This Phase 1b/2 inpatient study assessed the safety, pharmacokinetics, and early signs of efficacy of escalating doses of BXCL501 versus placebo following discontinuation of morphine maintenance. The opioid (morphine) maintenance phase (Phase 1b) included Days 1-5; the randomized BXCL501/placebo phase (Phase 2) included Days 6-12. The randomized phase was followed by 2 sequential days, Days 13 and 14, utilizing treatment of BXCL501-placebo sublingual films and morphine-placebo capsules for all subjects who remained in the study.

This Study included two phases, Phase 1b and Phase 2. Phase 1b was the morphine maintenance phase, Days 1 through 5 and Phase 2 was the randomized, double-blind, placebo-controlled, ascending-dose study of BXCL501 sublingual films on Days 6-12 to treat symptoms of acute opioid withdrawal in patients with opioid use disorder who are/were physically dependent on opioids. Day 12 was followed by 2 sequential days (Days 13 and 14) of BXCL501 vs. placebo and morphine vs. placebo treatment for all subjects who remained in the study.

After a 30-day screening period, eligible male and female adult subjects with Opioid Use Disorder (OID) who were physically dependent on opioids and were not seeking treatment for opioid withdrawal symptoms were admitted to an inpatient unit. The opioid maintenance phase of the study (Phase 1b, Days 1-5) began on Day 1 and continued through Day 5. Approximately 225 subjects were enrolled in the Phase 1b study in cohorts (approximately 25 subjects/cohort). All subjects enrolled in the Phase 1b portion of the study received oral morphine capsules. The total dose of morphine during the opioid maintenance phase varied at the discretion of the investigator, ranged between 120 mg and 150 mg per day, depending on patients abuse history and need for higher dose to stabilize withdrawal symptoms. In addition, these subjects received placebo sublingual films approximately 12 hours apart to simulate and thus blind treatment of BXCL501 during Phase 2 of the study (Days 6-12).

Abrupt discontinuation of active morphine began on Day 6 (Phase 2) and subjects were randomized in a 4:1 ratio to receive either BXCL501 sublingual films or placebo sublingual films, respectively. 135 subjects enrolled/rolled over from the Phase 1b portion of the study into the randomized, double-blind, placebo-controlled portion of the study (Phase 2). Subjects were treated according to their assigned, randomized treatment from Day 6 through Day 12. Treatment was administered approximately 12 hours apart at approximately 8am (±30 minutes) and 8pm (±30 minutes); the 2nd dose (evening dose) was administered only to subjects that were hemodynamically stable, not hypotensive (must be greater than 110/70 diastolic/systolic), and not bradycardic (must be greater than 55 beats per minute (bpm)). Subjects were not given the second dose if they were orthostatic (a drop of 20 points in either systolic blood pressure (SBP) or 10 points in Diastolic Blood Pressure (DBP)) or if they were experiencing an Adverse Event (AE) that when assessed by the Investigator. If a subject experienced SBP <90 mmHg; or DBT <60 millimeters of mercury (mmHg); or Heart Rate (HR) <50 bpm, immediately prior to the next dose, administration of the study medication for that subject was withheld until resolution of the BP and HR parameters. The administration hold did not exceed 2 hours. Safety and tolerability were monitored continuously and summarized upon completion of each cohort by medical safety review.

Studies of opioid withdrawal with placebo arms are likely to have high dropout rates, thus, the dropouts prior to Day 6 could be replaced to ensure enough sample size entering the treatment phase in Phase 2. Dropouts after Day 6 were not to be replaced. The study was intended to be flexible and adaptable, and as such, the dosing frequency, the doses, and the number of cohorts of BXCL501 allowed for change based on ongoing safety review and medical monitoring of safety, tolerability, and efficacy data after each dose-escalating cohort.

Phase 2 evaluated 6 cohorts (n=25 subjects per cohort according to the 4:1 randomization ratio; n= 20 active BXCL501 and n=5 placebo). The following doses were administered: 30 µg (Cohort 1), 60 µg (Cohort 2), 90 µg (Cohort 3), 120 µg (Cohort 4), and 180 µg (Cohort 5). The dose for Cohort 6 (240 μg) was determined from data acquired from Cohorts 1-5 and Cohort 6 was activated prior to the end of the study.

Other evaluations during the study included establishing the preliminary efficacy of multiple BXCL501 doses relative to placebo and evaluation of pharmacokinetics (PK) in subjects undergoing opiate withdrawal.

Inclusion Criteria

1. Male and female subjects who are 18 years of age to less than 65 years of age.
2. Meets criteria for moderate to severe opioid use disorder as per Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria and confirmed by the Mini International Neuropsychiatric Interview (MINI) with physiological dependence as evidenced by a Clinical Opiate Withdrawal (COWS) score of >5 or a positive naloxone challenge upon admission on Day 1.
3. Subjects who can read, understand, and provide written informed consent. Women of childbearing potential must have a negative pregnancy test and agree to be abstinent or use an acceptable method of contraception for the duration of the study.

Exclusion Criteria

1. Positive urine pregnancy test at screening or when tested or currently breast feeding.
2. Clinically significant history of cardiac disease, screening and baseline heart rate of <55 beats per minutes or systolic blood pressure <110 mmHg or diastolic blood pressure <70 mmHg.
3. History or presence of a significant medical disease or disorder which, in the opinion of the investigator, increases the risk or may confound the interpretation of study measures, as confirmed by screening laboratory results.
4. Hepatic dysfunction (marked by ascites, or bilirubin >10% above the upper limit of normal [ULN] or liver function tests >3 x ULN) at the screening visit.
5. Acute active Hepatitis B or C as evidenced by positive serology and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) >2 x ULN.
6. Clinically significant abnormal ECG findings such as second- or third-degree heart block, uncontrolled arrhythmia, or QTcF (Fridericia correction formula) interval >450 msec for males, and >470 msec for females at screening or prior to dosing.
7. Any psychiatric disorder that would compromise ability to complete study requirements.
8. Currently meets DSM-5 criteria for substance abuse disorder, moderate or severe for any substance other than opioids, caffeine, or nicotine and/or current physical dependence on drugs that pose risk of withdrawal that requires medical management such as alcohol or benzodiazepines.
9. History of suicidal behavior within the last 1 year prior to screening.
10. Participation in a clinical trial of a non-FDA-approved pharmacological agent within 30 days prior to screening.
11. Use of any excluded medication at screening or anticipated/required use during the study period.
12. Subjects with a history of intolerance to morphine.
13. Any finding that, in the view of the principal investigator, would compromise the subject's ability to fulfill the protocol visit schedule or visit requirements.

The Study Protocol and Statistical Analysis Plan (SAP) will be shared. Individual data is summarized by treatment group.

9 days

The number of subjects that experienced at least one Treatment Emergent Adverse Event (TEAE) during the double-blind randomized Phase. Treatment-Emergent Adverse Events (TEAEs) were exclusively documented during the double-blind Phase, aiming to evaluate the safety profile of BXCL501 in the context of opioid withdrawal subsequent to the cessation of oral morphine.

Phase 1b: morphine maintenance, blinded to BXCL501 sublingual treatment (placebo).

Phase 2: Randomized, Double-blind, placebo-controlled (4:1, active to placebo ratio, respectively).

Follow-On portion of Phase 2: Double-blind, placebo-controlled (treatment with morphine-placebo capsules and BXCL501-placebo sublingual films as administered during phase 1b)