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

Study Overview
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Brief Summary
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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 randomised to either AZD4041 and morphine (28 participants) or placebo and morphine (16 participants). This is to ensure completion of at least 36 subjects (24 AZD4041 + morphine, and 12 Placebo + morphine on Day 15). The total study duration will be up to 54 days (including screening) per participant.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Fixed Sequence Study to Assess the Effect on Respiratory Drive of Multiple Doses of AZD4041 When Co-administered With a Single Dose of Morphine in Healthy Recreational Opioid Users

Conditions
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Opioid Use Disorder

Intervention / Treatment
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* Drug: AZD4041 and morphine
* Other: Placebo and morphine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Provision of signed and dated informed consent form (ICF) prior to the initiation of any protocol-specific procedures Stated willingness to comply with all study procedures and availability for the duration of the study Healthy adult male or female, 18 to 55 years of age, inclusive, prior to the first study drug administration Body mass index (BMI) within 18.0 kg/m2 to 35.0 kg/m2, inclusive, and body weight at least 50 kg at Screening A female study subject of non-childbearing potential must meet 1 of the following criteria: (1) Physiological postmenopausal status, defined as the following: absence of menses for at least 1 year prior to the first study drug administration (without an alternative medical condition); and 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, oxygen saturation (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: Female who is pregnant according to the pregnancy test at Screening or prior to the first study drug administration. Male subjects with a history of oligospermia or azoospermia or any other disorder of the reproductive system. Male subjects who are undergoing treatment or investigation for infertility. 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. 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 subject safety or could compromise study data interpretation. 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. 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. 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. Oxygen saturation (SpO2) below 95% at Screening or prior to first study drug administration 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. Systolic BP < 90 mmHg or > 140 mmHg Diastolic BP < 50 mmHg or > 90 mmHg HR < 45 or > 90 beats per minute (bpm) 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). Prolonged QT interval corrected for HR using Fridericia's formula (QTcF) > 450 ms at Screening or prior to first study drug administration. Shortened QTcF < 340 ms at Screening or prior to first study drug administration. Family history of long QT syndrome 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. 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. 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. Subjects 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. 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. Any clinically significant illness in the 28 days prior to the first study drug administration. 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). 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. 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. Positive test result for alcohol and/or drugs of abuse upon admission on Day -1. Subjects with positive marijuana results at admission may be rescheduled at the discretion of an Investigator. If THC is positive at admission, a cannabis intoxication evaluation will be done by an Investigator and subjects 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 subject may be rescheduled, in the opinion of an Investigator. Positive test results for HIV-1/HIV-2 Antibodies, Hepatitis B surface Antigen (HBsAg) or Hepatitis C Virus Antibody (HCVAb). Any other clinically significant abnormalities in laboratory test results at Screening that would, in the opinion of an Investigator, increase the subject's risk of participation, jeopardize complete participation in the study, or compromise interpretation of study data. Treatment with an investigational drug within 30 days or 5 times the half-life (whichever is longer) prior to Screening. 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. Use of St. John's wort in the 28 days prior to the first study drug administration. 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. Donation of plasma in the 7 days prior to the first study drug administration. 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. Is, in the opinion of an Investigator or designee, considered unsuitable or unlikely to comply with the Study Protocol for any reason. Poor venous access at Screening, as judged by an Investigator. Use of any prescribed or nonprescribed oral and topical inhibitors/inducers of CYP3A4 (including shampoo). Is an AZ or study site employee or their close relatives.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD4041 and morphine<br>Participants will receive an IV dose of morphine on Days 1 and 15. From Days 2 to 15, participants will receive an oral dose of AZD4041 once daily. | Drug: AZD4041 and morphine<br>* Participants will receive 2 doses of morphine (IV administration) and multiple doses of AZD4041 (Oral solution)<br>|
| Placebo Comparator: Placebo and morphine<br>Participants will receive an IV dose of morphine on Days 1 and 15. From Days 2 to 15, participants will receive an oral dose of placebo once daily. | Other: Placebo and morphine<br>* Participants will receive 2 doses of morphine (IV administration) and multiple doses of Placebo (Oral solution)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of reduction in SpO2 | Incidence of reduction in SpO2 to <92% (sustained for at least 30 seconds) | 54 days | 
