Opioid Dependence, on Agonist Therapy
Conditions
Keywords
Opioid, Dependence, agonist, Buprenorphine, Naloxone
Brief summary
The purpose of this study was to assess safety, efficacy, and treatment retention following extended treatment with OX219, a higher-bioavailability buprenorphine/naloxone (BNX) sublingual tablet formulation in opioid-dependent patients who completed 1 of 2 primary efficacy and safety studies of OX219.
Detailed description
This was a multicenter, open-label, uncontrolled, single-arm, 24-week, extension study to assess safety, efficacy, and treatment retention during maintenance treatment. Eligible patients had completed 1 of 2 primary efficacy and safety studies of the higher-bioavailability BNX sublingual tablet formulation (primary study OX219-006 \[NCT01908842\] or OX219-007 \[NCT01848054\]). The total duration of study treatment was 24 weeks.
Interventions
DRUGHigher bioavailability BNX sublingual tablets
Once daily, open-label treatment with higher bioavailability BNX sublingual tablets for 24 weeks
Sponsors
Worldwide Clinical Trials
Orexo AB
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Signed informed consent form. * Completion of 1 of 2 primary efficacy safety studies of BNX sublingual tablets (OX219-006 or OX219-007). * Female patients of child bearing potential who used a reliable method of contraception (hormonal, condom with spermicide, intrauterine device) during the previous OX219-006 or OX219-007 study and continue to use it for the OX219-008 study. Females who are not of child-bearing potential who are either surgically sterile (by hysterectomy, bilateral oophorectomy, bilateral salpingectomy, or tubal ligation), or postmenopausal, as defined by being at least 50 years of age and having had an absence of menses for at least 2 years, were also eligible.
Exclusion criteria
* Females who are pregnant (positive pregnancy test result) or lactating, or planning to become pregnant during the study. * Participants who are unwilling or unable to comply with the requirements of the protocol (eg, pending incarceration) or are in a situation or condition that, in the opinion of the investigator, may interfere with participation in the study. * Participants who are participating in any other clinical study in which medication(s) are being delivered or who had used an investigational drug or device within the last 30 days. * Participants with any known allergy or sensitivity or intolerance to buprenorphine, naloxone, or any related drug, or history of any drug hypersensitivity or intolerance that, in the opinion of the investigator, would compromise the safety of the subject or the study. * Participant with a contra-indicated serious medical condition. * Participants who are at suicidal risk as determined by any of the following: a history of suicidal ideation ≤ 3 months prior to baseline with a score of 4 (intent to act) or 5 (specified plan and intent) on the Columbia Suicide Severity Risk Scale (C-SSRS).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Reporting Treatment-Emergent Adverse Events | Day 1 through week 24 | Number of patients reporting treatment-emergent adverse events during open-label, extension treatment with higher bioavailability BNX sublingual tablets |
| Number of Patients Reporting Treatment-Related, Treatment-Emergent Adverse Events | Day 1 through week 24 | Treatment-emergent adverse events considered related to treatment with the higher bioavailability BNX sublingual tablets |
| Number of Patients Reporting Treatment-Emergent Serious Adverse Events | Day 1 throught week 24 | Patients reporting treatment-emergent serious adverse events considered either related or not related to treatment with the higher bioavailability BNX sublingual tablets |
| Number of Patient Discontinuations Due to Treatment-Emergent Adverse Events | Day 1 through week 24 | Study discontinuations due to treatment-emergent adverse events that occurred during treatment with bioavailability BNX sublingual tablets |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Primary Study Baseline (OX219-006 or OX219-007) for Question 1 of the Work Productivity/Activity Impairment: 6-Question Specific Health Problem Questionnaire (WPAI:SHP) | Study Endpoint | Question 1 of the WPAI:SHP asks patients to provide a yes or no response to the question Are you employed?; The percentage of patients employed at the end of the 24-week open-label, extension study was calculated by subtracting the percentage of previously employed patients not employed at study end from the percentage of previously unemployed patients who were employed by study end |
| Retention in Treatment in the Safety Population | Treatment retention was assessed at weeks 4, 8, 12, 16, 20, and 24 | Retention in treatment by visit in the safety population at weeks 4, 8, 12, 16, 20, and 24, defined as the number of patients receiving treatment on the day of the visit (± 5 days for each visit) |
