Abstract
Background:
Like other alpha-2-adrenergic receptor agonists, dexmedetomidine may reduce the severity of opioid withdrawal but with fewer adverse cardiovascular effects.
Objective:
This study assessed the safety of sublingual dexmedetomidine (BXCL501) and its preliminary efficacy in treating opioid withdrawal (ClinicalTrials.gov: NCT04470050).
Methods:
Withdrawal was induced among individuals with physiological dependence on opioids via discontinuation of oral morphine (Days 1–5). Participants were randomized to receive placebo or active BXCL501: 30, 60, 90, 120, 180, and 240 μg twice daily (Days 6–12). Treatment-emergent adverse events (TEAEs) were the primary outcome measure. Secondary outcomes included the Clinical and Subjective Opiate Withdrawal Scales (COWS and SOWS-Gossop, respectively), and the Agitation and Calmness Evaluation Scale (ACES).
Results:
Of 225 participants enrolled, 90 discontinued during morphine stabilization. Post-BXCL501 randomization (Day 6) data were available from 135 participants (73% male), with 33% completing thru Day 12. In total, 36 subjects reported 1 or more TEAE. Higher doses of BXCL501 (i.e. 180 and 240 μg, twice daily) increased the frequency of: hypotension, orthostatic hypotension, and somnolence. TEAEs related to BXCL501 were mild or moderate in severity, except for one participant in the 120 μg condition whose orthostatic hypotension and bradycardia were classified as severe. Higher BXCL501 dose conditions (120, 180, and 240 μg) resulted in statistically significant reductions in COWS & SOWS scores. Mean ratings on the ACES were between 3 (mild), 4 (normal), and 5 (mild calmness), with few significant differences as a function of dose.
Conclusions:
These findings support the continued development of BXCL501 for the management of opioid withdrawal.
Keywords: Opioid withdrawal, dexmedetomidine, medications development, opioid use disorder, opioid dependence
Introduction
According to the most recent National Survey on Drug Use and Health (NSDUH), an estimated 1.6 million Americans (aged 12 or older) suffer from opioid use disorder (OUD) (1). OUD results in significant cognitive, emotional, and social impairments, and is a significant source of premature mortality (2,3). Physiological dependence on opioids is a significant contributor to the intractable nature of OUD (4). Medically supervised withdrawal is often a required first step in the initiation of efficacious OUD pharmacotherapies such as extended-release naltrexone and buprenorphine maintenance (5,6).
The symptoms of opioid withdrawal include: irritability, anxiety, muscular and abdominal pains, chills, nausea, diarrhea, yawning, lacrimation, sweating, sneezing, rhinorrhea, general weakness, tremor, piloerection, and insomnia. Symptoms typically begin six to 12 hours after the last dose for opioids with short half-lives (e.g., oxycodone and heroin) and 36 to 48 hours for those with longer half-lives (e.g., methadone and buprenorphine). Symptoms typically peak in severity within two to four days and resolve in seven to 14 days (7,8).
The potential of alpha-2-adrenergic agonists to aid in opioid withdrawal has been noted for over 40 years with drugs like clonidine typically being used “off-label” in conjunction with a gradual opioid taper (9,10). It is generally believed that alpha-2-adrenergic agonists attenuate opioid withdrawal by decreasing noradrenergic hyperactivity, particularly in the locus coeruleus (11). The alpha-2-adrenergic agonist, lofexidine, is currently the only FDA-approved medication for the treatment of opioid withdrawal (12,13). Several clinical trials over the last two decades have demonstrated the efficacy of lofexidine in treating opioid withdrawal (for reviews see (14,15). However, much of the re-invigoration of interest in lofexidine leading to FDA approval was improved marketability due to its reduced hypotensive effects in comparison to clonidine (16–18).
Dexmedetomidine is another selective alpha-2-adrenergic receptor agonist that is currently used as an intravenous anesthetic (19–21). A sublingual dexmedetomidine film (BXCL501) is under development for the treatment of opioid withdrawal. Sublingual dexmedetomidine is rapidly absorbed with measurable concentrations observed after 10 minutes with a Tmax of 1.5 hours (22). Dexmedetomidine is a full agonist with a higher affinity for alpha-2a-adrenergic receptors compared to clonidine and lofexidine and may produce a higher level of efficacy (23–26). Compared to other alpha-2-adrenergic agents, dexmedetomidine has fewer adverse effects such as hypotension, rebound hypertension, and bradycardia (27,28). Thus, the goal of the current study was to assess the safety, tolerability, and preliminary efficacy of BXCL501 for treating the symptoms of acute opioid withdrawal among patients with OUD who were physically dependent on opioids.
Methods
Recruitment and screening
Non-treatment-seeking individuals with moderate-to-severe OUD, between the ages of 18 and 65 years were recruited. Recruitment and screening were conducted independently by each of three respective study sites: Hassman Research Institute (Marlton, New Jersey), Columbia University Irving Medical Center (New York, New York), and Segal Trials (Miami, Florida). Screening consisted of assessments of drug use (e.g., Timeline Follow-Back (29): breath alcohol test, and urine drug toxicology) and mental health (e.g., Mini International Neuropsychiatric Interview or standard psychiatric examination, Columbia Suicide Severity Rating Scale (30). Physical health was assessed using laboratory tests (e.g., hematology, blood chemistry panel, liver, and thyroid functioning, and urinalysis), self-reported medical history, 12-lead electrocardiogram, a physical examination, and vital signs (heart rate, blood pressure, orthostatic vital signs, pulse, temperature, oxygen saturation, and respiratory rate).
Physical dependence on opioids was determined using the Clinical Opiate Withdrawal Scale (COWS (31): assessed on the day of admission (score of >5). Alternatively, participants could complete a naloxone-challenge procedure during which they were administered an intramuscular dose of the opioid-receptor antagonist naloxone (between 0.2 and 0.8 mg) and the presence or absence of naloxone-precipitated withdrawal was observed (32).
Generally, participants were excluded for any medical finding that would compromise participant safety (e.g., a significant history of cardiac disease or hepatic dysfunction), or any psychiatric disorder that would compromise their ability to provide informed consent or complete study requirements (e.g., active mania or suicidality). Participants were further excluded for use of an investigational pharmacological agent within 30 days before screening. All study procedures were approved by a federally registered Institutional Review Board (IRB), and the study was conducted per the 1964 Declaration of Helsinki. Informed consent was obtained before any screening or study procedures were initiated. The study was registered with ClinicalTrials.gov (NCT04470050).
Study design and procedures
Morphine stabilization (Days 1–5)
On the day of admission to the inpatient unit (Day 1), participants began maintenance on oral morphine [30 mg, Q.I.D: 8 am, 1 pm, 6 pm, and 11 pm (±30 minutes)], an additional 30 mg rescue dose was also made available each day, as needed (i.e., up to 150 mg/day). The morphine stabilization protocol was based on a trial of lofexidine that also utilized medically supervised opioid withdrawal (33). Throughout Days 1–5 participants were also administered a blinded placebo BXCL501 sublingual film at 8 am and 8 pm. During the stabilization phase participants had access to concomitant medications for: anxiety/restlessness, nausea, upset stomach, diarrhea, insomnia, muscle pain, and general discomfort (See Supplementary Table S1). The use of benzodiazepines was limited to an as-needed standardized clonazepam taper. On Day 1: 0.5 mg of clonazepam was available every 3–4 hrs, up to 2.0 mg total. Using this same schedule of availability, on Day 2, a total of 1.5 mg was available, Day 3, 1.0 mg total, and on Day 4, only one 0.5 mg dose was available. On Day 5, no clonazepam was available.
Morphine discontinuation (Days 6–12)
Morphine tablets were blinded using over-encapsulation and a lactose or riboflavin filler. Blinded discontinuation of active morphine began on Day 6 by replacing active morphine with placebo. Concurrently on Day 6, participants were randomized to active BXCL501 or continued placebo maintenance, which continued throughout the inpatient period. For safety, randomization occurred in cohorts of escalating doses of active BXCL501. Thus, participants in Cohort 1 were randomized in a 4:1 ratio to active BXCL501 30 μg, twice daily (N = 20) or placebo (N = 5), while Cohort 2 was randomized to active BXCL501 60 μg, twice daily (N = 20) or placebo (N = 5), and so on (See Figure 1). Neither the study sponsor nor the study sites were aware of which participants were randomized to active versus placebo BXCL501. In total, the study included 6 cohorts and tested active BXCL501 doses of: 30, 60, 90, 120, 180, and 240 μg, twice daily.
Figure 1.
Illustration of the randomization and allocation among the six BXCL501 dose cohorts.
