Combination Pharmacological Interventions for Multiple Mechanisms of Obstructive Sleep Apnea (ComboPlus)

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.

Study Overview

• Status: Completed
• Conditions: Sleep Apnea
• Intervention / Treatment: Drug: SAS0421a; Drug: SAS0421b; Drug: SAS0421c; Drug: placebo

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).

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash University
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 79 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

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

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Visual Analog Scale for Excessive Fatigue	Excessive Fatigue 0-10 scale, 0 no fatigue, 10 highly fatigued	3 days
Visual Analog Scale for Low Energy	Low Energy 0-10 scale, 0 no trouble with energy, 10 extremely low energy	3 days
Visual Analog Scale for Treatment Satisfaction	Treatment Satisfaction 0-10 scale, 0 extremely dissatisfied, 10 extremely satisfied	3 days
Proportion of Total Sleep Time in non-REM Stage 1	% Total sleep time	3 days

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: Apnimed

Study record dates

Study Major Dates

• Study Start (Actual): January 14, 2019
• Primary Completion (Actual): July 3, 2021
• Study Completion (Actual): July 3, 2021

Study Registration Dates

• First Submitted: March 26, 2019
• First Submitted That Met QC Criteria: March 26, 2019
• First Posted (Actual): March 27, 2019

Study Record Updates

• Last Update Posted (Actual): March 2, 2022
• Last Update Submitted That Met QC Criteria: February 28, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Respiratory Tract Diseases; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Signs and Symptoms, Respiratory; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Apnea
• Other Study ID Numbers: 2019P000421

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Will IPD be available? Yes What data will be shared? All IPD collected during the study, after deidentification.

When will data be available? Immediately after publication. No end date. With whom? Researchers who provide a methodologically sound proposal. For what types of analyses? Any purpose.

• IPD Sharing Time Frame: Immediately after publication. No end date.
• IPD Sharing Access Criteria: 1-page proposals should be directed to Dr. Scott Sands (sasands@bwh.harvard.edu). To gain access, requestors will be asked to sign a data use agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes