A Study to Assess the Effect of AZD4041 on Respiratory Drive in Recreational Opioid Users.

AstraZeneca45 enrolled

Overview

This is a Phase 1, single-centre, randomized, double-blind, placebo-controlled, 2 fixed sequences, multiple dose study in healthy male and/or female recreational opioid users. This study is being primarily conducted to assess the effect on respiratory drive of morphine administered after multiple doses of AZD4041 compared to morphine administered alone in healthy recreational opioid users. The study will include up to 44 participants who will be randomized to either AZD4041 and morphine (28 participants) or placebo and morphine (16 participants). This is to ensure completion of at least 36 participants (24 AZD4041 + morphine, and 12 Placebo + morphine on Day 15). The total study duration will be up to 54 days (including screening) per participant.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Opioid Use Disorder

Interventions

Eligibility

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

Medical Language ↔ Plain English

Inclusion Criteria: 1. Recreational opioid user, not currently considered to have moderate or severe substance use disorder for opioids (based on the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition \[DSM-5\] criteria) and has experience with opioid use for non-therapeutic purposes (ie, for psychoactive effects) on at least 10 occasions in their lifetime and at least 1 occasion in the last 12 weeks prior to screening. 2. Provision of signed and dated informed consent form (ICF) prior to the initiation of any protocol-specific procedures. 3. Stated willingness to comply with all study procedures and availability for the duration of the study. 4. Healthy adult male or female, 18 to 55 years of age, inclusive, prior to the first study drug administration. 5. Body mass index (BMI) within 18.0 kg/m\^2 to 35.0 kg/m\^2, inclusive, and body weight at least 50 kg at screening. 6. A female study participant of non-childbearing potential must meet 1 of the following criteria: (1) Physiological postmenopausal status, defined as the following: 1. absence of menses for at least 1 year prior to the first study drug administration (without an alternative medical condition); and 2. Follicle stimulating hormone (FSH) levels ≥ 40 mIU/mL at screening AND/OR (2) Surgical sterile, defined as those who have had hysterectomy, bilateral oophorectomy and/or bilateral salpingectomy, or bilateral tubal ligation. Women who are surgically sterile must provide documentation of the procedure by an operative report, ultrasound, or other verifiable documentation. 7\. If male, must agree to use a highly effective method of contraception when engaging in sexual activity and must not donate sperm during the study and for at least 4 months (120 days) after the last dose of study medication. 8\. Healthy in the opinion of an Investigator, as determined by no clinically significant findings from medical history, physical examination, 12-lead ECG, vital signs, SpO2, respiratory rate, or clinical laboratory (including hematology, coagulation, clinical chemistry, urinalysis, and serology \[screening visit only\]) at screening visit and/or prior to the first study drug administration. Exclusion Criteria: 1. Female who is pregnant according to the pregnancy test at screening or prior to the first study drug administration. 2. Male participants with a history of oligospermia or azoospermia or any other disorder of the reproductive system. 3. Male participants who are undergoing treatment or investigation for infertility. 4. History of moderate or severe substance or alcohol use disorder (excluding nicotine and caffeine) within the past 2 years, as defined by the DSM-5. 5. History of any significant psychiatric disorder according to the criteria of the DSM-5 which, in the opinion of the Investigator, could be detrimental to participant safety or could compromise study data interpretation. 6. History of significant hypersensitivity to AZD4041, morphine and/or other opioids, naloxone, or any related products (including excipients of the study formulations) as well as severe hypersensitivity reactions (like angioedema) to any drugs. 7. History of any significant disease, including \[but not necessarily limited to\] significant hepatic, renal, cardiovascular, pulmonary, hematologic, neurological, psychiatric, gastrointestinal, endocrine, immunologic, ophthalmologic, or dermatologic disease of any etiology (including infections) identified at screening. 8. Presence or history of significant gastrointestinal, liver or kidney disease, or any other condition \[including those that may result from surgery\] that is known to interfere with drug absorption, distribution, metabolism, or excretion, or known to potentiate or predispose to undesired effects. 9. SpO2 below 95% at screening or prior to first study drug administration. 10. Any abnormal vital signs, after no less than 5 minutes rest (supine position), as defined in the list below, at screening and/or prior to the first study drug administration. Out of range test may be repeated once for each visit at the discretion of the Investigator. 