Throughout the inpatient period, opioid withdrawal was assessed using the COWS and Short Opiate Withdrawal Scale (SOWS) immediately prior to the 8 am BXCL501 or placebo dose, 2 hours post-dose, immediately prior to the 8 pm BXCL501 or placebo dose, and 2 hours post-dose. Agitation and sedation were also assessed using the Agitation and Calmness Evaluation Scale (ACES) two hours after (−5/+15 mins) each BXCL501 or placebo dosing. Participants were assessed for adverse events (AEs) daily, and a buccal exam for signs of local irritation related to sublingual dosing was conducted on Days 1, 6, and 12 and before discharge.
Post-treatment phase (Days 13–14)
On Days 13–14, all participants received BXCL501 placebo film, while still receiving placebo morphine. During this time assessments of withdrawal and AEs continued. Additionally, a physical examination was conducted on the day of discharge.
One-week follow-up (Day 21)
Participants returned to the study site one week after discharge to complete a follow-up visit that included multiple assessments of health. Participants were compensated on a per-day basis of between $50 and $125 (depending on the study site). Differences in site payments were based on standard compensation amounts at each site. There were no differences in retention as a function of site.
Dependent measures
Treatment-Emergent Adverse Events and Serious Adverse Events were the primary dependent measures of the safety and tolerability of BXCL501. An adverse event was defined as any unfavorable and unintended symptom or laboratory finding. A Treatment-Emergent Adverse Event (TEAE) was defined as an adverse event with an onset equal to or after randomization (Day 6). TEAEs were coded using Medical Dictionary for Regulatory Activities (MedDRA) terminology and summarized descriptively by treatment condition (i.e., placebo vs active BXCL501), relationship to study drug, and severity (i.e., mild, moderate, or severe).
Vital sign measurements included orthostatic blood pressure, temperature, pulse rate, and measurement of oxygen saturation. Vitals were assessed immediately pre-dose and 2 hours post each BXCL501 dose. Of particular concern were cardiovascular adverse effects commonly seen among this class of medication (14) more specifically, bradycardia (pulse rate <60 beats per minute), hypotension (90/60 diastolic/systolic), and orthostatic hypotension (a drop of 20 points in systolic or of 10 points in diastolic blood pressure, upon standing).
Clinical Opiate Withdrawal Scale (31) is an 11-item, clinician-administered measure designed to quantify the severity of opioid withdrawal. The COWS evaluates the severity of the following symptoms on a scale of 0–4 or 5: resting pulse rate, sweating, restlessness, pupil size, bone or joint aches, runny nose or tearing, gastrointestinal upset, tremor, yawning, anxiety, or irritability, and gooseflesh. The total score on the COWS ranges from 0 to 48 points with withdrawal ratings between 5–12 considered mild, 13–24 as moderate, 25–36 as moderately severe, and >36 considered severe.
Short Opiate Withdrawal Scale (10) is a 10-item self-report measure designed to quantify the severity of opioid withdrawal. Participants are asked to rate the following 10 items as “None,” “Mild,” “Moderate” or “Severe:” “Feeling Sick,” “Stomach Cramps,” “Muscle Spasms/Twitching,” “Feeling of Coldness,” “Heart-Pounding,” “Muscular Tension,” “Aches and Pains,” “Yawning,” “Runny Eyes,” and “Insomnia/Problems Sleeping.” The total score on the SOWS-Gossop ranges from 0 to 30, with higher scores indicating greater severity of opioid withdrawal.
The Agitation and Calmness Scale (ACES) consist of a single item in which a clinician rates acute agitation and sedation on the following scale: 1=marked agitation, 2=moderate agitation, 3=mild agitation, 4=normal, 5=mild calmness, 6=moderate calmness, 7=marked calmness, 8=deep sleep, and 9=unarousable. This scale has high convergent validity and reliability and has been used in several clinical trials of medications for the treatment of agitation in emergency settings, along with the clinical trial of BXCL501 for the treatment of agitation associated with schizophrenia and bipolar disorder (34,35).
The trial coordinator, Cognitive Research Corporation (St. Petersburg, Florida), provided staff-required training on each of the above measures, along with training in the preparation and dosing of all study medications (described below).
Drugs
BXCL501 (dexmedetomidine sublingual film) was provided to the study site by BioXcel Therapeutics, Inc. The BXCL501 product was a solid-dose green film (22 mm × 8.8 mm) designed to completely dissolve in the sublingual mucosa. Matching placebo films were also provided by the study sponsor. Participants were asked to self-administer the film and the time required for the film to completely dissolve was recorded.
The BXCL501 dosing rationale was based on the safety and tolerability of FDA-approved dexmedetomidine for intravenous administration (36). The administration of twice daily 180 μg of sublingual BXCL501 was estimated to result in a Cmax (440 ng/L) significantly below the mean exposures resulting from the highest approved dose of intravenous Precedex® (139 ng/L). Because of the SL formulation, weight-based dosing could not be performed. Safety and tolerability were assessed after each cohort, and the investigative team conferred to approve the initiation of a higher dose BXCL501 cohort.
Morphine sulfate 30 mg immediate-release tablets (NDC: 00054–0236–25) were obtained from commercial vendors by each of the three study sites. For blinding purposes, morphine was over-encapsulated and backfilled with an inert filler (lactose or riboflavin) by the site pharmacist. Placebo morphine consisted of lactose or riboflavin-filled capsules.
A daily dose of 120 mg (up to 150 mg) of oral morphine was chosen as the standardized opioid maintenance condition as previous studies have found it to be a sufficient substitute for individuals with physiologic opioid dependence who primarily use short-acting opioids (i.e., heroin (37–39). Furthermore, abrupt discontinuation from this dose has been shown to elicit robust withdrawal in previous studies that have used the current laboratory withdrawal paradigm to assess the treatment utility of novel medications to treat opioid withdrawal (40).
Statistical analyses
The study sought to enroll a total of 150 participants (25 per dosing cohort). This sample size was estimated to provide at least 10 completers (i.e., thru Day 12) per dosing cohort, ensuring precise 95% confidence intervals, with a margin of error of <2.7. Demographic data were summarized descriptively by treatment condition (e.g., number, percentage, mean, standard deviation, and range). Chi-square tests were used to compare the distribution of demographics across the dosing conditions. All comparative statistical tests were two-sided, and the significance level was set at p < .05. Analyses were conducted on all subjects who completed at least one post-Day 6 (i.e., randomization) assessment of the outcome measures above. The distributions of all continuous variables were checked for normality before utilizing the parametric tests described below. Statistical analyses were performed using SAS version 9.3 (41).
Primary outcome and analysis plan
The safety and tolerability of BXCL501 were measured by the number of TEAEs (defined above) by treatment condition. The number and percentage of subjects experiencing 1 or more TEAEs was summarized by treatment condition and severity. Chi-square tests were used to compare the frequencies of TEAEs across the treatment conditions.
Secondary outcomes and analysis plans
COWS and SOWS scores during Days 6–12. COWS and SOWS scores on Days 6–12 were analyzed using a mixed-effects, repeated-measures model. These data were examined using average change scores from pre-dose. For these comparisons, “average” refers to the average of the change in score across the two administrations of BXCL501 (i.e., 2 hours post-dose from the respective pre-dose scores). Planned comparisons for each “Day” were used to identify which treatment groups (i.e., BXLC501 dose) were significantly different from placebo. This analytic strategy was chosen over the a priori analysis plan to mitigate the effects of the greater-than-anticipated attrition rates (see Discussion section).
Days of retention following discontinuation of active morphine (Days 6–12). Kaplan-Meier estimates were used to generate survival curves for each treatment group. A logistic regression model was used to compare the number of subjects dropping out after opioid discontinuation as a function of the BXCL501 maintenance condition.
Mean agitation and calmness as measured by the ACES (Days 6–12). Differences in mean agitation and sedation were compared between the treatment groups using the same mixed-effects, repeated-measures model described above.
Results
Participants
Between June 2020 and January 2021, 356 participants were screened and 225 participants were enrolled in the study. Subject disposition information is presented in Figure 2. Discontinuation during the morphine stabilization phase (Days 1–5) was high (40%) but did not significantly vary among the six cohorts: Cohort 1: 36%, Cohort 2: 46%, Cohort 3: 28%, Cohort 4: 36%, Cohort 5: 43%; Cohort 6: 49% (p = .19). Withdrawal of consent included persons who withdrew due to intolerable withdrawal symptoms. Post BXCL501 randomization/morphine discontinuation (Day 6) data were available from 135 participants; detailed demographics of this sample are presented in Table 1. Chi-square tests found no significant differences in demographics across the dosing conditions.
Figure 2.
Subject disposition flow chart. * Withdrawal of consent could include persons who withdrew due to intolerable withdrawal symptoms.
Table 1.
