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

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ClinicalTrials.gov Identifier: NCT03892772
Recruitment Status : Recruiting
First Posted : March 27, 2019
Last Update Posted : July 31, 2019
Sponsor:
Information provided by (Responsible Party):
Scott Aaron Sands, Brigham and Women's Hospital

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.

Condition or disease Intervention/treatment Phase
Sleep Apnea Drug: SAS0421a Drug: SAS0421b Drug: SAS0421c Drug: SAS0421d Drug: placebo Phase 1 Phase 2

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).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Combination Pharmacological Interventions for Multiple Mechanisms of Obstructive Sleep Apnea
Actual Study Start Date : April 8, 2019
Estimated Primary Completion Date : April 15, 2020
Estimated Study Completion Date : April 15, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Sleep Apnea

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

Experimental: SAS0421a, SAS0421b and SAS0421d
Participants will take SAS0421a, SAS0421b and SAS0421d 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: SAS0421d
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

Placebo Comparator: Placebo
Participants will take placebos for 3 days.
Drug: placebo
placebo will be given for 3 days




Primary Outcome Measures :
  1. Apnea-hypopnea index [AHI] [ Time Frame: 3 days ]
    Apneas and hypopneas per hour (3% desat and/or arousal), % change from baseline

  2. Arousal index [ Time Frame: 3 days ]
    Scored EEG arousals per hour (>3 s), % change from baseline


Secondary Outcome Measures :
  1. Proportion of Total Sleep Time in non-REM Stage 1 [ Time Frame: 3 days ]
    % Total sleep time

  2. Hypoxic Burden [ Time Frame: 3 days ]
    Desaturation area under curve × event frequency

  3. Visual Analog Scale for Sleep Quality [ Time Frame: 3 days ]
    Sleep Quality 0-10 scale, 0 worst sleep quality, 10 best sleep quality

  4. Visual Analog Scale for Waking Unrefreshed [ Time Frame: 3 days ]
    Waking Unrefreshed 0-10 scale, 0 extremely refreshed, 10 extremely unrefreshed

  5. Morning Systolic Blood Pressure [ Time Frame: 3 days ]
    mmHg

  6. Morning Diastolic Blood Pressure [ Time Frame: 3 days ]
    mmHg


Other Outcome Measures:
  1. Visual Analog Scale for Excessive Fatigue [ Time Frame: 3 days ]
    Excessive Fatigue 0-10 scale, 0 no fatigue, 10 highly fatigued

  2. Visual Analog Scale for Low Energy [ Time Frame: 3 days ]
    Low Energy 0-10 scale, 0 no trouble with energy, 10 extremely low energy

  3. Visual Analog Scale for Treatment Satisfaction [ Time Frame: 3 days ]
    Treatment Satisfaction 0-10 scale, 0 extremely dissatisfied, 10 extremely satisfied



Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  • Ages 21 - 70 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
  • Additional contraindications for SAS0421d:

    · Current use of drugs that interact with SAS0421d

  • Allergy to lidocaine or oxymetazoline.
  • Claustrophobia
  • Pregnancy or nursing

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03892772


Contacts
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Contact: Scott A Sands, PhD 617-278-0911 sasands@bwh.harvard.edu

Locations
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United States, Massachusetts
Brigham and Women's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Lauren Hess    617-732-8976    lhess1@bwh.harvard.edu   
Sponsors and Collaborators
Brigham and Women's Hospital
Investigators
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Principal Investigator: Scott A Sands, PhD Brigham and Women's Hospital

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Responsible Party: Scott Aaron Sands, Assistant Professor of Medicine, Brigham and Women's Hospital
ClinicalTrials.gov Identifier: NCT03892772     History of Changes
Other Study ID Numbers: 2019P000421
First Posted: March 27, 2019    Key Record Dates
Last Update Posted: July 31, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: Immediately after publication. No end date.
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.

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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

Additional relevant MeSH terms:
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Apnea
Sleep Apnea Syndromes
Sleep Apnea, Obstructive
Respiration Disorders
Respiratory Tract Diseases
Signs and Symptoms, Respiratory
Signs and Symptoms
Sleep Disorders, Intrinsic
Dyssomnias
Sleep Wake Disorders
Nervous System Diseases