A Study to Assess the Safety, Tolerability and Pharmacokinetics of Multiple Doses of ASP8062 With a Single Dose of Morphine in Recreational Opioid Using Participants

Study Overview
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Brief Summary
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The primary purpose of this study was to assess the safety and tolerability of multiple doses of ASP8062 or placebo alone and in combination with a single dose of morphine. This study also assessed the potential for pharmacokinetic interaction between ASP8062 and morphine.

Detailed Description
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Participants were screened for up to 28 days prior to first investigational product administration. Eligible participants were admitted to the clinical unit on day -1 and were residential for a single period of 17 days/16 nights. Participants were discharged from the clinical unit on day 16 on the condition that all required assessments had been performed and that there were no medical reasons for a longer stay in the clinical unit.

Official Title
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A Phase 1 Randomized, Placebo-controlled Study to Assess the Safety, Tolerability and Pharmacokinetics of Multiple Doses of ASP8062 With a Single Dose of Morphine in Recreational Opioid Using Participants

Conditions
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Opioid Use Disorder

Intervention / Treatment
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* Drug: ASP8082
* Drug: morphine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant is a recreational opioid user who has used opioids for nontherapeutic (recreational) purposes on at least 10 occasions within their lifetime, with at least 1 opioid use in the last 90 days. Participant has a body mass index (BMI) range of 18 to 36 kg/m^2, inclusive and weighs at least 50 kg at screening. Female participant is not pregnant and at least 1 of the following conditions apply: Not a woman of childbearing potential (WOCBP) WOCBP who agrees to follow the contraceptive guidance from the time of informed consent through at least 28 days after final investigational product (IP) administration. Female participant must agree not to breastfeed starting at screening and throughout the study period and for 28 days after final IP administration. Female participant must not donate ova starting at first dose of IP and throughout the study period and for 28 days after final IP administration. Male participant with female partner(s) of childbearing potential (including breastfeeding partner[s]) must agree to use contraception throughout the treatment period and for 90 days after final IP administration. Male participant must not donate sperm during the treatment period and for 90 days after final IP administration. Male participant with a pregnant partner(s) must agree to remain abstinent or use a condom with spermicide for the duration of the pregnancy throughout the study period and for 90 days after final IP administration. Participant agrees to not participate in another interventional study while participating in the present study. Exclusion Criteria: Participant has received any investigational therapy within 28 days or 5 half-lives, whichever is longer, prior to screening. Participant has any condition which makes the participant unsuitable for study participation. Female participant who has been pregnant within 6 months prior to screening or breastfeeding within 3 months prior to screening. Participant has a known or suspected hypersensitivity to ASP8062 or morphine and/or other opioids, or any components of the formulations used. Participant has had previous exposure with ASP8062. Participant has any of the liver function tests (alkaline phosphatase [ALP], alanine aminotransferase [ALT], aspartate aminotransferase [AST], gamma-glutamyl transferase and total bilirubin [TBL]) ≥ 1.5 × upper limit of normal (ULN) on day -1. In such a case, the assessment may be repeated once. Participant has any clinically significant history of allergic conditions (including drug allergies, asthma or