"Post-acute Pickwick Study" (Postacute-Pick-2020)

Obesity Hypoventilation Syndrome (OHS) Clinical Trial

Official title:

"Mid- and Long-term Effectiveness of Positive Airway Pressure in OHS After an Acute-on-chronic Hypercapnic Respiratory Failure"

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT04317326
• Other study ID #: PI19/00955
• Status: Withdrawn
• Phase: N/A
• Start date: January 2023
• Est. completion date: December 2029

Study information

• Verified date: May 2023
• Source: Sociedad Española de Neumología y Cirugía Torácica
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

We propose to carry out a large multicentric, multinational, randomized controlled trial with two phases (two sequential randomized controled trials) to answer two questions: 1) Should hospitalized patients with recently diagnosed OHS be discharged from the hospital on an auto-titratable NIV treatment until the diagnosis of OHS is confirmed in 3 months? 2) Is the long-term effectiveness of outpatient titrated CPAP non-inferior to titrated NIV in ambulatory patients with OHS 3 months after hospital discharge? Clinical practice, multicenter open-label controlled randomized clinical trial with preset allocation rate (1:1) with two parallel-groups conducted in centers from Spain, France, Portugal and USA. The study will have two phases with two randomizations. The first phase will be a superiority study and the second phase will be a non-inferiority study.

Description:

Objectives: First phase (medium-term): To evaluate the medium-term (3 months) efficacy of automatically adjusted noninvasive ventilation (NIV) treatment versus "life style modifications" treatment in obesity hypoventilation syndrome (OHS) after an episode of acute-on-chronic hypercapnic respiratory failure. The main outcome will be a composite that includes hospital resource utilization (hospital and ICU admissions and emergency department visits for any cause) and all-cause mortality. Key secondary outcomes will include incident cardiovascular events (new hypertension diagnosis or initiation of anti-hypertensive treatment, atrial fibrillation, hospitalization for nonfatal myocardial infarction or unstable angina, percutaneous coronary interventions, nonfatal stroke or transient ischemic attack or for acute heart failure episode, and cardiovascular death), blood pressure, arterial blood gases, clinical symptoms and quality of life. Second phase (long-term): Evaluate the long-term efficacy (36 months) of manually titrated NIV treatment versus manually titrated CPAP treatment in OHS after 3 months of an episode of acute-on-chronic hypercapnic respiratory failure, with a composite outcome of hospital resource utilization (hospital and ICU admissions, emergency department visits) and all-cause mortality analyzed as the primary outcome. Incident cardiovascular events, blood pressure, arterial blood gases, clinical symptoms and quality of life will be the main secondary outcomes.

Methods: Prospective, multinational, randomized open-label controlled trial with two parallel arms: 1,110 hospitalized patients with newly diagnosed OHS with acute-on-chronic hypercapnic respiratory failure treated with invasive or noninvasive mechanical ventilation who survive hospitalization and available for hospital discharge will be randomized to either automatically adjusted NIV (555 patients) or "life style modifications" (555 patients) for three months. Subsequently, both automatically adjusted NIV and "life style modifications" arms will be re-randomized to polysomnographically adjusted CPAP or to polysomnographically adjusted NIV groups to complete 36 months of follow up. The first phase of the proposal is a superiority study and the second phase is a non-inferiority study. The primary outcome and its components will be analyzed by a mixed-effects model with negative binomial. A mixed-effects Cox model will be used for hospital resource utilization, new cardiovascular events and overall survival. Other secondary outcomes such as repeated measures derived from the arterial blood gases (i.e. PaCO2, PaO2, pH, calculated bicarbonate), blood pressure, health-related quality of life tests and Epworth Sleepiness Scale during the follow-up will be analyzed by a linear mixed-effects model.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: December 2029
• Est. primary completion date: December 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

Inclusion Criteria:

1. º.- Patient between 18 and 85 years old.

2. º.- With diagnosis of OHS (according to Obesity (BMI =30 kg/m2) and Hypercapnic respiratory failure (PaCO2 =45 mmHg at hospital discharge) not secondary to other causes.

3. º - Hospitalized for an episode of acute-on-chronic hypercapnic respiratory failure, receiving hospital therapy with invasive or noninvasive ventilation, and just deemed stable for home discharge."

