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

Effectiveness of Noninvasive Ventilation Adjusted Automatically in the Obesity Hypoventilation Syndrome

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.

Study Overview

• Status: Completed
• Conditions: Obesity Hypoventilation Syndrome; Chronic Hypercapnic Respiratory Failure
• Intervention / Treatment: Device: Manual Non invasive ventilation titration; Device: Automatic Non invasive ventilation titration

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.

• Study Type: Interventional
• Enrollment (Actual): 200
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Spain
  • Cáceres, Spain, 10003
    • Juan F. Masa

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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).
2. Age between 18-80 years.
3. 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.
4. Overcome correctly a 30 minutes test of treatment with VNI in wakefulness.

Exclusion Criteria:

1. Psychophysical disability for questionnaires.
2. Patients who cannot be evaluated by quality of life questionnaires because they present debilitating chronic disease.
3. Chronic nasal obstruction that prevents the use of NIV.
4. Pregnancy.
5. No informed consent obtained.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Manual; 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; 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.
Active Comparator: Automatic; In this group the ventilator will run in an automatic mode (AVAPS) with the same Phillips A40 ventilator.	Device: Automatic Non invasive ventilation titration; Automatic Group: the A40 ventilator in the automatic AVAPS mode will be adjusted in order to achieve 8-10 ml/kg of ideal weight.

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adherent vs. non-adherent to noninvasive ventilation therapy subgroups	Efficacy between arms measuring Epworth sleepiness scale (from 0 to 24 points) comparing adherent vs. non-adherent to non-invasive ventilation therapy subgroups (higher and lower of 4 hours per day)	1 year
Sleep apnea severity subgroup	Efficacy between arms measuring Epworth sleepiness scale (from 0 to 24 points) comparing sleep apnea severity subgroups measured by apnea and hypopnea index at baseline (higher and lower of the median)	1 year
Hypercapnia severity subgroup	Efficacy between arms measuring Epworth sleepiness scale (from 0 to 24 points) comparing hypercapnia severity subgroups measured by PaCO2 (mmHg) at baseline (higher and lower of the median)	1 year
Systemic hypertension subgroup	Efficacy between arms measuring Epworth sleepiness scale (from 0 to 24 points) comparing the presence of hypertension diagnosis subgroups at baseline	1 year
Hypercapnia resolution subgroup	Efficacy between arms measuring Epworth sleepiness scale (from 0 to 24 points) comparing the resolution of hypercapnia measured by PaCO2 (mmHg) at the end of the follow-up (higher and lower of 45 mmHg)	1 year

Collaborators and Investigators

• Sponsor: Sociedad Española de Neumología y Cirugía Torácica
• Investigators: Principal Investigator: Juan F Masa, PhD, Hospital San Pedro de Alcantara