anaphylactic reactions, but excluding untreated, asymptomatic, seasonal allergies) prior to first IP administration. Participant has any history or evidence of any clinically significant cardiovascular, gastrointestinal, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, renal and/or other major disease or malignancy with exception of history of cholecystectomy. Participant has a history of moderate or severe use disorder for any substance other than caffeine or tobacco (based on the Diagnostic and Statistical Manual of Mental Disorders, edition 5 (DSM-5) criteria). Participant has a history or presence of any clinically significant psychiatric disorders such as, bipolar 1, schizophrenia, schizoaffective disorder or major depressive disorders. Participant has had recent suicidal ideation within the last 12 months or participant who is at significant risk to commit suicide using the Baseline/Screening Columbia-suicide severity rating scale (C-SSRS) at screening and the Since Last Visit C-SSRS on day -1. Participant has/had febrile illness or symptomatic, viral, bacterial (including upper respiratory infection) or fungal (noncutaneous) infection within 1 week prior to day -1. Participant has any clinically significant abnormality following an investigator's review of the physical examination, ECG and protocol-defined clinical laboratory tests at screening or on day -1. Participant has a mean pulse < 50 or > 90 bpm; mean systolic blood pressure > 150 mmHg; mean diastolic blood pressure > 95 mmHg (measurements taken in duplicate after participant has been resting in the supine position for at least 5 minutes) on day -1. If the mean blood pressure exceeds the limits above, 1 additional duplicate may be taken. Participant has a mean corrected QT interval using Fridericia's formula (QTcF) of > 450 msec (for male participants) and > 470 msec (for female participants) on day -1. If the mean QTcF exceeds the limits above, 1 additional triplicate ECG may be taken. Participant has a positive test for amphetamines, barbiturates, benzodiazepines, cocaine, phencyclidine, alcohol and/or opiates on day -1. Positive tetrahydrocannabinol is not exclusionary and a cannabis intoxication evaluation will be performed. Participant may be reconsidered. Participant has used any prescribed or nonprescribed drugs (including vitamins and natural and herbal remedies, e.g., St. John's Wort) in the 2 weeks prior to first IP administration, except for occasional use of acetaminophen (up to 2 g/day), topical dermatological products, including corticosteroid products, hormonal contraceptives and hormone replacement therapy (HRT). Participant must be willing to abstain from smoking (including use of tobacco-containing products and nicotine or nicotine-containing products [e.g., electronic vapes]) from at least 1 hour predose through at least 8 hours postdose on days 9 and 10. Participant has used any inducer of metabolism (e.g., barbiturates and rifampin) in the 3 months prior to day -1. Participant has had significant blood loss, donated approximately 500 mL of whole blood (excluding plasma donation) within 56 days prior to screening or donated plasma within 7 days prior to day -1. Participant has a positive serology test for hepatitis B surface antigen, hepatitis C virus antibodies or antibodies to human immunodeficiency virus (HIV) type 1 and/or type 2 at screening. Participant has loss of ability to freely provide consent through imprisonment or involuntary incarceration for treatment of either a psychiatric or physical (e.g., infectious disease) illness. Participant is an employee of Astellas, the study-related contract research organizations (CROs) or the clinical unit.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ASP8062 in combination with morphine<br>Participants received ASP8062 tablet, orally once daily on days 1 through 10. On day 10, participants also received morphine tablet as single oral dose immediately after the ASP8062 dose. | Drug: ASP8082<br>* oral<br>Drug: morphine<br>* oral<br>|