1. Systolic Blood Pressure (BP) \< 90 mmHg or \> 140 mmHg 2. Diastolic BP \< 50 mmHg or \> 90 mmHg 3. Heart Rate (HR) \< 45 or \> 90 beats per minute (bpm) 11. Any clinically important abnormalities in rhythm, conduction, or morphology of the resting ECG and any clinically important abnormalities in the 12-lead ECG, which in the Investigator's opinion, may interfere with the interpretation of QTc interval changes, including abnormal ST-T-wave morphology, particularly in the protocol-defined primary lead, or left ventricular hypertrophy at screening or prior to the first study drug administration (out of range test may be repeated once for each visit at the discretion of the Investigator). 12. Prolonged QT interval corrected for HR using Fridericia's formula (QTcF) \> 450 ms at screening or prior to first study drug administration. 13. Shortened QTcF \< 340 ms at screening or prior to first study drug administration. 14. Family history of long QT syndrome. 15. ECG interval measured from the onset of the P wave to the onset of the QRS complex (PR \[PQ\]) interval shortening \< 120 ms (PR \> 110 ms but \< 120 ms is acceptable if there is no evidence of ventricular preexcitation) at screening or prior to first study drug administration. 16. PR (PQ) interval prolongation (\> 220 ms), persistent or intermittent second (Wenckebach block while asleep is not exclusive) or third degree atrioventricular (AV) block, or AV dissociation at screening or prior to first study drug administration. 17. Persistent or intermittent complete bundle branch block, incomplete bundle branch block, or intraventricular conduction delay with ECG interval measured from the onset of the QRS complex to the J point (QRS) \> 110 ms. Participants with QRS \> 110 ms but \< 115 ms are acceptable if there is no evidence of ventricular hypertrophy or preexcitation at screening or prior to first study drug administration. 18. In the predose 24-hour telemetry, presence of ≥ 10 ventricular premature contractions (VPCs) during 1 hour, or ≥ 100 VPCs during 24 hours of telemetry, or any occurrence of paired VPCs (ventricular couplets) or other repetitive ventricular rhythms, including non-sustained or sustained (\> 30 second duration), slow (\< 100 bpm), or fast (≥ 100 bpm) ventricular tachycardias. 19. Any clinically significant illness in the 28 days prior to the first study drug administration. 20. Heavy smoker (\> 20 cigarettes per day) and/or is unable to abstain from smoking or unable to abstain from the use of prohibited nicotine containing products for at least 1 hour before and at least 6 hours after study drug administration (including e-cigarettes, pipes, cigars, chewing tobacco, nicotine topical patches, nicotine gum, or nicotine lozenges). 21. Regularly consumes excessive amounts of caffeine or xanthines within 30 days prior to screening, defined as greater than 6 servings (1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, or other caffeinated beverages per day. 22. History of suicidal ideation within 1 year of screening (score of 4 or 5 as per the C-SSRS) or any suicidal behavior (as per C-SSRS) within 2 years of screening, or is currently at risk of suicide in the opinion of an Investigator. 23. Positive test result for alcohol and/or drugs of abuse upon admission on Day -1. Participants with positive marijuana results at admission may be rescheduled at the discretion of an Investigator. If Tetrahydrocannabinol is positive at admission, a cannabis intoxication evaluation will be done by an Investigator and participants may be permitted to continue in the study at the discretion of an Investigator. Other positive test results should be reviewed to determine if the participant may be rescheduled, in the opinion of an Investigator. 24. Positive test results for Human Immunodeficiency Virus (HIV)-1/HIV-2 Antibodies, Hepatitis B surface Antigen (HBsAg) or Hepatitis C Virus Antibody (HCVAb). 25. Any other clinically significant abnormalities in laboratory test results at screening that would, in the opinion of an Investigator, increase the participant's risk of participation, jeopardize complete participation in the study, or compromise interpretation of study data. 26. Treatment with an investigational drug within 30 days or 5 times the half-life (whichever is longer) prior to screening. 27. Use of any prescription drugs (with the exception of hormone replacement therapy) in the 14 days prior to the first study drug administration, that in the opinion of an Investigator would put into question the status of the participant as healthy. 28. Use of St. John's wort in the 28 days prior to the first study drug administration. 29. Use of over-the-counter (OTC) products (including herbal preparations and supplements) within 7 days prior to the first study drug administration, with the exception of ibuprofen or acetaminophen. 30. Donation of plasma in the 7 days prior to the first study drug administration. 31. Donation of 1 unit of blood to American Red Cross or equivalent organization or donation of over 500 mL of blood in the 56 days prior to the first study drug administration. 32. Is, in the opinion of an Investigator or designee, considered unsuitable or unlikely to comply with the Study Protocol for any reason. 33. Poor venous access at screening, as judged by an Investigator. 34. Use of any prescribed or nonprescribed oral and topical inhibitors/inducers of CYP3A4 (including shampoo). 35. Is an AstraZeneca or study site employee or their close relatives.

Outcomes

Primary Outcomes

Number of Participants With Increased End-tidal Carbon Dioxide (EtCO2) of at Least 10 mmHg Compared to Baseline or > 50 mmHg on Day 1

ETCo2 measurement is performed in the clinical pharmacology setting studies for the evaluation of respiratory function. EtCO2 is monitored and measured using a standardized methodology and configuration using MICROSREAM\^TM consumables to sample gas via nasal cannulae and the CAPNOSTREAM\^TM20P bedside monitor according to Altasciences SOP on Capnography. Using this configuration, for the spontaneously breathing healthy volunteer participant, baseline EtCO2 measurements is expected to fall within the range of 34 to 48 mmHg. An increase in EtCO2 is defined as an increase of at least 10 mmHg compared to baseline or \> 50 mmHg (sustained for at least 30 seconds). Number of participants with increased EtCO2 of at least 10 mmHg compared to baseline or \> 50 mmHg on Day 1 are reported.

Time frame: Day 1

Number of Participants With Increased End-tidal Carbon Dioxide (EtCO2) of at Least 10 mmHg Compared to Baseline or > 50 mmHg on Day 15

ETCo2 measurement is performed in the clinical pharmacology setting studies for the evaluation of respiratory function. EtCO2 is monitored and measured using a standardized methodology and configuration using MICROSREAM\^TM consumables to sample gas via nasal cannulae and the CAPNOSTREAM\^TM20P bedside monitor according to Altasciences SOP on Capnography. Using this configuration, for the spontaneously breathing healthy volunteer participant, baseline EtCO2 measurements is expected to fall within the range of 34 to 48 mmHg. An increase in end tidal carbon dioxide (EtCO2) is defined as an increase of at least 10 mmHg compared to baseline or \> 50 mmHg (sustained for at least 30 seconds). Number of participants with increased EtCO2 of at least 10 mmHg compared to baseline or \> 50 mmHg on Day 15 are reported.

Time frame: Day 15

Number of Participants With Reduction in Blood Oxygen Saturation (SpO2) to < 92% on Day 1

A reduction in SpO2 is defined as a reduction from baseline to \< 92% (sustained for at least 30 seconds). Number of participants with reduction in SpO2 to \< 92% on Day 1 are reported.

Time frame: Day 1

Number of Participants With Reduction in Blood Oxygen Saturation (SpO2) to < 92% on Day 15

A reduction in SpO2 is defined as a reduction from baseline to \< 92% (sustained for at least 30 seconds). Number of participants with reduction in SpO2 to \< 92% on Day 15 are reported.

Time frame: Day 15

Secondary Outcomes

Time to Reduction in SpO2 to < 92%

Mean time to reduction from baseline in SpO2 to \< 92% (sustained for at least 30 seconds) is reported.

Time frame: Day 1 and Day 15

Duration of Reduction in SpO2 to < 92%

Mean duration of reduction from baseline in SpO2 to \< 92% (sustained for at least 30 seconds) is reported.

Time frame: Day 1 and Day 15

Post-dose Reduction of SpO2 Adjusted for Baseline

Maximum post-dose reduction of SpO2 adjusted for baseline is reported.

Time frame: Day 1, Day 8, and Day 15

Post-dose SpO2

Mean post-dose SpO2 is reported.

Time frame: Day 15

Time to Each Increased EtCO2 Episode of at Least 10 mmHg Compared to Baseline or > 50 mmHg

Mean time to each increased EtCO2 episode of at least 10 mmHg compared to baseline or \> 50 mmHg (sustained for at least 30 seconds) is reported.

Time frame: Day 1 and Day 15

Duration of Each Increased EtCO2 Episode of at Least 10 mmHg Compared to Baseline or > 50 mmHg

Mean duration of each increased EtCO2 episode of at least 10 mmHg compared to baseline or \> 50 mmHg (sustained for at least 30 seconds) is reported.

Time frame: Day 1 and Day 15

Post-dose Increase in EtCO2 Adjusted for Baseline

Maximum post-dose increase in EtCO2 adjusted for baseline is reported.

Time frame: Day 1, Day 8, and Day 15

Post-dose EtCO2

Mean post-dose EtCO2 is reported.

Time frame: Day 15

Time to Each Reduced Respiratory Rate Episode of < 6 Breaths/Min

Mean time to each reduced respiratory rate episode of \< 6 breaths/min (sustained for at least 30 seconds) is reported.

Time frame: Day 1, Day 8, and Day 15

Duration of Each Reduced Respiratory Rate Episode of < 6 Breaths/Min

Mean duration of each reduced respiratory rate episode of \< 6 breaths/min (sustained for at least 30 seconds) is reported.

Time frame: Day 1, Day 8, and Day 15

Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.

Time frame: Day 1 through end of study (Day 24)

Number of TEAEs

The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. Here, Number of TEAEs are reported.

