PF614 Analgesic Activity in Acute Postoperative Pain (PF614-301)

The goal of this clinical trial is to evaluate the analgesic activity of PF614 (an oral oxycodone prodrug extended-release analgesic) for control of postsurgical pain in subjects scheduled for abdominoplasty surgery. The main question to be answered is:

• To assess the analgesic efficacy of PF614 compared to oxycodone hydrochloride (an immediate-release opioid analgesic) and placebo in subjects with moderate to severe pain following abdominoplasty Participants will be asked to take oral blinded doses of study medication at about one hour before surgery starts, and then every 6 hours after surgery for up to 4 days.

Participants will be asked to:

* Rate their pain on a 0-10 numerical rating scale (NRS) at various timepoints up to 5 days following surgery;
* Tell us about the need for rescue medication if they continue to have moderate-to-severe pain;
* Tell us about any side effects or adverse effects that they may experience to help us understand the safety and tolerability of the test medications;
* Provide periodic blood samples to help us understand how much study drug is in their system.

Participants will stay in a clinic setting and be monitored for safety for 5 days following surgery. We anticipate that participants will be discharged on Day 5, pending medical review, and then keep a diary to record study-related pain and adverse effects for an additional 2-4 days after discharge.

This will be a Phase 3, multicenter, randomized, double-blind, placebo- and active-controlled study to evaluate the efficacy and safety of PF614 in the treatment of moderate-to-severe pain following abdominoplasty. The study will be conducted in 4 phases: Screening, Treatment, Outpatient and Follow-up. Study assessments will be performed at the visits and time points outlined in the Schedule of Assessments.

Screening Phase Eligible participants will complete a standard medical screening within 28 days of the abdominoplasty procedure. At Screening, participants will provide written informed consent to participate in the study before any protocol-specified procedures or assessments are conducted.

Treatment Phase The Treatment Phase will begin on the day of the abdominoplasty procedure (Day 1) and will end on postoperative Day 5. Participants will be admitted to the study center on the morning of the scheduled procedure and will be confined throughout the Treatment Phase (5 days, 4 nights).

Days 1-4 (0-72 hours): Randomized Treatment Period Following admission to the study center, presurgical procedures will include participant training on pain intensity and nausea assessments, which will both be administered as 11 point numerical rating scales (NRS). Participants who continue to meet all study entry criteria will be randomized prior to the abdominoplasty procedure in a 1:1:1:1:1 ratio to 1 of 5 treatment groups.

Treatment groups will include the following doses: PF614 25 mg, PF614 37.5 mg, PF614 50 mg, Oxycodone HCl 10 mg, and Placebo.

The first dose of study drug will be administered approximately 1 hour prior to the abdominoplasty procedure. Time 0 is defined as the time of first study drug administration. Additional doses of study drug will be provided every 6 hours, with the last scheduled study drug administration at 72 hours. Qualified medical personnel and/or investigators who are ACLS (Advanced Cardiovascular Life Support) certified will be present in the clinic during the inpatient treatment phase when participants are administered opioid medications.

Participants will undergo a full abdominoplasty procedure without liposuction or other collateral procedures under a standardized anesthetic protocol. Prior to wound closure the surgeon will perform a local anesthetic field block by infiltrating 1.5% lidocaine with epinephrine 7 mg/kg with a maximum dose of 500 mg. Participants will be administered supplemental oxygen for at least the first 2 hours postoperatively, and the participant will be weaned as clinically appropriate. Subsequently, if oxygen is required beyond 4 hours postoperatively, this will be considered a respiratory-related adverse event (AE), and the use of supplemental oxygen will be documented as a concomitant medication.

A graduated rescue medication protocol will be implemented, such that participants may receive ibuprofen 400 mg every 4 to 6 hours, up to a maximum of 2400 mg/24 hours, as the first line rescue medication, if needed. Participants who receive ibuprofen will not be permitted to receive additional ibuprofen for a minimum of 4 hours ("lockout period"). In cases where ibuprofen does not provide adequate pain relief within approximately 1 hour of administration, participants may receive hydrocodone/acetaminophen APAP (HC/APAP) 5 mg/325 mg as a second line rescue medication, up to a maximum of 20 mg/1300 mg every 24 hours. If HC/APAP is administered, participants will not be eligible to receive additional HC/APAP for the following 4 hours but may be permitted to receive additional ibuprofen provided that they are not still within an ibuprofen lockout period.

Pain intensity (11-point NRS) assessments at rest (NRS-R; minimum 15-minute rest) and with movement (NRS-A, where movement is defined as moving from a supine to sitting position) will be recorded at scheduled times during the inpatient period after Time 0 and immediately before each use of rescue medication. Study drug will be administered after assessment of pain at each timepoint when dosing and pain assessments overlap. During the night, participants will be wakened to administer the study drug. Pain assessments will be performed throughout the night when participants are awake; however, sleeping participants will not be awakened for assessments during a designated period of 6 consecutive hours. Pain intensity will also be recorded before early study discontinuation. Blood will be collected for pharmacokinetic (PK) analysis and participant-rated assessments of nausea (using an 11-point NRS) and observer rated assessments of sedation (using the Modified Observer's Assessment of Alertness/Sedation Scale \[MOAA/S\]) will be conducted at pre-specified timepoints. Participants will complete a Global Assessment of Satisfaction with Study Treatment at 84 (±2) hours or early discontinuation.

Days 4-5 (72-96 hours): Predischarge Period Participants will remain inpatient for approximately 24 hours after the last scheduled study drug administration. During this period, participants may be administered ibuprofen and HC/APAP for pain relief using the same dosing regimen as the graduated rescue medication protocol described above. Pain intensity, PK, and safety assessments will be conducted at pre-specified timepoints until discharge on Day 5 (\~96 hours).

Outpatient and Follow-up Phases Before discharge from the study center, study personnel will dispense a prescription for pain medication (if necessary) and an outpatient participant diary. Participants will be instructed to complete the Brief Pain Inventory (BPI; Short Form) at the end of each day during the Outpatient Phase, and record use of any concomitant medications and AEs experienced after discharge in their electronic outpatient participant diary. Participants will be instructed to return the outpatient participant diary to study personnel at the Follow up-Visit, scheduled to occur 7 to 9 days after the abdominoplasty procedure.

Eligibility Criteria:
Inclusion Criteria:

1. Subject must provide written informed consent prior to the initiation of any protocol-specific procedures.
2. Male or female subject, between 18 and 75 years of age, inclusive, at the time of Screening.
3. Subject must be scheduled to undergo a full abdominoplasty procedure without liposuction with no collateral procedures.
4. Subject must have physical status rated as I-II on the American Society of Anesthesiologists rating scale.
5. Subject must have a body mass index (BMI) within 18.0 to 32.0 kg/m2, inclusive (minimum weight of at least 50.0 kg).
6. If female, subject must be either not of childbearing potential (defined as postmenopausal for at least 1 year or surgically sterile \[bilateral tubal ligation, bilateral oophorectomy, or hysterectomy\]) or subject must use a medically acceptable method of birth control (oral or transdermal contraceptives, condom, spermicidal foam, intrauterine device \[IUD\], progestin implant or injection, heterosexual abstinence, vaginal ring, or sterilization of partner) from 30 days prior to Screening through 4 weeks after the last study drug administration.
7. If male, subject must agree to use medically acceptable methods of contraception (diaphragm/sponge/condom with spermicide, vasectomy); female sexual partners of childbearing potential must be using and willing to continue using medically acceptable contraception (i.e., hormonal oral contraceptive pills, patches, or vaginal rings, contraceptive implant or injection intrauterine contraceptive system \[with or without hormone\]) from Screening and for at least 90 days after the last study drug administration.
8. Must be able to speak, read, and understand English or Spanish sufficiently to allow completion of all study assessments.
9. Subject must be willing and able to follow study instructions and be likely to complete all study requirements.

Exclusion Criteria:

1. Subject has a history or presence of a clinically significant abnormality as assessed by physical examination, medical history, electrocardiograms (ECGs; including a QT interval corrected for heart rate \[Fridericia; QTcF interval\] of \&amp;gt;470 milliseconds at Screening; a repeat test is permitted and the average QTcF value will be used to determine eligibility), vital signs, or laboratory values, which, in the opinion of the investigator, would jeopardize the safety of the subject or the validity of the study results.
2. Subject has a significant cardiac (e.g., ischemia or infarct, complete bundle branch blocks, symptomatic arrhythmias or predominantly non-sinus-conducted rhythm), pulmonary, gastrointestinal, endocrine, metabolic (except diabetes mellitus), neurological, psychiatric disorders (resulting in disorientation, memory impairment or inability to report accurately; for instance, schizophrenia, Alzheimer's disease), or any other clinically significant disease that in the investigator\&amp;#39;s opinion may affect efficacy or safety assessments, or that may compromise subject safety during trial participation.
3. Subject has a history of malignancy within the past 2 years, with the exception of basal cell carcinoma that has been treated and is no longer present.
4. Subject has a history or presence of acute respiratory depression, chronic pulmonary disease, cor pulmonale, delirium tremens, central nervous system (CNS) depression, or increased cerebrospinal or intracranial pressure.
5. Subject has a documented history of, or currently active, seizure disorder (excluding febrile seizures in childhood) or history of clinically significant head injury or syncope of unknown origin.
6. Subject has a current painful condition that could confound the interpretation of efficacy, safety, or tolerability data in the study, in the opinion of the investigator.
7. Subject has a history or presence of obstructive sleep apnea.
8. Subject has a history of or presence of trypsin deficiency.
9. Subject has a history of severe bronchial asthma, hypercarbia, or hypoxia.
10. Subject has any chronic gastrointestinal disease or major previous abdominal surgery (e.g., Billroth procedure, enteroanastomosis, bariatric surgery, gastric bypass) that might affect the absorption, distribution, metabolism or excretion of PF614.
11. Subject has evidence of clinically significant hepatic or renal impairment including alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \&amp;gt;3× the upper limit of normal (ULN), estimated creatinine clearance \&amp;lt;60 mL/min (estimated by the 2021 Chronic Kidney Disease Epidemiology Collaboration \[CKD-EPI\] creatinine equation).
12. Subject has used chronic opioid therapy, defined as \&amp;gt;15 mg oral morphine equivalent units per day, for \&amp;gt;3 out of 7 days per week, for \&amp;gt;1 month, within 12 months prior to first study drug administration.
13. Subject has used any analgesic medication within 5 half-lives (or, if half-life is unknown, within 48 hours) before the abdominoplasty procedure, or has used chronic non-steroidal anti-inflammatory drug (NSAID) therapy, defined as daily use for \&amp;gt;2 weeks within 2 months prior to first study drug administration (aspirin ≤325 mg daily is permitted for cardiovascular prophylaxis if the subject has been on a stable regimen for ≥30 days before the abdominoplasty procedure).
14. Subject has used systemic steroid therapy, excluding topical nasal products, within 3 months prior to first study drug administration.
15. Subject has used any enzyme-modifying drugs or products, including strong inhibitors of cytochrome P450 (CYP) 3A4 and 2D6 enzymes (e.g., clarithromycin, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, voriconazole, cimetidine, fluoxetine, quinidine, erythromycin, ciprofloxacin, fluconazole, diltiazem and HIV antivirals) or strong inducers of CYP enzymes (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, and St. John's Wort) within 30 days of first study drug administration.
16. Subject has used medications that, in the opinion of the investigator, could affect the analgesic response (such as central alpha-adrenergic agents \[clonidine and tizanidine\], antiepileptic drugs, benzodiazepines, antidepressants, neuroleptic agents or other antipsychotic agents) that are not stably dosed within at least 30 days prior to first study drug administration. Antidepressants are permitted if prescribed for anxiety or depression.
17. Subject has used a glucagon-like peptide-1 (GLP-1) receptor agonist, such as semaglutide, within 30 days prior to first study drug administration.
18. Subject is unable to discontinue any of the prohibited medications (Section 9.7.1).
19. Subject has a history or presence of any substance or alcohol use disorder, as defined by the Diagnostic and Statistical Manual of Mental Disorders - 5th Edition, Text Revision (DSM V TR).
20. Subject has a positive urine drug screen (UDS) or alcohol breathalyzer test at Screening or on the day of the abdominoplasty procedure. A positive UDS resulting from use of a prescribed medication not prohibited by the protocol may be allowed if, in the opinion of the investigator, the medication will not interfere with the study.
21. Subject has a history of suicidal ideation or suicidal behavior in the past 5 years, as assessed by the Columbia Suicide Severity Rating Scale (C-SSRS; baseline version).
22. Subject has a history of allergy or hypersensitivity to any opioid analgesics, anesthetics, ondansetron, acetaminophen, or NSAIDs.
23. Female subject who is currently pregnant (positive pregnancy test) or lactating or who is planning to become pregnant within 30 days of last study drug administration.
24. Subject is positive for hepatitis B surface antigen (HBsAg), hepatitis C, or human immunodeficiency virus (HIV).
25. Subject has previously participated in a clinical trial using PF614 or had an abdominoplasty in the last 3 months.
26. Subject has received any investigational drugs or devices within 4 weeks (or 5 times the half life of the drug, if known) prior to first study drug administration.
27. Subject has any medical condition that, in the opinion of the investigator, might interfere with the study procedures or data integrity or compromise the safety of the subject.
28. Subject is an employee of the sponsor or research site personnel directly affiliated with this study, or their immediate family member, defined as a spouse, parent, child or sibling, whether biological or legally adopted.
29. Subject who, in the opinion of the investigator, is considered unsuitable or unlikely to comply with the study protocol for any reason.