| Placebo Comparator: Placebo in combination with morphine<br>Participants received ASP8062 matching placebo tablet, orally once daily on days 1 through 10. On day 10, participants also received morphine tablet as single oral dose immediately after the ASP8062 matching placebo dose. | Drug: morphine<br>* oral<br>Drug: Placebo<br>* oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) | Safety was assessed by adverse events (AEs), which included abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, etc.) if the abnormality induced clinical signs or symptoms, needed active intervention, interruption or discontinuation of study drug or was clinically significant. A Treatment emergent AE (TEAE) was defined as any AE that started or worsened after the first dose of study drug up to 30 days after the last dose of study drug. AEs were considered serious (SAEs) if the AE resulted in death, was life-threatening, resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, resulted in congenital anomaly, or birth defect or required inpatient hospitalization or led to prolongation of hospitalization. | From first dose of study drug up to end of study visit (up to day 25) | 
| Number of Participants With At Least One Event of Suicidal Ideation And/or Suicidal Behavior as Assessed by The Columbia-Suicide Severity Rating Scale (C-SSRS) | The C-SSRS is a clinician administered assessment tool that evaluates suicidal ideation and behavior. Number of participants with at least one affirmative response to the 5 items for suicidal ideation (1. Wish to be dead, 2. Non-specific active suicidal thoughts, 3. Active suicidal ideation with any methods (not plan) without intent to act, 4. Active suicidal ideation with some intent to act, without specific plan, 5. Active suicidal ideation with specific plan and intent) and/or to the 5 items for suicidal behavior (1. Preparatory acts or behavior, 2. Aborted attempt, 3. Interrupted attempt, 4. Actual attempt, 5. Completed suicide) were reported. | Up to day 25 | 
| Change From Baseline in Blood Oxygen Saturation (SpO2) at Predose | The SpO2 was measured using a pulse oximeter placed on the participant's fingertip. Change from baseline in SpO2 was calculated as Day 9 minus Baseline for arms 'ASP8062' and 'Placebo', and Day 10 minus Baseline for arms 'ASP8062 in combination with morphine' and 'Placebo in combination with morphine'. Baseline observation was last non-missing observation prior to first dose. | 'ASP8062' and 'Placebo': Baseline and predose Day 9; 'ASP8062 in combination with morphine' and 'Placebo in combination with morphine': Baseline and predose Day 10 | 
| Change From Baseline in Blood Oxygen Saturation (SpO2) at 1 Hour Postdose | The SpO2 was measured using a pulse oximeter placed on the participant's fingertip. Change from baseline in SpO2 was calculated as Day 9 minus Baseline for arms 'ASP8062' and 'Placebo', and Day 10 minus Baseline for arms 'ASP8062 in combination with morphine' and 'Placebo in combination with morphine'. Baseline observation was last non-missing observation prior to first dose. | 'ASP8062' and 'Placebo': Baseline and 1 hour postdose Day 9; 'ASP8062 in combination with morphine' and 'Placebo in combination with morphine': Baseline and 1 hour postdose Day 10 | 
| Change From Baseline in Blood Oxygen Saturation (SpO2) at 2 Hour Postdose | The SpO2 was measured using a pulse oximeter placed on the participant's fingertip. Change from baseline in SpO2 was calculated as Day 9 minus Baseline for arms 'ASP8062' and 'Placebo', and Day 10 minus Baseline for arms 'ASP8062 in combination with morphine' and 'Placebo in combination with morphine'. Baseline observation was last non-missing observation prior to first dose. | 'ASP8062' and 'Placebo': Baseline and 2 hour postdose Day 9; 'ASP8062 in combination with morphine' and 'Placebo in combination with morphine': Baseline and 2 hour postdose Day 10 | 
| Change From Baseline in Blood Oxygen Saturation (SpO2) at 4 Hour Postdose | The SpO2 was measured using a pulse oximeter placed on the participant's fingertip. Change from baseline in SpO2 was calculated as Day 9 minus Baseline for arms 'ASP8062' and 'Placebo', and Day 10 minus Baseline for arms 'ASP8062 in combination with morphine' and 'Placebo in combination with morphine'. Baseline observation was last non-missing observation prior to first dose. | 'ASP8062' and 'Placebo': Baseline and 4 hour postdose Day 9; 'ASP8062 in combination with morphine' and 'Placebo in combination with morphine': Baseline and 4 hour postdose Day 10 | 
