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

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Juan F. Masa

THỬ NGHIỆM LÂM SÀNG: NCT04317326

BioSeek: nct04317326

Từ khóa

trừu tượng

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.

Sự miêu tả

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.

ngày

Xác minh lần cuối:	04/30/2020
Đệ trình đầu tiên:	02/13/2020
Đăng ký ước tính đã được gửi:	03/19/2020
Đăng lần đầu:	03/22/2020
Cập nhật lần cuối được gửi:	05/11/2020
Cập nhật lần cuối đã đăng:	05/12/2020
Ngày bắt đầu nghiên cứu thực tế:	09/30/2020
Ngày hoàn thành chính ước tính:	06/30/2022
Ngày hoàn thành nghiên cứu ước tính:	09/30/2025

Tình trạng hoặc bệnh tật

Acute on Chronic Hypercapnic Respiratory Failure

Obesity Hypoventilation Syndrome (OHS)

Can thiệp / điều trị

Procedure: Life style modification

Procedure: Life style modificacion and automatic NIV(AVAPS-AE)

Procedure: Life style modification and titrated NIV(S/T mode)

Procedure: Life style modification and titrated CPAP

Giai đoạn

Nhóm cánh tay

Cánh tay	Can thiệp / điều trị
Experimental: Life style modification "Lifestyle modifications" group (Control) 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)	Procedure: Life style modification 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.
Active Comparator: Life style modificacion and automatic NIV(AVAPS-AE) 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: 20 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. These parameters may be modified according to patient tolerance or non-compensated leak.	Procedure: Life style modificacion and automatic NIV(AVAPS-AE) 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.
Experimental: Life style modification and titrated NIV(S/T mode) In-laboratory polysomnographic NIV titration will be performed according to published guidelines (Berry R et al JCSM 2010). 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 PAP with backup respiratory rate (BIPAP S/T mode). The ventilator adjustment will be firstly performed in awake situation and then during sleep by means of a PSG.	Procedure: Life style modification and titrated NIV(S/T mode) 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.
Active Comparator: Life style modification and titrated CPAP In-laboratory polysomnographic CPAP titration will be performed according to published guidelines (SEPAR guideline or AASM guideline). In addition to lifestyle modification and oxygen (if required), home CPAP therapy at a fixed pressure will be initiated.	Procedure: Life style modification and titrated CPAP 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.

Đủ tiêu chuẩn

Tuổi đủ điều kiện để học	18 Years Đến 18 Years
Giới tính đủ điều kiện để nghiên cứu	All
Chấp nhận tình nguyện viên lành mạnh	Đúng
Tiêu chí	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.- Pregnancy.[] 2. º.- With moderate or severe chronic obstructive pulmonary disease (FEV1<70% of predicted when FEV1/FVC is below 70%). 3. º.- With neuromuscular disease, thoracic wall or metabolic disease that may cause diurnal hypercapnia. 4. º.- Inability to maintain a patent airway or adequately clear secretions. 5. º.- With bullous lung disease or with pneumothorax. 6. º.- With bypassed upper airway (i.e. endotracheal tube or tracheostomy). 7. º.- With anatomical abnormalities of the craniofacial structure leading to cerebral spinal fluid leaks, abnormalities of the cribriform plate, and/or pneumocephalus. 8. º.- At risk for aspiration of gastric contents. 9. º.- Diagnosed with acute sinusitis or otitis media. 10. º.- With active hemoptysis or epistaxis if presenting a risk of causing pulmonary aspiration of blood. 11. º.- With symptomatic hypotension. 12. º.- With clinical diagnosis of narcolepsy or restless leg syndrome. 13. º.- Psycho-physical incapacity to complete questionnaires. 14. 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). 15. º.- Suffering other clinically relevant disease that, under the opinion of the investigator, might affect the evaluations of efficacy or safety. 16. º.- Participating simultaneously in other clinical study or had participated in other clinical study within the last 30 days before the inclusion in this study. 17. º.- If for any reason (planned 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. [] Women becoming pregnant during the study can continue the treatment. Pregnancy is not a contraindication for the treatment. 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).

