Effect of AD128 to Treat Obstructive Sleep Apnea

Study Overview
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Brief Summary
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This study evaluates the combination of two drugs (AD128), to treat obstructive sleep apnea (OSA) severity. After a baseline evaluation and during 7 days, half of the participants will randomly receive this drug combination (AD128) and the other will receive a placebo, i.e. a drug without pharmaceutical effect. Neither the participants, nor the investigators will know in which arm participants are until the end of the study. After one week of trial, an evaluation will be perform and will be follow by one week without any treatment. During the third and last week of trial, there will be a crossover of the groups, i.e. the participants of the first group who took the two drugs (AD128) during the first week will take a placebo and those who took the placebo will take the drugs combination.

Official Title
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Effect of AD128 on Obstructive Sleep Apnea Severity: a Randomized, Placebo-controlled, Double-blind, Cross-over Study

Conditions
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Sleep Apnea, Obstructive

Intervention / Treatment
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* Drug: AD128
* Drug: Mannitol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults (>18 years and ≤ 65 years) New or previous diagnosis of OSA with an AHI > 15/h on a polygraphic or polysomnographic recording (Participants already treated with continuous positive airway pressure (CPAP) or mandibular advancement device can be included but a 7-days wash-out period is required before the beginning of the protocol and CPAP usage will not be possible during the whole protocol duration), Informed Consent as documented by signature (Appendix Informed Consent Form) Exclusion Criteria: History of seizures, History of glaucoma, History of benign prostatic hyperplasia, organic miction disorder or urinary retention, Gastrointestinal disease (e.g. stenosis, occlusion, ulcerative colitis, toxic megacolon, hiatal hernia…) Cardiac arrhythmia, History of bipolar disorder, Use of respiratory stimulants or depressants, Use of Hypnotics, Use of Central nervous system stimulants, Use of Monoamine oxidase inhibitors (MAOIs) antidepressant, Major depressive disorder, Central sleep apnea representing more than 10% of all respiratory events Contraindications to the class of drugs under study, e.g. known hypersensitivity or allergy to class of drugs or the investigational product, Pregnant or breast feeding female participants or participants who intend to become pregnant during the study (However, there is no contraindication to contraception), Other clinically significant concomitant disease states (renal failure, hepatic dysfunction, severe cardiovascular or respiratory disease, myasthenia gravis, cerebral sclerosis), Known or suspected non-compliance, drug or alcohol abuse, Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant, Participation in another study with investigational drug within the 30 days preceding and during the present study Use or morphinic and derivatives which may influence sleep, Refusal to be informed in case of incidental findings.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This is a randomized, placebo-controlled, double-blind crossover study
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AD128<br>The study specific intervention includes per oral administration of two capsules of AD128, once daily, just before lights out, for 7 days. | Drug: AD128<br>* Oral administration of two capsules before sleep for 7 days.<br>|
| Placebo Comparator: placebo<br>Two placebo capsules (Mannitol) will be administered for the control intervention once daily, just before light outs, for one week. | Drug: Mannitol<br>* Oral administration of two capsules before sleep for 7 days.<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Apnea-hypopnea index (AHI) | Change from baseline AHI (events/h) measured via polysomnography between the week of investigational treatment (AD128) and the week of placebo treatment. | Day 7 and 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oxygen desaturation index (ODI) | Change from baseline ODI (events/h) measured via polysomnography between the week of investigational treatment (AD128) and the week of placebo treatment. | Day 7 and 21 | 
| Oxygen desaturation index (ODI) in REM and NREM | Change from baseline ODI (events/h) measured via polysomnography during rapid eye movement (REM) and non rapid eye movement (NREM) sleep between the week of investigational treatment (AD128) and the week of placebo treatment. | Day 7 and 21 | 
| Hypoxic load | Change from baseline hypoxic load (area under the curve of 3% oxygen desaturation related to apnea-hypopnea events) measured via polysomnography between the week of investigational treatment (AD128) and the week of placebo treatment. | Day 7 and 21 | 
| Hypoxic load in REM and NREM | Change from baseline hypoxic load (area under the curve of 3% oxygen desaturation related to apnea-hypopnea events) measured via polysomnography during rapid eye movement (REM) and non rapid eye movement (NREM) sleep between the week of investigational treatment (AD128) and the week of placebo treatment. | Day 7 and 21 | 
| Arousal index | Change from baseline arousal index (events/h) measured via polysomnography between the week of investigational treatment (AD128) and the week of placebo treatment. | Day 7 and 21 | 
| Arousal index in REM and NREM | Change from baseline arousal index (events/h) measured via polysomnography during rapid eye movement (REM) and non rapid eye movement (NREM) sleep between the week of investigational treatment (AD128) and the week of placebo treatment. | Day 7 and 21 | 
| Pulse wave amplitude (PWA) drops | Change from baseline PWA drops (events/h) measured via polysomnography between the week of investigational treatment (AD128) and the week of placebo treatment. | Day 7 and 21 | 
| Pulse wave amplitude (PWA) drops in REM and NREM | Change from baseline PWA drops (events/h) measured via polysomnography during rapid eye movement (REM) and non rapid eye movement (NREM) sleep between the week of investigational treatment (AD128) and the week of placebo treatment. | Day 7 and 21 | 
| Apnea-hypopnea index (AHI) in REM and NREM | Change from baseline AHI (events/h) measured via polysomnography during rapid eye movement (REM) and non rapid eye movement (NREM) sleep between the week of investigational treatment (AD128) and the week of placebo treatment. | Day 7 and 21 | 
| Percentage of REM sleep | Change from baseline REM sleep (% of total sleep time) measured via polysomnography between the week of investigational treatment (AD128) and the week of placebo treatment. | Day 7 and 21 | 
| Percentage of N1 | Change from baseline sleep stage 1 (N1: % of total sleep time) measured via polysomnography between the week of investigational treatment (AD128) and the week of placebo treatment. | Day 7 and 21 | 
| Percentage of N2 | Change from baseline sleep stage 2 (N2: % of total sleep time) measured via polysomnography between the week of investigational treatment (AD128) and the week of placebo treatment. | Day 7 and 21 | 
| Percentage of N3 | Change from baseline sleep stage 3 (N3: % of total sleep time) measured via polysomnography between the week of investigational treatment (AD128) and the week of placebo treatment. | Day 7 and 21 | 
| Percentage of alpha wave | Change from baseline alpha wave frequency (8-13 Hz - % of total sleep time) measured via polysomnography in REM and NREM between the week of investigational treatment (AD128) and the week of placebo treatment. | Day 7 and 21 | 
| Percentage of beta wave | Change from baseline beta wave frequency (13-30 Hz - % of total sleep time) measured via polysomnography in REM and NREM between the week of investigational treatment (AD-128) and the week of placebo treatment. | Day 7 and 21 | 
| Percentage of gamma wave | Change from baseline gamma wave frequency (30-100 Hz - % of total sleep time) measured via polysomnography in REM and NREM between the week of investigational treatment (AD128) and the week of placebo treatment. | Day 7 and 21 | 
| Percentage of theta wave | Change from baseline theta wave frequency (4-8 Hz - % of total sleep time) measured via polysomnography in REM and NREM between the week of investigational treatment (AD128) and the week of placebo treatment. | Day 7 and 21 | 
| Percentage of delta wave | Change from baseline delta wave frequency (1-4 Hz - % of total sleep time) measured via polysomnography in REM and NREM between the week of investigational treatment (AD128) and the week of placebo treatment. | Day 7 and 21 | 
| Reaction time PVT | Change from baseline reaction time (in ms) during Psychomotor Vigilance Task (PVT). During 10 min, subjects were instructed to press a button as quickly as possible when a red millisecond-counter appeared on a small screen (PVT-192, Ambulatory Monitoring Inc.). | Day 7 and 21 | 
| Lapse PVT | Change from baseline lapse time (in ms) during Psychomotor Vigilance Task (PVT) and defined as reaction time > 500 ms). During 10 min, subjects were instructed to press a button as quickly as possible when a red millisecond-counter appeared on a small screen (PVT-192, Ambulatory Monitoring Inc.). | Day 7 and 21 | 
| Chronic Excessive daytime sleepiness (EDS) | Change from baseline Epworth Sleepiness Scale (ESS) score between the week of investigational treatment (AD128) and the week of placebo treatment. The ESS is a 8-item questionnaire. ESS score can range from 0 to 24. The higher the ESS score, the higher daytime sleepiness. | Day 7 and 21 | 
| Acute Excessive daytime sleepiness (EDS) | Change from baseline Stanford Sleepiness Scale (SSS) score between the week of investigational treatment (AD128) and the week of placebo treatment. Consisting of only one item, the scale requires respondents to select one of seven statements best representing their level of perceived sleepiness. The scale range from 1 to 7. Higher score indicates greater sleepiness. | Day 7 and 21 | 
| Sleep quality | Change from baseline visual analogic scale (VAS) sleep quality score between the week of investigational treatment (AD128) and the week of placebo treatment. Score ranges from 0 to 10. Higher score indicates better sleep quality. | Day 7 and 21 | 
| Fatigue | Change from baseline Pichot scale score between the week of investigational treatment (AD128) and the week of placebo treatment. The Pichot scale is a 8-items auto-questionnaire to assess excessive fatigue. Score varies between 0 and 32, a score > 22 indicates excessive fatigue. | Day 7 and 21 | 
| Systolic and diastolic blood pressure | Change from baseline office systolic and diastolic blood pressure (BP in mm Hg) between the week of investigational treatment (AD128) and the week of placebo treatment. The Pichot scale is a 8-items auto-questionnaire to assess excessive fatigue. Score varies between 0 and 32, a score > 22 indicates excessive fatigue. | Day 7 and 21 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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obstructive sleep apnea, pharmacologic treatment, sleepiness, vigilance