Combination Pharmacological Interventions for Multiple Mechanisms of Obstructive Sleep Apnea

Sleep Apnea Clinical Trial

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Official title:

Combination Pharmacological Interventions for Multiple Mechanisms of Obstructive Sleep Apnea

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03892772
• Other study ID #: 2019P000421
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: January 14, 2019
• Est. completion date: July 3, 2021

Study information

• Verified date: February 2022
• Source: Brigham and Women's Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 23
• Est. completion date: July 3, 2021
• Est. primary completion date: July 3, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 79 Years

Eligibility

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

Related Conditions & MeSH terms

• Apnea
• Sleep Apnea
• Sleep Apnea Syndromes
• Sleep Apnea, Obstructive

Intervention

Drug:
• SAS0421a
treatment will be given for 3 days
• SAS0421b
treatment will be given for 3 days
• SAS0421c
treatment will be given for 3 days
• placebo
placebo will be given for 3 days

Locations

Country	Name	City	State
Australia	Monash University	Clayton	Victoria
United States	Brigham and Women's Hospital	Boston	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Brigham and Women's Hospital	Apnimed

Countries where clinical trial is conducted

United States,  Australia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Visual Analog Scale for Excessive Fatigue	Excessive Fatigue 0-10 scale, 0 no fatigue, 10 highly fatigued	3 days
Other	Visual Analog Scale for Low Energy	Low Energy 0-10 scale, 0 no trouble with energy, 10 extremely low energy	3 days
Other	Visual Analog Scale for Treatment Satisfaction	Treatment Satisfaction 0-10 scale, 0 extremely dissatisfied, 10 extremely satisfied	3 days
Other	Proportion of Total Sleep Time in non-REM Stage 1	% Total sleep time	3 days
Primary	Apnea-hypopnea index [AHI]	Apneas and hypopneas per hour (3% desat and/or arousal), % change from baseline	3 days
Secondary	Hypoxic Burden	Desaturation area under curve × event frequency	3 days
Secondary	Arousal Index	Number of arousals per hour (>=3-sec), % change from baseline	3 days
Secondary	Visual Analog Scale for Sleep Quality	Sleep Quality 0-10 scale, 0 worst sleep quality, 10 best sleep quality	3 days
Secondary	Visual Analog Scale for Waking Unrefreshed	Waking Unrefreshed 0-10 scale, 0 extremely refreshed, 10 extremely unrefreshed	3 days