| Mean Change From Primary Study Baseline (OX219-006 or OX219-007) for Questions 5-6 of the WPAI:SHP | Week 24 | Mean change from primary study baseline to week 24 of the open-label extension study for questions 5-6 of the WPAI:SHP; Question 5: During the past 7 days, how much did your opioid dependence affect your productivity while you were working?; Question 6: During the past 7 days, how much did your opioid dependence affect your ability to do regular daily activities, other than work at a job?; Questions 5 and 6 of the WPAI:SHP are scored on an 11-point scale (0 = problem had no effect; 10 = problem completely prevented me from doing my work/daily activities) |
| Mean Change From Primary Study Baseline (OX219-006 or OX219-007) for Questions 2-4 of the WPAI:SHP | Week 24 | Mean change from primary study baseline to week 24 of the open-label, extension study for questions 2-4 of the WPAI:SHP; Question 2: During the past 7 days, how many hours did you miss from work because of problems associated with your opioid dependence?; Question 3: During the past 7 days, how many hours did you miss from work because of any other reason, such as vacation, holidays, time off to participate in this study?; Question 4: During the past 7 days, how many hours did you actually work? |
| Mean Change From Primary Study Baseline (OX219-006 or OX219-007) in Clinical Opioid Withdrawal Scale (COWS) Score | Prior to dosing on day 1, at weeks 4, 8,12,16, 20, 24, and at study endpoint | Mean change from primary study baseline in COWS total scores during the 24-week open-label, extension study; COWS scores range from 0 to 48, with a lower score being more favorable; study endpoint was defined as the last post-baseline value recorded for COWS |
| Mean Change From Primary Study Baseline (OX219-006 or OX219-007) in Subjective Opioid Withdrawal Scale (SOWS) Score | Prior to dosing on day 1, at weeks 4, 8,12,16, 20, and 24, and at study endpoint | Mean change from primary study baseline in SOWS total scores during the 24-week open-label, extension study; SOWS scores range from 0 to 64, with a lower score being more favorable; study endpoint was defined as the last post-baseline value recorded for SOWS |
| Mean Change From Primary Study Baseline (OX219-006 and OX219-007) in Visual Analog Scale (VAS) Craving Scores | Prior to dosing on day 1, at weeks 4, 8, 12, 16, 20, and 24, and at study endpoint | Mean change from primary study baseline in VAS craving scores during the 24-week open-label, extension study; VAS craving scores range from 0 (no cravings) to 100 mm (most intense craving I have ever had); study endpoint was defined as the last post-baseline value recorded for VAS craving |
Countries
United States
Participant flow
Pre-assignment details
A total of 668 patients who completed primary study OX219-006 (NCT01908842) or OX219-007 (NCT01848054) were enrolled. Three patients entered the study without taking any study medication and were excluded. A total of 665 patients were included in the data analyses.
Participants by arm
| Arm | Count |
|---|---|
| OX219-006 Completers Weeks 1-24: Higher bioavailability BNX sublingual tablets (open-label) were titrated at doses ranging from 5.7/1.4 mg and 17.1/4.2 mg, to a dose that relieved opioid cravings and withdrawal symptoms with minimal side effects. | 475 |
| OX219-007 Completers Weeks 1-24: Higher bioavailability BNX sublingual tablets (open-label) were titrated at doses ranging from 5.7/1.4 mg and 17.1/4.2 mg, to a dose that relieved opioid cravings and withdrawal symptoms with minimal side effects. | 190 |
| Total | 665 |
Baseline characteristics
| Characteristic | OX219-007 Completers | Total | OX219-006 Completers |
|---|---|---|---|
| Age, Continuous | 39.0 years STANDARD_DEVIATION 10.8 | 36.8 years STANDARD_DEVIATION 11.3 | 35.9 years STANDARD_DEVIATION 11.4 |
| Body Mass Index | 26.26 kg/m^2 STANDARD_DEVIATION 6.63 | 26.41 kg/m^2 STANDARD_DEVIATION 6.26 | 26.47 kg/m^2 STANDARD_DEVIATION 6.11 |
| Duration of Opioid Use | 9.6 years STANDARD_DEVIATION 8.79 | 7.95 years STANDARD_DEVIATION 9.32 | 7.20 years STANDARD_DEVIATION 9.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 17 Participants | 82 Participants | 65 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 173 Participants | 583 Participants | 410 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height | 173.35 cm STANDARD_DEVIATION 10.01 | 172.38 cm STANDARD_DEVIATION 9.61 | 171.99 cm STANDARD_DEVIATION 9.43 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 21 Participants | 83 Participants | 62 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 5 Participants | 5 Participants |
| Race (NIH/OMB) White | 167 Participants | 569 Participants | 402 Participants |
| Sex: Female, Male Female | 63 Participants | 259 Participants | 196 Participants |
| Sex: Female, Male Male | 127 Participants | 406 Participants | 279 Participants |
| Weight | 78.98 kg STANDARD_DEVIATION 20.73 | 78.53 kg STANDARD_DEVIATION 19.49 | 78.34 kg STANDARD_DEVIATION 18.99 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 41 / 665 |
