Sleep Apnea, Obstructive
Conditions
Brief summary
This is a proof of concept study to determine the safety and efficacy of dronabinol for the treatment of obstructive sleep apnea syndrome (OSA).
Interventions
DRUGDronabinol
DRUGPlacebo (for Dronabinol)
Sponsors
Northwestern University
University of Chicago
Hektoen Institute for Medical Research
National Heart, Lung, and Blood Institute (NHLBI)
University of Illinois at Chicago
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
* Adult 21 to 64 years of age; * 15≤AHI ≤ 50 on screening polysomnogram (PSG) * ESS score ≥ 7 * Able to understand and complete informed consent and all study assessments and forms, presented in an English-speaking format; * Women of child-bearing potential (WCBP) must have a negative urine pregnancy test. In addition sexually active WCBP must agree to use adequate contraceptive methods (oral, injectable or implantable hormonal contraceptive; tubal ligation; intra-uterine devices; barrier contraceptive with spermicide; or vasectomized partner).
Exclusion criteria
* Arterial oxygen saturation \< 75% for \> 5% of sleep period time on screening PSG; * Occupation or life situation that may impart risk by study participation (e.g. commercial driver, pilot, police officer, fireman); * Motor vehicle accident or near-miss related to sleepiness (self-report) within 2 years of the first dose of study drug (Day 8); * Body mass index \> 45 kg/m2 * Severe obstructive sleep apnea syndrome (OSAS) that, based on the clinical judgment of the Investigator, precludes delaying positive airway pressure treatment; * History of shift work or rotating shifts within the month prior to the first dose of study drug (Day 8); * Prior upper airway surgery for snoring or OSAS as an adult (≥ 18 years of age); * Prior non-invasive treatment for OSAS within 6 months prior to the first dose of study drug (Day 8); * Major surgery within 6 months prior to the first dose of study drug (Day 8); * Bariatric surgery within 2 years prior to the first dose of study drug (Day 8). If post-bariatric surgery, weight must be stable ±5% (self-report) for at least 6 months prior to first dose of study drug (Day 8). * Any form of medically managed weight loss program within 6 months prior to the first dose of study drug (Day 8); * Significant defect in nasal patency due to anatomical abnormalities or uncontrolled or recurrent episodes of rhinitis; * Any clinically significant unstable or progressive medical condition; * Any primary sleep disorder other than OSAS as determined by history, physical examination, or Visit 2 PSG (after 7-day screening run-in period); * Clinically significant or uncontrolled: chronic obstructive pulmonary disease (COPD), cardiovascular disease, gastrointestinal, respiratory, pancreatic, hepatic, renal, hematologic, endocrine \[including insulin-dependent diabetes mellitus (IDDM)\], neurological, urogenital, connective tissue, dermatological, thyroid, or other medical disorder; * Any clinically significant psychiatric disorder; * History of seizure disorder; * Treatment with any prescription antidepressant medication within 1 month prior to the first dose of study drug (Day 8); * Treatment with sedatives, hypnotics or other psychoactive drugs within 30 days prior to the first dose of study drug (Day 8); * Any complete blood count (CBC) or liver function test (LFT) laboratory value outside the normal range which, in the clinical judgment of the Investigator renders a subject inappropriate for randomization to treatment; * Pregnancy \[as demonstrated by positive urine human chorionic gonadotropin (hCG) test\] or lactation; * Allergic to cannabinoids or sesame oil; * History of substance abuse (including alcohol abuse or dependence) or laboratory evidence of drug abuse on the Visit 1 drug-screening panel; * Use of dietary supplements which in the judgment of the Investigator may impact sleep or breathing behaviors; * Average daily caffeine consumption \> 500 mg/day (\ 5 cups of coffee); * Average weekly alcohol consumption \> 10 units; * Unwillingness to abstain from caffeine and alcohol on all days when overnight or daytime testing will be performed; * Participation in any other investigational protocol within the 30 days prior to the first dose of study drug (Day 8); * Any condition which, in the opinion of the Investigator, places the patient at unacceptable risk if he or she were to participate in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Apnea/Hypopnea Index (AHI) | Baseline and Week 6 | Change in AHI derived as: AHI (end of treatment) minus AHI (pre-treatment) |
| Change in Epworth Sleepiness Scale (ESS) | Baseline and Week 6 | Change in ESS derived as: ESS (end of treatment) minus ESS (pre-treatment). The ESS scale has a range of 0 to 24, with 0 representing the least degree of sleepiness and 24 the greatest degree of sleepiness. There are no subscales. |
| Change in Sleep Latency: Maintenance of Wakefulness Test (MWT) | Baseline and Week 6 | Change in MWT derived as: MWT (end of treatment) minus MWT (pre-treatment). The Maintenance of Wakefulness Test measures a person's ability to stay awake in a quiet, dark and nonstimulating room for a period of time. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tolerability by Treatment Satisfaction Questionnaire for Medications (TSQM) Overall Score. | Week 6 | The TSQM measures a person's satisfaction with treatment based on a 7-point scale ranging from Extremely Dissatisfied to Extremely Satisfied in response to the question, Taking all things into account, how satisfied or dissatisfied are you with this medication?. |
| Adverse Events (AEs) | Up to 8 weeks | AEs will be evaluated and tracked throughout subject participation (up to 8 weeks) |
| Change in Desaturation Time (DT) | 6 weeks | Change in DT (total minutes with arterial oxygen saturation below 85% during 8-hour polysomnography) derived as: DT (end of treatment) minus DT (pre-treatment) |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from physician referrals at two academic medical centers as well as from the community based upon print and radio advertising between January 2013 and May 2016. The first participant was enrolled in February 2013 and the last participant was enrolled in April 2016.
Participants by arm
| Arm | Count |
|---|---|
| Sugar Pill Placebo, once per day (QD) by mouth, 60 minutes before bedtime for 6 weeks after 1-week run-in
Placebo (for Dronabinol) | 26 |
| 2.5 mg/Day Dronabinol, 2.5 mg QD by mouth, 60 minutes before bedtime for 6 weeks after 1-week placebo run-in
Dronabinol | 22 |
| 10 mg/Day Dronabinol, 10 mg QD by mouth, 60 minutes before bedtime for 4 weeks after 1-week placebo run-in and 2-week dose escalation
Dronabinol | 27 |
| Total | 75 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 | 1 |
| Overall Study | Physician Decision | 1 | 1 | 2 |
| Overall Study | Withdrawal by Subject | 6 | 1 | 3 |
Baseline characteristics
| Characteristic | 10 mg/Day | Total | Sugar Pill | 2.5 mg/Day |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 27 Participants | 75 Participants | 26 Participants | 22 Participants |
| Apnea/Hypopnea Index | 26.04 events/hour STANDARD_DEVIATION 11.92 | 25.67 events/hour STANDARD_DEVIATION 11.29 | 23.72 events/hour STANDARD_DEVIATION 9.47 | 27.54 events/hour STANDARD_DEVIATION 12.57 |
| Body Mass Index | 33.45 kg/m^2 STANDARD_DEVIATION 4.85 | 33.35 kg/m^2 STANDARD_DEVIATION 6.33 | 33.39 kg/m^2 STANDARD_DEVIATION 6.33 | 33.19 kg/m^2 STANDARD_DEVIATION 5.09 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 10 Participants | 4 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants | 64 Participants | 22 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Minimum Arterial Oxygen Saturation | 79.96 % STANDARD_DEVIATION 6.93 | 79.79 % STANDARD_DEVIATION 7.84 | 79.58 % STANDARD_DEVIATION 9.62 | 79.82 % STANDARD_DEVIATION 6.83 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 3 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants | 33 Participants | 15 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 37 Participants | 9 Participants | 16 Participants |