Sample demographics and baseline characteristics.
| BXCL501 Dose | 30 ug BID* (N=17) | 60 ug BID (N=17) | 90 ug BID (N=21) | 120 ug BID (N=19) | 180 ug BID (N=21) | 240 ug BID (N=15) | Placebo BID (N=25) | Total (N=135) | ||
|---|---|---|---|---|---|---|---|---|---|---|
|
| ||||||||||
| Age (Years) | Mean (SD) | 41.6 (13.9) | 45.5 (12.6) | 39.3 (9.64) | 41.3 (9.55) | 42.9 (9.57) | 42.0 (11.9) | 42.1 (10.9) | 42.0 (10.9) | |
| Sex | Male | n (%) | 11 (64.7) | 9 (52.9) | 19 (90.5) | 15 (78.9) | 15 (71.4) | 11 (73.3) | 19 (76.0) | 99 (73.3) |
| Female | 6 (35.3) | 8 (47.1) | 2 (9.5) | 4(21.1) | 6 (28.6) | 4 (26.7) | 6 (24.0) | 36 (26.7) | ||
| Race | White | n (%) | 10 (58.8) | 7 (41.2) | 16 (76.2) | 12 (63.2) | 13 (61.9) | 10 (66.7) | 16 (64.0) | 84 (62.2) |
| Black or African American | 7 (41.2) | 10 (58.8) | 4 (19.0) | 6 (31.6) | 7 (33.3) | 5 (33.3) | 9 (36.0) | 48 (35.6) | ||
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
| Asian | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
| American Indian or Alaska Native | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
| Multiple | 0 | 0 | 0 | 1 (5.3) | 0 | 0 | 0 | 1 (0.7) | ||
| Other | 0 | 0 | 1 (4.8) | 0 | 1 (4.8) | 0 | 0 | 2(1.5) | ||
| Ethnicity | Hispanic or Latino | n (%) | 1 (5.9) | 0 | 5 (23.8) | 2 (10.5) | 4 (19.0) | 4 (26.7) | 2 (8.0) | 18 (13.3) |
| Not Hispanic or Latino | 16 (94.1) | 17 (100.0) | 16 (76.2) | 17 (89.5) | 17 (81.0) | 11 (73.3) | 23 (92.0) | 117 (86.7) | ||
| Body Mass Index (kg/m2) | Mean (SD) | 24.65 (4.14) | 22.95 (3.22) | 25.05 (3.82) | 28.16 (7.86) | 28.05 (8.25) | 27.47 (6.59) | 26.21 (7.72) | 26.12 (6.49) | |
| Past 7-Day Opioid Use | Mean (SD) | 2.9 (3.27) | 1.3 (2.59) | 1.8 (2.78) | 3.8 (3.39) | 3.5 (3.35) | 3.4 (3.40) | 2.8 (3.31) | 2.8 (3.50) | |
| Screening Urine Toxicology | Opioids (e.g., morphine, heroin, oxycodone) | n (%) | 4 (23.5) | 4 (23.5) | 7 (33.3) | 7 (38.9) | 8 (38.1) | 3 (20.0) | 10 (41.7) | 43 (31.9) |
| Fentanyl | 13 (76.5) | 14 (82.4) | 17 (81.0) | 17 (89.5) | 19 (90.5) | 13 (86.7) | 22 (91.7) | 115 (85.2) | ||
| Buprenorphine | 3 (17.6) | 3(17.6) | 2 (9.5) | 3 (15.8) | 2 (9.5) | 3 (20.0) | 3 (12.5) | 19 (14.1) | ||
| Methadone | 0 | 2 (11.8) | 0 | 2 (10.5) | 0 | 0 | 1 (4.2) | 5 (3.7) | ||
| Cocaine | 10 (58.8) | 10 (58.8) | 11 (52.4) | 11 (57.9) | 10 (47.6) | 7 (46.7) | 14 (58.3) | 73 (54.1) | ||
| Cannabinoids | 7 (41.2) | 6 (35.3) | 8 (38.1) | 10 (52.6) | 9 (42.9) | 2 (13.3) | 10 (41.7) | 52 (38.5) | ||
| Benzodiazepines | 6 (35.3) | 2 (11.8) | 2 (9.5) | 1 (5.3) | 4 (19.0) | 2 (13.3) | 2 (8.3) | 19 (14.1) | ||
| Amphetamines | 1 (5.9) | 2 (11.8) | 1 (4.8) | 3 (15.8) | 0 | 0 | 1 (4.2) | 8 (5.9) | ||
| Phencyclidine | 0 | 2 (11.8) | 1 (4.8) | 0 | 1 (4.8) | 0 | 0 | 4 (3.0) | ||
| Ketamine | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
| Any Concomitant Medication | n (%) | 12 (70.6) | 16 (94.1) | 18 (85.7) | 17 (89.5) | 17 (81.0) | 13 (86.7) | 19 (76.0) | 112 (83.0) | |
| Completed thru Day 12 | n (%) | 7 (41.2) | 5 (29.4) | 6 (28.6) | 7 (36.8) | 5 (23.8) | 6 (40.0) | 6 (24.0) | 42 (31.1) | |
| Reason for Discontinuation | Adverse Event | n (%) | 0 | 0 | 0 | 1 (5.3) | 0 | 0 | 0 | 1 (0.7) |
| Lost to Follow-up | 0 | 0 | 0 | 0 | 1 (4.8) | 0 | 0 | 1 (0.7) | ||
| Withdrawal of Consent by Subject | 10 (58.8) | 12 (70.6) | 15 (71.4) | 11 (57.9) | 15 (71.4) | 9 (60.0) | 19 (76.0) | 91 (67.4) | ||
Bolded numbers would indicate a statistically significant (p<.05) Chi-Square test across the dose conditions, but none were found.
Bis In Die (BID): twice daily.
Safety and tolerability
A total of 36 subjects reported 1 or more Treatment-emergent adverse events (TEAE). Higher doses of BXCL501 (i.e., 180 and 240 μg, twice daily) significantly increased the frequency of hypotension, orthostatic hypotension, and somnolence. Among the TEAEs that were determined to be probably or definitely related to BXCL501, the severity of each occurrence was rated as “mild” or “moderate” by a site physician. However, three TEAEs of orthostatic hypotension, bradycardia, and back/musculoskeletal pain, were designated as “severe.” All severe TEAEs occurred within the same participant who was randomized to the 120 μg (twice daily) condition. The frequency of all TEAEs as a function of BXCL501 dose (Days 6–12) is presented in Table 2.
Table 2.
Treatment-emergent adverse events by system organ class.
| System Organ Class* & Medical Dictionary for Regulatory Activities (MedDRA) Term | 30 ug BID** (N=17) n (%) |
60 ug BID (N=17) n (%) |
90 ug BID (N=21) n (%) |
120 ug BID (N=19) n (%) |
180 ug BID (N=21) n (%) |
240 ug BID (N=15) n (%) |
Placebo BID (N=25) n (%) |
X2 p-value |
|---|---|---|---|---|---|---|---|---|
|
| ||||||||
| Cardiac disorders | ||||||||
| Bradycardia | 0 | 0 | 0 | 0 | 0 | 1 (6.7) | 0 | 0.5 |
| Eye disorders | ||||||||
| Lacrimation | 0 | 0 | 0 | 1 (5.3) | 0 | 0 | 0 | 0.5 |
| Gastrointestinal disorders | ||||||||
| Abdominal pain | 0 | 0 | 0 | 1 (5.3) | 1 (4.8) | 1 (6.7) | 0 | 0.7 |
| Diarrhea | 1 (5.9) | 2 (11.8) | 0 | 1 (5.3) | 0 | 0 | 3 (12.0) | 0.2 |
| Nausea | 0 | 1 (5.9) | 1 (4.8) | 1 (5.3) | 2 (9.5) | 1 (6.7) | 1 (4.0) | 0.7 |
| Toothache | 0 | 0 | 0 | 1 (5.3) | 0 | 0 | 0 | 0.5 |
| Vomiting | 0 | 1 (5.9) | 0 | 1 (5.3) | 1 (4.8) | 3 (20.0) | 0 | 0.2 |
| General disorders | ||||||||
| Chills | 0 | 0 | 0 | 1 (5.3) | 0 | 0 | 0 | 0.5 |
| Fatigue | 0 | 0 | 0 | 0 | 1 (4.8) | 0 | 0 | 0.5 |
| Infections & infestations | ||||||||
| Furuncle | 0 | 0 | 0 | 0 | 1 (4.8) | 0 | 0 | 0.5 |
| Urinary tract infection | 0 | 0 | 0 | 0 | 0 | 0 | 1 (4.0) | 0.5 |
| Metabolism & nutrition disorders | ||||||||
| Dehydration | 0 | 0 | 0 | 0 | 1 (4.8) | 0 | 0 | 0.5 |
| Musculoskeletal & connective tissue disorders | ||||||||
| Back pain | 0 | 0 | 0 | 1 (5.3) | 0 | 0 | 0 | 0.5 |
| Groin pain | 0 | 0 | 0 | 0 | 0 | 0 | 1 (4.0) | 0.5 |
| Myalgia | 0 | 0 | 0 | 1 (5.3) | 1 (4.8) | 0 | 1 (4.0) | 0.7 |
| Nervous system disorders | ||||||||
| Dizziness | 0 | 0 | 0 | 0 | 1 (4.8) | 0 | 0 | 0.5 |
| Presyncope | 0 | 0 | 0 | 0 | 0 | 1 (6.7) | 0 | 0.5 |
| Somnolence | 0 | 0 | 0 | 0 | 2 (9.5) | 7 (46.7) | 0 | <0.001 |
| Psychiatric disorders | ||||||||
| Anxiety | 0 | 2 (11.8) | 0 | 0 | 1 (4.8) | 0 | 0 | 0.2 |
| Insomnia | 0 | 0 | 0 | 1 (5.3) | 0 | 0 | 0 | 0.5 |
| Irritability | 0 | 2 (11.8) | 0 | 0 | 0 | 0 | 0 | 0.06 |
| Restlessness | 0 | 0 | 1 (4.8) | 0 | 0 | 0 | 0 | 0.5 |
| Respiratory, thoracic, & mediastinal disorders | ||||||||
| Cough | 0 | 0 | 0 | 1 (5.3) | 3 (14.3) | 0 | 1 (4.0) | 0.1 |
| Vascular disorders | ||||||||
| Hypertension | 0 | 0 | 0 | 0 | 0 | 1 (6.7) | 0 | 0.5 |
| Hypotension | 0 | 1 (5.9) | 0 | 0 | 0 | 5 (33.3) | 0 | <0.001 |
| Orthostatic hypotension | 0 | 0 | 0 | 0 | 2 (9.5) | 4 (26.7) | 0 | <0.01 |
Participants are counted once within each system organ class and adverse event.
Bis In Die (BID): twice daily.
No TEAEs that were found during the Day 14 physical examination or from the Day 21 clinical laboratory tests occurred at a greater frequency among participants who received active versus placebo BXCL501. Finally, the sublingual administration of the BXCL501 film did not produce any reports of local irritation of the oral mucosa.
Effects of BXCL 501 on opioid withdrawal and retention
COWS and SOWS data were examined as a function of average change from pre-dose (i.e., 2-hour post-dose score subtracted from the respective pre-dose score and then averaged across the morning and evening dosing times). A statistically significant reduction from pre-dose SOWS and COWS scores was observed on various days for the 120, 180, and 240 μg (twice daily) dose conditions (Figure 3: Upper Left and Right Panels). Average change for each of the individual SOWS and COWS items is presented in Table 3. Overall dropout rates (i.e., % retention) during Days 6–12 did not significantly vary across the dose conditions (p = .6). However, there is a trend toward improved retention with higher doses of BXCL501 compared to placebo (Figure 3: Lower Panel).
Figure 3.
Mean (standard error) of the change in Clinical Opiate Withdrawal Scale (COWS) & Short Opiate Withdrawal Scale (SOWS) score (upper panels) following the two administrations of BXCL501 (i.e., 2 hours post-dose from the respective pre-dose scores). Shown as a function of BXCL501 maintenance condition following the abrupt discontinuation of morphine (Days 6–12). The lower left panel shows the percentage of participants retained in the trial. The lower right panel shows the mean (standard error) pulse rate 2 hours after the 2nd BXCL501 dose. * Indicates a statistically significant difference from placebo at p < .05, ** = p < .01, and *** = p < .001. Bis in Die (BID)= twice daily.
Table 3.
Average change from pre-dose score*.
| BXCL501 Dose Condition |
|||||||
|---|---|---|---|---|---|---|---|
| 30 ug (N=17) | 60 ug (N=17) | 90 ug (N=21) | 120 ug (N=19) | 180 ug (N=21) | 240 ug (N=15) | Placebo (N=25) | |
| n (SD) | n (SD) | n (SD) | n (SD) | n (SD) | n (SD) | n (SD) | |
|
| |||||||
| Short Opiate Withdrawal Scale (SOWS) | |||||||
| Feeling Sick | |||||||
| Day 6 | −0.21 (0.708) | 0.22 (1.048) | 0.00 (0.397) | 0.03 (0.612) | 0.19 (0.622) | 0.03 (0.915) | −0.04 (0.576) |
| Day 7 | −0.19 (0.663) | −0.04 (1.177) | 0.14 (1.096) | 0.08 (0.449) | 0.22 (0.515) | −0.33 (0.685) | 0.14 (0.819) |
| Day 8 | −0.15 (0.826) | −0.14 (0.378) | 0.28 (0.912) | 0.20 (0.350) | −0.47 (0.741) | −0.20 (0.483) | 0.31 (0.805) |
| Day 9 | 0.00 (0.000) | 0.07 (0.673) | 0.20 (1.059) | −0.20 (0.422) | −0.25 (0.691) | −0.31 (0.530) | 0.19 (0.843) |
| Day 10 | −0.29 (0.809) | 0.00 (0.316) | 0.00 (0.000) | −0.10 (0.211) | 0.00 (0.775) | −0.08 (0.585) | −0.13 (0.582) |
| Day 11 | 0.07 (0.189) | 0.30 (0.758) | 0.00 (0.000) | 0.06 (0.177) | −0.18 (0.513) | −0.08 (0.801) | 0.00 (0.289) |
| Day 12 | 0.00 (0.289) | 0.20 (0.274) | −0.33 (0.816) | 0.06 (0.177) | 0.14 (0.452) | −0.17 (0.683) | 0.50 (0.775) |
| Stomach Cramps | |||||||
| Day 6 | 0.00 (0.612) | 0.13 (0.885) | −0.13 (0.483) | −0.03 (0.676) | −0.10 (0.584) | −0.07 (0.863) | −0.28 (0.579) |
| Day 7 | −0.27 (0.725) | −0.13 (1.110) | −0.17 (0.786) | −0.10 (0.584) | 0.06 (0.727) | −0.33 (0.913) | 0.14 (0.795) |
| Day 8 | −0.08 (0.838) | 0.21 (0.636) | 0.00 (1.304) | 0.15 (0.530) | −0.38 (0.592) | −0.45 (0.798) | 0.12 (0.893) |
| Day 9 | −0.06 (0.167) | −0.21 (0.809) | 0.20 (0.675) | −0.10 (0.516) | −0.58 (0.793) | −0.63 (0.694) | 0.06 (0.623) |
| Day 10 | −0.14 (0.378) | −0.17 (0.753) | 0.07 (0.189) | −0.35 (0.474) | −0.45 (0.789) | −0.17 (0.683) | −0.19 (0.458) |
| Day 11 | −0.14 (0.244) | −0.10 (0.224) | −0.07 (0.189) | 0.13 (0.518) | −0.18 (0.603) | −0.67 (0.683) | −0.14 (0.378) |
| Day 12 | −0.07 (0.189) | 0.00 (0.354) | −0.17 (0.408) | −0.19 (0.372) | 0.00 (0.632) | −0.50 (0.632) | 0.17 (0.258) |
| Muscle Spasm/Twitching | |||||||
| Day 6 | 0.12 (0.332) | 0.06 (0.602) | −0.05 (0.456) | −0.24 (0.510) | −0.02 (0.558) | 0.13 (0.790) | −0.08 (0.553) |
| Day 7 | 0.04 (0.828) | 0.04 (0.753) | −0.17 (0.686) | 0.12 (0.583) | −0.25 (0.753) | −0.21 (1.137) | −0.18 (0.464) |
| Day 8 | 0.04 (0.877) | −0.29 (0.567) | 0.16 (0.507) | −0.20 (0.483) | −0.44 (0.655) | 0.05 (0.798) | −0.08 (0.572) |
| Day 9 | 0.00 (0.354) | −0.07 (0.189) | 0.00 (0.471) | −0.05 (0.284) | −0.38 (0.956) | −0.44 (0.623) | 0.19 (0.259) |
| Day 10 | −0.07 (0.673) | 0.00 (0.000) | −0.14 (0.244) | −0.15 (0.337) | 0.14 (1.027) | 0.00 (0.548) | −0.38 (0.582) |
| Day 11 | −0.14 (0.378) | 0.10 (0.224) | 0.07 (0.189) | −0.06 (0.177) | −0.23 (0.344) | −0.33 (0.606) | −0.07 (0.189) |
| Day 12 | −0.21 (0.267) | 0.00 (0.000) | −0.25 (0.880) | −0.06 (0.177) | −0.64 (0.595) | 0.00 (0.548) | 0.17 (0.683) |
| Feelings of Coldness | |||||||
| Day 6 | −0.21 (0.398) | 0.38 (0.885) | −0.20 (0.377) | −0.21 (0.561) | 0.12 (0.631) | 0.23 (0.942) | −0.06 (0.464) |
| Day 7 | −0.08 (0.449) | −0.67 (1.155) | −0.08 (0.845) | 0.12 (0.768) | 0.06 (0.704) | −0.21 (0.753) | 0.04 (0.692) |
| Day 8 | 0.23 (0.881) | −0.14 (0.852) | 0.00 (0.365) | −0.15 (0.709) | −0.19 (0.929) | −0.10 (0.394) | 0.23 (0.881) |
| Day 9 | −0.11 (0.220) | −0.36 (0.476) | −0.30 (0.483) | −0.05 (0.369) | −0.42 (0.597) | −0.94 (0.821) | −0.13 (0.354) |
| Day 10 | 0.00 (0.408) | 0.00 (0.000) | 0.07 (0.189) | 0.00 (0.527) | −0.50 (0.548) | −0.25 (0.880) | −0.31 (0.594) |
| Day 11 | −0.14 (0.378) | 0.20 (0.274) | −0.07 (0.189) | 0.19 (0.530) | −0.36 (0.674) | −0.25 (0.880) | −0.07 (0.345) |
| Day 12 | 0.00 (0.289) | −0.20 (0.447) | −0.17 (0.683) | 0.00 (0.463) | −0.27 (0.754) | −0.17 (0.683) | 0.08 (0.204) |
| Heart Pounding | |||||||
| Day 6 | −0.24 (0.589) | 0.16 (0.790) | −0.08 (0.766) | −0.33 (0.816) | −0.19 (0.402) | −0.10 (0.828) | −0.08 (0.607) |
| Day 7 | −0.12 (0.219) | −0.21 (0.582) | 0.00 (0.594) | 0.04 (0.431) | 0.16 (0.747) | −0.25 (1.055) | −0.04 (0.634) |
| Day 8 | −0.23 (0.927) | −0.07 (0.607) | 0.13 (0.847) | 0.00 (0.408) | −0.06 (0.704) | −0.05 (0.643) | 0.00 (0.500) |
| Day 9 | 0.06 (0.464) | −0.14 (0.476) | 0.10 (0.316) | −0.05 (0.284) | −0.04 (0.689) | −0.31 (0.753) | 0.00 (0.000) |
| Day 10 | −0.57 (0.838) | −0.33 (0.816) | −0.07 (0.189) | −0.15 (0.337) | −0.41 (0.701) | −0.25 (0.418) | 0.00 (0.000) |
| Day 11 | −0.14 (0.378) | −0.10 (0.224) | 0.00 (0.000) | −0.06 (0.177) | −0.27 (0.564) | −0.25 (0.689) | −0.14 (0.378) |
| Day 12 | 0.07 (0.450) | −0.20 (0.447) | −0.33 (0.816) | 0.00 (0.000) | −0.32 (0.462) | −0.33 (0.516) | −0.08 (0.376) |
| Muscle Tension | |||||||
| Day 6 | 0.00 (0.433) | 0.16 (0.926) | −0.05 (0.484) | −0.18 (0.628) | 0.02 (0.680) | 0.17 (0.748) | −0.12 (0.696) |
| Day 7 | −0.04 (0.380) | −0.04 (0.656) | 0.11 (0.654) | 0.00 (0.707) | 0.00 (0.447) | −0.21 (1.076) | −0.07 (0.852) |
| Day 8 | 0.15 (0.944) | 0.14 (0.852) | −0.06 (0.727) | −0.35 (0.626) | −0.16 (0.831) | 0.30 (0.422) | 0.00 (0.500) |
| Day 9 | 0.17 (0.354) | −0.07 (0.345) | 0.15 (0.474) | 0.05 (0.158) | 0.08 (0.793) | −0.56 (0.678) | 0.19 (0.372) |
| Day 10 | −0.07 (0.189) | −0.17 (0.408) | −0.07 (0.189) | −0.10 (0.211) | −0.41 (0.539) | −0.08 (0.492) | −0.31 (0.594) |
| Day 11 | −0.21 (0.267) | 0.10 (0.224) | 0.14 (0.244) | 0.06 (0.177) | 0.00 (0.387) | −0.67 (0.606) | −0.14 (0.627) |
| Day 12 | 0.00 (0.500) | −0.10 (0.224) | −0.42 (0.801) | −0.06 (0.177) | −0.36 (0.595) | 0.08 (0.376) | −0.42 (0.585) |
| Aches and Pains | |||||||
| Day 6 | −0.03 (0.483) | 0.03 (1.024) | −0.13 (0.604) | 0.03 (0.754) | 0.00 (0.671) | −0.03 (0.719) | −0.12 (0.650) |
| Day 7 | 0.08 (0.607) | 0.25 (0.452) | −0.22 (0.492) | −0.08 (0.400) | −0.13 (0.619) | −0.42 (1.145) | 0.14 (0.770) |
| Day 8 | 0.12 (1.024) | −0.21 (0.699) | −0.25 (0.658) | −0.10 (0.516) | −0.25 (0.658) | 0.25 (0.589) | −0.04 (1.108) |
| Day 9 | −0.28 (0.712) | −0.07 (0.345) | 0.00 (0.527) | 0.00 (0.236) | −0.21 (0.582) | −0.88 (0.744) | 0.19 (0.458) |
| Day 10 | −0.36 (0.378) | 0.00 (1.095) | 0.00 (0.289) | −0.15 (0.412) | −0.14 (0.745) | −0.50 (0.707) | −0.13 (0.354) |
| Day 11 | 0.07 (0.450) | 0.00 (0.354) | 0.07 (0.189) | −0.31 (0.458) | −0.27 (0.607) | −1.00 (0.548) | −0.14 (0.476) |
| Day 12 | 0.00 (0.408) | 0.00 (0.354) | −0.50 (0.775) | 0.06 (0.177) | −0.32 (0.643) | −0.33 (0.408) | −0.17 (0.683) |
| Yawning | |||||||
| Day 6 | 0.06 (0.166) | 0.22 (0.774) | 0.05 (0.320) | 0.00 (0.500) | −0.05 (0.350) | −0.07 (0.776) | 0.04 (0.498) |
| Day 7 | 0.19 (0.325) | −0.04 (0.722) | −0.11 (0.502) | −0.12 (0.300) | −0.06 (0.479) | −0.21 (1.252) | −0.14 (0.691) |
| Day 8 | 0.00 (1.307) | 0.00 (0.764) | −0.06 (0.704) | 0.10 (0.211) | 0.16 (0.651) | −0.15 (0.818) | −0.04 (0.721) |
| Day 9 | −0.28 (0.618) | 0.00 (0.289) | −0.15 (0.337) | 0.00 (0.236) | −0.08 (0.557) | −0.81 (0.704) | −0.13 (0.231) |
| Day 10 | −0.07 (0.189) | −0.17 (0.258) | −0.07 (0.189) | 0.00 (0.236) | −0.23 (0.564) | −0.33 (0.753) | −0.31 (0.594) |
| Day 11 | 0.00 (0.289) | 0.00 (0.000) | 0.00 (0.000) | 0.00 (0.000) | −0.09 (0.539) | −0.50 (0.775) | −0.43 (0.535) |
| Day 12 | −0.07 (0.345) | −0.30 (0.671) | −0.25 (0.418) | 0.06 (0.417) | −0.18 (0.337) | −0.42 (0.585) | 0.17 (0.258) |
| Runny Eyes | |||||||
| Day 6 | 0.15 (0.386) | 0.00 (0.632) | 0.05 (0.394) | −0.03 (0.456) | 0.00 (0.524) | 0.00 (0.681) | 0.04 (0.320) |
| Day 7 | 0.00 (0.500) | 0.13 (1.025) | 0.36 (0.637) | 0.00 (0.677) | 0.19 (0.443) | 0.25 (1.138) | 0.25 (0.643) |
| Day 8 | 0.15 (0.658) | −0.07 (0.450) | 0.31 (0.512) | 0.00 (0.408) | 0.28 (0.515) | −0.15 (0.474) | 0.31 (0.480) |
| Day 9 | 0.00 (0.433) | −0.07 (0.673) | 0.20 (0.675) | 0.10 (0.211) | 0.08 (0.469) | −0.31 (0.704) | −0.06 (0.563) |
| Day 10 | 0.21 (0.636) | −0.17 (0.258) | 0.14 (0.244) | 0.00 (0.408) | −0.27 (0.754) | −0.08 (0.376) | −0.31 (0.651) |
| Day 11 | −0.29 (0.488) | −0.20 (0.274) | −0.14 (0.244) | 0.00 (0.000) | −0.05 (0.611) | −0.58 (0.665) | −0.29 (0.567) |
| Day 12 | 0.00 (0.289) | −0.20 (0.447) | −0.17 (0.408) | 0.00 (0.000) | 0.18 (0.462) | −0.08 (0.492) | 0.00 (0.000) |
| Insomnia or Problems Sleeping ** | |||||||
| Day 6 | −0.12 (0.697) | 0.13 (1.204) | 0.08 (0.534) | 0.13 (0.684) | 0.14 (1.142) | −0.40 (0.910) | 0.04 (1.050) |
| Day 7 | −0.04 (0.691) | −0.33 (0.961) | 0.39 (0.832) | −0.04 (0.749) | 0.22 (0.632) | −0.67 (0.961) | 0.18 (0.639) |
| Day 8 | 0.15 (0.427) | −0.07 (0.535) | 0.31 (1.078) | 0.30 (0.483) | −0.41 (0.779) | −0.45 (1.039) | 0.08 (1.017) |
| Day 9 | 0.28 (1.064) | −0.14 (0.802) | 0.20 (0.753) | −0.15 (0.580) | −0.38 (0.644) | −0.88 (0.991) | 0.31 (0.651) |