| serious Total, serious adverse events | 15 / 665 |
Outcome results
Primary
Number of Patient Discontinuations Due to Treatment-Emergent Adverse Events
Study discontinuations due to treatment-emergent adverse events that occurred during treatment with bioavailability BNX sublingual tablets
Time frame: Day 1 through week 24
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Population | Number of Patient Discontinuations Due to Treatment-Emergent Adverse Events | 14 participants |
Primary
Number of Patients Reporting Treatment-Emergent Adverse Events
Number of patients reporting treatment-emergent adverse events during open-label, extension treatment with higher bioavailability BNX sublingual tablets
Time frame: Day 1 through week 24
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Safety Population | Number of Patients Reporting Treatment-Emergent Adverse Events | Constipation | 20 participants |
| Safety Population | Number of Patients Reporting Treatment-Emergent Adverse Events | Headache | 21 participants |
Primary
Number of Patients Reporting Treatment-Emergent Serious Adverse Events
Patients reporting treatment-emergent serious adverse events considered either related or not related to treatment with the higher bioavailability BNX sublingual tablets
Time frame: Day 1 throught week 24
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Safety Population | Number of Patients Reporting Treatment-Emergent Serious Adverse Events | Possibly treatment-related | 1 participants |
| Safety Population | Number of Patients Reporting Treatment-Emergent Serious Adverse Events | Not treatment-related | 8 participants |
Primary
Number of Patients Reporting Treatment-Related, Treatment-Emergent Adverse Events
Treatment-emergent adverse events considered related to treatment with the higher bioavailability BNX sublingual tablets
Time frame: Day 1 through week 24
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Safety Population | Number of Patients Reporting Treatment-Related, Treatment-Emergent Adverse Events | Gastrointestinal disorders | 32 participants |
| Safety Population | Number of Patients Reporting Treatment-Related, Treatment-Emergent Adverse Events | Constipation | 19 participants |
Secondary
Mean Change From Primary Study Baseline (OX219-006 and OX219-007) in Visual Analog Scale (VAS) Craving Scores
Mean change from primary study baseline in VAS craving scores during the 24-week open-label, extension study; VAS craving scores range from 0 (no cravings) to 100 mm (most intense craving I have ever had); study endpoint was defined as the last post-baseline value recorded for VAS craving
Time frame: Prior to dosing on day 1, at weeks 4, 8, 12, 16, 20, and 24, and at study endpoint
Population: Safety population; patient population at day 1 (n=646) is lower than overall safety population (n=665) due to missing data
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Safety Population | Mean Change From Primary Study Baseline (OX219-006 and OX219-007) in Visual Analog Scale (VAS) Craving Scores | Day 1 (n=646) | -52.8 units on a scale |
| Safety Population | Mean Change From Primary Study Baseline (OX219-006 and OX219-007) in Visual Analog Scale (VAS) Craving Scores | Week 4 (n=563) | -56.6 units on a scale |
| Safety Population | Mean Change From Primary Study Baseline (OX219-006 and OX219-007) in Visual Analog Scale (VAS) Craving Scores | Week 8 (n=479) | -59.4 units on a scale |
| Safety Population | Mean Change From Primary Study Baseline (OX219-006 and OX219-007) in Visual Analog Scale (VAS) Craving Scores | Week 12 (n=426) | -59.4 units on a scale |
| Safety Population | Mean Change From Primary Study Baseline (OX219-006 and OX219-007) in Visual Analog Scale (VAS) Craving Scores | Week 16 (n=384) | -61.5 units on a scale |
| Safety Population | Mean Change From Primary Study Baseline (OX219-006 and OX219-007) in Visual Analog Scale (VAS) Craving Scores | Week 20 (n=338) | -61.4 units on a scale |
| Safety Population | Mean Change From Primary Study Baseline (OX219-006 and OX219-007) in Visual Analog Scale (VAS) Craving Scores | Week 24 (n=289) | -60.5 units on a scale |
| Safety Population | Mean Change From Primary Study Baseline (OX219-006 and OX219-007) in Visual Analog Scale (VAS) Craving Scores | Study Endpoint (n=598) | -57.3 units on a scale |
Secondary
Mean Change From Primary Study Baseline (OX219-006 or OX219-007) for Questions 2-4 of the WPAI:SHP
Mean change from primary study baseline to week 24 of the open-label, extension study for questions 2-4 of the WPAI:SHP; Question 2: During the past 7 days, how many hours did you miss from work because of problems associated with your opioid dependence?; Question 3: During the past 7 days, how many hours did you miss from work because of any other reason, such as vacation, holidays, time off to participate in this study?; Question 4: During the past 7 days, how many hours did you actually work?
Time frame: Week 24
Population: Safety population; patients with missing data were excluded from the analysis and are reflected in the number of participants analyzed
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Safety Population | Mean Change From Primary Study Baseline (OX219-006 or OX219-007) for Questions 2-4 of the WPAI:SHP | Missed work hours due to opioid dependence (n=79) | -4.8 hours |
| Safety Population | Mean Change From Primary Study Baseline (OX219-006 or OX219-007) for Questions 2-4 of the WPAI:SHP | Missed work hours due to other reason (n=79) | -0.2 hours |
| Safety Population | Mean Change From Primary Study Baseline (OX219-006 or OX219-007) for Questions 2-4 of the WPAI:SHP | Number of hours actually worked (n=78) | 7.7 hours |
Secondary
Mean Change From Primary Study Baseline (OX219-006 or OX219-007) for Questions 5-6 of the WPAI:SHP
Mean change from primary study baseline to week 24 of the open-label extension study for questions 5-6 of the WPAI:SHP; Question 5: During the past 7 days, how much did your opioid dependence affect your productivity while you were working?; Question 6: During the past 7 days, how much did your opioid dependence affect your ability to do regular daily activities, other than work at a job?; Questions 5 and 6 of the WPAI:SHP are scored on an 11-point scale (0 = problem had no effect; 10 = problem completely prevented me from doing my work/daily activities)
Time frame: Week 24
Population: Safety population; patients with missing data were excluded from the analysis and are reflected in the number of participants analyzed
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Safety Population | Mean Change From Primary Study Baseline (OX219-006 or OX219-007) for Questions 5-6 of the WPAI:SHP | Problem affects work productivity (n=70) | -3.9 units on a scale |
| Safety Population | Mean Change From Primary Study Baseline (OX219-006 or OX219-007) for Questions 5-6 of the WPAI:SHP | Problem affects daily activities (n=283) | -4.3 units on a scale |
Secondary
Mean Change From Primary Study Baseline (OX219-006 or OX219-007) in Clinical Opioid Withdrawal Scale (COWS) Score
Mean change from primary study baseline in COWS total scores during the 24-week open-label, extension study; COWS scores range from 0 to 48, with a lower score being more favorable; study endpoint was defined as the last post-baseline value recorded for COWS
Time frame: Prior to dosing on day 1, at weeks 4, 8,12,16, 20, 24, and at study endpoint
Population: Safety population; patient population at day 1 (n=658) is lower than overall safety population (n=665) due to missing data
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Safety Population | Mean Change From Primary Study Baseline (OX219-006 or OX219-007) in Clinical Opioid Withdrawal Scale (COWS) Score | Week 8 (n=477) | -12.7 units on a scale |
| Safety Population | Mean Change From Primary Study Baseline (OX219-006 or OX219-007) in Clinical Opioid Withdrawal Scale (COWS) Score | Week 16 (n=384) | -13.1 units on a scale |
| Safety Population | Mean Change From Primary Study Baseline (OX219-006 or OX219-007) in Clinical Opioid Withdrawal Scale (COWS) Score | Week 20 (n=336) | -13.3 units on a scale |
| Safety Population | Mean Change From Primary Study Baseline (OX219-006 or OX219-007) in Clinical Opioid Withdrawal Scale (COWS) Score | Week 24 (completers only; n=288) | -13.1 units on a scale |
| Safety Population | Mean Change From Primary Study Baseline (OX219-006 or OX219-007) in Clinical Opioid Withdrawal Scale (COWS) Score | Study Endpoint (n=597) | -12.5 units on a scale |
| Safety Population | Mean Change From Primary Study Baseline (OX219-006 or OX219-007) in Clinical Opioid Withdrawal Scale (COWS) Score | Week 4 (n=557) | -12.2 units on a scale |
| Safety Population | Mean Change From Primary Study Baseline (OX219-006 or OX219-007) in Clinical Opioid Withdrawal Scale (COWS) Score | Day 1 (n=658) | -12.0 units on a scale |
| Safety Population | Mean Change From Primary Study Baseline (OX219-006 or OX219-007) in Clinical Opioid Withdrawal Scale (COWS) Score | Week 12 (n=423) | -12.9 units on a scale |
Secondary
Mean Change From Primary Study Baseline (OX219-006 or OX219-007) in Subjective Opioid Withdrawal Scale (SOWS) Score
Mean change from primary study baseline in SOWS total scores during the 24-week open-label, extension study; SOWS scores range from 0 to 64, with a lower score being more favorable; study endpoint was defined as the last post-baseline value recorded for SOWS