4. º.- No NIV or CPAP home therapy in the last 6 months[*].

5. º.- Being able to tolerate and correctly execute a 15-minute test with automatic NIV (AVAPS-AE) and another 15-minute test with fixed CPAP treatments during wakefulness.

6. º.- Providing informed consent (dated and signed).

[*] Patients who have objective evidence of minimal PAP therapy during the 6 months prior to hospital admission (i.e. average daily use of less than 2 hours of PAP therapy) can also be enrolled at the discretion of the investigators if they feel the patient is now more interested in being adherent to NIV therapy.

Inclusion criteria for the second phase of the study:

1º.- Included three months ago in the first phase of the study (followed by a washout period of 5 days).

Exclusion Criteria:

Exclusion criteria for the first phase of the study:

1. º.- With moderate or severe chronic obstructive pulmonary disease (FEV1<70% of predicted when FEV1/FVC is below 70%).

2. º.- With neuromuscular disease, thoracic wall or metabolic disease that may cause diurnal hypercapnia.

3. º.- Inability to maintain a patent airway or adequately clear secretions.

4. º.- With bullous lung disease or with pneumothorax.

5. º.- With bypassed upper airway (i.e. endotracheal tube or tracheostomy).

6. º.- With anatomical abnormalities of the craniofacial structure leading to cerebral spinal fluid leaks, abnormalities of the cribriform plate, and/or pneumocephalus.

7. º.- At risk for aspiration of gastric contents.

8. º.- Diagnosed with acute sinusitis or otitis media.

9. º.- With active hemoptysis or epistaxis if presenting a risk of causing pulmonary aspiration of blood.

10. º.- With symptomatic hypotension.

11. º.- With clinical diagnosis of narcolepsy or restless leg syndrome.

12. º.- Psycho-physical incapacity to complete questionnaires.

13. º.- With diagnosis of chronic illness that might interfere the evaluation using quality of life questionnaires (neoplasia, severe chronic pain of any type, and any other severe chronic debilitating illness).

14. º.- Suffering other clinically relevant disease that, under the opinion of the investigator, might affect the evaluations of efficacy or safety.

15. º.- Participating simultaneously in other clinical study with intervention (or without intervention at the discretion of the investigator and with the consent of the Sponsor) or had participated in other clinical study with intervention within the last 30 days before the inclusion in this study. [‡]

16. º.- If for any reason (planned surgery [including bariatric surgery], trips of long duration, etc.) would not be able to receive the treatment and/or attend the follow-up visits of this study within the next three years and three months.

17. º.- Persons deprived of liberty by judicial or administrative decision, persons under psychiatric treatment and persons placed in a health or social institution for purposes other than those of this clinical study.

18. º.- Adults who are subject to a legal protection measure or who are unable to express their consent.

[‡] This prohibition shall be maintained for the duration of the patients' participation in the study. This is because, if patients received other treatments, it could be difficult to interpret the causality of the results obtained (whether beneficial or harmful effects) and the possible contraindications.

vi. Exclusion criteria for the second phase of the study:

1º.- With apnea hypopnea index (AHI) lower than 5 (absence or very mild obstructive sleep apnea).

Related Conditions & MeSH terms

• Acute on Chronic Hypercapnic Respiratory Failure
• Hypercapnia
• Hypoventilation
• Obesity Hypoventilation Syndrome
• Obesity Hypoventilation Syndrome (OHS)
• Respiratory Insufficiency

Intervention

Procedure:
• "Lifestyle modifications" group (Control)
It will consist of a 1,000-calorie/day diet and to maintain proper sleep hygiene and habits (avoid supine decubitus position, maintain regular sleep habits and exercise, not take sedatives, stimulants, alcohol, tobacco or heavy meals within four hours before bedtime). Oxygen therapy can be prescribed by the treating team using standard criteria (awake PaO2 <55 mmHg or room air oxygen saturation below 88% (Masa JF et al. J Clin Sleep Med. 2016 ;12:1379-88). The treatment period will be three months.
• Automatic NIV
In addition to lifestyle modification and oxygen (if required), the ventilator will be adjusted to a range of predetermined parameters with the intelligent ventilation mode (pressure of intelligent support with guaranteed volume with automatic backup frequency) with the following adjustment: maximum pressure: 35 cmH2O; respiratory rate: automatic; maximum pressure support: 18 cm H2O; minimum pressure support: 4 cmH2O; maximum EPAP pressure: 15 cmH2O; minimum EPAP pressure: 4 cmH2O; and tidal volume (Vt) based on 8-10 ml/kg of predicted body weight, being able to be modified according to tolerance.The treatment period will be three months.
• CPAP treatment group
In-laboratory polysomnographic CPAP titration will be performed according to published guidelines for CPAP titration (SEPAR guideline or AASM guideline).In addition to lifestyle modification and oxygen (if require), a home titrated CPAP therapy will be initiated.The treatment period will be three years.
• NIV treatment groups
In-laboratory polysomnographic NIV titration will be performed according to published guidelines In addition to lifestyle modification and oxygen (if required) home NIV therapy with fixed pressures will be started. The ventilator mode will be a bilevel pressure in S/T mode. The ventilator adjustment will be firstly performed in awake situation and then during sleep by means of a PSG. The treatment period will be three years.

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Juan F. Masa	Rush University Medical Center

References & Publications (35)

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Lee WY, Mokhlesi B. Diagnosis and management of obesity hypoventilation syndrome in the ICU. Crit Care Clin. 2008 Jul;24(3):533-49, vii. doi: 10.1016/j.ccc.2008.02.003. — View Citation

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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. P — View Citation

Masa JF, Corral J, Caballero C, Barrot E, Teran-Santos J, Alonso-Alvarez ML, Gomez-Garcia T, Gonzalez M, Lopez-Martin S, De Lucas P, Marin JM, Marti S, Diaz-Cambriles T, Chiner E, Egea C, Miranda E, Mokhlesi B; Spanish Sleep Network; Garcia-Ledesma E, San — View Citation

Masa JF, Corral J, Romero A, Caballero C, Teran-Santos J, Alonso-Alvarez ML, Gomez-Garcia T, Gonzalez M, Lopez-Martin S, De Lucas P, Marin JM, Marti S, Diaz-Cambriles T, Chiner E, Merchan M, Egea C, Obeso A, Mokhlesi B; Spanish Sleep Network( *). Protecti — View Citation

Masa JF, Mokhlesi B, Benitez I, Gomez de Terreros FJ, Sanchez-Quiroga MA, Romero A, Caballero-Eraso C, Teran-Santos J, Alonso-Alvarez ML, Troncoso MF, Gonzalez M, Lopez-Martin S, Marin JM, Marti S, Diaz-Cambriles T, Chiner E, Egea C, Barca J, Vazquez-Polo — View Citation

Masa JF, Rubio M, Findley LJ. Habitually sleepy drivers have a high frequency of automobile crashes associated with respiratory disorders during sleep. Am J Respir Crit Care Med. 2000 Oct;162(4 Pt 1):1407-12. doi: 10.1164/ajrccm.162.4.9907019. — View Citation

McArdle N, Rea C, King S, Maddison K, Ramanan D, Ketheeswaran S, Erikli L, Baker V, Armitstead J, Richards G, Singh B, Hillman D, Eastwood P. Treating Chronic Hypoventilation With Automatic Adjustable Versus Fixed EPAP Intelligent Volume-Assured Positive — View Citation

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Palm A, Midgren B, Janson C, Lindberg E. Gender differences in patients starting long-term home mechanical ventilation due to obesity hypoventilation syndrome. Respir Med. 2016 Jan;110:73-8. doi: 10.1016/j.rmed.2015.11.010. Epub 2015 Nov 26. — View Citation

