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

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

45 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a new drug, AZD4041, combined with morphine in healthy recreational opioid users. The goal is to see if AZD4041 changes how morphine affects breathing. Up to 44 participants will be involved, and the study will last several weeks per person. Morphine has been extensively studied for its effects on breathing, pain relief, and other physiological responses.

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 morphine generally safe for human use?

Morphine, including its extended-release forms like Avinza and MS Contin, has been studied for safety in humans. Common side effects include nausea, dizziness, vomiting, and constipation, with serious risks like respiratory depression in some cases. Long-term studies show that adverse events are most common in the first month and tend to decrease over time. ^{1 2 3 4 5}

How does the drug AZD4041 differ from other treatments for pain management?

The treatment AZD4041 is unique because it combines morphine, a well-known pain reliever, with a placebo, which is often used as a control in clinical trials to measure the drug's effectiveness. This combination may offer insights into the drug's specific effects compared to standard morphine treatments. ^{1 5 6 7 8}

Research Team

Debra Kelsh, MD

Principal Investigator

Altasciences Company Inc.

Eligibility Criteria

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

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

Treatment Details

Interventions

• AZD4041
• Morphine
• Placebo

Participant Groups

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

Findings from Research

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Morphine at gramme doses: kinetics, dynamics and clinical need. [2013]

2. United States pubmed.ncbi.nlm.nih.gov

Long-term safety of MorphiDex. [2019]

3. United States 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. [2022]

4. Netherlands pubmed.ncbi.nlm.nih.gov

[Respiratory depression following controlled-release morphine sulfate tablets]. [2013]

5. United States pubmed.ncbi.nlm.nih.gov

A study of AVINZA (morphine sulfate extended-release capsules) for chronic moderate-to-severe noncancer pain conducted under real-world treatment conditions--the ACCPT Study. [2015]

6. Germany pubmed.ncbi.nlm.nih.gov

Relative bioavailability of controlled-release oral morphine sulfate during naltrexone blockade. [2013]

7. United States 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. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

The United States experience with oral controlled-release morphine (MS Contin tablets). Parts I and II. Review of nine dose titration studies and clinical pharmacology of 15-mg, 30-mg, 60-mg, and 100-mg tablet strengths in normal subjects. [2019]