| Incidence of increased end tidal carbon dioxide (EtCO2) | Incidence of increased end tidal carbon dioxide (EtCO2) of at least 10 mmHg compared to baseline or >50 mmHg (sustained for at least 30 seconds) | 16 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess SpO2 (%) time | Mean time to reduction in SpO2 (%) to <92% (sustained for at least 30 seconds) | 54 days | 
| Assess SpO2 (%) duration | Mean duration of reduction in SpO2 (%) to <92% (sustained for at least 30 seconds) | 54 days | 
| Assess SpO2 (%) postdose reduction | Maximum postdose reduction of SpO2 (%) adjusted for baseline | 54 days | 
| Assess SpO2 (%) postdose | Mean postdose SpO2 (%) | 54 days | 
| Assess EtCO2 time | Mean time to each increased EtCO2 (mmHg) episode of at least 10 mmHg compared to baseline or >50 mmHg (sustained for at least 30 seconds) | 16 days | 
| Assess EtCO2 duration | Mean duration of each increased EtCO2 (mmHg) episode of at least 10 mmHg compared to baseline or >50 mmHg (sustained for at least 30 seconds) | 16 days | 
| Assess EtCO2 postdose increase | Maximum postdose increase in EtCO2 (mmHg) adjusted for baseline | 16 days | 
| Assess EtCO2 postdose | Mean postdose EtCO2 (mmHg) | 16 days | 
| Assess respiratory rate incidence | Incidence of reduced respiratory rate (breaths/min) to <6 breaths/min (sustained for at least 30 seconds) | 54 days | 
| Assess respiratory rate time | Mean time to each reduced respiratory rate (breaths/min) episode of <6 breaths/min (sustained for at least 30 seconds) | 54 days | 
| Assess respiratory rate duration | Mean duration to each reduced respiratory rate (breaths/min) episode of <6 breaths/min (sustained for at least 30 seconds) | 54 days | 
| Assess respiratory rate postdose decrease | Maximum postdose decrease in respiratory rate (breaths/min) adjusted for baseline | 54 days | 
| Assess respiratory rate postdose | Mean postdose respiratory rate (breaths/min) | 54 days | 
| Incidence and severity of Adverse Events | Incidence, frequency, severity and relationship of adverse events from screening | 54 days | 
| Safety clinical laboratory tests | Changes from baseline in abnormal laboratory test results | 54 days | 
| Vital signs (Blood pressure) | Change from baseline in both systolic and diastolic blood pressure measured in millimetres of Mercury | 54 days | 
| Vital signs (Temperature) | Change in baseline in body temperature measured in degrees Celcius | 54 days | 
| Vital signs (Heart rate) | Change in baseline in heart rate measured in beats per minute | 54 days | 
| Physical examinations | Changes from baseline in abnormal physical examination findings | 54 days | 
| Neurological examinations | Changes from baseline in abnormal neurological examination findings | 54 days | 
| Suicidal Ideation | Evaluation of presence or absence of suicidal ideation as measured by the Columbia Suicide Rating Scale (C-SSRS) | 54 days | 
| Suicidal Behaviour | Evaluation of presence or absence of suicidal behavior as measured by the Columbia Suicide Severity Rating Scale (C-SSRS) | 54 days | 
| Electrocardiogram QTcF interval | Change from baseline in ECG QTcF interval | 54 days | 
| Electrocardiogram QRS duration | Change from baseline in ECG QRS duration | 54 days | 
| Electrocardiogram QT interval | Change from baseline in ECG QT interval | 54 days | 
| Electrocardiogram PR interval | Change from baseline in ECG PR interval | 54 days | 
| Electrocardiogram RR interval | Change from baseline in ECG RR interval | 54 days | 
| Electrocardiogram HR | Change from baseline in ECG HR values | 54 days | 
| Medical intervention used | Type of medical intervention used, summarized for each event of significantly increased EtCO2, reduced SpO2, or respiratory rate | 54 days | 
| Maximum (peak) plasma concentration of morphine and its metabolites | Cmax | 18 days | 
| Time to reach maximum (peak) plasma concentration of morphine and its metabolites | Tmax | 18 days | 
| Area under the curve of morphine and its metabolites from time 0 to time t (AUC from zero to the last measurable concentration) | AUC0-t | 18 days | 
| Extrapolation of the area under the curve of morphine and its metabolites from zero to infinity | AUC0-inf | 18 days | 
| Terminal half-life of morphine and its metabolites | t1/2λz | 18 days | 
| Time of last measurable observed concentration of morphine and its metabolites | Tlast | 18 days | 
| Apparent total clearance of the morphine and its metabolites from plasma | CL | 18 days | 
| Volume of distribution based on terminal phase of morphine and its metabolites | Vz | 18 days | 
| Predose concentration of AZD4041 observed immediately prior to the next successive dose | Ctrough | 17 days | 
| Maximum (peak) plasma concentration of AZD4041 at steady state | Cmax,ss | 8 days | 
| Time to reach maximum (peak) plasma concentration of AZD4041 at steady state | Tmax,ss | 8 days | 
| Area under the concentration time curve over the dosing interval of AZD4041 at steady-state | AUCτ | 8 days | 
| Terminal half-life of AZD4041 | t1/2λz | 8 days | 
| Apparent total clearance of the AZD4041 from plasma at steady state | CLss/F | 8 days | 
| Volume of distribution based on terminal phase of AZD4041 at steady state | Vzss/F | 8 days | 
| Average concentration during a dosing interval, after the last dose of a multiple dose regimen of AZD4041 | Cav (calculated as AUCτ/τ) | 8 days | 
| Amount of drug (AZD4041) excreted in urine | Aeτ | 4 days | 
| Cumulative fraction of unchanged drug (AZD4041) excreted in urine over the dosing interval | feτ | 4 days | 
| Apparent renal clearance of AZD4041 in urine | CLr | 4 days | 
| Elimination half-life of AZD4041 | t1/2 | 4 days |