| Day 10 | 0.14 (0.244) | 0.00 (0.316) | 0.07 (0.189) | −0.30 (0.978) | −0.27 (0.564) | −0.58 (1.393) | 0.19 (0.594) |
| Day 11 | −0.14 (0.945) | −0.20 (0.570) | −0.36 (0.627) | −0.19 (0.594) | −0.41 (0.769) | −0.42 (0.861) | −0.29 (0.699) |
| Day 12 | −0.07 (0.189) | −0.70 (0.570) | −0.33 (0.876) | 0.25 (0.598) | 0.27 (1.272) | −0.83 (0.816) | −0.08 (0.665) |
| Clinical Opiate Withdrawal Scale (COWS) | |||||||
| Resting Pulse Rate | |||||||
| Day 6 | 0.15 (0.523) | −0.09 (1.255) | −0.08 (0.494) | −0.05 (0.329) | −0.26 (0.515) | −0.13 (0.550) | 0.32 (0.690) |
| Day 7 | 0.12 (0.650) | −0.21 (0.782) | 0.06 (0.539) | −0.08 (0.572) | −0.06 (0.704) | −0.13 (0.569) | −0.11 (0.881) |
| Day 8 | −0.31 (0.560) | 0.00 (0.408) | −0.13 (0.428) | −0.20 (0.537) | −0.19 (0.873) | 0.05 (0.725) | 0.35 (1.197) |
| Day 9 | 0.11 (0.858) | −0.21 (0.636) | 0.05 (0.550) | −0.10 (0.394) | 0.00 (0.522) | 0.19 (0.884) | 0.56 (0.982) |
| Day 10 | 0.00 (0.408) | −0.17 (1.033) | −0.14 (0.627) | 0.15 (0.337) | 0.05 (0.416) | 0.00 (0.447) | 0.19 (0.651) |
| Day 11 | 0.64 (0.556) | −0.30 (0.570) | −0.29 (1.113) | 0.13 (0.518) | −0.23 (0.410) | −0.08 (0.492) | −0.07 (0.787) |
| Day 12 | |||||||
| Restlessness | |||||||
| Day 6 | −0.03 (0.413) | 0.25 (0.658) | −0.13 (0.483) | −0.55 (0.705) | −0.31 (0.622) | −0.17 (0.900) | −0.02 (0.699) |
| Day 7 | 0.46 (0.776) | −0.08 (0.764) | −0.14 (0.703) | 0.04 (0.776) | −0.25 (0.658) | −0.42 (0.821) | −0.14 (0.886) |
| Day 8 | 0.08 (0.607) | −0.14 (0.244) | 0.03 (0.562) | −0.20 (0.675) | −0.78 (0.816) | −0.28 (0.618) | −0.27 (0.665) |
| Day 9 | 0.06 (0.391) | 0.14 (0.627) | −0.10 (0.394) | −0.15 (0.412) | −0.25 (0.866) | −0.94 (0.863) | −0.06 (0.464) |
| Day 10 | −0.14 (1.029) | −0.33 (0.408) | −0.07 (0.345) | −0.25 (0.264) | −0.25 (0.866) | −0.17 (0.606) | −0.19 (0.259) |
| Day 11 | 0.00 (0.289) | −1.00 (0.612) | −0.25 (0.418) | −0.13 (0.231) | −0.50 (0.500) | −0.25 (0.418) | 0.17 (0.516) |
| Day 12 | |||||||
| Pupil | |||||||
| Day 6 | −0.06 (0.243) | 0.00 (0.000) | −0.13 (0.222) | 0.00 (0.236) | 0.05 (0.269) | 0.20 (0.316) | 0.00 (0.144) |
| Day 7 | 0.04 (0.247) | −0.08 (0.289) | −0.08 (0.192) | −0.12 (0.300) | −0.13 (0.289) | 0.17 (0.326) | 0.04 (0.237) |
| Day 8 | 0.04 (0.139) | −0.14 (0.378) | 0.16 (0.507) | −0.10 (0.316) | −0.13 (0.289) | 0.00 (0.354) | −0.08 (0.277) |
| Day 9 | 0.06 (0.167) | 0.00 (0.000) | −0.05 (0.158) | −0.10 (0.316) | −0.08 (0.195) | −0.19 (0.458) | 0.22 (0.667) |
| Day 10 | −0.07 (0.189) | 0.00 (0.000) | −0.05 (0.158) | 0.00 (0.000) | −0.05 (0.151) | 0.00 (0.000) | −0.13 (0.354) |
| Day 11 | 0.00 (0.000) | 0.10 (0.224) | 0.00 (0.000) | 0.00 (0.000) | 0.00 (0.224) | 0.00 (0.316) | 0.00 (0.000) |
| Day 12 | 0.00 (0.000) | 0.00 (0.000) | 0.00 (0.000) | 0.00 (0.000) | −0.09 (0.202) | −0.17 (0.258) | 0.00 (0.000) |
| Bone and Joint Pain | |||||||
| Day 6 | −0.09 (0.404) | 0.00 (0.632) | −0.25 (0.473) | −0.08 (0.584) | 0.05 (0.650) | 0.03 (0.694) | −0.04 (0.455) |
| Day 7 | 0.12 (0.506) | 0.00 (0.603) | −0.22 (0.624) | −0.04 (0.431) | −0.09 (0.638) | −0.08 (0.417) | 0.04 (0.571) |
| Day 8 | 0.35 (0.427) | −0.07 (0.450) | −0.13 (0.645) | −0.15 (0.530) | −0.25 (0.483) | 0.00 (0.707) | −0.08 (0.760) |
| Day 9 | −0.33 (0.433) | −0.07 (0.535) | −0.20 (0.632) | −0.30 (0.350) | −0.08 (0.515) | −0.06 (0.320) | 0.44 (0.726) |
| Day 10 | 0.00 (0.500) | 0.17 (0.816) | 0.21 (0.488) | 0.00 (0.236) | −0.09 (0.491) | −0.33 (0.516) | 0.06 (0.320) |
| Day 11 | −0.07 (0.345) | 0.10 (0.418) | 0.07 (0.189) | −0.13 (0.354) | 0.00 (0.447) | −0.33 (0.408) | 0.00 (0.500) |
| Day 12 | 0.00 (0.408) | 0.00 (0.354) | −0.33 (0.408) | 0.13 (0.231) | −0.36 (0.452 | −0.25 (0.274) | 0.08 (0.204) |
| Runny Nose | |||||||
| Day 6 | 0.00 (0.433) | −0.19 (0.574) | −0.13 (0.222) | −0.29 (0.481) | 0.00 (0.316) | 0.03 (0.516) | 0.08 (0.493) |
| Day 7 | 0.12 (0.546) | −0.17 (0.807) | 0.03 (0.675) | −0.42 (0.400) | −0.03 (0.562) | 0.04 (0.542) | 0.21 (0.642) |
| Day 8 | 0.19 (0.693) | −0.07 (0.189) | −0.03 (0.464) | −0.05 (0.550) | −0.16 (0.769) | 0.06 (0.527) | 0.31 (0.778) |
| Day 9 | −0.11 (0.546) | −0.36 (0.627) | −0.25 (0.717) | −0.05 (0.284) | −0.25 (0.544) | −0.38 (0.518) | 0.11 (0.220) |
| Day 10 | 0.00 (0.000) | −0.50 (0.548) | −0.21 (0.393) | −0.05 (0.438) | −0.23 (0.261) | −0.17 (0.408) | 0.00 (0.535) |
| Day 11 | −0.14 (0.476) | −0.10 (0.224) | −0.14 (0.378) | 0.19 (0.530) | 0.00 (0.548) | −0.25 (0.418) | −0.07 (0.189) |
| Day 12 | −0.29 (0.488) | 0.00 (0.000) | −0.08 (0.492) | −0.13 (0.231) | 0.00 (0.447) | 0.00 (0.000) | 0.00 (0.000) |
| Gastrointestinal Upset | |||||||
| Day 6 | 0.24 (0.903) | 0.06 (0.772) | −0.20 (0.523) | −0.24 (0.695) | −0.36 (0.615) | −0.07 (0.372) | 0.04 (0.519) |
| Day 7 | −0.12 (0.740) | 0.00 (0.879) | −0.17 (0.728) | −0.08 (0.760) | −0.44 (0.964) | 0.29 (1.373) | −0.11 (0.738) |
| Day 8 | 0.35 (1.125) | −0.21 (0.488) | −0.13 (0.866) | −0.10 (0.810) | −0.47 (0.670) | −0.50 (0.866) | 0.19 (0.663) |
| Day 9 | 0.28 (1.034) | −0.86 (0.988) | 0.35 (1.634) | −0.10 (0.394) | −0.08 (0.557) | −0.25 (0.655) | 0.33 (1.199) |
| Day 10 | −0.29 (0.488) | −0.08 (0.736) | 0.07 (0.345) | −0.30 (0.587) | −0.23 (0.564) | −0.50 (0.632) | −0.13 (0.991) |
| Day 11 | −0.07 (0.189) | −0.30 (0.274) | −0.36 (0.476) | 0.06 (0.320) | 0.00 (0.447) | −0.33 (0.683) | −0.07 (0.345) |