Time frame: Prior to dosing on day 1, at weeks 4, 8,12,16, 20, and 24, and at study endpoint
Population: Safety population; patient population at day 1 (n=650) is lower than overall safety population (n=665) due to missing data
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Safety Population | Mean Change From Primary Study Baseline (OX219-006 or OX219-007) in Subjective Opioid Withdrawal Scale (SOWS) Score | Day 1 (n=650) | -26.8 units on a scale |
| Safety Population | Mean Change From Primary Study Baseline (OX219-006 or OX219-007) in Subjective Opioid Withdrawal Scale (SOWS) Score | Week 4 (n=550) | -27.4 units on a scale |
| Safety Population | Mean Change From Primary Study Baseline (OX219-006 or OX219-007) in Subjective Opioid Withdrawal Scale (SOWS) Score | Week 8 (n=472) | -28.0 units on a scale |
| Safety Population | Mean Change From Primary Study Baseline (OX219-006 or OX219-007) in Subjective Opioid Withdrawal Scale (SOWS) Score | Week 12 (n=418) | -27.7 units on a scale |
| Safety Population | Mean Change From Primary Study Baseline (OX219-006 or OX219-007) in Subjective Opioid Withdrawal Scale (SOWS) Score | Week 20 (n=331) | -28.9 units on a scale |
| Safety Population | Mean Change From Primary Study Baseline (OX219-006 or OX219-007) in Subjective Opioid Withdrawal Scale (SOWS) Score | Week 24 (n=282) | -27.7 units on a scale |
| Safety Population | Mean Change From Primary Study Baseline (OX219-006 or OX219-007) in Subjective Opioid Withdrawal Scale (SOWS) Score | Study Endpoint (n=588) | -27.3 units on a scale |
| Safety Population | Mean Change From Primary Study Baseline (OX219-006 or OX219-007) in Subjective Opioid Withdrawal Scale (SOWS) Score | Week 16 (n=376) | -28.7 units on a scale |
Secondary
Percent Change From Primary Study Baseline (OX219-006 or OX219-007) for Question 1 of the Work Productivity/Activity Impairment: 6-Question Specific Health Problem Questionnaire (WPAI:SHP)
Question 1 of the WPAI:SHP asks patients to provide a yes or no response to the question Are you employed?; The percentage of patients employed at the end of the 24-week open-label, extension study was calculated by subtracting the percentage of previously employed patients not employed at study end from the percentage of previously unemployed patients who were employed by study end
Time frame: Study Endpoint
Population: Safety population; patients with missing data were excluded from the analysis and are reflected in the number of patients analyzed
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Safety Population | Percent Change From Primary Study Baseline (OX219-006 or OX219-007) for Question 1 of the Work Productivity/Activity Impairment: 6-Question Specific Health Problem Questionnaire (WPAI:SHP) | Unemployed at baseline; employed at study endpoint | 21.3 percentage of patients |
| Safety Population | Percent Change From Primary Study Baseline (OX219-006 or OX219-007) for Question 1 of the Work Productivity/Activity Impairment: 6-Question Specific Health Problem Questionnaire (WPAI:SHP) | Employed at baseline; unemployed at study endpoint | 6.0 percentage of patients |
| Safety Population | Percent Change From Primary Study Baseline (OX219-006 or OX219-007) for Question 1 of the Work Productivity/Activity Impairment: 6-Question Specific Health Problem Questionnaire (WPAI:SHP) | Increase in patients employed at study endpoint | 15.3 percentage of patients |
Secondary
Retention in Treatment in the Safety Population
Retention in treatment by visit in the safety population at weeks 4, 8, 12, 16, 20, and 24, defined as the number of patients receiving treatment on the day of the visit (± 5 days for each visit)
Time frame: Treatment retention was assessed at weeks 4, 8, 12, 16, 20, and 24
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Safety Population | Retention in Treatment in the Safety Population | Week 4 | 563 participants |
| Safety Population | Retention in Treatment in the Safety Population | Week 8 | 483 participants |
| Safety Population | Retention in Treatment in the Safety Population | Week 12 | 425 participants |
| Safety Population | Retention in Treatment in the Safety Population | Week 16 | 383 participants |
| Safety Population | Retention in Treatment in the Safety Population | Week 20 | 333 participants |
| Safety Population | Retention in Treatment in the Safety Population | Week 24 | 292 participants |