Randomized Controlled Trial Between Auto-titration and Manual Titration of Non-invasive Ventilation in Obesity Hypoventilation Syndrome

Study Overview
=================
Brief Summary
-----------------
Primary Objectives: To evaluate the effectiveness in the obesity hypoventilation syndrome (OHS) treatment with non-invasive ventilation (NIV) set manually by polysomnography compared to the same treatment with a respirator with automatic NIV adjustment, analyzing as primary variable PaCO2 and as operational variables dropout rate for medical reasons and mortality. Secondary objectives: cost-effectiveness, clinical and functional improvement in wakefulness and during sleep, quality of life, blood pressure monitoring for 24 hours, incidence and evolution of cardiovascular events and use of health resources. Other objectives: 1) effectiveness of treatments in the following subgroups of patients: gender, age, socioeconomic status, severity of sleep apnea, VNI compliance, quality of life and comorbidities; 2) To evaluate the profile of patients with poor adherence to NIV based on clinical severity, gender, age and socioeconomic status in the whole sample and in both intervention groups.

Detailed Description
-----------------
Method: Prospective, blind researchers, randomized, controlled non-inferiority and cost-effectiveness relationship, with two parallel open groups. 200 OHS patients will be divided into two groups by simple randomization 1:1 and followed for one year. The premise of non-inferiority is -2 at the lower limit of the confidence interval 95% for the change in PCO2 between the arms being assessed by analysis of covariance, adjusted for 2-sided, age, sex, body mass index in intention-to-treat and per-protocol analysis. The cost-effectiveness will be performed by Bayesian techniques with sensitivity analysis.

Official Title
-----------------
Effectiveness of Noninvasive Ventilation Adjusted Automatically in the Obesity Hypoventilation Syndrome

Conditions
-----------------
Chronic Hypercapnic Respiratory Failure, Obesity Hypoventilation Syndrome

Intervention / Treatment
-----------------
* Device: Manual Non invasive ventilation titration
* Device: Automatic Non invasive ventilation titration


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Obesity Hypoventilation Syndrome defined by obesity (IMC≥30) and Hypercapnic respiratory failure (PCO 2> 45 mm Hg) in stable phase (PH≥7.35 without clinical signs of worsening in at least one previous month). Age between 18-80 years. Absence of other diseases causing hypercapnia as moderate or severe chronic obstructive pulmonary disease (FEV1> 70% predicted if FEV1 / FVC <70), neuromuscular, thoracic wall or metabolic disease; d) Absence of narcolepsy or restless legs syndrome. Overcome correctly a 30 minutes test of treatment with VNI in wakefulness. Exclusion Criteria: Psychophysical disability for questionnaires. Patients who cannot be evaluated by quality of life questionnaires because they present debilitating chronic disease. Chronic nasal obstruction that prevents the use of NIV. Pregnancy. No informed consent obtained.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, Randomized, double arm, double blind controlled trial.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Manual<br>In this group non invasive mechanical ventilation will be manually titrated during a polysomnography. The Philips A40 ventilator will be used in Spontaneous-Timed (ST) mode. | Device: Manual Non invasive ventilation titration<br>* Manual Group: during a complete polysomnography, adding transcutaneous capnography and the basic ventilators curves, the ventilators setting will be adjusted in order to correct respiratory events and patient-ventilator asyncrony. A 10 hours face-to-face investigator training meeting is programmed before opening the inclusion period.<br>|
| Active Comparator: Automatic<br>In this group the ventilator will run in an automatic mode (AVAPS) with the same Phillips A40 ventilator. | Device: Automatic Non invasive ventilation titration<br>* Automatic Group: the A40 ventilator in the automatic AVAPS mode will be adjusted in order to achieve 8-10 ml/kg of ideal weight.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in PaCO2 between arms | Arterial blood gases while room air breathing expressed in mmHg | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cost-effectiveness analysis by primary outcome | Cost-effectiveness analysis based on the primary outcome in mmHg Differences in within trial costs will be related with the differences in effectiveness (primary outcome) between arms using a probabilistic Bayesian approach to calculate the cost-effectiveness plane. | 1 year | 
| Cost-effectiveness analysis by QALY | Cost-effectiveness analysis based on the quality adjusted life year (QALY) Differences in within trial costs will be related with the differences in effectiveness (QALY) between arms using a probabilistic Bayesian approach to calculate the cost-effectiveness plane. | 1 year | 
| Change in subjective daytime sleepiness | Sleepiness evaluated by Epworth sleepiness scale, range from 0 to 24, being 0 the best result and 24 the worst. | 1 year | 
| Change in Quality of life measured by Functional Sleep Outcomes of Sleep Questionnaire (FOSQ) | Quality of life measured by Functional Sleep Outcomes of Sleep Questionnaire (FOSQ), range from 0 to 120, being 0 the worst result and 120 the best result . | 1 year | 
| Change in Quality of life measured by visual analogical wellbeing scale (VAWS) | Quality of life measured by visual analogical well-being scale (VAWS), range from 0 to 100, being 0 the worst result and 120 the best result . | 1 year | 
| Change in Quality of life measured by Euroqol 5D. | Quality of life measured by Euroqol 5D, range from 0 to 1, being 0 the worst result and 1 the best result . | 1 year | 
| Change in Quality of life measured by Short Form-36 (SF36), Mental component | Quality of life measured by Short Form-36 (SF36) Mental component,range from 0 to 100, being 0 the worst result and 100 the best result. | 1 year | 
| Change in Quality of life measured by Short Form-36 (SF36), Physical component | Quality of life measured by Short Form-36 (SF36) Physical component,range from 0 to 100, being 0 the worst result and 100 the best result. | 1 year | 
| Change in Bicarbonate arterial blood concentration | Arterial blood gases while breathing room air expressed in mmol/L | 1 year | 
| Change in PaO2 | Arterial blood gases while breathing room air expressed PaO2 in mmHg | 1 year | 
| Change in pH | Arterial blood gases while breathing room air | 1 year | 
| Change in polysomnographic Sleep periods | Standard polysomnography. time of sleep periods (Stage 1,2,3,4 and REM) in minutes. | 1 year | 
| Change in Arousal Index | Standard polysomnography, number of arousals per sleep hour | 1 year | 
| Change in Apnea-Hypopnea index | Standard polysomnography, number of apneas and hypoapneas per sleep hour | 1 year | 
| Change in Oxygen desaturation index | Standard polysomnography, number of 3% or more Oxygen desaturations per sleep hour | 1 year | 
| Change in Sleep time with Oxygen saturation below 90% | Standard polysomnography, percentage of sleep time with oxygen saturation below 90% | 1 year | 
| Change in polysomnographic parameters: Total Sleep time (TTS) | Standard polysomnography, time in minutes | 1 year | 
| Change in the blood pressure monitoring | The blood pressure will be monitored during 24 hours with a Blood Pressure Monitoring device before (baseline) and after intervention (1 year) in both arms measured in mmHg. Change in the mean blood pressure will be compared between arms | at baseline and after a year | 
| Incidental cardiovascular events | New hypertension diagnosis or anti-hypertensive treatment, atrial fibrillation, hospitalization for nonfatal myocardial infarction or instable angina, nonfatal stroke or transient ischemic attack or for heart failure episode, and cardiovascular death. Data obtained from official electronic health care databases | 1 year | 
| Health care resources utilization: Hospital admission | Hospital admission measured in number of events | 1 year | 
| Health care resources utilization: Hospital duration | Hospital duration measured in days of hospitalization | 1 year | 
| Health care resources utilization: ICU admission | ICU admission measured in numbers of events | 1 year | 
| Health care resources utilization: ICU duration | ICU duration measured in days of UCI admissions | 1 year | 
| Health care resources utilization: emergency visits | Emergency visits measured in number of events | 1 year | 
| Health care resources utilization: primary care visits | Primary care visits measured in number of events | 1 year | 
| Health care resources utilization: specialist visits | Specialist visits measured in number of events | 1 year | 
| Incidence of new adverse event | Number of adverse events based in CTCAE v4.0 | 1 year | 
| Side effects | Incidence or side effects of NIV in follow-up visits: excessive noise, headache, claustrophobia, difficulty in sleep conciliation or maintenance, expiration discomfort. | 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Chronic respiratory failure, Obesity, Non invasive mechanical ventilation