| Day 12 | −0.14 (0.244) | −0.10 (0.224) | −0.42 (0.801) | −0.19 (0.594) | 0.09 (1.114) | −0.50 (0.447) | 0.17 (0.516) |
| Tremor | |||||||
| Day 6 | −0.18 (0.431) | −0.03 (0.427) | −0.10 (0.348) | −0.08 (0.301) | −0.14 (0.392) | 0.07 (0.530) | 0.00 (0.323) |
| Day 7 | −0.08 (0.400) | −0.50 (0.477) | −0.19 (0.349) | −0.12 (0.219) | −0.25 (0.408) | −0.04 (0.450) | 0.00 (0.196) |
| Day 8 | 0.23 (0.725) | −0.07 (0.535) | −0.19 (0.443) | −0.15 (0.337) | −0.19 (0.602 | −0.50 (0.433) | −0.04 (0.139) |
| Day 9 | 0.00 (0.433) | −0.07 (0.450) | −0.10 (0.316) | 0.00 (0.236) | −0.33 (0.389) | −0.50 (0.655) | 0.06 (0.167) |
| Day 10 | 0.14 (0.378) | −0.08 (0.376) | 0.07 (0.450) | −0.05 (0.158) | −0.14 (0.234) | −0.17 (0.258) | 0.06 (0.177) |
| Day 11 | 0.00 (0.000) | −0.10 (0.224) | −0.07 (0.189) | 0.13 (0.354) | −0.18 (0.337) | −0.33 (0.408) | 0.00 (0.289) |
| Day 12 | 0.07 (0.189) | 0.00 (0.000) | 0.00 (0.000) | 0.00 (0.000) | −0.09 (0.302) | −0.25 (0.418) | 0.00 (0.000) |
| Yawning | |||||||
| Day 6 | 0.03 (0.121 | 0.06 (0.310) | 0.00 (0.162) | −0.11 (0.488) | −0.02 (0.109) | 0.13 (0.352) | 0.10 (0.323) |
| Day 7 | 0.08 (0.344) | −0.08 (0.359) | −0.06 (0.162) | 0.08 (0.188) | −0.09 (0.272) | −0.08 (0.515) | 0.04 (0.365) |
| Day 8 | 0.23 (0.330) | −0.14 (0.244) | 0.00 (0.365) | 0.10 (0.316) | −0.16 (0.397) | 0.06 (0.464) | −0.04 (0.380) |
| Day 9 | −0.22 (0.363) | 0.00 (0.500) | 0.10 (0.316) | −0.10 (0.211) | −0.17 (0.537) | −0.25 (0.535) | 0.00 (0.250) |
| Day 10 | 0.00 (0.000) | 0.00 (0.000) | 0.07 (0.189) | 0.00 (0.236) | 0.00 (0.224) | 0.00 (0.000) | 0.00 (0.267) |
| Day 11 | 0.07 (0.189) | 0.20 (0.758) | −0.07 (0.189) | −0.06 (0.177) | 0.00 (0.224) | 0.00 (0.447) | −0.14 (0.244) |
| Day 12 | 0.07 (0.189) | 0.10 (0.224) | −0.25 (0.418) | −0.06 (0.177) | 0.00 (0.000) | −0.33 (0.408) | −0.08 (0.204) |
| Anxiety | |||||||
| Day 6 | −0.03 (0.739) | −0.06 (0.629) | −0.18 (0.520) | −0.05 (0.575) | −0.29 (0.734) | 0.00 (0.535) | −0.20 (0.722) |
| Day 7 | 0.12 (0.583) | −0.04 (0.940) | 0.06 (0.539) | 0.12 (0.618) | 0.06 (0.443) | −0.38 (0.711) | 0.07 (0.385) |
| Day 8 | −0.23 (0.599) | −0.29 (0.567) | 0.00 (0.483) | −0.05 (0.438) | −0.13 (0.387) | −0.33 (0.612) | 0.19 (0.435) |
| Day 9 | 0.28 (1.064) | 0.14 (0.900) | −0.45 (0.643) | −0.10 (0.394) | 0.00 (0.369) | −0.38 (0.443) | 0.11 (0.333) |
| Day 10 | −0.07 (0.673) | 0.00 (0.632) | −0.07 (0.450) | −0.20 (0.483 | −0.09 (0.625) | −0.17 (0.516) | −0.06 (0.320) |
| Day 11 | −0.07 (0.345) | 0.00 (0.612) | −0.14 (0.244) | 0.00 (0.267) | 0.14 (0.452) | −0.17 (0.683) | 0.07 (0.189) |
| Day 12 | 0.07 (0.189) | −0.40 (0.962) | −0.25 (0.418) | −0.06 (0.320) | −0.14 (0.505) | −0.33 (0.606) | 0.25 (0.418) |
| Gooseflesh | |||||||
| Day 6 | −0.09 (0.364) | 0.00 (0.548) | −0.23 (0.550) | −0.08 (0.607) | −0.14 (0.655) | 0.10 (0.687) | −0.12 (0.415) |
| Day 7 | 0.46 (0.721) | −0.46 (1.076) | −0.08 (0.354) | −0.23 (1.033 | −0.47 (0.903) | 0.00 (0.000) | −0.11 (0.401) |
| Day 8 | 0.58 (0.976) | −0.43 (0.732) | 0.19 (0.750) | 0.15 (0.474) | −0.19 (1.078) | −0.33 (0.661) | 0.11 (0.924) |
| Day 9 | −0.83 (1.090) | −0.21 (0.567) | 0.00 (0.000) | 0.15 (0.474) | −0.08 (1.258) | −0.38 (1.061) | 0.33 (1.000) |
| Day 10 | −0.21 (0.567) | 0.00 (0.000) | 0.00 (0.000) | 0.00 (0.000) | −0.55 (1.011) | −0.50 (0.775) | 0.00 (0.000) |
| Day 11 | 0.00 (0.866) | 0.00 (0.000) | 0.00 (0.000) | 0.00 (0.000) | −0.27 (0.905) | 0.00 (0.000) | 0.00 (0.000) |
| Day 12 | 0.00 (0.000) | −0.30 (0.671) | 0.00 (0.000) | 0.00 (0.000) | −0.55 (1.011) | 0.00 (0.000) | 0.00 (0.000) |
| Agitation and Calmness Scale (ACES) Total Score | |||||||
| Post First Dose | |||||||
| Day 6 | 4.6 (1.27) | 3.4 (1.71) | 4.4 (1.35) | 4.9 (1.31) | 4.7 (1.35) | 4.9 (1.73) | 4.3 (1.40) |
| Day 7 | 4.3 (0.95) | 3.6 (1.83) | 3.8 (1.29) | 3.9 (0.76) | 4.1 (1.48) | 4.4 (1.73) | 4.1 (0.86) |
| Day 8 | 3.8 (1.17) | 4.1 (1.07) | 4.0 (1.26) | 4.6 (1.43) | 4.2 (1.17) | 5.0 (1.83) | 4.1 (0.83) |
| Day 9 | 3.0 (0.87) | 4.1 (1.46) | 3.7 (0.67) | 4.5 (1.18) | 3.5 (0.80) | 4.7 (2.06) | 3.8 (0.46) |
| Day 10 | 4.1 (1.77) | 3.8 (0.98) | 4.1 (0.38) | 4.3 (1.06) | 4.3 (1.01) | 4.3 (1.37) | 4.4 (0.92) |
| Day 11 | 4.7 (1.50) | 4.0 (0.71) | 4.1 (0.38) | 4.1 (0.64) | 3.9 (0.94) | 4.2 (0.41) | 4.6 (1.13) |
| Day 12 | 4.3 (0.76) | 4.4 (1.14) | 4.7 (1.21) | 4.0 (0.00) | 4.1 (0.83) | 4.8 (1.33) | 4.0 (1.10) |
| Post Second Dose | |||||||
| Day 6 | 3.9 (0.73) | 3.5 (0.78) | 3.7 (0.75) | 3.6 (0.61) | 4.1 (1.00) | 3.6 (0.77) | 3.8 (0.73) |
| Day 7 | 3.8 (0.38) | 3.2 (0.75) | 3.7 (0.70) | 3.9 (1.04) | 3.8 (0.41) | 3.5 (0.71) | 4.1 (0.27) |
| Day 8 | 3.8 (0.67) | 3.9 (0.38) | 3.7 (0.63) | 3.6 (0.70) | 4.0 (0.43) | 3.9 (0.35) | 3.7 (0.90) |
| Day 9 | 4.3 (0.49) | 4.0 (0.58) | 4.1 (0.38) | 3.8 (0.42) | 3.8 (0.60) | 4.4 (1.06) | 3.9 (0.83 |
| Day 10 | 4.0 (0.00) | 3.6 (0.89) | 4.0 (0.00) | 3.7 (0.48) | 3.9 (0.54) | 4.2 (0.41) | 3.9 (0.35) |
| Day 11 | 4.0 (0.00) | 3.2 (1.30) | 4.0 (0.00) | 3.8 (0.46) | 3.7 (0.47) | 4.3 (1.37) | 3.8 (0.41) |
| Day 12 | 3.9 (0.69) | 4.0 (0.00) | 4.2 (0.41) | 4.0 (0.00) | 3.9 (0.33) | 3.7 (0.82) | 3.6 (0.89) |
Average change refers to the average of the two change scores at 2-hour post-dose from the respective pre-dose scores. Bolded numbers indicate a statistically significant difference from placebo (p<.05).
Assessment of insomnia referred to the previous night.
Agitation and calmness scale (ACES)
ACES total score during Days 6–12, following the first and second BXCL501 is shown in Table 3. Mean observer ratings were between 3 (mild agitation), 4 (normal), and 5 (mild calmness), with few significant differences being observed as a function of BXCL501 dose.
Discussion
The primary aim of the current trial was to assess the safety of a novel sublingual dexmedetomidine formulation (i.e., BXCL501). The secondary aim was to assess the preliminary efficacy of BXCL501 to treat the symptoms of opioid withdrawal. Concerning safety, both self-reported and clinician-observed (e.g., abnormal laboratory tests) TEAEs were infrequent and mild, and none resulted in participant discontinuation from the trial. Compared to placebo, higher BXCL501 doses increased the incidence of hypotension, orthostatic hypotension, and somnolence. Cardiovascular AEs were mild and transient, with none requiring medical intervention. Incidences of somnolence did not result in any participants who were un-arousable or required medical intervention. Furthermore, there was no clinically meaningful observer-rated sedation, as assessed by the ACES. Cardiovascular AEs and somnolence were expected given the mechanism of action of BXCL501 (i.e., alpha-2-adrenergic receptor agonism). The occurrence of cardiovascular changes and somnolence during sublingual dexmedetomidine treatment is consistent with previous investigations employing oral, intranasal, and intravenous administration (25,26,42–45).
The safety profile observed for the dose range of BXCL501 tested in the current study suggests that higher doses could be explored for greater efficacy. Nonetheless, the current study did support the utility of BXCL501 for the treatment of opioid withdrawal. In comparison to placebo, higher BXCL501 doses (120, 180, and 240 μg, twice daily) reduced COWS and SOWS scores. Closer examination of the individual COWS and SOWS items revealed improvements in withdrawal symptomology not typically seen with other alpha-2-adrenergic agonists including insomnia, anxiety, and irritability (46–48), though further research is needed to verify these unique treatment effects. These findings may be useful in informing future trials but should be interpreted with caution as the study was not powered for such a granular analysis and lacked controls for multiple testing.
Limitations
Though these findings are promising, several limitations should be noted. Dexmedetomidine is a cytochrome P450 2A6 substrate (49). The current investigation did not assess for genetic variation in CYP2A6 that may alter its metabolism.
Because of the high rate of attrition after BXCL501 randomization, the investigators did not meet the recruitment goals outlined in the power analysis. As a result, the study may have been underpowered in its assessment of BXCL’s preliminary efficacy. Drop-out rates during the morphine stabilization period (Days 1–5) were higher than projected. As a result, we had lower-than-expected enrollment on Day 6 (randomization) and completion through Day 12 was only between 24–41%. The current statistical comparison was therefore revised from the original analysis plan of “peak SOWS/COWS” on each day of the post-randomization phase (Days 6–12). Assessing the change in COWS and SOWS scores across the two administrations of BXCL501 (i.e., 2 hours post-dose from the respective pre-dose scores) allowed the investigators to observe the acute BXLC501 dose effect within those participants who remained at each day of the trial and thus mitigate the effect of the greater than anticipated attrition rates.
As noted above, 40% of patients withdrew during morphine stabilization (Days 1–5), whereas in an analogous lofexidine trial, 0% of participants dropped out while being stabilized on up to 100 mg/day (33). The investigators attribute this difference in attrition during morphine stabilization to the presence of fentanyl. In the current trial, fentanyl was the most frequently observed drug in screening urine toxicology. The increasing prevalence of fentanyl in the illicit opioid market has been well established (50,51). Fentanyl (and its analogs) can be anywhere between 100–10,000 times more potent than morphine and is rapidly sequestered into body fat (see (52)for a review). Participants who were fentanyl positive had higher mean and maximum COWS scores during the first 3 days of stabilization (53). Greater withdrawal severity due to fentanyl dependence may have also reduced the efficacy of BXCL501. This should be noted when making comparisons to previous medication trials. However, we know little about the severity of fentanyl dependence, thus standard opioid stabilization protocols may need to be revised. The investigators continued to observe a high rate of discontinuation post-randomization even among those receiving the higher doses of BXCL501, questioning the clinical significance of the observed reductions in COWS and SOWS scores. Controlled clinical research is needed to understand the potential implications of the fentanyl epidemic on the development of medications for treating opioid withdrawal.
Conclusions
The safety, tolerability, and preliminary efficacy observed in the current trial support the further development of BXCL501 (sublingual dexmedetomidine) in the treatment of opioid withdrawal. Currently, only one medication is FDA-approved for this indication, lofexidine. Lofexidine’s clinical utility was partially based on its improved safety profile in comparison to clonidine, which had been used off-label for this indication for years. In the current study, BXCL501 reduced the symptoms of opioid withdrawal at doses that produced fewer cardiovascular adverse effects that are major concerns for lofexidine treatment (e.g., orthostatic hypotension, bradycardia, dizziness, somnolence). Unique treatment effects included reductions in insomnia, anxiety, and irritability, which often necessitate the co-prescribing of sleep medication and anxiolytics with lofexidine. Furthermore, the more rapid pharmacokinetics of the sublingual route of administration may offer an advantage of BXCL501 over oral treatments. In sum, in individuals with physiologic opioid dependence undergoing managed opioid withdrawal, BXCL501 was safe, well-tolerated, and reduced withdrawal symptoms. Thus, BXCL501 may prove to be an effective medication with novel treatment benefits so further testing and clinical development are warranted.
Supplementary Material
Acknowledgments
The research team would like to thank the study participants, along with the support staff who helped ensure the safe and successful completion of this study.
Funding
This study was funded by BioXcel Therapeutics who contributed to the design of this study as well as the preparation, review, and approval of the manuscript. The first (JDJ) and senior authors (FRL and SDC) of Columbia University Irving Medical Center, were provided with full access to the study data.
Footnotes
Disclosure statement
In the past three years, Dr. Jones has received compensation in the form of partial salary support from studies supported by BioXcel Therapeutics. Dr. Comer has received research funding from Alkermes, BioXcel Therapeutics, Braeburn Pharmaceuticals, Cerecor Inc., Corbus, Go Medical, Intra-cellular Therapies, Janssen, and Lyndra. Dr. Comer has also consulted for: Alkermes, Charleston Labs, Clinilabs, Collegium, Depomed, Epiodyne, Mallinckrodt, Nektar, Newron, Opiant, Otsuka, and Sun Pharma. Dr. Levin has no pertinent disclosures. The remaining authors are employees of BioXcel Therapeutics.
Supplemental data for this article can be accessed online at https://doi.org/10.1080/00952990.2022.2144743
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