| Change From Baseline in Blood Oxygen Saturation (SpO2) at 8 Hour Postdose | The SpO2 was measured using a pulse oximeter placed on the participant's fingertip. Change from baseline in SpO2 was calculated as Day 9 minus Baseline for arms 'ASP8062' and 'Placebo', and Day 10 minus Baseline for arms 'ASP8062 in combination with morphine' and 'Placebo in combination with morphine'. Baseline observation was last non-missing observation prior to first dose. | 'ASP8062' and 'Placebo': Baseline and 8 hour postdose Day 9; 'ASP8062 in combination with morphine' and 'Placebo in combination with morphine': Baseline and 8 hour postdose Day 10 | 
| Change From Baseline in Blood Oxygen Saturation (SpO2) at 12 Hour Postdose | The SpO2 was measured using a pulse oximeter placed on the participant's fingertip. Change from baseline in SpO2 was calculated as Day 9 minus Baseline for arms 'ASP8062' and 'Placebo', and Day 10 minus Baseline for arms 'ASP8062 in combination with morphine' and 'Placebo in combination with morphine'. Baseline observation was last non-missing observation prior to first dose. | 'ASP8062' and 'Placebo': Baseline and 12 hour postdose Day 9; 'ASP8062 in combination with morphine' and 'Placebo in combination with morphine': Baseline and 12 hour postdose Day 10 | 
| Change From Baseline in End Tidal Carbon Dioxide (CO2) at Predose | End tidal CO2 measurement was obtained per participant utilizing a portable bedside capnography device. Change from baseline in CO2 was calculated as Day 9 minus Baseline for arms 'ASP8062' and 'Placebo', and Day 10 minus Baseline (baseline observation was observation before first dose at Day 9) for arms 'ASP8062 in combination with morphine' and 'Placebo in combination with morphine'. | 'ASP8062' and 'Placebo': Baseline and predose Day 9; 'ASP8062 in combination with morphine' and 'Placebo in combination with morphine': Baseline (observation taken at Day 9), and predose Day 10 | 
| Change From Baseline in End Tidal Carbon Dioxide (CO2) at 1 Hour Postdose | End tidal CO2 measurement was obtained per participant utilizing a portable bedside capnography device. Change from baseline in CO2 was calculated as Day 9 minus Baseline for arms 'ASP8062' and 'Placebo', and Day 10 minus Baseline (baseline observation was observation before first dose at Day 9) for arms 'ASP8062 in combination with morphine' and 'Placebo in combination with morphine'. | 'ASP8062' and 'Placebo': Baseline and 1 hour postdose Day 9; 'ASP8062 in combination with morphine' and 'Placebo in combination with morphine': Baseline (observation taken at Day 9), and 1 hour postdose Day 10 | 
| Change From Baseline in End Tidal Carbon Dioxide (CO2) at 2 Hour Postdose | End tidal CO2 measurement was obtained per participant utilizing a portable bedside capnography device. Change from baseline in CO2 was calculated as Day 9 minus Baseline for arms 'ASP8062' and 'Placebo', and Day 10 minus Baseline (baseline observation was observation before first dose at Day 9) for arms 'ASP8062 in combination with morphine' and 'Placebo in combination with morphine'. | 'ASP8062' and 'Placebo': Baseline and 2 hour postdose Day 9; 'ASP8062 in combination with morphine' and 'Placebo in combination with morphine': Baseline (observation taken at Day 9), and 2 hour postdose Day 10 | 
| Change From Baseline in End Tidal Carbon Dioxide (CO2) at 4 Hour Postdose | End tidal CO2 measurement was obtained per participant utilizing a portable bedside capnography device. Change from baseline in CO2 was calculated as Day 9 minus Baseline for arms 'ASP8062' and 'Placebo', and Day 10 minus Baseline (baseline observation was observation before first dose at Day 9) for arms 'ASP8062 in combination with morphine' and 'Placebo in combination with morphine'. | 'ASP8062' and 'Placebo': Baseline and 4 hour postdose Day 9; 'ASP8062 in combination with morphine' and 'Placebo in combination with morphine': Baseline (observation taken at Day 9), and 4 hour postdose Day 10 | 
