Obstructive Sleep Apnea
Conditions
Brief summary
This is a randomized, double blind, placebo-controlled, repeat-dose, parallel arm, outpatient and inpatient phase 2 clinical study to examine the efficacy and safety of three dose levels of AD036 versus placebo in patients with obstructive sleep apnea.
Detailed description
This was a randomized, double-blind, placebo-controlled, repeat-dose, parallel arm, outpatient and inpatient, multicenter, dose-finding study of the combination of atomoxetine and oxybutynin in adults with OSA documented by polysomnography (PSG). Approximately 140 subjects were to be randomized 1:1:1:1 to receive 1 of 3 different fixed-dose combinations of oxybutynin and atomoxetine or matching placebo. For all subjects, the study consisted of: * A screening and baseline period in which subjects' eligibility was determined * An initial 2-night, at-home blinded baseline period in which all subjects received placebo * A 3-night, run-in period in which subjects received: * Low-dose combination for subjects randomized to one of the 3 study treatment arms * Placebo for subjects randomized to the placebo treatment arm * A 7-night treatment period in which subjects received the treatment to which they were randomized, i.e., 1 of the 3 different fixed-dose combinations of drugs, or placebo * An end of study visit
Interventions
DRUGAD036 Dose 1
AD036 Dose 1 oral capsule administered before sleep
DRUGAD036 Dose 2
AD036 Dose 2 oral capsule administered before sleep
DRUGAD036 Dose 3
AD036 Dose 3 oral capsule administered before sleep
DRUGPlacebo
Placebo oral capsule administered before sleep
Sponsors
Apnimed
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
25 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
Male participants between 25 to 65 years of age or female participants between 25 to 70 years of age. Key Inclusion Criteria: * AHI ≥ 20 based on screening polysomnography * Epworth Sleepiness Scale (ESS) score ≥ 4 for participants not using CPAP * Previous surgical treatment for OSA is allowed if ≥ 1 year prior to enrollment Key
Exclusion criteria
* Clinically significant craniofacial malformation. * Clinically significant cardiac disease (e.g., rhythm disturbances, coronary artery disease or cardiac failure) or hypertension requiring more than 2 medications for control. * Clinically significant neurological disorder, including epilepsy/convulsions. * Positive screen for drugs of abuse or substance use disorder as defined in DSM-V within 24 months prior to Screening Visit. * A significant illness or infection requiring medical treatment in the past 30 days. * Women who are pregnant or nursing. * History of using oral or nasal devices for the treatment of OSA may enroll as long as the devices are not used during participation in the study. * History of using devices to affect participant sleeping position for the treatment of OSA, e.g. to discourage supine sleeping position, may enroll as long as the devices are not used during participation in the study. * Treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors, strong cytochrome P450 2D6 (CYP2D6) inhibitors, or monoamine oxidase inhibitors (MAOI) within 14 days of the start of treatment, or concomitant with treatment. * Use of another investigational agent within 90 days or 5 half-lives, whichever is longer, prior to dosing. * ESS total score \> 18. * Central apnea index \> 5/hour on baseline PSG. * Periodic limb movement arousal index \>15/hour on baseline PSG. * Hepatic transaminases \>3X the upper limit of normal (ULN), total bilirubin \>2X ULN (unless confirmed Gilbert syndrome), serum creatinine \>2X ULN. * \<6 hours typical sleep duration. * Night- or shift-work sleep schedule. * Employment as a commercial driver or operator of heavy or hazardous equipment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Apnea Hypopnea Index (AHI) | 10 days | Number of participants with ≥50% reduction in apnea hypopnea index (AHI). AHI is the average number of apneas and hypopneas a person experiences each hour during sleep, to register as an event an apnea or hypopnea must last at least 10 seconds or longer. To measure this, doctors divide the total number of apneic and hypopneic events by the total number of hours the person was asleep. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from 12 clinical sites (hospitals and sleep centers). The study population consisted of male and female subjects between 25 and 65 years of age, inclusive, with OSA documented by PSG. Overall study duration was up to 8 weeks. Dosing of the study treatment was to occur approximately 30 minutes prior to bedtime. Subjects who withdrew from the study were not replaced.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo oral capsule administered orally at bedtime | 36 |
| AD036 Dose 1 AD036 Dose 1 (Low Dose 25/5) administered orally before bedtime | 36 |
| AD036 Dose 2 75/1.5 administered orally at bedtime. | 34 |
| AD036 Dose 3 AD036 75/5 administered orally at bedtime | 34 |
| Total | 140 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Follow-Up (14 Days) | Adverse Event | 0 | 0 | 1 | 1 |
| Follow-Up (14 Days) | Lost to Follow-up | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | AD036 Dose 1 | AD036 Dose 2 | AD036 Dose 3 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 1 Participants | 1 Participants | 3 Participants | 8 Participants |
| Age, Categorical Between 18 and 65 years | 33 Participants | 35 Participants | 33 Participants | 31 Participants | 132 Participants |
| BMI (kg/m^2) | 32.930 kg/m^2 | 33.445 kg/m^2 | 32.555 kg/m^2 | 33.170 kg/m^2 | 32.745 kg/m^2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 2 Participants | 3 Participants | 4 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 34 Participants | 34 Participants | 31 Participants | 30 Participants | 129 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 3 Participants | 1 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants | 10 Participants | 8 Participants | 11 Participants | 44 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 18 Participants | 25 Participants | 23 Participants | 21 Participants | 87 Participants |
| Sex: Female, Male Female | 11 Participants | 12 Participants | 7 Participants | 12 Participants | 42 Participants |
| Sex: Female, Male Male | 25 Participants | 24 Participants | 27 Participants | 22 Participants | 98 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 140 | 0 / 104 | 0 / 34 | 0 / 34 |
| other Total, other adverse events | 7 / 140 | 13 / 104 | 16 / 34 | 14 / 34 |
| serious Total, serious adverse events | 0 / 140 | 1 / 104 | 0 / 34 | 0 / 34 |
Outcome results
Primary
Apnea Hypopnea Index (AHI)
Number of participants with ≥50% reduction in apnea hypopnea index (AHI). AHI is the average number of apneas and hypopneas a person experiences each hour during sleep, to register as an event an apnea or hypopnea must last at least 10 seconds or longer. To measure this, doctors divide the total number of apneic and hypopneic events by the total number of hours the person was asleep.
Time frame: 10 days
Population: All randomized subjects were included in the mITT
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Apnea Hypopnea Index (AHI) | No (subjects that did not have a 50% reduction in AHI) | 33 Participants |
| Placebo | Apnea Hypopnea Index (AHI) | Yes (subjects that had a 50% reduction in AHI) | 3 Participants |
| AD036 Dose 1 | Apnea Hypopnea Index (AHI) | Yes (subjects that had a 50% reduction in AHI) | 2 Participants |
| AD036 Dose 1 | Apnea Hypopnea Index (AHI) | No (subjects that did not have a 50% reduction in AHI) | 34 Participants |
| AD036 Dose 2 | Apnea Hypopnea Index (AHI) | Yes (subjects that had a 50% reduction in AHI) | 6 Participants |
| AD036 Dose 2 | Apnea Hypopnea Index (AHI) | No (subjects that did not have a 50% reduction in AHI) | 28 Participants |
| AD036 Dose 3 | Apnea Hypopnea Index (AHI) | No (subjects that did not have a 50% reduction in AHI) | 26 Participants |
| AD036 Dose 3 | Apnea Hypopnea Index (AHI) | Yes (subjects that had a 50% reduction in AHI) | 8 Participants |