Publications and helpful links

General Publications

• Masa JF, Celli BR, Riesco JA, Hernandez M, Sanchez De Cos J, Disdier C. The obesity hypoventilation syndrome can be treated with noninvasive mechanical ventilation. Chest. 2001 Apr;119(4):1102-7. doi: 10.1378/chest.119.4.1102.
• Berg G, Delaive K, Manfreda J, Walld R, Kryger MH. The use of health-care resources in obesity-hypoventilation syndrome. Chest. 2001 Aug;120(2):377-83. doi: 10.1378/chest.120.2.377.
• Mokhlesi B, Kryger MH, Grunstein RR. Assessment and management of patients with obesity hypoventilation syndrome. Proc Am Thorac Soc. 2008 Feb 15;5(2):218-25. doi: 10.1513/pats.200708-122MG.
• Nowbar S, Burkart KM, Gonzales R, Fedorowicz A, Gozansky WS, Gaudio JC, Taylor MR, Zwillich CW. Obesity-associated hypoventilation in hospitalized patients: prevalence, effects, and outcome. Am J Med. 2004 Jan 1;116(1):1-7. doi: 10.1016/j.amjmed.2003.08.022.
• Lopez-Jimenez MJ, Masa JF, Corral J, Teran J, Ordaz E, Troncoso MF, Gonzalez-Mangado N, Gonzalez M, Lopez-Martinez S, De Lucas P, Marin JM, Marti S, Diaz-Cambriles T, Diaz-de-Atauri J, Chiner E, Aizpuru F, Egea C, Romero A, Benitez JM, Sanchez-Gomez J, Golpe R, Santiago-Recuerda A, Gomez S, Barbe F, Bengoa M; Grupo cooperativo. Mid- and Long-Term Efficacy of Non-Invasive Ventilation in Obesity Hypoventilation Syndrome: The Pickwick's Study. Arch Bronconeumol. 2016 Mar;52(3):158-65. doi: 10.1016/j.arbres.2015.10.003. Epub 2015 Dec 4. English, Spanish.
• Perez de Llano LA, Golpe R, Ortiz Piquer M, Veres Racamonde A, Vazquez Caruncho M, Caballero Muinelos O, Alvarez Carro C. Short-term and long-term effects of nasal intermittent positive pressure ventilation in patients with obesity-hypoventilation syndrome. Chest. 2005 Aug;128(2):587-94. doi: 10.1378/chest.128.2.587.
• Janssens JP, Derivaz S, Breitenstein E, De Muralt B, Fitting JW, Chevrolet JC, Rochat T. Changing patterns in long-term noninvasive ventilation: a 7-year prospective study in the Geneva Lake area. Chest. 2003 Jan;123(1):67-79. doi: 10.1378/chest.123.1.67.
• Masa JF, Corral J, Alonso ML, Ordax E, Troncoso MF, Gonzalez M, Lopez-Martinez S, Marin JM, Marti S, Diaz-Cambriles T, Chiner E, Aizpuru F, Egea C; Spanish Sleep Network. Efficacy of Different Treatment Alternatives for Obesity Hypoventilation Syndrome. Pickwick Study. Am J Respir Crit Care Med. 2015 Jul 1;192(1):86-95. doi: 10.1164/rccm.201410-1900OC.
• Piper AJ, Wang D, Yee BJ, Barnes DJ, Grunstein RR. Randomised trial of CPAP vs bilevel support in the treatment of obesity hypoventilation syndrome without severe nocturnal desaturation. Thorax. 2008 May;63(5):395-401. doi: 10.1136/thx.2007.081315. Epub 2008 Jan 18.
• Borel JC, Tamisier R, Gonzalez-Bermejo J, Baguet JP, Monneret D, Arnol N, Roux-Lombard P, Wuyam B, Levy P, Pepin JL. Noninvasive ventilation in mild obesity hypoventilation syndrome: a randomized controlled trial. Chest. 2012 Mar;141(3):692-702. doi: 10.1378/chest.10-2531. Epub 2011 Sep 1.
• Berry RB, Chediak A, Brown LK, Finder J, Gozal D, Iber C, Kushida CA, Morgenthaler T, Rowley JA, Davidson-Ward SL; NPPV Titration Task Force of the American Academy of Sleep Medicine. Best clinical practices for the sleep center adjustment of noninvasive positive pressure ventilation (NPPV) in stable chronic alveolar hypoventilation syndromes. J Clin Sleep Med. 2010 Oct 15;6(5):491-509.
• Gonzalez-Bermejo J, Perrin C, Janssens JP, Pepin JL, Mroue G, Leger P, Langevin B, Rouault S, Rabec C, Rodenstein D; SomnoNIV Group. Proposal for a systematic analysis of polygraphy or polysomnography for identifying and scoring abnormal events occurring during non-invasive ventilation. Thorax. 2012 Jun;67(6):546-52. doi: 10.1136/thx.2010.142653. Epub 2010 Oct 22.
• Johnson KG, Johnson DC. Treatment of sleep-disordered breathing with positive airway pressure devices: technology update. Med Devices (Auckl). 2015 Oct 23;8:425-37. doi: 10.2147/MDER.S70062. eCollection 2015.
• Jaye J, Chatwin M, Dayer M, Morrell MJ, Simonds AK. Autotitrating versus standard noninvasive ventilation: a randomised crossover trial. Eur Respir J. 2009 Mar;33(3):566-71. doi: 10.1183/09031936.00065008.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2020
• Primary Completion (Actual): July 1, 2023
• Study Completion (Actual): July 14, 2023

Study Registration Dates

• First Submitted: May 15, 2018
• First Submitted That Met QC Criteria: March 28, 2020
• First Posted (Actual): March 31, 2020

Study Record Updates

• Last Update Posted (Actual): November 27, 2023
• Last Update Submitted That Met QC Criteria: November 23, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Obesity; Chronic respiratory failure; Non invasive mechanical ventilation
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Respiratory Tract Diseases; Apnea; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Disease; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Signs and Symptoms, Respiratory; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Syndrome; Obesity; Respiratory Insufficiency; Hypoventilation; Obesity Hypoventilation Syndrome
• Other Study ID Numbers: PI16/01704

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