| Sex: Female, Male Female | 9 Participants | 23 Participants | 8 Participants | 6 Participants |
| Sex: Female, Male Male | 18 Participants | 52 Participants | 18 Participants | 16 Participants |
| Sleep Efficiency | 82.74 % STANDARD_DEVIATION 12.22 | 79.58 % STANDARD_DEVIATION 12.25 | 75.51 % STANDARD_DEVIATION 12.5 | 80.52 % STANDARD_DEVIATION 11.11 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 26 | 13 / 22 | 26 / 27 |
| serious Total, serious adverse events | 1 / 26 | 1 / 22 | 0 / 27 |
Outcome results
Primary
Change in Apnea/Hypopnea Index (AHI)
Change in AHI derived as: AHI (end of treatment) minus AHI (pre-treatment)
Time frame: Baseline and Week 6
Population: Analysis performed including all participants who completed the full 6-weeks of treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sugar Pill | Change in Apnea/Hypopnea Index (AHI) | 7.99 events/hour | Standard Deviation 13.16 |
| 2.5 mg/Day | Change in Apnea/Hypopnea Index (AHI) | -1.71 events/hour | Standard Deviation 11.74 |
| 10 mg/Day | Change in Apnea/Hypopnea Index (AHI) | -5.21 events/hour | Standard Deviation 9.52 |
Primary
Change in Epworth Sleepiness Scale (ESS)
Change in ESS derived as: ESS (end of treatment) minus ESS (pre-treatment). The ESS scale has a range of 0 to 24, with 0 representing the least degree of sleepiness and 24 the greatest degree of sleepiness. There are no subscales.
Time frame: Baseline and Week 6
Population: Data are missing for 2 participants randomized to receive Placebo treatment; due to technical error in not completing this instrument.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sugar Pill | Change in Epworth Sleepiness Scale (ESS) | -1.47 units on a scale | Standard Deviation 3.29 |
| 2.5 mg/Day | Change in Epworth Sleepiness Scale (ESS) | -.26 units on a scale | Standard Deviation 2.94 |
| 10 mg/Day | Change in Epworth Sleepiness Scale (ESS) | -4.00 units on a scale | Standard Deviation 5.13 |
Primary
Change in Sleep Latency: Maintenance of Wakefulness Test (MWT)
Change in MWT derived as: MWT (end of treatment) minus MWT (pre-treatment). The Maintenance of Wakefulness Test measures a person's ability to stay awake in a quiet, dark and nonstimulating room for a period of time.
Time frame: Baseline and Week 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sugar Pill | Change in Sleep Latency: Maintenance of Wakefulness Test (MWT) | -2.50 minutes | Standard Deviation 13.09 |
| 2.5 mg/Day | Change in Sleep Latency: Maintenance of Wakefulness Test (MWT) | -3.70 minutes | Standard Deviation 9.73 |
| 10 mg/Day | Change in Sleep Latency: Maintenance of Wakefulness Test (MWT) | 1.40 minutes | Standard Deviation 11.71 |
Secondary
Adverse Events (AEs)
AEs will be evaluated and tracked throughout subject participation (up to 8 weeks)
Time frame: Up to 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sugar Pill | Adverse Events (AEs) | 3.4 Number of adverse events per participant | Standard Deviation 2.9 |
| 2.5 mg/Day | Adverse Events (AEs) | 2.8 Number of adverse events per participant | Standard Deviation 3.6 |
| 10 mg/Day | Adverse Events (AEs) | 5.8 Number of adverse events per participant | Standard Deviation 4.7 |
Secondary
Change in Desaturation Time (DT)
Change in DT (total minutes with arterial oxygen saturation below 85% during 8-hour polysomnography) derived as: DT (end of treatment) minus DT (pre-treatment)
Time frame: 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sugar Pill | Change in Desaturation Time (DT) | 1.21 minutes | Standard Deviation 3.46 |
| 2.5 mg/Day | Change in Desaturation Time (DT) | -0.19 minutes | Standard Deviation 2.78 |
| 10 mg/Day | Change in Desaturation Time (DT) | -0.17 minutes | Standard Deviation 6.68 |
Secondary
Tolerability by Treatment Satisfaction Questionnaire for Medications (TSQM) Overall Score.