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* Note: There are 35 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	A composite outcome in adherent vs. non-adherent to PAP therapy subgroups	Efficacy of automatic NIV treatment versus "lifestyle modifications" treatment measuring a composite outcome including hospital and ICU admissions, emergency department visits for any cause, and all-cause mortality measured as the number of events comparing adherent vs. non-adherent to PAP therapy subgroups (lower and higher of a mean of 4 h/day)	During 3 months for the first phase or RCT
Other	A composite outcome in adherent vs. non-adherent to PAP therapy subgroups	Efficacy of automatic NIV treatment versus CPAP treatment measuring a composite outcome including hospital and ICU admissions, emergency department visits for any cause, and all-cause mortality measured as the number of events comparing adherent vs. non-adherent to PAP therapy subgroups (lower and higher of a mean of 4 h/days)	During 3 years for the second phase or RCT
Other	Subgroups according to whether hypercapnia was resolved or not	Comparative efficacy between treatment arms measuring a composite outcome including hospital and ICU admissions, emergency department visits for any cause, and all-cause mortality measured as the number of events in the subgroups with PaCO2 higher or lower of 45 mmHg at the end of follow-up	During 3 months and during 3 years for first and second phases or sequential RCTs respectively
Other	A composite outcome in subgroups with or without supplemental oxygen at baseline	Comparative efficacy between treatment arms measuring a composite outcome including hospital and ICU admissions, emergency department visits for any cause, and all-cause mortality measured as the number of events in the subgroups with or without supplemental oxygen therapy at baseline	During 3 months and during 3 years for first and second phases or sequential RCTs respectively
Other	A composite outcome in subgroups of hypercapnia severity at baseline	Comparative efficacy between treatment arms measuring a composite outcome including hospital and ICU admissions, emergency department visits for any cause, and all-cause mortality measured as the number of events in the subgroups with higher and lower hypercapnia at baseline (above and below of the median PaCO2 measured in mmHg)	During 3 months and During 3 years for first and second phases or sequential RCTs respectively
Other	A composite outcome in subgroups of the apnea-hypopnea index severity at baseline	Comparative efficacy between treatment arms measuring a composite outcome including hospital and ICU admissions, emergency department visits for any cause, and all-cause mortality measured as the number of events in the subgroups with higher and lower apnea-hypopnea index at baseline (above and below of the median apnea-hypopnea index at baseline)	During 3 months and during 3 years for first and second phases or sequential RCTs respectively
Other	A composite outcome in subgroups with or without hypertension diagnosis at baseline	Comparative efficacy between treatment arms measuring a composite outcome including hospital and ICU admissions, emergency department visits for any cause, and all-cause mortality measured as the number of events in the subgroups with or without hypertension diagnosis at baseline	During 3 months and during 3 years for first and second phases or sequential RCTs respectively
Other	A composite outcome in subgroups with different home care providers	Comparative efficacy between treatment arms measuring a composite outcome including hospital and ICU admissions, emergency department visits for any cause, and all-cause mortality measured as the number of events in the subgroups with different home care providers (i.e. AirLiquide)	During 3 months and during 3 years for first and second phases or sequential RCTs respectively
Other	Validity analysis of EQ 5D-5L test	To perform a validity analysis of EQ 5D-5L test	During 3 months and during 3 years for first and second phases or sequential RCTs respectively
Primary	Medium-term composite hospital resource utilization-mortality	Primary (medium-term from the first phase or RCT): the medium-term efficacy of automatic NIV treatment versus "lifestyle modifications" treatment in OHS measuring as primary outcome a composite including hospital and ICU admissions, emergency department visits for any cause, and all-cause mortality measured as the number of events	3 months
Primary	Long-term composite hospital resource utilization-mortality	Primary (long-term from the second phase or RCT): the long-term efficacy of titrated CPAP therapy versus titrated NIV therapy in OHS measuring as primary outcome a composite including hospital and ICU admissions, emergency department visits for any cause, and all-cause mortality measured as the number of events	3 years
Secondary	Hospital admissions	Separately the components of the primary outcome: hospital admissions measured as the number of events	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	ICU admissions	Separately the components of the primary outcome: ICU admissions measured as the number of events	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	Emergency department visits	Separately the components of the primary outcome: emergency department visits for any cause measured as the number of events	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	All-cause mortality	Separately the components of the primary outcome: All-cause mortality number	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	Duration of hospital admissions	Duration of hospital admissions measured in days of hospital admission	During 3 months and during 3 years for the first and second phase or sequential RCTs respectively
Secondary	Duration of ICU admissions	Duration of ICU admissions measured in days of ICU admission	During 3 months and during 3 years for the first and second phase or sequential RCTs respectively
Secondary	Number of patients who change of the allocated arms	Number of patients who change of the allocated arms	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	Causes of change of the allocated treatment	Causes of change of the allocated arms	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	Clinical symptoms: lower extremity edema	Number of patients into four levels of frequency (no, sometimes, usually and always)	During 3 months and during 3 years for first and second phases or sequential RCTs respectively
Secondary	Clinical symptoms: unrefreshing sleep	Number of patients into four levels of frequency (no, sometimes, usually and always)	During 3 months and during 3 years for first and second phases or sequential RCTs respectively
Secondary	Clinical symptoms: morning fatigue	Number of patients into four levels of frequency (no, sometimes, usually and always)	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	Clinical symptoms: nocturia	Number of patients into four levels of frequency (no, sometimes, usually and always)	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	Clinical symptoms: headache	Number of patients into four levels of frequency (no, sometimes, usually and always)	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	Clinical symptoms: tiredness	Number of patients into four levels of frequency (no, sometimes, usually and always)	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	Clinical symptoms: morning confusion	Number of patients into four levels of frequency (no, sometimes, usually and always)	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	Clinical symptoms: dysnea	Number of patients with dysnea according to the Medical Research Council scale classified into five levels of intensity (from 0 to 4)	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	Clinical symptoms: sleepiness	Level of perceived sleepiness measured by the Epworth Sleepiness Scale	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	Health related quality of life (HRQL): Functional Outcomes of Sleep Questionnaire-- FOSQ--	Scoring of Functional Outcomes of Sleep Questionnaire-- FOSQ---	During 3 months and during 3 years for first and second phases or sequential RCTs respectively
Secondary	Health related quality of life (HRQL): European health-related quality of life questionnaire (EuroQol) EQ-5D-5L	Scoring of European health-related quality of life questionnaire (EuroQol) EQ-5D-5L	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	Health related quality of life (HRQL): Subjective state of illness on a visual analogical scale: Visual Analogical Well-being Scale -VAWS (Masa JF et al. Sleep Breath. 2011;15:549-59) (EuroQol) EQ-5D-5L	Scoring of Subjective state of illness on a visual analogical scale: Visual Analogical Well-being Scale -VAWS (Masa JF et al. Sleep Breath. 2011;15:549-59) measured in percentage.	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	Arterial blood gases (ABG): PaO2	PaO2 in mmHg	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	Arterial blood gases (ABG): PaCO2	PaCO2 in mmHg	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	Arterial blood gases (ABG): Bicarbonate	bicarbonate measured in mmol/L	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	Arterial blood gases (ABG): pH	pH	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	Weight	weight in Kg	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	Standardized blood pressure measures	Systolic and diastolic blood pressure measured in mmHg	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	Incidence of cardiovascular events: systemic hypertension	Incidence of hypertension diagnosis or initiation of a new anti-hypertensive treatment	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	Incidence of cardiovascular events: arrhythmia	Incidence of arrhythmia	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	Incidence of cardiovascular events: nonfatal myocardial infarction	Incidence of nonfatal myocardial infarction	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	Incidence of cardiovascular events: hospitalization for unstable angina	Incidence of hospitalization for unstable angina	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	Incidence of cardiovascular events: coronary percutaneous interventions	Incidence of coronary percutaneous interventions	After 3 months and after 3 years for first and second phases or sequential RCTs respectively
Secondary	Incidence of cardiovascular events: nonfatal stroke or transient ischemic attack	Incidence of nonfatal stroke or transient ischemic attack	During 3 months and during 3 years for first and second phases or sequential RCTs respectively
Secondary	Incidence of cardiovascular events: heart failure episode	Incidence of heart failure episode	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	Incidence of cardiovascular events: cardiovascular death	Incidence of cardiovascular death.	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	Incidence of adverse event	Number of adverse events according to Treatment-Related Adverse Events as assessed by CTCAE v5.0	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	Cost-effectiveness analysis based on the primary outcome and quality adjusted life year (QALY)	Differences in within trial costs will be related with the differences in effectiveness (primary outcome and QALY) between arms using a probabilistic approach to calculate the cost-effectiveness plane.	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	Number of oro-tracheal intubation	Number of the tracheal intubations	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively
Secondary	Duration of tracheal intubation	Duration of tracheal intubation	During 3 months and during 3 years for the first and second phases or sequential RCTs respectively