Change in respiratory rate pre and post drug administration measured by counting breaths	over 6 sessions from baseline up to 3 weeks
Change in oxygenation saturation	Change in oxygenation saturation pre and post drug administration measured by pulse-oximeter	over 6 sessions from baseline up to 3 weeks
Change in blood pressure	Change in blood pressure pre and post drug administration measured by blood pressure monitor	over 6 sessions from baseline up to 3 weeks
Change in heart rate	Change in heart rate pre and post drug administration measured by blood pressure monitor	over 6 sessions from baseline up to 3 weeks
Change in body temperature	Change in body temperature pre and post drug administration measured by temperature monitor	over 6 sessions from baseline up to 3 weeks
Change in cardiac rate	Change in cardiac rate pre and post drug administration measured by EKG cardiac monitor	over 6 sessions from baseline up to 3 weeks
Change in cardiac rhythm	Change in cardiac rhythm pre and post drug administration measured by EKG cardiac monitor	over 6 sessions from baseline up to 3 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
treatment emergent adverse events (TEAES) from Systematic Assessment for Treatment Emergent Effects (SAFTEE)	The SAFTEE is a technique for the systematic assessment of side effects in clinical trials that rates the current severity of a wide range of somatic, behavioral and affective symptoms and tabulates occurrence of each TEAE symptom	over 6 sessions from baseline up to 3 weeks
Change in Clinical Opiate Withdrawal Scale (COWS)	COWS is an 11-item scale to rate common signs and symptoms of opiate withdrawal and monitor these symptoms over time. The summed score determines the stage/severity of opiate withdrawal and assess the level of physical dependence on opioids. Score: 5- 12 = mild; 13-24 = moderate; 25-36 = moderately severe; more than 36 = severe withdrawal	over 6 sessions from baseline up to 3 weeks
Change in Subjective Opioid Withdrawal Scale (SOWS)	SOWS is a self-administered scale for opioid withdrawal symptoms. It has16 symptoms whose intensity is rated on a scale of 0 (not at all) to 4 (extremely). Mild Withdrawal = score of 1-10, Moderate withdrawal = 11-20, Severe withdrawal = 21-30	over 6 sessions from baseline up to 3 weeks
Change in Drug Effects Questionnaire (DEQ)	The DEQ measures Good Drug Effect and consists of 11 questions with total score range from 0-100. Higher scores indicate more positive effects.	over 6 sessions from baseline up to 3 weeks
Change in Visual Analog Scale (VAS)	The VAS scales are 5 item drug effect self report ratings The visual analog questions were "Do you feel any Drug Effect?" "Do you like the drug?" "How high are you?" "Does the drug have any Good Effects?" "Does the drug have any Bad Effects?" and "How much do you DESIRE opiates?" The subjects responded by positioning an arrow along a 100-point line labeled with "not at all" at one end and "extremely" at the other. High scores show drug effect and craving, low scores show low drug effect and low craving	over 6 sessions from baseline up to 3 weeks
Change in Opioid Symptom Checklist (OSC)	The OSC is a 13-item opioid symptom checklist consisting of true/false questions designed to measure opioid effects (e.g., "My skin is itchy"). True scores total up to acute opiate positive and negative symptoms and low true scores will mean not feeling any of the negative and positive symptoms.	over 6 sessions from baseline up to 3 weeks
Change in pupillary diameter	pupil diameter size using pupilometer	over 6 sessions from baseline up to 3 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic (PK) levels of study medication	plasma levels drawn repeatedly in 3 experimental sessions	across 3 sessions during the 3 weeks assessment period

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute on Drug Abuse (NIDA); Aptinyx
• Investigators: Principal Investigator: Rajita Sinha, PhD, Yale University

Study record dates

Study Major Dates

• Study Start (Actual): May 15, 2023
• Primary Completion (Actual): December 30, 2024
• Study Completion (Actual): December 30, 2024

Study Registration Dates

• First Submitted: June 21, 2022
• First Submitted That Met QC Criteria: June 30, 2022
• First Posted (Actual): July 7, 2022

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 20, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Narcotic-Related Disorders; Mental Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Opioid-Related Disorders; Physiological Effects of Drugs; Peripheral Nervous System Agents; Central Nervous System Depressants; Sensory System Agents; Analgesics; Analgesics, Opioid; Narcotics; Oxycodone
• Other Study ID Numbers: 2000033008; UG3DA050322 (U.S. NIH Grant/Contract); NYX-783-1009 (Other Identifier: Aptinyx)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No