Pharmacokinetics of Oxycodone and PF614 Co-Administered with Nafamostat (PF614-MPAR-101)

(MPAR-101 Trial)

Overseen By William K Schmidt, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Ensysce Biosciences

Must not be taking: Nicotine, Alcohol, Drugs of abuse

Disqualifiers: Drug abuse, Smoking, Cardiovascular, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 48

Duration: 48 hours

111 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a new painkiller combination in healthy people. It includes a painkiller, a drug to manage its release, and another to block side effects. Researchers aim to see how these drugs are processed in the body.

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

The trial information does not specify if you need to stop taking your current medications. However, you must not have a positive drugs of abuse test result, and you should not have taken any investigational medical product recently.

What data supports the effectiveness of the drug in the clinical trial?

Research shows that oxycodone, a component of the treatment, is effective in managing pain. In a study, a combination of oxycodone and acetaminophen (Percocet) was found to provide better pain relief than oxycodone alone, with fewer side effects. Additionally, Xtampza ER, an extended-release form of oxycodone, was shown to reduce pain scores in cancer patients, although the changes were not clinically significant. ^{1 2 3 4 5}

Is the treatment generally safe for humans?

Xtampza ER, an abuse-deterrent formulation of oxycodone, has been shown to have less severe medical outcomes compared to other opioid analgesics, indicating a favorable safety profile. PF614, another oxycodone formulation, was well tolerated in animal studies, showing a favorable safety profile for further clinical evaluation. ^{5 6 7 8 9}

What makes the drug PF614 solution (Oxycodone) unique compared to other pain treatments?

PF614 solution, also known as Xtampza ER, is unique because it is an extended-release formulation designed to deter abuse and can be administered in various ways without losing its effectiveness. It retains its extended-release properties even if the capsule is crushed or chewed, making it less likely to be abused compared to other oxycodone formulations. ^{2 3 4 5 10}

Research Team

Jeffrey Levy, MD, PhD

Principal Investigator

Medical Director, Quotient Sciences

Eligibility Criteria

Inclusion Criteria

Minimum weight of 50kg at screening

Healthy males or non-pregnant, non-lactating healthy females

Body mass index of 18.0 to 32.0 kg/m2 as measured at screening or, if outside the range, considered not clinically significant by the investigator

Exclusion Criteria

Donation of blood within 2 months or donation of plasma within 7 days prior to first dose of study medication

Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients

Subjects who have received any Investigational Medical Product (IMP) in a clinical research study within 5 half-lives or within 30 days prior to first dose

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Subjects receive PF614 solution alone and concomitantly with nafamostat, with naltrexone blockade to reduce opioid-related side effects

48 hours

Multiple visits for dosing and monitoring within 48 hours

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 days

Follow-up visits to monitor adverse events and collect safety data

Treatment Details

Interventions

• Nafamostat Mesylate
• Naltrexone Hydrochloride
• Oxycodone
• PF614 solution

Participant Groups

Group I: PF614 solution concomitantly with nafamostat Experimental Treatment 3 Interventions

Cohort 1 and 6 will consist of 6 evaluable subjects. Subjects will receive the PF614 solution alone and concomitantly with nafamostat as an IR solution and/or ER prototype capsules. Subjects will receive naltrexone prior to and following each regimen. Cohorts 2 to 5 and Cohorts 7 to 10 will consist of 5 evaluable subjects in each cohort. Only 2 sentinel subjects will be dosed (one male and one female) in Period 2, Cohort 1. After review of the PK data and safety data, the safety advisory committee will decide the nafamostat dose level. After Cohorts 3 and 8 only: The fed vs fasted regimen will be determined for Cohorts 4 and 9.

Group II: PF614 solution Experimental Treatment 2 Interventions

Cohort 1 and 6 will consist of 6 evaluable subjects. Subjects will receive the PF614 solution alone and concomitantly with nafamostat as an IR solution and/or ER prototype capsules. Subjects will receive naltrexone prior to and following each regimen. Cohorts 2 to 5 and Cohorts 7 to 10 will consist of 5 evaluable subjects in each cohort. Only 2 sentinel subjects will be dosed (one male and one female) in Period 2, Cohort 1. After review of the PK data and safety data, the safety advisory committee will decide the nafamostat dose level. After Cohorts 3 and 8 only: The fed vs fasted regimen will be determined for Cohorts 4 and 9.

Oxycodone is already approved in United States, European Union, Canada for the following indications:

Approved in United States as OxyContin for:

• Moderate to severe pain
• Chronic pain

Approved in European Union as OxyContin for:

• Severe pain
• Cancer pain

Approved in Canada as OxyContin for:

• Moderate to severe pain

Who Is Running the Clinical Trial?

Ensysce Biosciences

Lead Sponsor

Trials

9

Recruited

700+

Quotient Sciences

Industry Sponsor

Trials

52

Recruited

1,600+

National Institute on Drug Abuse (NIDA)

Collaborator

Trials

2,658

Recruited

3,409,000+

Findings from Research

The new oxycodone 10-mg/acetaminophen 325-mg formulation (Percocet) was found to be more effective than a higher dose of oxycodone alone in managing acute pain after oral surgery, based on a study of 141 patients.