| Change From Baseline in End Tidal Carbon Dioxide (CO2) at 8 Hour Postdose | End tidal CO2 measurement was obtained per participant utilizing a portable bedside capnography device. Change from baseline in CO2 was calculated as Day 9 minus Baseline for arms 'ASP8062' and 'Placebo', and Day 10 minus Baseline (baseline observation was observation before first dose at Day 9) for arms 'ASP8062 in combination with morphine' and 'Placebo in combination with morphine'. | 'ASP8062' and 'Placebo': Baseline and 8 hour postdose Day 9; 'ASP8062 in combination with morphine' and 'Placebo in combination with morphine': Baseline (observation taken at Day 9), and 8 hour postdose Day 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK) of ASP8062 in Plasma: Area Under the Concentration From Time of Dosing to 24 Hours (AUC24) | AUC24 was recorded from the PK plasma samples collected. Samples for AUC24 were collected for arm 'ASP8062' at Day 9, and for arm 'ASP8062 in combination with morphine' at Day 10. | 'ASP8062': Predose, 0.25, 0.5, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 h postdose Day 9; 'ASP8062 in combination with morphine': Predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120, 144 h postdose Day 10 | 
| Pharmacokinetics (PK) of ASP8062 in Plasma: Maximum Plasma Concentration (Cmax) | Cmax was recorded from the PK plasma samples collected. Samples for Cmax were collected for arm 'ASP8062' at Day 9, and for arm 'ASP8062 in combination with morphine' at Day 10. | 'ASP8062': Predose, 0.25, 0.5, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 h Day 9; 'ASP8062 in combination with morphine': Predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120, 144 h postdose Day 10 | 
| Pharmacokinetics (PK) of Morphine in Plasma: Area Under the Concentration From Time of Dosing Extrapolated to Time Infinity (AUCinf) | AUCinf was recorded from the PK plasma samples collected. | Predose, 0.25, 0.5, 1.5, 2, 3, 4, 8, 12, 16, 24, 36, 48 h postdose Day 10 | 
| Pharmacokinetics (PK) of Morphine in Plasma: Area Under the Concentration Time Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) | AUClast was recorded from the PK plasma samples collected. | Predose, 0.25, 0.5, 1.5, 2, 3, 4, 8, 12, 16, 24, 36, 48 h postdose Day 10 | 
| Pharmacokinetics (PK) of Morphine in Plasma: Cmax | Cmax was recorded from the PK plasma samples collected. | Predose, 0.25, 0.5, 1.5, 2, 3, 4, 8, 12, 16, 24, 36, 48 h postdose Day 10 | 
| Pharmacokinetics (PK) of Morphine-3β-D-glucuronide(M3G) (Morphine Metabolite) in Plasma: AUCinf | AUCinf was recorded from the PK plasma samples collected. | Predose, 0.25, 0.5, 1.5, 2, 3, 4, 8, 12, 16, 24, 36, 48 h postdose Day 10 | 
| Pharmacokinetics (PK) of Morphine-3β-D-glucuronide (M3G) (Morphine Metabolite) in Plasma: AUClast | AUClast was recorded from the PK plasma samples collected. | Predose, 0.25, 0.5, 1.5, 2, 3, 4, 8, 12, 16, 24, 36, 48 h postdose Day 10 | 
| Pharmacokinetics (PK) of Morphine-3β-D-glucuronide (M3G) (Morphine Metabolite) in Plasma: Cmax | Cmax was recorded from the PK plasma samples collected. | Predose, 0.25, 0.5, 1.5, 2, 3, 4, 8, 12, 16, 24, 36, 48 h postdose Day 10 | 
| Pharmacokinetics (PK) of Morphine-6β-D-glucuronide (M6G) (Morphine Metabolite) in Plasma: AUCinf | AUCinf was recorded from the PK plasma samples collected. | Predose, 0.25, 0.5, 1.5, 2, 3, 4, 8, 12, 16, 24, 36, 48 h postdose Day 10 | 
| Pharmacokinetics (PK) of Morphine-6β-D-glucuronide (M6G) (Morphine Metabolite) in Plasma: AUClast | AUClast was recorded from the PK plasma samples collected. | Predose, 0.25, 0.5, 1.5, 2, 3, 4, 8, 12, 16, 24, 36, 48 h postdose Day 10 | 
| Pharmacokinetics (PK) of Morphine-6β-D-glucuronide (M6G) (Morphine Metabolite) in Plasma: Cmax | Cmax was recorded from the PK plasma samples collected. | Predose, 0.25, 0.5, 1.5, 2, 3, 4, 8, 12, 16, 24, 36, 48 h postdose Day 10 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Opioid Use Disorder, pharmacokinetic, ASP8062, morphine