The TSQM measures a person's satisfaction with treatment based on a 7-point scale ranging from Extremely Dissatisfied to Extremely Satisfied in response to the question, Taking all things into account, how satisfied or dissatisfied are you with this medication?.
Time frame: Week 6
Population: Data are missing for one participant randomized to receive Placebo treatment due to technical error in not collecting the instrument.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sugar Pill | Tolerability by Treatment Satisfaction Questionnaire for Medications (TSQM) Overall Score. | Very Dissatisfied | 1 Participants |
| Sugar Pill | Tolerability by Treatment Satisfaction Questionnaire for Medications (TSQM) Overall Score. | Somewhat Satisfied | 5 Participants |
| Sugar Pill | Tolerability by Treatment Satisfaction Questionnaire for Medications (TSQM) Overall Score. | Dissatisfied | 0 Participants |
| Sugar Pill | Tolerability by Treatment Satisfaction Questionnaire for Medications (TSQM) Overall Score. | Extremely Dissatisfied | 3 Participants |
| Sugar Pill | Tolerability by Treatment Satisfaction Questionnaire for Medications (TSQM) Overall Score. | Extremely Satisfied | 1 Participants |
| Sugar Pill | Tolerability by Treatment Satisfaction Questionnaire for Medications (TSQM) Overall Score. | Very Satisfied | 5 Participants |
| Sugar Pill | Tolerability by Treatment Satisfaction Questionnaire for Medications (TSQM) Overall Score. | Satisfied | 1 Participants |
| 2.5 mg/Day | Tolerability by Treatment Satisfaction Questionnaire for Medications (TSQM) Overall Score. | Dissatisfied | 3 Participants |
| 2.5 mg/Day | Tolerability by Treatment Satisfaction Questionnaire for Medications (TSQM) Overall Score. | Extremely Dissatisfied | 2 Participants |
| 2.5 mg/Day | Tolerability by Treatment Satisfaction Questionnaire for Medications (TSQM) Overall Score. | Somewhat Satisfied | 6 Participants |
| 2.5 mg/Day | Tolerability by Treatment Satisfaction Questionnaire for Medications (TSQM) Overall Score. | Very Dissatisfied | 2 Participants |
| 2.5 mg/Day | Tolerability by Treatment Satisfaction Questionnaire for Medications (TSQM) Overall Score. | Satisfied | 4 Participants |
| 2.5 mg/Day | Tolerability by Treatment Satisfaction Questionnaire for Medications (TSQM) Overall Score. | Very Satisfied | 1 Participants |
| 2.5 mg/Day | Tolerability by Treatment Satisfaction Questionnaire for Medications (TSQM) Overall Score. | Extremely Satisfied | 1 Participants |
| 10 mg/Day | Tolerability by Treatment Satisfaction Questionnaire for Medications (TSQM) Overall Score. | Satisfied | 4 Participants |
| 10 mg/Day | Tolerability by Treatment Satisfaction Questionnaire for Medications (TSQM) Overall Score. | Somewhat Satisfied | 4 Participants |
| 10 mg/Day | Tolerability by Treatment Satisfaction Questionnaire for Medications (TSQM) Overall Score. | Extremely Satisfied | 6 Participants |
| 10 mg/Day | Tolerability by Treatment Satisfaction Questionnaire for Medications (TSQM) Overall Score. | Very Satisfied | 5 Participants |
| 10 mg/Day | Tolerability by Treatment Satisfaction Questionnaire for Medications (TSQM) Overall Score. | Dissatisfied | 0 Participants |
| 10 mg/Day | Tolerability by Treatment Satisfaction Questionnaire for Medications (TSQM) Overall Score. | Very Dissatisfied | 0 Participants |
| 10 mg/Day | Tolerability by Treatment Satisfaction Questionnaire for Medications (TSQM) Overall Score. | Extremely Dissatisfied | 1 Participants |