Time frame: Day 1 through end of study (Day 24)

Number of TEAEs by Severity

Time frame: Day 1 through end of study (Day 24)

Number of TEAEs by Relationship

Time frame: Day 1 through end of study (Day 24)

Number of Participants With Clinically Significant Abnormal Vital Signs

Number of participants with clinically significant abnormal vital signs are reported. Abnormal clinical vital signs are defined as any abnormal finding in the vital sign parameters (blood pressure, heart rate, and oral temperature).

Time frame: Screening (Day -30 to -3) through Day 24 (end of study)

Number of Participants With Clinically Significant Abnormal Electrocardiograms (ECGs)

Number of participants with clinically significant abnormal ECGs are reported. Abnormal clinical ECG parameters are defined as any abnormal finding during analysis of 12-lead safety ECGs, 12-lead digital ECGs, and ECG telemetry.

Time frame: Screening (Day -30 to -3) through end of study (Day 24)

Number of Participants With Clinically Significant Abnormal Laboratory Values

Number of participants with clinically significant abnormal laboratory values are reported. Abnormal clinical laboratory parameters are defined as any abnormal finding during analysis of hematology, clinical chemistry, coagulation, and urinalysis.

Time frame: Screening (Day -30 to Day -3) through end of study (Day 24)

Number of Participants With Clinically Significant Abnormal Physical Examination Findings

Number of participants with clinically significant abnormal physical examination findings are reported. The physical examination included a general review of the following body systems (at minimum): head and neck, cardiovascular, respiratory, gastrointestinal, brief neurological and general appearance, unless a symptom oriented physical exam is indicated.

Time frame: Screening (Day -30 to Day -3) through end of study (Day 24)

Number of Participants With Clinically Significant Neurological Examinations Findings

Number of participants with clinically significant neurological examinations findings are reported. Neurological examinations included assessments of basic mental status, cranial nerves, motor function, reflexes, sensation, proprioception, coordination, and gait.

Time frame: Screening (Day -30 to Day -3) through end of study (Day 24)

Number of Participants With Suicidal Ideation or Behaviors Per Columbia-Suicide Severity Rating Scale (C-SSRS) Assessments

The C-SSRS is a suicidal ideation and behavior rating scale with yes/no responses. Items 1-5 rates an individual's degree of suicidal ideation on a 0 (wish to be dead) to 5 (active suicidal ideation with specific plan and intent and behaviors) scale. C-SSRS outcomes are categories and have binary responses (yes/no). Suicidal ideation is considered when the participant responds a 'yes' to any one of the five suicidal ideation questions (Categories 1-5) on the C-SSRS at any time during treatment. Items 6-10 of C-SSRS rates suicidal behavior where outcome is a simple yes/no response. Suicidal behavior was considered if participant answers a 'yes' to any one of the five suicidal behavior questions (Categories 6-10) on C-SSRS at any time during treatment. Number of participants with suicidal behavior and ideation per C-SSRS assessments are reported.

Time frame: Screening (Day -30 to Day -3) through end of study (Day 24)

Number of Participants With Type of Medical Intervention Used for Each Event of Significantly Increased EtCO2, Reduced SpO2, or RR

Number of participants with type of medical intervention used for each event of significantly increased EtCO2, reduced SpO2, or RR are reported.

Time frame: Screening (Day -30 to Day -3) through end of study (Day 24)

Maximum Observed Concentration (Cmax) of Morphine and Its Metabolites

The Cmax of morphine and its metabolites (morphine-3-glucuronide and morphine-6-glucuronide) are reported.

Time frame: Day 1: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 hours postdose, and additionally 48 hours postdose for morphine metabolites

Time to Reach Maximum Observed Concentration (Tmax) of Morphine and Its Metabolites

The Tmax of morphine and its metabolites (morphine-3-glucuronide and morphine-6-glucuronide) are reported.

Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUC0-t) of Morphine and Its Metabolites

The AUC0-t of morphine and its metabolites (morphine-3-glucuronide and morphine-6-glucuronide) are reported.

Area Under Plasma Concentration-time Curve Extrapolated to Infinity (AUC0-∞) of Morphine and Its Metabolites

The (AUC0-∞) of morphine and its metabolites (morphine-3-glucuronide and morphine-6-glucuronide) are reported.

Terminal Elimination Half-life (t1/2λz) of Morphine and Its Metabolites

The t1/2λz of morphine and its metabolites (morphine-3-glucuronide and morphine-6-glucuronide) are reported.

Time of Last Quantifiable Concentration (Tlast) of Morphine and Its Metabolites

The tlast of morphine and its metabolites (morphine-3-glucuronide and morphine-6-glucuronide) are reported.

Total Body Clearance (CL) of Morphine

The CL of morphine are reported.

Volume of Distribution Based on the Terminal Phase (Vz) of Morphine

The Vz of morphine are reported.

Maximum Observed Concentration at Steady-state (Cmax,ss) of AZD4041

The Cmax,ss of AZD4041 are reported.