This combination not only provided faster pain relief but also resulted in fewer treatment-related side effects, highlighting its potential as a safer alternative for pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized, double-blind, placebo-controlled comparison of the analgesic efficacy of oxycodone 10 mg/acetaminophen 325 mg versus controlled-release oxycodone 20 mg in postsurgical pain. Gammaitoni, AR., Galer, BS., Bulloch, S., et al.[2019]

In a study of 66 cancer patients using Xtampza ER™, an oxycodone extended-release capsule, there was a statistically significant reduction in pain scores after starting the medication, with mean reductions of -0.7 and -1.1 at follow-up visits.

Despite the reduction in pain scores, the changes were clinically insignificant (less than the 2-point threshold), and over half of the patients discontinued OERC by the second follow-up, indicating a need for further research on its long-term efficacy and safety in palliative care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oxycodone Extended-Release Capsule Utilization for Pain Management in a Cancer Palliative Care Clinic: A Retrospective Review. Fortunato, J., Kullgren, J., Houchard, G., et al.[2023]

In a study of 243 patients over 5 weeks, oxycodone/naloxone prolonged-release (OXN PR) significantly improved bowel function compared to oxycodone prolonged-release (OxyPR), with greater reductions in opioid-induced constipation as measured by the bowel function index.

Both treatments provided similar levels of pain relief, but patients on OXN PR required less laxative rescue medication and experienced a doubling in complete spontaneous bowel movements, indicating that OXN PR can effectively manage pain without compromising bowel health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase III randomized controlled study on the efficacy and improved bowel function of prolonged-release (PR) oxycodone-naloxone (up to 160/80 mg daily) vs oxycodone PR. Dupoiron, D., Stachowiak, A., Loewenstein, O., et al.[2018]

Xtampza® ER (oxycodone DETERx®) is an extended-release opioid formulation designed to deter abuse, and studies show that even when physically manipulated (crushed or chewed), it maintains its extended-release pharmacokinetic profile, making it less likely to be abused compared to immediate-release formulations.

In contrast, when OxyContin is crushed, it loses its extended-release properties and behaves like immediate-release oxycodone, highlighting Xtampza ER's potential as a safer option for patients needing chronic pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of physical manipulation on the oral pharmacokinetic profile of Xtampza® ER (oxycodone DETERx® formulation): A review of published studies. Gudin, J.[2020]

PF614, a new prodrug of oxycodone designed for chronic pain relief, demonstrated a favorable safety profile in nonclinical studies, with no significant genotoxicity or metabolic instability observed in rats, dogs, and humans.

In toxicity studies, PF614 was well tolerated at daily doses of 25 mg/kg in rats and 18 mg/kg in dogs over 14 days, supporting its potential for further clinical evaluation as an analgesic with abuse-resistant properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonclinical safety assessment of PF614: A novel TAAP prodrug of oxycodone for chronic pain indication. Joshi, PS., Sanakkayala, N., Kirkpatrick, L., et al.[2020]

In a comprehensive analysis of 1,106 participants across multiple trials, immediate-release (IR) and extended-release (ER) oxycodone/acetaminophen (OC/APAP) demonstrated a safety profile comparable to other low-dose opioid combinations, with no serious adverse events reported in phase 1 trials.

Common adverse events included pruritus, nausea, and dizziness, but these occurred at similar rates to other opioid treatments, indicating that IR/ER OC/APAP is generally well-tolerated among users.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Tolerability of Biphasic Immediate-Release/Extended-Release Oxycodone/Acetaminophen Tablets: Analysis of 11 Clinical Trials. Barrett, T., Kostenbader, K., Nalamachu, S., et al.[2018]

References

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

Randomized, double-blind, placebo-controlled comparison of the analgesic efficacy of oxycodone 10 mg/acetaminophen 325 mg versus controlled-release oxycodone 20 mg in postsurgical pain. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Oxycodone Extended-Release Capsule Utilization for Pain Management in a Cancer Palliative Care Clinic: A Retrospective Review. [2023]

3. England pubmed.ncbi.nlm.nih.gov

A phase III randomized controlled study on the efficacy and improved bowel function of prolonged-release (PR) oxycodone-naloxone (up to 160/80 mg daily) vs oxycodone PR. [2018]

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

Effect of physical manipulation on the oral pharmacokinetic profile of Xtampza® ER (oxycodone DETERx® formulation): A review of published studies. [2020]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Use of a Long-Acting Opioid Microsphere Formulation to Overcome Difficulties in Swallowing Pain Medication. [2022]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Nonclinical safety assessment of PF614: A novel TAAP prodrug of oxycodone for chronic pain indication. [2020]

7. England pubmed.ncbi.nlm.nih.gov

Differences in severity of poison centers exposures involving XTAMPZA® ER versus other opioid analgesics. [2023]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Oxycodone DETERx®: A Novel Abuse-Deterrent, Extended-Release Analgesic Option for the Treatment of Patients with Chronic Pain. [2020]

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

Safety and Tolerability of Biphasic Immediate-Release/Extended-Release Oxycodone/Acetaminophen Tablets: Analysis of 11 Clinical Trials. [2018]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Oxycodone DETERx® ER Capsules: A Review in Severe, Chronic Pain. [2018]