Acute on Chronic Hypercapnic Respiratory Failure, Obesity Hypoventilation Syndrome (OHS)
Conditions
Keywords
Hypercapnic respiratory failure, Obesity, Non invasive mechanical ventilation, CPAP
Brief 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.
Detailed 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.
Interventions
PROCEDURELifestyle 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.
PROCEDUREAutomatic 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.
PROCEDURECPAP 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.
PROCEDURENIV 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.
Sponsors
Rush University Medical Center
Juan F. Masa
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Prospective, open label, randomized controlled trial with two sequential phases
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Medium-term composite hospital resource utilization-mortality | 3 months | 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 |
| Long-term composite hospital resource utilization-mortality | 3 years | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of cardiovascular events: cardiovascular death | During 3 months and during 3 years for the first and second phases or sequential RCTs respectively | Incidence of cardiovascular death. |
| Incidence of cardiovascular events: hospitalization for unstable angina | During 3 months and during 3 years for the first and second phases or sequential RCTs respectively | Incidence of hospitalization for unstable angina |
| Incidence of cardiovascular events: coronary percutaneous interventions | After 3 months and after 3 years for first and second phases or sequential RCTs respectively | Incidence of coronary percutaneous interventions |
| Incidence of cardiovascular events: nonfatal stroke or transient ischemic attack | During 3 months and during 3 years for first and second phases or sequential RCTs respectively | Incidence of nonfatal stroke or transient ischemic attack |
| Incidence of cardiovascular events: heart failure episode | During 3 months and during 3 years for the first and second phases or sequential RCTs respectively | Incidence of heart failure episode |
| Incidence of adverse event | During 3 months and during 3 years for the first and second phases or sequential RCTs respectively | Number of adverse events according to Treatment-Related Adverse Events as assessed by CTCAE v5.0 |
| Cost-effectiveness analysis based on the primary outcome and quality adjusted life year (QALY) | During 3 months and during 3 years for the first and second phases or sequential RCTs respectively | 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. |
| Number of oro-tracheal intubation | During 3 months and during 3 years for the first and second phases or sequential RCTs respectively | Number of the tracheal intubations |
| Duration of tracheal intubation | During 3 months and during 3 years for the first and second phases or sequential RCTs respectively | Duration of tracheal intubation |
| 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 | Number of patients who change of the allocated arms |
| Hospital admissions | During 3 months and during 3 years for the first and second phases or sequential RCTs respectively | Separately the components of the primary outcome: hospital admissions measured as the number of events |
| ICU admissions | During 3 months and during 3 years for the first and second phases or sequential RCTs respectively | Separately the components of the primary outcome: ICU admissions measured as the number of events |
| Emergency department visits | During 3 months and during 3 years for the first and second phases or sequential RCTs respectively | Separately the components of the primary outcome: emergency department visits for any cause measured as the number of events |
| All-cause mortality | During 3 months and during 3 years for the first and second phases or sequential RCTs respectively | Separately the components of the primary outcome: All-cause mortality number |
| Duration of hospital admissions | During 3 months and during 3 years for the first and second phase or sequential RCTs respectively | Duration of hospital admissions measured in days of hospital admission |
| Duration of ICU admissions | During 3 months and during 3 years for the first and second phase or sequential RCTs respectively | Duration of ICU admissions measured in days of ICU admission |
| Causes of change of the allocated treatment | During 3 months and during 3 years for the first and second phases or sequential RCTs respectively | Causes of change of the allocated arms |
| Clinical symptoms: lower extremity edema | During 3 months and during 3 years for first and second phases or sequential RCTs respectively | Number of patients into four levels of frequency (no, sometimes, usually and always) |
| Clinical symptoms: unrefreshing sleep | During 3 months and during 3 years for first and second phases or sequential RCTs respectively | Number of patients into four levels of frequency (no, sometimes, usually and always) |
| Clinical symptoms: morning fatigue | During 3 months and during 3 years for the first and second phases or sequential RCTs respectively | Number of patients into four levels of frequency (no, sometimes, usually and always) |
| Clinical symptoms: nocturia | During 3 months and during 3 years for the first and second phases or sequential RCTs respectively | Number of patients into four levels of frequency (no, sometimes, usually and always) |
| Clinical symptoms: headache | During 3 months and during 3 years for the first and second phases or sequential RCTs respectively | Number of patients into four levels of frequency (no, sometimes, usually and always) |
| Clinical symptoms: tiredness | During 3 months and during 3 years for the first and second phases or sequential RCTs respectively | Number of patients into four levels of frequency (no, sometimes, usually and always) |
| Clinical symptoms: morning confusion | During 3 months and during 3 years for the first and second phases or sequential RCTs respectively | Number of patients into four levels of frequency (no, sometimes, usually and always) |
| Clinical symptoms: dysnea | During 3 months and during 3 years for the first and second phases or sequential RCTs respectively | Number of patients with dysnea according to the Medical Research Council scale classified into five levels of intensity (from 0 to 4) |
| Clinical symptoms: sleepiness | During 3 months and during 3 years for the first and second phases or sequential RCTs respectively | Level of perceived sleepiness measured by the Epworth Sleepiness Scale |
| Health related quality of life (HRQL): Functional Outcomes of Sleep Questionnaire-- FOSQ-- | During 3 months and during 3 years for first and second phases or sequential RCTs respectively | Scoring of Functional Outcomes of Sleep Questionnaire-- FOSQ--- |
| Health related quality of life (HRQL): 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 | Scoring of European health-related quality of life questionnaire (EuroQol) EQ-5D-5L |
| 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 | During 3 months and during 3 years for the first and second phases or sequential RCTs respectively | 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. |
| Arterial blood gases (ABG): PaO2 | During 3 months and during 3 years for the first and second phases or sequential RCTs respectively | PaO2 in mmHg |
| Arterial blood gases (ABG): PaCO2 | During 3 months and during 3 years for the first and second phases or sequential RCTs respectively | PaCO2 in mmHg |
| Arterial blood gases (ABG): Bicarbonate | During 3 months and during 3 years for the first and second phases or sequential RCTs respectively | bicarbonate measured in mmol/L |
| Arterial blood gases (ABG): pH | During 3 months and during 3 years for the first and second phases or sequential RCTs respectively | pH |
| Weight | During 3 months and during 3 years for the first and second phases or sequential RCTs respectively | weight in Kg |
| Standardized blood pressure measures | During 3 months and during 3 years for the first and second phases or sequential RCTs respectively | Systolic and diastolic blood pressure measured in mmHg |
| Incidence of cardiovascular events: systemic hypertension | During 3 months and during 3 years for the first and second phases or sequential RCTs respectively | Incidence of hypertension diagnosis or initiation of a new anti-hypertensive treatment |
| Incidence of cardiovascular events: arrhythmia | During 3 months and during 3 years for the first and second phases or sequential RCTs respectively | Incidence of arrhythmia |
| Incidence of cardiovascular events: nonfatal myocardial infarction | During 3 months and during 3 years for the first and second phases or sequential RCTs respectively | Incidence of nonfatal myocardial infarction |
Other
| Measure | Time frame | Description |
|---|---|---|
| A composite outcome in subgroups of hypercapnia severity at baseline | During 3 months and During 3 years for first and second phases or sequential RCTs respectively | 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) |
| A composite outcome in subgroups of the apnea-hypopnea index severity at baseline | During 3 months and during 3 years for first and second phases or sequential RCTs respectively | 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) |
| A composite outcome in subgroups with or without hypertension diagnosis at baseline | During 3 months and during 3 years for first and second phases or sequential RCTs respectively | 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 |
| A composite outcome in subgroups with different home care providers | During 3 months and during 3 years for first and second phases or sequential RCTs respectively | 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) |
| Validity analysis of EQ 5D-5L test | During 3 months and during 3 years for first and second phases or sequential RCTs respectively | To perform a validity analysis of EQ 5D-5L test |
| A composite outcome in adherent vs. non-adherent to PAP therapy subgroups | During 3 months for the first phase or RCT | 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) |
| A composite outcome in subgroups with or without supplemental oxygen at baseline | During 3 months and during 3 years for first and second phases or sequential RCTs respectively | 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 |
| Subgroups according to whether hypercapnia was resolved or not | During 3 months and during 3 years for first and second phases or sequential RCTs respectively | 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 |
Outcome results
None listed