Clinical trial NCT04444778: Intermitent Hypoxia and Its Pathophysiology Consequences in the Sleep Apnea-Hypopnea Syndrome.
Official title: Intermitent Hypoxia and Its Pathophysiology Consequences in the Sleep Apnea-Hypopnea Syndrome. Basic, Clinical and Therapeutically Study.
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: NA
Conditions: Sleep Apnea, Obstructive
Keywords: sleep apnea syndrome
Lead sponsor: Fundació d'investigació Sanitària de les Illes Balears
Sponsor class: OTHER_GOV
Collaborators: name: Instituto de Salud Carlos III
First posted: 2020-06-24
Enrollment: 130
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Clinical trial on the effect of continuous positive pressure (CPAP). Objectives: 1) To assess the total or partial recovery of oxidative and inflammatory damage after recovering IH. 2) To check whether the results obtained in vitro on the recovery of the damage according to the form of manifestation of IH are validated in SAHS patients. 3) To determine if CPAP reduces nighttime blood pressure and arterial stiffness depending on whether or not patients have a non-dipping pattern of blood pressure and depending on the degree of correction of IH. 4) To clarify whether residual nocturnal hypoxemia influences the recovery of oxidative and inflammatory damage in patients. 5) To determine nasal and intestinal microbioma and the effect of CPAP treatment

Detailed description: Design: Randomized, parallel group, non-blinded, controlled clinical trial compared with conventional treatment.

A. Protocol and intervention Patients with an AHI\>30 h-1 will be assigned, using a 1:1 randomization table, to lifestyle recommendations treatment or to lifestyle recommendations plus nasal CPAP, for a period of 4 months. CPAP pressure will be titled with automatic using an AutoSet II device, ResMed.

B. Sample size For the estimation of the sample size, previous data from our group were used. In this case, in order to compare the effect of CPAP in a subgroup of patients with well-controlled OSA and in another with residual hypoxemia; it would be necessary to randomize a total of 85 patients with OSA.

C. Ethical considerations

* Indication of CPAP treatment for the prevention of cardiovascular morbidity and mortality in OSA patients without daytime sleepiness is not yet accepted.
* Those patients with a urgent study indication for the diagnosis and treatment of respiratory sleep disorders (professional drivers, respiratory failure or risk professions) will be excluded from the project. In the other cases, the delay in healthcare for the performance of Polysomnography and CPAP titration exceeds the duration of the study, therefore that patients assigned to the control arm (conventional treatment) will not be exposed to a higher risk than the general population.

D. Methods

* Polysomnography. It will be used as a screening test previous the randomization of the included patients. The exploration and its interpretation will be carried out following the recommendations of the American Academy of Sleep Medicine. Based on the results of this test, only those patients with an AHI will continue in the study when AHI \>30 h-1. In these patients the determinations listed below will be carried out immediately before randomization (visit 1), at 4 weeks (visit 2), 16 weeks (visit 4) of allocation to the corresponding treatment group
* Clinical data: The medication used and other associated diseases already diagnosed will be recorded.
* Vital signs: recording of blood pressure, by means of a conventional triple taking, and heart rate.
* Anthropometric characteristics: age and weight in basal conditions, the perimeter of the neck and waist / hip index will be measured. The lean mass index will be determined using a Bodystat 1500 impedance system (Bodystat Ltd, United Kingdom).
* Questionnaires: Epworth Sleepiness Scale, generic health-related quality of life (SF-12 and EuroQoL) and daily physical activity (International Physical Activity Questionnaire or iPAQ).
* Laboratory findings: blood count, coagulation, creatinine, serum sodium and potassium; glycated hemoglobin (HbA1c) and blood glucose and insulin levels in fasting, from these values will determine the resistance and sensitivity to insulin using the HOMA and QUICKI indices; total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides; and troponin I, homocysteine, NT-pro BNP and highly sensitive C-reactive protein.
* Blood venous samples. 20 mL of venous blood will be collected, storing the plasma obtained at -80 ºC for subsequent determination of inflammatory markers (IL-1ß, IL-6, IL-8, HIF 1- 'NF \* + and TNF-a), oxidative stress (8-isoprostane), endothelial damage (endothelin, angiotensin II, VCAM-1 and ICAM-1), of sympathetic activity (neuropeptide Y, metanephrines) and appetite-regulating hormones (leptin and adiponectin).
* Plasma proteins from peripheral blood samples will be analyzed using a high-throughput multiplex immunoassay technology based on the Proximity Extension Assays (PEA) (OLINK Bioscience, Uppsala, Sweden). Olink (OLINK Bioscience, Uppsala, Sweden).
* Night pulse oximetry. To assess the existence of residual nocturnal hypoxemia.
* Arterial stiffness. According to the recommendations by Sphygmo-Corsystem (version 7, AtCor Medical, Sydney, Australia).
* Study of the gut and pharyngeal microbiota by massive sequencing (next generation sequencing) after PCR amplification of the 16S rRNA gene, paired-end sequencing with Illumina technology (16S Amplicon and XT Nextera Metagenomic) and subsequent metataxonomic analysis of the microbial populations.
* Ambulatory blood pressure monitoring (ABPM) with Mortara's Ambulo 2400 ambulatory blood pressure device.
* In the patients assigned to the CPAP treatment arm, a count of the hours of use of the CPAP will be carried out at each visit by directly reading the automatic counter of each equipment.

Statistic analysis The data will be expressed as mean ± standard deviation, median (interquartile range) or percentage, depending on their type and distribution. For comparison between groups Student's t-test, the U-Mann-Whitney or the chi-square test will be used, as appropriate. The relations between variables will be analyzed using Pearson's correlation and multiple linear regression analysis. The effect of treatment will be evaluated using general linear models and repeated measures analysis of variance, with multiple comparisons post-hoc using the Bonferroni test. A multiple logistic regression model will be applied to determine the related variables with a response to treatment. Values of p \<0.05 will be considered statistically significant. The statistical study will be performed with the SPSS program version 15.0.

Eligibility criteria: Inclusion Criteria:

* Cases: patients with AHI \> 30
* Controls: subjects with AHI \< 5 and Epworth \>10

Exclusion Criteria:

* Epworth\>18
* BMI\<40Kg/M2
* Arterial Hypertension
* Mellitus Diabetes
* Cerebrovascular disease
* Ischemic heart disease
* Cardiac arrhythmia
* Chronic cardiovascular diseases
* Daytime Oxygen saturation\>95%
* Risk professions (professional drivers)
* Concomitant treatment with antihypertensives, statins, antidiabetics, beta-blockers or systemics corticosteroids.
* Pretreatment with CPAP.
* Participation in another clinical trial thirty days prior to randomization

Primary outcomes:
measure: Change from baseline in 8 isoprostane levels
timeFrame: 4 months
measure: Change from baseline in microbiota population diversity from stool samples
timeFrame: 4 months
measure: Change from baseline in microbiota population diversity from nasopharyngeal samples
timeFrame: 4 months
measure: Change from baseline in microbiota population abundance from stool samples
timeFrame: 4 months
measure: Change from baseline in microbiota population abundance from nasopharyngeal samples
timeFrame: 4 months
measure: Change from baseline in microbiota population color maps from stool samples
timeFrame: 4 months
measure: Change from baseline in microbiota color maps from nasopharyngeal samples
timeFrame: 4 months
Secondary outcomes:
measure: Augmentation index (%)
timeFrame: Baseline and 4 months
measure: Pulse wave velocity (m/sec)
timeFrame: Baseline and 4 months
measure: Aortic systolic blood pressure central (mmHg)
timeFrame: Baseline and 4 months
measure: Diastolic blood pressure central (mmHg)
timeFrame: Baseline and 4 months
measure: Subendocardial viability ratio (%)
timeFrame: Baseline and 4 months
measure: Central augmentation pressure (mmHg)
timeFrame: Baseline and 4 months
measure: Time to reflection (ms)
timeFrame: Baseline and 4 months
measure: Peripheral systolic blood pressure (mmHg)
timeFrame: Baseline and 4 months
measure: Peripheral diastolic blood pressure (mmHg)
timeFrame: Baseline and 4 months
measure: Nocturnal blood pressure dipping
timeFrame: Baseline and 4 months
measure: Nocturnal hypertension.
timeFrame: Baseline and 4 months
measure: Patients with undiagnosed hypertension
timeFrame: Baseline and 4 months
measure: C-reactive protein (CRP)
timeFrame: Baseline and 4 months
measure: Homocysteine
timeFrame: Baseline and 4 months
measure: Endothelin
timeFrame: Baseline and 4 months
measure: 8 isoprostane levels in OSA and in non-OSA patients
timeFrame: Baseline
measure: Lipid profile
timeFrame: Baseline and 4 months
measure: Circulating inflammatory proteomic profile in OSA
timeFrame: Baseline and 4 months
measure: Systemic inflammation.
timeFrame: Baseline and 4 months
measure: Intake-regulating hormones.
timeFrame: Baseline and 4 months
measure: Change from baseline in number of patients with desaturation index >3%
timeFrame: 4 months
measure: Microbiota population abundance from stool and nasopharyngeal samples in OSA and in non-OSA patients
timeFrame: Baseline
measure: Microbiota population diversity from stool and nasopharyngeal samples in OSA and in non-OSA patients
timeFrame: Baseline
measure: Microbiota population color maps from stool and nasopharyngeal samples in OSA and in non-OSA patients
timeFrame: Baseline
measure: Relationships of microbiota population diversity from stool and nasopharyngeal samples in OSA to blood pressure profile.
timeFrame: Baseline and 4 months
measure: Relationships of microbiota population abundance from stool and nasopharyngeal samples in OSA to blood pressure profile
timeFrame: Baseline and 4 months
measure: Relationships of microbiota population color maps from stool and nasopharyngeal samples in OSA to blood pressure profile
timeFrame: Baseline and 4 months
measure: Relationships of microbiota population diversity from stool and nasopharyngeal samples in OSA to augmentation index.
timeFrame: Baseline and 4 months
measure: Relationships of microbiota population abundance from stool and nasopharyngeal samples in OSA to augmentation index.
timeFrame: Baseline and 4 months
measure: Relationships of microbiota population color maps from stool and nasopharyngeal samples in OSA to augmentation index.
timeFrame: Baseline and 4 months
measure: Relationships of microbiota population diversity from stool and nasopharyngeal samples in OSA to pulse wave velocity.
timeFrame: Baseline and 4 months
measure: Relationships of microbiota population abundance from stool and nasopharyngeal samples in OSA to pulse wave velocity.
timeFrame: Baseline and 4 months
measure: Relationships of microbiota population color maps from stool and nasopharyngeal samples in OSA to pulse wave velocity.
timeFrame: Baseline and 4 months
Other outcomes:
Locations:
city: Palma
country: Spain
facility: Hospital Son Espases
state: Balearic Islands
city: Palma
country: Spain
facility: Hospital Son Llatzer
state: Balearic Islands
Study officials:
affiliation: Fundació d'investigació Sanitària de les Illes Balears
name: Alberto Alonso, Dr
role: PRINCIPAL_INVESTIGATOR
References: