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

NCT05587998 | Completed Phase 1 Results FDA Drug

• 1 other identifier: D7460C00003
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 1

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.

Conditions

Opioid Use Disorder

Outcome Measures

Primary Outcomes (4)

• 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.

  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.

  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.

  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.

  Day 15

Secondary Outcomes (48)

• Time to Reduction in SpO2 to < 92%

  Day 1 and Day 15

• Duration of Reduction in SpO2 to < 92%

  Day 1 and Day 15

• Post-dose Reduction of SpO2 Adjusted for Baseline

  Day 1, Day 8, and Day 15

• Post-dose SpO2

  Day 15

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

  Day 1 and Day 15

Study Arms (2)

Morphine then AZD4041 then Morphine + AZD4041

EXPERIMENTAL

Participants will receive a single intravenous (IV) dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of AZD4041 Dose Level 1, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of AZD4041 Dose Level 1 in combination with a single IV dose of morphine Dose Level 1.

Drug: Morphine; Drug: AZD4041

Morphine then Placebo then Morphine + Placebo

PLACEBO COMPARATOR

Participants will receive a single IV dose of morphine Dose Level 1 on Day 1. From Day 2 to Day 15, participants will receive an oral dose of placebo matched to AZD4041, once daily for 14 consecutive days. On Day 15, participants will receive an oral dose of placebo matched to AZD4041 in combination with a single IV dose of morphine Dose Level 1.

Drug: Morphine; Other: Placebo

Interventions

Morphine DRUG

Participants will receive IV dose of Morphine as stated in arm description.

Also known as: Duramorph PF®

Morphine then AZD4041 then Morphine + AZD4041; Morphine then Placebo then Morphine + Placebo

AZD4041 DRUG

Participants will receive oral doses of AZD4041 as stated in arm description.

Also known as: No other names

Morphine then AZD4041 then Morphine + AZD4041

Placebo OTHER

Participants will receive oral doses of placebo as stated in arm description.

Also known as: No other names

Morphine then Placebo then Morphine + Placebo

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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/m\^2 to 35.0 kg/m\^2, inclusive, and body weight at least 50 kg at screening.
• A female study participant 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.
• \. 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.
• \. 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.

You may not qualify if:

• Female who is pregnant according to the pregnancy test at screening or prior to the first study drug administration.
• Male participants with a history of oligospermia or azoospermia or any other disorder of the reproductive system.
• Male participants 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 participant 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.
• 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 Blood Pressure (BP) \< 90 mmHg or \> 140 mmHg
• Diastolic BP \< 50 mmHg or \> 90 mmHg
• Heart Rate (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.

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (1)

Research Site

Overland Park, Kansas, 66212, United States

Location

Related Links

• CSR Synopsis

MeSH Terms

Conditions

Opioid-Related Disorders

Interventions

Morphine

Condition Hierarchy (Ancestors)

Narcotic-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Morphine Derivatives; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds

Results Point of Contact

• Title: Global Clinical Lead
• Organization: AstraZeneca

information.center@astrazeneca.com

+1-877-240-9479

Study Officials

• Debra Kelsh, MD

  Altasciences Company Inc.

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 21, 2022
• First Posted: October 20, 2022
• Study Start: August 31, 2022
• Primary Completion: May 25, 2023
• Study Completion: May 25, 2023
• Last Updated: November 15, 2024
• Results First Posted: November 15, 2024

Record last verified: 2024-09

Locations

US (1)