Drug-Drug Interaction and Safety of AZD4041 Study (Part 1) and Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of AZD4041 Study in Opioid Use Disorder (Part 2).

NCT06406400 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: D7460C00004
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of the study is to assess drug-drug interaction (DDI) and safety of AZD4041 and itraconazole in healthy participants (Part 1), and to assess efficacy, safety, pharmacokinetics (PK) and pharmacodynamics (PD) of AZD404 when administered with buprenorphine/buprenorphine + naloxone in participants with moderate to severe opioid use disorder (OUD)

Conditions

Opioid Use Disorder

Keywords

Drug-drug interactions; Adjunctive treatment; Itraconazole; Buprenorphine; Naloxone; Pharmacokinetics

Outcome Measures

Primary Outcomes (4)

• Part 1a: Maximum observed drug concentration (Cmax) of AZD4041

  To assess the effect of itraconazole on the PK of a AZD4041 single oral dose.

  Day 1 to Day 5, Day 9 to Day 22

• Part 1a: Area under concentration-time curve from time 0 to infinity (AUCinf) of AZD4041

  To assess the effect of itraconazole on the PK of a AZD4041 single oral dose.

  Day 1 to Day 5, Day 9 to Day 22

• Part 1b: Number of participants with adverse events (AEs) and serious adverse events (SAEs)

  To assess the safety and tolerability of AZD4041 following oral administration of a single dose.

  For SAE - From screening (Day -28 to Day -3), For AE - From Treatment period (Day 1) up to Follow-Up Visit [Day 7 (+ 2 days) post-dose]

• Part 2: Change from baseline in Self-reported withdrawal symptoms measured by the Short Opioid Withdrawal Scale-Gossop (SOWS-G)

  To evaluate the effects of AZD4041, as an adjunctive treatment to buprenorphine when administered after hydromorphone, on clinical measures of withdrawal in participants with OUD. SOWS-G is a 10-item psychometrically validated scale that measures participant reported withdrawal symptoms. Each of the items of the scale is scored as follows: none=0; mild=1; moderate=2; severe=3. The SOWS-G score is computed as the total sum of the item scores (giving a range for SOWS-G scores of 0 - 30). A high score indicates more severe withdrawal symptoms.

  From Day 4 pre-dose value (Day 4 baseline) to last Day 4 evaluation

Secondary Outcomes (14)

• Part 1a: Number of participants with adverse events (AEs) and serious adverse events (SAEs)

  For SAE - From screening (Day -28 to Day -3), For AE - From Treatment period (Day 1) to Follow-up visit (7-14 days after last PK sample)

• Part 1a and Part 1b: Time to Maximum Concentration (tmax) of AZD4041

  Part 1a: Day 1 to Day 5 and Day 9 to Day 22; Part 1b: Day 1 to Day 4

• Part 1a and Part 1b: Area under concentration-time curve from time 0 to the last quantifiable concentration (AUClast) of AZD4041

  Part 1a: Day 1 to Day 5 and Day 9 to Day 22; Part 1b: Day 1 to Day 4

• Part 1a: Area under concentration-time curve from time 0 to 72h (AUC0-72) of AZD4041

  Day 1 to Day 5 (72 h) post dose, Day 9 to Day 22 (72 h) post dose

• Part 1a and Part 1b: Terminal elimination half-life (t1/2λz) of AZD4041

  Part 1a: Day 1 to Day 5 and Day 9 to Day 22; Part 1b: Day 1 to Day 4

Study Arms (5)

Part 1a: AZD4041 (Dose 1) and Itraconazole

EXPERIMENTAL

Healthy participants will receive a single dose of AZD4041 (Dose 1) in period 1, followed by repeat dose of itraconazole for 3 days in period 2, and a single dose of AZD4041 co-administered with itraconazole on Day 9, followed by continued itraconazole daily dosing until Day 21 in period 3.

Drug: AZD4041; Drug: Itraconazole

Part 1b: AZD4041 (Dose 2)

EXPERIMENTAL

Healthy participants will receive AZD4041 (Dose 2) orally as a single dose.

Drug: AZD4041

Part 1b: Placebo

PLACEBO COMPARATOR

Healthy participants will receive matching placebo orally as a single dose.

Drug: Placebo

Part 2: AZD4041 (Dose 3)

EXPERIMENTAL

Participants will receive AZD4041 (Dose 3) with hydromorphone on Days 1, 2 and 3, and buprenorphine/buprenorphine + naloxone on Days 4, 5, 6 and 7.

Drug: AZD4041; Drug: Buprenorphine; Drug: Buprenorphine / Naloxone; Drug: Hydromorphone

Part 2: Placebo

PLACEBO COMPARATOR

Participants will receive matching placebo with hydromorphone on Days 1, 2 and 3, and buprenorphine/buprenorphine + naloxone on Days 4, 5, 6 and 7.

Drug: Buprenorphine; Drug: Buprenorphine / Naloxone; Drug: Hydromorphone; Drug: Placebo

Interventions

AZD4041 DRUG

Part 1a: Healthy participants will receive AZD4041 (Dose 1) orally on Day 1 and Day 9. Part 1b: Healthy participants will receive AZD4041 (Dose 2) orally on Day 1 as a single dose. Part 2: Participants with OUD will receive daily doses of AZD4041 from Days 1 to 7.

Part 1a: AZD4041 (Dose 1) and Itraconazole; Part 1b: AZD4041 (Dose 2); Part 2: AZD4041 (Dose 3)

Itraconazole DRUG

Healthy participants will receive itraconazole orally from Days 6 to 8 in Period 2 and Days 9 to 21 in Period 3.

Also known as: Sporanox®

Part 1a: AZD4041 (Dose 1) and Itraconazole

Buprenorphine DRUG

Participants with OUD will receive buprenorphine (as standard of care treatment) on Day 4.

Also known as: Belbuca®

Part 2: AZD4041 (Dose 3); Part 2: Placebo

Buprenorphine / Naloxone DRUG

Participants with OUD will receive buprenorphine + naloxone (as standard of care treatment) on Days 4, 5, 6 and 7

Also known as: Suboxone®

Part 2: AZD4041 (Dose 3); Part 2: Placebo

Hydromorphone DRUG

Participants with OUD will receive hydromorphone (as a replacement opioid) on Days 1, 2 and 3.

Also known as: Dilaudid®

Part 2: AZD4041 (Dose 3); Part 2: Placebo

Placebo DRUG

Part 1b: Healthy participants will receive matching placebo orally on Day 1 as a single dose. Part 2: Participants with OUD will receive placebo daily from Days 1 to 7.

Part 1b: Placebo; Part 2: Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male participants:
• with female partner(s) of childbearing potential (including breastfeeding partner) must be willing to use a reliable method of contraception throughout the study period for 30 days) after final investigational medicinal product (IMP) administration for Part 1a, and for 5 drug elimination half-lives after final IMP administration for Part 1b and Part 2.
• must not donate sperm starting at screening and throughout the study period and for 30 days) after final IMP administration for Part 1a and for 5 drug elimination half-lives after final IMP administration for Part 1b and Part 2.
• with pregnant partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy throughout the study period and for 5 drug elimination half-lives after final IMP administration.
• Part 1
• Body mass index (BMI) within 18.0 kg/m2 to 30.0 kg/m2, inclusive.
• Body weight of within 50 kg to 100 kg, inclusive.
• Non- or ex-smoker (an ex-smoker is defined as someone who completely stopped using nicotine products for at least 180 days prior to the first drug administration).
• Part 2
• BMI within the range of ≥ 18 and ≤ 35 kg/m2 at the screening visit.
• Participant has a diagnosis of moderate to severe OUD according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) using the Mini International Neuropsychiatric Interview (MINI) version 7.02.
• Participant is voluntarily seeking treatment for OUD.
• Participant is not currently receiving Medication for Opioid Use Disorder (MOUD), and has not received MOUD within 60 days prior to screening and is:
• Willing to initiate buprenorphine therapy;
• Considered to be a good candidate for buprenorphine treatment based on medical and psychosocial history;

You may not qualify if:

• Participant has a history of attempted suicide or suicidal behavior within 12 months prior to screening or has any suicidal ideation that meets criteria at a level of 4 or 5 by using the Columbia Suicide Severity Rating Scale (C-SSRS) within 12 months prior to Screening or who is at significant risk to commit suicide, as assessed at Screening and at Day -1.
• Male participants with a history of oligospermia or azoospermia or any other disorder of the reproductive system or who are undergoing treatment or evaluation for infertility.
• Females who are lactating or pregnant according to the pregnancy test at Screening or prior to the first study intervention administration.
• A family history of long QT syndrome.
• Any abnormal or clinically significant findings in laboratory test results at Screening.
• Participant has HIV per screening serology test.
• Any clinically important abnormalities in rhythm, conduction, or morphology of the resting electrocardiogram (ECG) and any clinically important abnormalities in the 12-lead ECG.
• History of significant allergy/ hypersensitivity to AZD4041 or to products related to AZD4041 or other study drugs (including excipients of the formulation), as well as history of severe allergy/hypersensitivity reactions (like angioedema) to any drugs.
• Any vaccination (including with COVID-19 vaccine) less than 14 days prior to first study intervention administration.
• Participants who have a history of exposure to psilocybin and 3,4-methylenedioxymethamphetamine (MDMA) within the last 3 months.
• Part 1 Only:
• Past medical history of any clinically significant systemic illness including (but not necessarily limited to) cardiovascular, gastrointestinal, pulmonary, hematologic, neurological, hepatic, endocrinologic, metabolic, genito-urinary, musculoskeletal, immunologic, dermatologic, renal and/or major disease.
• Maintenance therapy with any drug for long-term chronic conditions or significant history of drug dependency or alcohol abuse (\> 21 units/week or \> 3 units/day for men; \> 14 units/week or \> 2 units/day for women; intake of excessive alcohol, acute or chronic).
• History of any significant psychiatric disorder according to the criteria of the Diagnostic and Statistical manual of Mental Disorders, 5th Edition (American Psychiatric Association 2013).
• History of any substance use disorder (as per DSM-5 criteria).

Sponsors & Collaborators

• AstraZeneca: lead
• Parexel: collaborator

Study Sites (1)

Research Site

Baltimore, Maryland, 21225, United States

Location

MeSH Terms

Conditions

Opioid-Related Disorders

Interventions

Itraconazole; Buprenorphine; Buprenorphine, Naloxone Drug Combination; Hydromorphone

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Piperazines; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Naloxone; Drug Combinations; Pharmaceutical Preparations; Morphine Derivatives

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Participant (Part 1b, Part 2) Care Provider (Part 1b, Part 2) Investigator (Part 1b, Part 2)
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 6, 2024
• First Posted: May 9, 2024
• Study Start: May 13, 2024
• Primary Completion: July 31, 2024
• Study Completion: July 31, 2024
• Last Updated: March 26, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will share
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA/PhRMA Data-Sharing Principles. For details of our timelines, please refer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment Vivli.org. A Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.

Locations

US (1)