Clinical trial NCT04447287: A Study to Assess the Effect of a Single Dose of ASP8062 on the Multiple Dose Safety, Tolerability and Pharmacokinetics of Buprenorphine/Naloxone in Participants With Opioid Use Disorder
Official title: Phase 1b Randomized, Placebo-controlled Study to Assess the Effect of a Single Dose of ASP8062 on the Multiple Dose Safety, Tolerability and Pharmacokinetics of Buprenorphine/Naloxone in Subjects With Opioid Use Disorder
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Opioid Use Disorder
Keywords: Suboxone®
Opioid Use Disorder
buprenorphine/naloxone
ASP8062
pharmacokinetic
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
Collaborators: name: National Institute on Drug Abuse (NIDA)
First posted: 2020-06-25
Enrollment: 23
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary purpose of this study was to assess the safety and tolerability of multiple doses of buprenorphine/naloxone alone and buprenorphine/naloxone in combination with a single dose of ASP8062.

This study also assessed the potential for pharmacokinetic interaction between ASP8062 and buprenorphine/naloxone.

Detailed description: Participants were screened for up to 28 days prior to first investigational product (IP) administration. Eligible participants were admitted to the clinical unit on day -1 and were residential for a single period of 27 days/26 nights.

Participants were discharged from the clinical unit after completion of down-titration on the condition that all required assessments were performed and that there were no medical reasons for a longer stay in the clinical unit; which was the end-of-study visit (ESV). Prior to discharge, participants were provided with local buprenorphine and methadone providers for their reference.

Eligibility criteria: Inclusion Criteria:

* Subject has a body mass index range of 18 to 36 kg/m\^2, inclusive and weighs at least 50 kg at screening.
* Subject has a diagnosis of moderate or severe opioid use disorder (OUD) according to the Diagnostic and Statistical Manual of Mental Disorders, edition 5 (DSM-5) at screening.
* Subject tests positive for opioids at screening and/or on day -1 or subject shows signs of opioid withdrawal on day -1.
* Subject is willing to take buprenorphine/naloxone and is not taking buprenorphine or buprenorphine/naloxone at screening.
* Female subject 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 30 days after final investigational product (IP) administration.
* Female subject must agree not to breastfeed starting at screening and throughout the study period and for 30 days after final IP administration.
* Female subject must not donate ova starting at first dose of IP and throughout the study period and for 30 days after final IP administration.
* Male subject with female partner(s) of childbearing potential (including breastfeeding partner) must agree to use contraception throughout the study period and for 90 days after final IP administration.
* Male subject must not donate sperm during the treatment period and for 90 days after final IP administration.
* Male subject with pregnant partner(s) must agree to remain abstinent or use a condom and spermicide for the duration of the pregnancy throughout the study period and for 90 days after final IP administration.
* Subject agrees not to participate in another interventional study while participating in the present study.
* Subject 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 11 and 12.

Exclusion Criteria:

* Subject has received any investigational therapy within 28 days or 5 half-lives, whichever is longer, prior to screening.
* Subject has any condition which makes the subject unsuitable for study participation.
* Female subject who has been pregnant within 6 months prior to screening or breastfeeding within 3 months prior to screening.
* Subject has a known or suspected hypersensitivity to ASP8062, buprenorphine, naloxone or any components of the formulations used.
* Subject has had previous exposure with ASP8062.
* Subject has any of the liver function tests (alkaline phosphatase \[ALP\], alanine aminotransferase \[ALT\], aspartate aminotransferase \[AST\], gamma-glutamyl transferase and total bilirubin \[TBL\]) \> 2 × upper limit of normal (ULN) on day -1. In such a case, the assessment may be repeated once.
* Subject 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.
* Subject 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.
* Subject has current or recent diagnosis (within the last 12 months) of moderate or severe alcohol, sedative, hypnotic, anxiolytic, cocaine or any other substance use disorder (except for opioids, caffeine, tobacco or nicotine) according to the DSM-5 at screening.
* Subject has a history or presence of any clinically significant psychiatric disorders such as, bipolar 1, schizophrenia, schizoaffective disorder or major depressive disorders.
* Subject tests positive for alcohol, benzodiazepine or methadone on day -1. Subject tests positive for buprenorphine on day -1.
* Subject has had recent suicidal ideation within the last 12 months or subject who is at significant risk to commit suicide using the Columbia-Suicide Severity Rating Scale (C-SSRS) at screening or since the last visit on day -1.
* Subject has/had febrile illness or symptomatic, viral, bacterial (including upper respiratory infection) or fungal (noncutaneous) infection within 1 week prior to day -1.
* Subject has any clinically significant abnormality following physical examination, electrocardiogram (ECG) and protocol-defined clinical laboratory tests at screening or on day -1.
* Subject has a mean pulse \< 45 or \> 110 beats per minute (unless out of range \[\> 110 beats per minute\] pulse is deemed to be secondary to opioid withdrawal); mean systolic blood pressure \> 150 mmHg; mean diastolic blood pressure \> 95 mmHg (unless out of range blood pressure is deemed to be secondary to opioid withdrawal)(measurements taken in duplicate after subject has been resting in the supine position for at least 5 minutes; pulse will be measured automatically) on day -1. If the mean blood pressure exceeds the limits above, 1 additional duplicate may be taken.
* Subject has a mean corrected QT interval using Fridericia's formula (QTcF) of \> 450 msec (for male subjects) and \> 470 msec (for female subjects) on day -1. If the mean QTcF exceeds the limits above, 1 additional duplicate ECG may be taken.
* Subject has used any prescribed drugs, vitamins and natural or herbal remedies (including, St. John's Wort) in the 2 weeks prior to first IP administration, except for rescue medications, milk of magnesia, acetaminophen, topical dermatological products, including corticosteroid products, hormonal contraceptives and hormone replacement therapy (HRT).
* Subject has used any inducer of metabolism (e.g., barbiturates and rifampin) in the 3 months prior to day -1.
* Subject has had significant blood loss or 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.
* Subject has a positive serology test for antibodies to human immunodeficiency virus type 1 and/or type 2, acute hepatitis B virus infection or acute hepatitis C virus infection, excluding asymptomatic hepatitis C virus infection at screening.
* Subject 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.
* Subject is an employee of Astellas, the study-related contract research organizations or the clinical unit.
* Subject has used any inducer of CYP2C8, 2C9 or 3A4-related metabolism (e.g., barbiturates, rifampin, aprepitant, ritonavir, apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John's wort, bosentan, efavirenz, etravirine, phenobarbital, primidone, armodafinil, modafinil, and rufinamide) in the 3 months prior to day -1.

Primary outcomes:
measure: Number of Participants With Adverse Events (AEs)
timeFrame: From first dose of study drug up to end of study visit (up to day 27)
measure: Number of Participants With Suicidal Ideation and/or Suicidal Behavior as Assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS)
timeFrame: Up to day 27
measure: Change From Baseline in Blood Oxygen Saturation (SpO2) at Predose
timeFrame: 'buprenorphine/naloxone': Baseline and 1 hour postdose Day 11; 'ASP8062 in combination with buprenorphine/naloxone' and 'Placebo ASP8062 in combination with buprenorphine/naloxone': Baseline and 1 hour postdose Day 12
measure: Change From Baseline in Blood Oxygen Saturation (SpO2) at 1 Hour Postdose
timeFrame: 'buprenorphine/naloxone': Baseline and 1 hour postdose Day 11; 'ASP8062 in combination with buprenorphine/naloxone' and 'Placebo ASP8062 in combination with buprenorphine/naloxone': Baseline and 1 hour postdose Day 12
measure: Change From Baseline in Blood Oxygen Saturation (SpO2) at 2 Hour Postdose
timeFrame: 'buprenorphine/naloxone': Baseline and 2 hour postdose Day 11; 'ASP8062 in combination with buprenorphine/naloxone' and 'Placebo ASP8062 in combination with buprenorphine/naloxone': Baseline and 2 hour postdose Day 12
measure: Change From Baseline in Blood Oxygen Saturation (SpO2) at 4 Hour Postdose
timeFrame: 'buprenorphine/naloxone': Baseline and 4 hour postdose Day 11; 'ASP8062 in combination with buprenorphine/naloxone' and 'Placebo ASP8062 in combination with buprenorphine/naloxone': Baseline and 4 hour postdose Day 12
measure: Change From Baseline in Blood Oxygen Saturation (SpO2) at 8 Hour Postdose
timeFrame: 'buprenorphine/naloxone': Baseline and 8 hour postdose Day 11; 'ASP8062 in combination with buprenorphine/naloxone' and 'Placebo ASP8062 in combination with buprenorphine/naloxone': Baseline and 8 hour postdose Day 12
measure: Change From Baseline in Blood Oxygen Saturation (SpO2) at 12 Hour Postdose
timeFrame: 'buprenorphine/naloxone': Baseline and 12 hour postdose Day 11; 'ASP8062 in combination with buprenorphine/naloxone' and 'Placebo ASP8062 in combination with buprenorphine/naloxone': Baseline and 12 hour postdose Day 12
measure: Change From Baseline in End Tidal Carbon Dioxide (CO2) at Predose
timeFrame: 'ASP8062 in combination with buprenorphine/naloxone' and 'Placebo ASP8062 in combination with buprenorphine/naloxone': Baseline and predose Day 12
measure: Change From Baseline in End Tidal Carbon Dioxide (CO2) at 1 Hour Postdose
timeFrame: 'buprenorphine/naloxone': Baseline and 1 hour postdose Day 11; 'ASP8062 in combination with buprenorphine/naloxone' and 'Placebo ASP8062 in combination with buprenorphine/naloxone': Baseline and 1 hour postdose Day 12
measure: Change From Baseline in End Tidal Carbon Dioxide (CO2) at 2 Hour Postdose
timeFrame: 'buprenorphine/naloxone': Baseline and 2 hour postdose Day 11; 'ASP8062 in combination with buprenorphine/naloxone' and 'Placebo ASP8062 in combination with buprenorphine/naloxone': Baseline and 2 hour postdose Day 12
measure: Change From Baseline in End Tidal Carbon Dioxide (CO2) at 4 Hour Postdose
timeFrame: 'buprenorphine/naloxone': Baseline and 4 hour postdose Day 11; 'ASP8062 in combination with buprenorphine/naloxone' and 'Placebo ASP8062 in combination with buprenorphine/naloxone': Baseline and 4 hour postdose Day 12
measure: Change From Baseline in End Tidal Carbon Dioxide (CO2) at 8 Hour Postdose
timeFrame: 'buprenorphine/naloxone': Baseline and 8 hour postdose Day 11; 'ASP8062 in combination with buprenorphine/naloxone' and 'Placebo ASP8062 in combination with buprenorphine/naloxone': Baseline and 8 hour postdose Day 12
Secondary outcomes:
measure: Pharmacokinetics (PK) of ASP8062 in Plasma: Area Under the Concentration-time Curve From the Time of Dosing Extrapolated to Time Infinity (AUCinf)
timeFrame: Predose on day 12 and at the following postdose time points on day 12: 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120, 144, 168, 216 and 264 hour(s)
measure: Pharmacokinetics (PK) of ASP8062 in Plasma: Area Under the Concentration-time Curve From the Time of Dosing to the Last Measurable Concentration (AUClast)
timeFrame: Predose on day 12 and at the following postdose time points on day 12: 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120, 144, 168, 216 and 264 hour(s)
measure: Pharmacokinetics (PK) of ASP8062 in Plasma: Maximum Concentration (Cmax)
timeFrame: Predose on day 12 and at the following postdose time points on day 12: 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120, 144, 168, 216 and 264 hour(s)
measure: Pharmacokinetics (PK) of Buprenorphine in Plasma: Area Under the Concentration-time Curve From the Time of Dosing to 24 Hours (AUC24)
timeFrame: Predose on day 11 and at the following postdose time points on day 11: 0.25, 0.5, 1, 1.5, 2, 3, 4, 8, 12 and 16 hour(s)
measure: Pharmacokinetics (PK) of Buprenorphine in Plasma: Cmax
timeFrame: Predose on day 11 and at the following postdose time points on day 11: 0.25, 0.5, 1, 1.5, 2, 3, 4, 8, 12 and 16 hour(s)
measure: Pharmacokinetics (PK) of Norbuprenorphine (Buprenorphine's Metabolite) in Plasma: AUC24
timeFrame: Predose on day 11 and at the following postdose time points on day 11: 0.25, 0.5, 1, 1.5, 2, 3, 4, 8, 12 and 16 hour(s)
measure: Pharmacokinetics (PK) of Norbuprenorphine (Buprenorphine's Metabolite) in Plasma: Cmax
timeFrame: Predose on day 11 and at the following postdose time points on day 11: 0.25, 0.5, 1, 1.5, 2, 3, 4, 8, 12 and 16 hour(s)
measure: Pharmacokinetics (PK) of Naloxone in Plasma: AUC24
timeFrame: Predose on day 12 and at the following postdose time points on day 12: 0.25, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 16, 24, 168, 216 and 264 hour(s)
measure: Pharmacokinetics (PK) of Naloxone in Plasma: Cmax
timeFrame: Predose on day 12 and at the following postdose time points on day 12: 0.25, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 16, 24, 168, 216 and 264 hour(s)
Other outcomes:
Locations:
city: Overland Park
country: United States
facility: Altasciences Clinical Kansas, Inc.
state: Kansas
Study officials:
affiliation: Astellas Pharma Global Development, Inc.
name: Executive Medical Director
role: STUDY_DIRECTOR
References: