Clinical trial NCT05587998: A Study to Assess the Effect of AZD4041 on Respiratory Drive in Recreational Opioid Users.
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Opioid Use Disorder
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2022-10-20
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Increased End-tidal Carbon Dioxide (EtCO2) of at Least 10 mmHg Compared to Baseline or > 50 mmHg on Day 1
timeFrame: Day 1
measure: Number of Participants With Increased End-tidal Carbon Dioxide (EtCO2) of at Least 10 mmHg Compared to Baseline or > 50 mmHg on Day 15
timeFrame: Day 15
measure: Number of Participants With Reduction in Blood Oxygen Saturation (SpO2) to < 92% on Day 1
timeFrame: Day 1
measure: Number of Participants With Reduction in Blood Oxygen Saturation (SpO2) to < 92% on Day 15
timeFrame: Day 15
Secondary outcomes:
measure: Time to Reduction in SpO2 to < 92%
timeFrame: Day 1 and Day 15
measure: Duration of Reduction in SpO2 to < 92%
timeFrame: Day 1 and Day 15
measure: Post-dose Reduction of SpO2 Adjusted for Baseline
timeFrame: Day 1, Day 8, and Day 15
measure: Post-dose SpO2
timeFrame: Day 15
measure: Time to Each Increased EtCO2 Episode of at Least 10 mmHg Compared to Baseline or > 50 mmHg
timeFrame: Day 1 and Day 15
measure: Duration of Each Increased EtCO2 Episode of at Least 10 mmHg Compared to Baseline or > 50 mmHg
timeFrame: Day 1 and Day 15
measure: Post-dose Increase in EtCO2 Adjusted for Baseline
timeFrame: Day 1, Day 8, and Day 15
measure: Post-dose EtCO2
timeFrame: Day 15
measure: Number of Participants With Reduced Respiratory Rate (RR) of < 6 Breaths/Min
timeFrame: Day 1, Day 8, and Day 15
measure: Time to Each Reduced Respiratory Rate Episode of < 6 Breaths/Min
timeFrame: Day 1, Day 8, and Day 15
measure: Duration of Each Reduced Respiratory Rate Episode of < 6 Breaths/Min
timeFrame: Day 1, Day 8, and Day 15
measure: Post-dose Decrease in RR Adjusted for Baseline
timeFrame: Day 1, Day 8, and Day 15
measure: Post-dose RR
timeFrame: Day 15
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
timeFrame: Day 1 through end of study (Day 24)
measure: Number of TEAEs
timeFrame: Day 1 through end of study (Day 24)
measure: Number of TEAEs by Severity
timeFrame: Day 1 through end of study (Day 24)
measure: Number of TEAEs by Relationship
timeFrame: Day 1 through end of study (Day 24)
measure: Number of Participants With Clinically Significant Abnormal Vital Signs
timeFrame: Screening (Day -30 to -3) through Day 24 (end of study)
measure: Number of Participants With Clinically Significant Abnormal Electrocardiograms (ECGs)
timeFrame: Screening (Day -30 to -3) through end of study (Day 24)
measure: Number of Participants With Clinically Significant Abnormal Laboratory Values
timeFrame: Screening (Day -30 to Day -3) through end of study (Day 24)
measure: Number of Participants With Clinically Significant Abnormal Physical Examination Findings
timeFrame: Screening (Day -30 to Day -3) through end of study (Day 24)
measure: Number of Participants With Clinically Significant Neurological Examinations Findings
timeFrame: Screening (Day -30 to Day -3) through end of study (Day 24)
measure: Number of Participants With Suicidal Ideation or Behaviors Per Columbia-Suicide Severity Rating Scale (C-SSRS) Assessments
timeFrame: Screening (Day -30 to Day -3) through end of study (Day 24)
measure: Number of Participants With Type of Medical Intervention Used for Each Event of Significantly Increased EtCO2, Reduced SpO2, or RR
timeFrame: Screening (Day -30 to Day -3) through end of study (Day 24)
measure: Maximum Observed Concentration (Cmax) of Morphine and Its Metabolites
timeFrame: 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
measure: Time to Reach Maximum Observed Concentration (Tmax) of Morphine and Its Metabolites
timeFrame: 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
measure: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration (AUC0-t) of Morphine and Its Metabolites
timeFrame: 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
measure: Area Under Plasma Concentration-time Curve Extrapolated to Infinity (AUC0-∞) of Morphine and Its Metabolites
timeFrame: 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
measure: Terminal Elimination Half-life (t1/2λz) of Morphine and Its Metabolites
timeFrame: 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
measure: Time of Last Quantifiable Concentration (Tlast) of Morphine and Its Metabolites
timeFrame: 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
measure: Total Body Clearance (CL) of Morphine
timeFrame: 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
measure: Volume of Distribution Based on the Terminal Phase (Vz) of Morphine
timeFrame: 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
measure: Maximum Observed Concentration at Steady-state (Cmax,ss) of AZD4041
timeFrame: Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose
measure: Time to Reach Maximum Observed Concentration at Steady State (Tmax,ss) of AZD4041
timeFrame: Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose
measure: Area Under Plasma Concentration-time Curve Over a Dosing Interval (AUCτ) of AZD4041
timeFrame: Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose
measure: Terminal Elimination Half-life (t1/2λz) of AZD4041
timeFrame: Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose
measure: Average Concentration Over a Dosing Interval (Cav) of AZD4041
timeFrame: Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose
measure: Apparent Total Body Clearance at Steady State (CLss/F) of AZD4041
timeFrame: Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose
measure: Apparent Volume of Distribution at Steady State Based on the Terminal Phase (Vzss/F) of AZD4041
timeFrame: Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose
measure: Observed Lowest Concentration Before the Next Dose is Administered at Steady State (Ctrough,ss) of AZD4041
timeFrame: Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose
measure: Amount of AZD4041 Excreted Unchanged in Urine (Aeτ)
timeFrame: Day 15: Predose spot collection, 0 to 6 hours, 6 to 12 hours, 12 to 24 hours, 24 to 48 hours, and 48 to 72 hours postdose
measure: Apparent Fraction of AZD4041 Excreted Unchanged in Urine (Feτ/F)
timeFrame: Day 15: Predose spot collection, 0 to 6 hours, 6 to 12 hours, 12 to 24 hours, 24 to 48 hours, and 48 to 72 hours postdose
measure: Renal Clearance (CLR) of AZD4041
timeFrame: Day 15: Predose spot collection, 0 to 6 hours, 6 to 12 hours, 12 to 24 hours, 24 to 48 hours, and 48 to 72 hours postdose
measure: Terminal Elimination Half-life (t1/2) of AZD4041
timeFrame: Day 15: Predose spot collection, 0 to 6 hours, 6 to 12 hours, 12 to 24 hours, 24 to 48 hours, and 48 to 72 hours postdose
measure: Plasma Concentration of Morphine Over Time
timeFrame: 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
measure: Plasma Concentration of Morphine-3-glucuronide Over Time
timeFrame: 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
measure: Plasma Concentration of Morphine-6-glucuronide Over Time
timeFrame: 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
measure: Plasma Concentration of AZD4041 Over Time
timeFrame: Day 8: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose, and Day 15: predose, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours postdose
Other outcomes:
Locations:
city: Overland Park
country: United States
facility: Research Site
state: Kansas
Study officials:
affiliation: Altasciences Company Inc.
name: Debra Kelsh, MD
role: PRINCIPAL_INVESTIGATOR
References: