Intermitent Hypoxia and Its Pathophysiology Consequences in the Sleep Apnea-Hypopnea Syndrome.

April 29, 2025 updated by: Alberto Alonso Fernandez

Intermitent Hypoxia and Its Pathophysiology Consequences in the Sleep Apnea-Hypopnea Syndrome. Basic, Clinical and Therapeutically Study.

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

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Enrolling by invitation

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
130

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

  • Spain
    • Balearic Islands
      • Palma, Balearic Islands, Spain, 07006
        • Hospital Son Espases
      • Palma, Balearic Islands, Spain, 07006
        • Hospital Son Llatzer

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Active Comparator: Continuous positive airway pressure
Diet and general life style recommendations plus continuous positive airway pressure (CPAP).
Device: CPAP
Continuous positive airway pressure
No Intervention: Conservative treatment
Diet and general life style recommendations.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Change from baseline in 8 isoprostane levels
Time Frame: 4 months
To compare the change in 8 isoprostane levels between the patients allocated to CPAP group and the control group
4 months
Change from baseline in microbiota population diversity from stool samples
Time Frame: 4 months
To compare the change in in microbiota population diversity, after massive sequencing and amplification of the 16S rRNA gene from stool samples between the patients allocated to CPAP group and the control group
4 months
Change from baseline in microbiota population diversity from nasopharyngeal samples
Time Frame: 4 months
To compare the change in microbiota population diversity, after massive sequencing and amplification of the 16S rRNA gene from nasopharyngeal samples between the patients allocated to CPAP group and the control group
4 months
Change from baseline in microbiota population abundance from stool samples
Time Frame: 4 months
To compare the change in microbiota population abundance, after massive sequencing and amplification of the 16S rRNA gene from stool samples between the patients allocated to CPAP group and the control group
4 months
Change from baseline in microbiota population abundance from nasopharyngeal samples
Time Frame: 4 months
To compare the change in microbiota population abundance, after massive sequencing and amplification of the 16S rRNA gene from nasopharyngeal samples between the patients allocated to CPAP group and the control group
4 months
Change from baseline in microbiota population color maps from stool samples
Time Frame: 4 months
To compare the change in microbiota population color maps, after massive sequencing and amplification of the 16S rRNA gene from stool samples between the patients allocated to CPAP group and the control group
4 months
Change from baseline in microbiota color maps from nasopharyngeal samples
Time Frame: 4 months
To compare the change in microbiota population color maps, after massive sequencing and amplification of the 16S rRNA gene from nasopharyngeal samples between the patients allocated to CPAP group and the control group
4 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Change from baseline in number of patients with desaturation index >3%
Time Frame: 4 months
To compare the change from baseline in number of patients with desaturation index >3% between the patients allocated to CPAP group and the control group
4 months
Microbiota population diversity from stool and nasopharyngeal samples in OSA and in non-OSA patients
Time Frame: Baseline
To compare microbiota population diversity from stool and nasopharyngeal samples in OSA and in non-OSA patients
Baseline
Microbiota population color maps from stool and nasopharyngeal samples in OSA and in non-OSA patients
Time Frame: Baseline
To compare microbiota population color maps from stool and nasopharyngeal samples in OSA and in non-OSA patients
Baseline
Augmentation index (%)
Time Frame: Baseline and 4 months
To compare Augmentation index (%) in OSA and in non-OSA patients, and the change from baseline between the patients allocated to CPAP group and the control group.
Baseline and 4 months
Pulse wave velocity (m/sec)
Time Frame: Baseline and 4 months
To compare pulse wave velocity (m/sec) in OSA and in non-OSA patients, and the change from baseline between the patients allocated to CPAP group and the control group.
Baseline and 4 months
Aortic systolic blood pressure central (mmHg)
Time Frame: Baseline and 4 months
To compare systolic blood pressure central (mmHg) in OSA and in non-OSA patients, and the change from baseline between the patients allocated to CPAP group and the control group.
Baseline and 4 months
Diastolic blood pressure central (mmHg)
Time Frame: Baseline and 4 months
To compare diastolic blood pressure central (mmHg) in OSA and in non-OSA patients, and the change from baseline between the patients allocated to CPAP group and the control group.
Baseline and 4 months
Subendocardial viability ratio (%)
Time Frame: Baseline and 4 months
To compare subendocardial viability ratio (%) in OSA and in non-OSA patients, and the change from baseline between the patients allocated to CPAP group and the control group.
Baseline and 4 months
Central augmentation pressure (mmHg)
Time Frame: Baseline and 4 months
To compare central augmentation pressure (mmHg) in OSA and in non-OSA patients, and the change from baseline between the patients allocated to CPAP group and the control group.
Baseline and 4 months
Time to reflection (ms)
Time Frame: Baseline and 4 months
To compare time to reflection (ms) in OSA and in non-OSA patients, and the change from baseline between the patients allocated to CPAP group and the control group.
Baseline and 4 months
Peripheral systolic blood pressure (mmHg)
Time Frame: Baseline and 4 months
To compare peripheral systolic blood pressure (mmHg) in OSA and in non-OSA patients, and the change from baseline between the patients allocated to CPAP group and the control group.
Baseline and 4 months
Peripheral diastolic blood pressure (mmHg)
Time Frame: Baseline and 4 months
To compare diastolic blood pressure central (mmHg) in OSA and in non-OSA patients, and the change from baseline between the patients allocated to CPAP group and the control group.
Baseline and 4 months
Nocturnal blood pressure dipping
Time Frame: Baseline and 4 months
To compare number of patients with nocturnal blood pressure dipping in OSA and in non-OSA patients, and the change from baseline between the patients allocated to CPAP group and the control group.
Baseline and 4 months
Nocturnal hypertension.
Time Frame: Baseline and 4 months
To compare number of patients with nocturnal hypertension in OSA and in non-OSA patients, and the change from baseline between the patients allocated to CPAP group and the control group.
Baseline and 4 months
Patients with undiagnosed hypertension
Time Frame: Baseline and 4 months
To compare number of patients with undiagnosed hypertension in OSA and in non-OSA patients, and the change from baseline between the patients allocated to CPAP group and the control group.
Baseline and 4 months
C-reactive protein (CRP)
Time Frame: Baseline and 4 months
To compare CRP in OSA and in non-OSA patients, and the change from baseline between the patients allocated to CPAP group and the control group.
Baseline and 4 months
Homocysteine
Time Frame: Baseline and 4 months
To compare homocysteine (μmol/L) in OSA and in non-OSA patients, and the change from baseline between the patients allocated to CPAP group and the control group.
Baseline and 4 months
Endothelin
Time Frame: Baseline and 4 months
To compare endothelin levels in OSA and in non-OSA patients, and the change from baseline between the patients allocated to CPAP group and the control group.
Baseline and 4 months
8 isoprostane levels in OSA and in non-OSA patients
Time Frame: Baseline
To compare 8 isoprostane levels in OSA and in non-OSA patients.
Baseline
Lipid profile
Time Frame: Baseline and 4 months
To compare lipid profile with same units of measure (all in mg/dL) in OSA and in non-OSA patients and to compare baseline (OSA vs. non-OSA), and the change from baseline in lipid profile between the patients allocated to CPAP group and the control group.
Baseline and 4 months
Circulating inflammatory proteomic profile in OSA
Time Frame: Baseline and 4 months
To compare the circulating inflammatory proteomic profile using proximity expression assay technology (Olink®, Sweden, which comprised 96 proteins. All data are expressed as normalized protein expression values) in OSA and in non-OSA patients and to compare the change from baseline the circulating inflammatory proteomic profile between the patients allocated to CPAP group and the control group.
Baseline and 4 months
Systemic inflammation.
Time Frame: Baseline and 4 months
To compare systemic inflammation (IL-6, IL-8, TNF-1alpha) with same units of measure (all in pg/mL) in OSA and in non-OSA patients and to compare the change from baseline between the patients allocated to CPAP group and the control group.
Baseline and 4 months
Intake-regulating hormones.
Time Frame: Baseline and 4 months
To compare intake-regulating hormones with same units of measure (all in µg/mL) in OSA and in non-OSA patients and to compare the change from baseline between the patients allocated to CPAP group and the control group.
Baseline and 4 months
Microbiota population abundance from stool and nasopharyngeal samples in OSA and in non-OSA patients
Time Frame: Baseline
To compare microbiota population abundance from stool and nasopharyngeal samples in OSA and in non-OSA patients
Baseline
Relationships of microbiota population diversity from stool and nasopharyngeal samples in OSA to blood pressure profile.
Time Frame: Baseline and 4 months
To relate microbiota population diversity from stool and nasopharyngeal samples to blood pressure profile.
Baseline and 4 months
Relationships of microbiota population abundance from stool and nasopharyngeal samples in OSA to blood pressure profile
Time Frame: Baseline and 4 months
To relate microbiota population diversity from stool and nasopharyngeal samples to blood pressure profile.
Baseline and 4 months
Relationships of microbiota population color maps from stool and nasopharyngeal samples in OSA to blood pressure profile
Time Frame: Baseline and 4 months
To relate microbiota population color maps from stool and nasopharyngeal samples to blood pressure profile.
Baseline and 4 months
Relationships of microbiota population diversity from stool and nasopharyngeal samples in OSA to augmentation index.
Time Frame: Baseline and 4 months
To relate microbiota population diversity from stool and nasopharyngeal samples to augmentation index.
Baseline and 4 months
Relationships of microbiota population abundance from stool and nasopharyngeal samples in OSA to augmentation index.
Time Frame: Baseline and 4 months
To relate microbiota population diversity from stool and nasopharyngeal samples to augmentation index.
Baseline and 4 months
Relationships of microbiota population color maps from stool and nasopharyngeal samples in OSA to augmentation index.
Time Frame: Baseline and 4 months
To relate microbiota population color maps from stool and nasopharyngeal samples to augmentation index.
Baseline and 4 months
Relationships of microbiota population diversity from stool and nasopharyngeal samples in OSA to pulse wave velocity.
Time Frame: Baseline and 4 months
To relate microbiota population diversity from stool and nasopharyngeal samples to pulse wave velocity.
Baseline and 4 months
Relationships of microbiota population abundance from stool and nasopharyngeal samples in OSA to pulse wave velocity.
Time Frame: Baseline and 4 months
To relate microbiota population diversity from stool and nasopharyngeal samples to pulse wave velocity.
Baseline and 4 months
Relationships of microbiota population color maps from stool and nasopharyngeal samples in OSA to pulse wave velocity.
Time Frame: Baseline and 4 months
To relate microbiota population color maps from stool and nasopharyngeal samples to pulse wave velocity.
Baseline and 4 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Alberto Alonso Fernandez

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Instituto de Salud Carlos III

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Alberto Alonso, Dr, Fundació d'investigació Sanitària de les Illes Balears

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
July 20, 2020

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
April 16, 2025

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
May 6, 2025

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
June 6, 2020

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 19, 2020

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
June 24, 2020

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
May 1, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 29, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
April 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • PI19/00875

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Sleep Apnea, Obstructive

Clinical Trials on CPAP

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Cookie Settings

We use cookies to ensure that we give you the best experience on our website. For more details carefully read our Privacy and Cookies Policy. ...>>>You can change your preferences or withdraw your consent at any time by deleting the cookies from your website or computer as described in the policy. Please accept it and choose your preferences by ticking the corresponding boxes in the "Manage Settings" section below. Please carefully read our Terms of Service before you proceed with using any part of this website.
«Manage Settings