AZD4041 + Morphine for Opioid Use Disorder

No longer recruiting at 1 trial location

Overseen By AstraZeneca Clinical Study Information Center

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: AstraZeneca

Must not be taking: CYP3A4 inhibitors/inducers, St. John's wort

Disqualifiers: Substance use disorder, Psychiatric disorder, Hypersensitivity, others

Compensation: Varies

Number of Visits: Unknown

Duration: 15 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug, AZD4041, to determine its effects on breathing when combined with morphine, a common opioid. The goal is to assess whether AZD4041 can help maintain normal breathing in healthy individuals who occasionally use opioids for non-medical reasons. Participants will receive either AZD4041 plus morphine or a placebo plus morphine to compare the effects. The trial seeks individuals who have used opioids recreationally at least 10 times in their life and once in the last 12 weeks, but who do not have a serious substance use disorder. As a Phase 1 trial, this research focuses on understanding how AZD4041 works in people, offering participants the opportunity to be among the first to receive this new treatment.

Do I need to stop my current medications to join the trial?

Yes, participants must stop using any prescription drugs (except hormone replacement therapy) 14 days before the first study drug administration. Over-the-counter products, including herbal supplements, should be stopped 7 days before the study starts, except for ibuprofen or acetaminophen.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that AZD4041 has been tested for safety in healthy adults. In several studies, participants took increasing doses without major problems. When side effects occurred, they were usually mild, indicating that AZD4041 is generally safe for healthy individuals.

Morphine, a well-known pain reliever, has been used for many years and is usually safe when taken as directed. However, it can cause side effects like nausea or dizziness. In this study, morphine is administered in a controlled setting, which helps manage these side effects.

Overall, both AZD4041 and morphine have safety data supporting their use. If there are concerns about joining the trial, discussing them with the study team or a doctor is important. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about AZD4041 because it offers a potential new way to address respiratory issues in recreational opioid users. Unlike standard treatments that primarily focus on managing opioid dependency or overdose symptoms, AZD4041 aims to specifically target and enhance respiratory drive, which is often compromised by opioid use. This could be a game-changer, as it might help prevent respiratory depression, a dangerous side effect of opioids, without compromising pain relief.

What evidence suggests that this trial's treatments could be effective for respiratory drive in opioid users?

Research has shown that AZD4041 might reduce the desire to use opioids and decrease behaviors linked to relapse, based on animal studies. This suggests it could help manage opioid use by lowering cravings. Morphine is well-known for relieving pain and providing consistent pain control. In this trial, one group of participants will receive AZD4041 with morphine to evaluate its effect on the breathing side effects of morphine in people who use opioids for non-medical reasons. Another group will receive a placebo with morphine for comparison. Although AZD4041 has shown promise in early research, more studies are needed to confirm its effectiveness in humans. ^{2 4 6 7 8}

Who Is on the Research Team?

Debra Kelsh, MD

Principal Investigator

Altasciences Company Inc.

Are You a Good Fit for This Trial?

Inclusion Criteria

If you are a male, you must use effective birth control during sexual activity and not donate sperm during the study and for at least 4 months after completing the study medication.

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

You must sign and date the informed consent form before any study procedures can begin.

Exclusion Criteria

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

Male subjects with a history of oligospermia or azoospermia or any other disorder of the reproductive system

You have a significant history of gastrointestinal, liver or kidney disease, or any other condition that could affect how the drug works in your body, or could increase the chances of side effects.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single IV dose of morphine on Day 1, followed by daily oral doses of AZD4041 or placebo for 14 days, with a final combination dose on Day 15

15 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• AZD4041
• Morphine
• Placebo

How Is the Trial Designed?

Group I: Morphine then AZD4041 then Morphine + AZD4041 Experimental Treatment 2 Interventions

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.

Group II: Morphine then Placebo then Morphine + Placebo Placebo Group 2 Interventions

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.

Who Is Running the Clinical Trial?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Published Research Related to This Trial

In a study involving healthy recreational opioid users, morphine sulfate and naltrexone hydrochloride extended-release (MSN) capsules showed significantly lower subjective drug liking and positive effects compared to controlled-release morphine sulfate (MS) when administered intranasally.

Both MSN and MS produced similar peak plasma concentrations of morphine, but MSN's formulation resulted in reduced euphoric effects, suggesting it may be a safer alternative for pain management with a lower potential for abuse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessing the subjective and physiological effects of intranasally administered crushed extended-release morphine formulations with and without a sequestered naltrexone core in recreational opioid users. Setnik, B., Goli, V., Levy-Cooperman, N., et al.[2021]

In a study involving 10 patients with chronic moderate-to-severe pain, the once-daily extended-release morphine formulation (MSER) showed a 19% lower maximum concentration and a 66% higher minimum concentration compared to the twice-daily controlled-release morphine (CRM), indicating a more stable drug level throughout the day.

Both MSER and CRM had similar overall bioavailability and safety profiles, but MSER maintained effective morphine levels longer and with less fluctuation, suggesting it may provide more consistent pain control for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Steady-state pharmacokinetic comparison of a new, extended-release, once-daily morphine formulation, Avinza, and a twice-daily controlled-release morphine formulation in patients with chronic moderate-to-severe pain. Portenoy, RK., Sciberras, A., Eliot, L., et al.[2022]

A patient with severe neuralgia experienced respiratory depression after taking a single 20 mg dose of controlled release morphine sulfate (MS Contin), highlighting a potential safety concern with this medication.

The immediate reversal of respiratory depression was achieved with nalorphine chloride, demonstrating the effectiveness of this intervention in managing opioid-related side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Respiratory depression following controlled-release morphine sulfate tablets]. Hoogslag, PA., van Dijk, B., Vinks, AA.[2013]

The 200 mg MS Contin tablet provides the same absorption rate and effectiveness as taking two 100 mg tablets, ensuring consistent pain relief.

This new higher strength formulation allows for easier dosing for patients needing larger morphine doses, giving doctors more options for managing pain effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Morphine at gramme doses: kinetics, dynamics and clinical need. Smith, KJ., Miller, AJ., McKellar, J., et al.[2013]

Citations

1. clinicaltrialsarena.com clinicaltrialsarena.com/analyst-comment/azd4041-non-opioid-oud-treatments/

Failure of AZD4041 a blow for non-opioid OUD treatments Opioid agonists are the gold standard for the treatment of OUD but have not been able to solve the opioid crisis.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05587998

A Study to Assess the Effect of AZD4041 on Respiratory ... This study is being primarily conducted to assess the effect on respiratory drive of morphine administered after multiple doses of AZD4041 compared to morphine ...

3. astrazenecaclinicaltrials.com astrazenecaclinicaltrials.com/study/D7460C00002

A Safety Study of AZD4041 in Healthy Participants A randomized, double-blind, placebo-controlled study to assess the safety, tolerability, and pharmacokinetics of multiple ascending doses of AZD4041 in healthy ...

4. reporter.nih.gov reporter.nih.gov/project-details/10322644

AZD4041 Specifically, AZD4041 reduced the motivation to consume opioids (or nicotine) and attenuated relapse-like drug seeking behaviors in laboratory animals while ...

5. globaldata.com globaldata.com/media/pharma/astrazenecas-azd4041-failure-major-blow-non-opioid-medications-treating-opioid-addiction-says-globaldata/

AstraZeneca's AZD4041 failure major blow for non-opioid ... The failure of the trial highlights the challenges in developing non-opioid medications that treat addiction and withdrawal, says GlobalData, a ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05209334

A Safety Study of AZD4041 in Healthy Participants This is a Phase 1, single-centre, randomized, double-blind, placebo-controlled, multiple ascending doses (MAD) study in healthy male and female adult ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT06406400

Drug-Drug Interaction and Safety of AZD4041 Study (Part 1 ... The purpose of the study is to assess drug-drug interaction (DDI) and safety of AZD4041 and itraconazole in healthy participants (Part 1)

8. ctv.veeva.com ctv.veeva.com/study/a-safety-study-of-azd4041-in-healthy-volunteers-1

A Safety Study of AZD4041 in Healthy Participants The study will include up to 48 participants (12 participants per cohort) who will be randomized 9:3 to active drug or placebo. Each cohort will ...