Combination Pharmacological Interventions for Multiple Mechanisms of Obstructive Sleep Apnea

Study Overview
=================
Brief Summary
-----------------
Currently, there is no pharmacological intervention for OSA that targets multiple pathophysiological deficits in combination. Here the investigators study the effect on sleep apnea severity of combinations of pharmacological agents that stimulate the pharyngeal muscles, stabilize ventilatory control, and increase the arousal threshold.

Detailed Description
-----------------
The primary goal of the current study is to determine the effect of combination therapy targeting phenotypic traits on OSA severity. Specifically, the investigators will assess the effect of combination pharmacological therapy on OSA severity as measured by the apnea-hypopnea index and the arousal index (co-primary outcome variables). The investigators will also estimate the effects of the interventions on the physiological traits responsible for OSA using polysomnography, namely: Pharyngeal anatomy and its propensity towards collapse The ability of the upper airway dilator muscles to activate and reopen the airway during sleep (i.e. neuromuscular compensation) Arousal threshold from sleep (i.e. the propensity for hypopneas/apneas to lead to arousal and fragmented sleep). Stability of the ventilatory control system feedback loop (i.e. loop gain). Baseline traits will be used to examine whether patient characteristics influence the responses to each combination of interventions (i.e. muscles, muscles plus loop gain, muscles plus arousal threshold).

Official Title
-----------------
Combination Pharmacological Interventions for Multiple Mechanisms of Obstructive Sleep Apnea

Conditions
-----------------
Sleep Apnea

Intervention / Treatment
-----------------
* Drug: SAS0421a
* Drug: SAS0421b
* Drug: SAS0421c
* Drug: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Ages 18 - 79 years Suspected or diagnosed OSA 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 SAS0421a and SAS0421b, including: hypersensitivity to SAS0421a and SAS0421b (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 Additional contraindications for SAS0421c, including: Use more than 500 mg/day of Aspirin Allergies to this drug class Adrenocortical insufficiency Low sodium or potassium hyperchloremic acidosis Claustrophobia Pregnancy or nursing

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 79 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAS0421a, SAS0421b and SAS0421c<br>Participants will take SAS0421a, SAS0421b and SAS0421c for 3 days. Half doses will be given on the first night. | Drug: SAS0421a<br>* treatment will be given for 3 days<br>Drug: SAS0421b<br>* treatment will be given for 3 days<br>Drug: SAS0421c<br>* treatment will be given for 3 days<br>|
| Active Comparator: SAS0421a and SAS0421b<br>Participants will take SAS0421a and SAS0421b for 3 days. Half doses will be given on the first night. | Drug: SAS0421a<br>* treatment will be given for 3 days<br>Drug: SAS0421b<br>* treatment will be given for 3 days<br>|
| Active Comparator: SAS0421c<br>Participants will take SAS0421c for 3 days. Half doses will be given on the first night. | Drug: SAS0421c<br>* treatment will be given for 3 days<br>|
| Placebo Comparator: Placebo<br>Participants will take placebos for 3 days. | Drug: placebo<br>* placebo will be given for 3 days<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Apnea-hypopnea index [AHI] | Apneas and hypopneas per hour (3% desat and/or arousal), % change from baseline | 3 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hypoxic Burden | Desaturation area under curve × event frequency | 3 days | 
| Arousal Index | Number of arousals per hour (>=3-sec), % change from baseline | 3 days | 
| Visual Analog Scale for Sleep Quality | Sleep Quality 0-10 scale, 0 worst sleep quality, 10 best sleep quality | 3 days | 
| Visual Analog Scale for Waking Unrefreshed | Waking Unrefreshed 0-10 scale, 0 extremely refreshed, 10 extremely unrefreshed | 3 days |