Sleep Apnea
Conditions
Brief summary
A pharmacological, non-mechanical therapy for OSA that is efficacious and tolerable remains elusive. Here the investigators study the effect on sleep apnea severity of a combination of pharmacological agents (atomoxetine and oxybutynin, "AtoOxy") over a 1 month period of time. The current study will answer the following questions: Does ongoing, repeated-dose administration of atomoxetine-plus-oxybutynin (referred to as "AtoOxy") improve OSA severity, and do patients exhibit signs of symptomatic relief? Most importantly, which phenotypic subgroup of patients preferentially benefit from this intervention?
Detailed description
Aim 1 - Effect of AtoOxy on sleep apnea severity. In a randomized controlled double-blind crossover study, 48 patients with moderate-to-severe OSA will take atomoxetine-plus-oxybutynin ("AtoOxy") versus placebo nightly for 1 month, with a 2-week washout in between. The investigators will test the hypothesis that AtoOxy reduces the Apnea-hypopnea index (primary outcome measure), and improves the following secondary outcomes: * Nocturnal oxygenation, per "hypoxic burden of sleep apnea" * Frequency of arousals from sleep (Arousal index) * Self-reported sleepiness (Epworth Sleepiness Scale) * Disease-specific quality of life (Functional Outcomes of Sleep Questionnaire, Short Form). * Disease-specific quality of life (Sleep Apnea Quality of Life Index, Short Form) Additional pre-specified exploratory outcome measures will be assessed, including Visual Analog Scales (Sleep Quality, Treatment Satisfaction) and additional polysomnographic measures of sleep (Stage 1 sleep, %total sleep time). Adherence and adverse events will also be carefully monitored to assess repeated-dose tolerance of the intervention. Aim 2 - Determine which patient phenotypes respond best to AtoOxy. Patients will also take part in an additional night before initiating study medication to measure the key mechanisms causing OSA. The investigators will prospectively test the hypothesis that greater pharyngeal collapsibility determines a reduced response to therapy. They will also separately test the hypotheses that a reduced muscle responsiveness, reduced baseline muscle activation, a higher arousal threshold, and a lower loop gain will facilitate a greater response to therapy.
Interventions
DRUGAtomoxetine
Atomoxetine 80 mg, per mouth, before bed. Participants will take the intervention nightly for one month. Half doses will be given on the first three nights.
DRUGOxybutynin
Oxybutynin 5 mg, per mouth, before bed. Participants will take the intervention nightly for one month. Half doses will be given on the first three nights.
DRUGPlacebo
Placebo, per mouth, before bed.Participants will take the intervention nightly for one month. Half doses will be given on the first three nights.
Sponsors
Brigham and Women's Hospital
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Ages 21-70 years * Diagnosed OSA or clinically-suspected OSA * Not using CPAP (\>1 month).
Exclusion criteria
* Any uncontrolled medical condition * Current use of the medications under investigation * Use of medications expected to stimulate or depress respiration (including opioids, barbiturates, doxapram, almitrine, theophylline, 4-hydroxybutanoic acid). * Current use of hypnotic medications (trazodone, eszopiclone, benzodiazepines). * Current use of SNRIs/SSRIs or anticholinergic medications. * Conditions likely to affect obstructive sleep apnea physiology: neuromuscular disease or other major neurological disorder, heart failure (also below), or any other unstable major medical condition. * Respiratory disorders other than sleep disordered breathing: chronic hypoventilation/hypoxemia (awake SaO2 \< 92% by oximetry) due to chronic obstructive pulmonary disease or other respiratory conditions. * Other sleep disorders: periodic limb movements (periodic limb movement arousal index \> 10/hr), narcolepsy, or parasomnias. * Contraindications for atomoxetine and oxybutynin, including: * hypersensitivity to study drugs (angioedema or urticaria) * pheochromocytoma * use of monoamine oxidase inhibitors * benign prostatic hypertrophy, urinary retention * untreated narrow angle glaucoma * bipolar disorder, mania, psychosis * history of major depressive disorder (age\<24). * history of attempted suicide or suicidal ideation within one year prior to screening * clinically significant constipation, gastric retention * pre-existing seizure disorders * clinically-significant kidney disorders (eGFR\<60 ml/min/1.73m2) * clinically-significant liver disorders * clinically-significant cardiovascular conditions * severe hypertension (SBP\>180 mmHg or DBP\>110 mmHg measured at baseline) * cardiomyopathy (LVEF\<50%) or heart failure * advanced atherosclerosis * history of cerebrovascular events * history of cardiac arrhythmias e.g., atrial fibrillation, QT prolongation * other serious cardiac conditions that would raise the consequences of an increase in blood pressure or heart rate * myasthenia gravis * pregnancy/breast-feeding * Allergy to lidocaine (Aim 2 only) * Claustrophobia * Pregnancy or nursing
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Apnea-hypopnea Index [AHI] | one month | Apneas and hypopneas per hour (3% desat and/or arousal), % change from baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Functional Outcomes of Sleep Questionnaire, Short Form | one month | Disease-specific daytime function on scale of 5-20, higher values indicate greater function and quality of life |
| Sleep Apnea Quality of Life Index, Short Form | one month | Disease-specific quality of life on scale of 1-7, higher values indicate greater sleep-apnea related quality of life |
| Hypoxic Burden | one month | Desaturation area under curve × event frequency, % change from baseline |
| Arousal Index | one month | Scored EEG arousals per hour (\>3 s), % change from baseline |
| Epworth Sleepiness Scale | one month | Self-reported sleepiness on scale of 0-24, higher values indicated greater sleepiness |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORScott A Sands, PhD
Brigham and Women's Hospital
Participant flow
Pre-assignment details
117 were enrolled, 58 passed baseline screening and were randomized.
Participants by arm
| Arm | Count |
|---|---|
| All Participants All participants | 58 |
| Total | 58 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 52 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 50 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 11 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 35 Participants |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 55 | 0 / 55 |
| other Total, other adverse events | 39 / 55 | 20 / 55 |
| serious Total, serious adverse events | 1 / 55 | 0 / 55 |
Outcome results
Primary
Apnea-hypopnea Index [AHI]
Apneas and hypopneas per hour (3% desat and/or arousal), % change from baseline
Time frame: one month
Population: Population reported here is the population who completed a given treatment period. (Rather, formal statistical analysis was performed using multiple imputation.)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Active Intervention | Apnea-hypopnea Index [AHI] | -11.8 events/hr; % change from baseline |
| Placebo Intervention | Apnea-hypopnea Index [AHI] | -2.3 events/hr; % change from baseline |
Secondary
Arousal Index
Scored EEG arousals per hour (\>3 s), % change from baseline
Time frame: one month
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Active Intervention | Arousal Index | -0.3 events/hr; % change from baseline |
| Placebo Intervention | Arousal Index | -3.7 events/hr; % change from baseline |
Secondary
Epworth Sleepiness Scale
Self-reported sleepiness on scale of 0-24, higher values indicated greater sleepiness
Time frame: one month
Population: All participants who completed questionnaires on treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Active Intervention | Epworth Sleepiness Scale | 0 units on a scale; change from baseline |
| Placebo Intervention | Epworth Sleepiness Scale | -1 units on a scale; change from baseline |
Secondary
Functional Outcomes of Sleep Questionnaire, Short Form
Disease-specific daytime function on scale of 5-20, higher values indicate greater function and quality of life
Time frame: one month
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Active Intervention | Functional Outcomes of Sleep Questionnaire, Short Form | 0.33 units on a scale; change from baseline |
| Placebo Intervention | Functional Outcomes of Sleep Questionnaire, Short Form | 0 units on a scale; change from baseline |
Secondary
Hypoxic Burden
Desaturation area under curve × event frequency, % change from baseline
Time frame: one month
Population: secondary outcomes are presented as per primary outcome
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Active Intervention | Hypoxic Burden | -15.0 %.min/hr; % change from baseline |
| Placebo Intervention | Hypoxic Burden | -8.7 %.min/hr; % change from baseline |
Secondary
Sleep Apnea Quality of Life Index, Short Form
Disease-specific quality of life on scale of 1-7, higher values indicate greater sleep-apnea related quality of life
Time frame: one month
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Active Intervention | Sleep Apnea Quality of Life Index, Short Form | 0.3 units on a scale; change from baseline |
| Placebo Intervention | Sleep Apnea Quality of Life Index, Short Form | 0.4 units on a scale; change from baseline |