Kết quả

Các biện pháp kết quả chính

1. 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/year

2. 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/year

Các biện pháp kết quả thứ cấp

1. Hospital admissions [After 3 months and after 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/year

2. UCI admissions [After 3 months and after 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

3. Emergency department visits [After 3 months and after 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/year

4. All-cause mortality [After 3 months and after 3 years for the first and second phases or sequential RCTs respectively]

Separately the components of the primary outcome: All-cause mortality number

5. Duration of hospital admissions [After 3 months and after 3 years for the first and second phase or sequential RCTs respectively]

Duration of hospital admissions measured in days of hospital admission

6. Duration of ICU admissions [After 3 months and after 3 years for the first and second phase or sequential RCTs respectively]

Duration of ICU admissions measured in days of ICU admission

7. Number of patients who change of the allocated arms [After 3 months and after 3 years for the first and second phases or sequential RCTs respectively]

Number of patients who change of the allocated arms

8. Causes of change of the allocated treatment [After 3 months and after 3 years for the first and second phases or sequential RCTs respectively]

Causes of change of the allocated arms

9. Clinical symptoms: lower extremity edema [After 3 months and after 3 years for first and second phases or sequential RCTs respectively]

Number of patients with lower extremity edema classified into four levels of intensity (from 1 to 4)

10. Clinical symptoms: unrefreshing sleep [After 3 months and after 3 years for first and second phases or sequential RCTs respectively]

Number of patients with unrefreshing sleep classified into four levels of intensity (from 1 to 4)

11. Clinical symptoms: morning fatigue [After 3 months and after 3 years for the first and second phases or sequential RCTs respectively]

Number of patients with morning fatigue classified into four levels of intensity (from 1 to 4)

12. Clinical symptoms: nocturia [After 3 months and after 3 years for the first and second phases or sequential RCTs respectively]

Number of patients with nocturia classified into four levels of intensity (from 1 to 4)

13. Clinical symptoms: headache [After 3 months and after 3 years for the first and second phases or sequential RCTs respectively]

Number of patients with headache classified into four levels of intensity (from 1 to 4)

14. Clinical symptoms: morning confusion [After 3 months and after 3 years for the first and second phases or sequential RCTs respectively]

Number of patients with morning confusion classified into four levels of intensity (from 1 to 4)

15. Clinical symptoms: dysnea [After 3 months and after 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 four levels of intensity (from 1 to 4)

16. Clinical symptoms: sleepiness [After 3 months and after 3 years for the first and second phases or sequential RCTs respectively]

Level of perceived sleepiness measured by the Epworth Sleepiness Scale

17. Health related quality of life (HRQL): Functional Outcomes of Sleep Questionnaire-- FOSQ-- [After 3 months and after 3 years for first and second phases or sequential RCTs respectively]

Scoring of Functional Outcomes of Sleep Questionnaire-- FOSQ---

18. Health related quality of life (HRQL): European health-related quality of life questionnaire (EuroQol) EQ-5D-5L [After 3 months and after 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

19. 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 [After 3 months and after 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.

20. Arterial blood gases (ABG): PaO2 [After 3 months and after 3 years for the first and second phases or sequential RCTs respectively]

Change in PaO2 in mmHg

21. Arterial blood gases (ABG): PaCO2 [After 3 months and after 3 years for the first and second phases or sequential RCTs respectively]

Change in PaCO2 in mmHg

22. Arterial blood gases (ABG): Bicarbonate [After 3 months and after 3 years for the first and second phases or sequential RCTs respectively]

Change in bicarbonate measured in mmol/L

23. Arterial blood gases (ABG): pH [After 3 months and after 3 years for the first and second phases or sequential RCTs respectively]

Change in pH

24. Weight [After 3 months and after 3 years for the first and second phases or sequential RCTs respectively]

Change in weight in Kg

25. Standardized blood pressure measures [After 3 months and after 3 years for the first and second phases or sequential RCTs respectively]

Systolic and diastolic blood pressure measured in mmHg

26. Incidence of new cardiovascular events: systemic hypertension [After 3 months and after 3 years for the first and second phases or sequential RCTs respectively]

Incidence of new hypertension diagnosis or initiation of a new anti-hypertensive treatment

27. Incidence of new cardiovascular events: atrial fibrillation [After 3 months and after 3 years for the first and second phases or sequential RCTs respectively]

Incidence of new atrial fibrillation diagnosis

28. Incidence of new cardiovascular events: hospitalization for nonfatal myocardial infarction [After 3 months and after 3 years for the first and second phases or sequential RCTs respectively]

Incidence of new hospitalization for nonfatal myocardial infarction

29. Incidence of new cardiovascular events: hospitalization for nonfatal angina [After 3 months and after 3 years for the first and second phases or sequential RCTs respectively]

Incidence of new hospitalization for nonfatal angina

30. Incidence of new cardiovascular events: coronary percutaneous interventions [After 3 months and after 3 years for first and second phases or sequential RCTs respectively]

Incidence of new hospitalization for coronary percutaneous interventions

31. Incidence of new cardiovascular events: nonfatal stroke or transient ischemic attack [After 3 months and after 3 years for first and second phases or sequential RCTs respectively]

Incidence of new hospitalization for nonfatal stroke or transient ischemic attack

32. Incidence of new cardiovascular events: acute heart failure episode [After 3 months and after 3 years for the first and second phases or sequential RCTs respectively]

Incidence of new hospitalization for acute heart failure episode

33. Incidence of cardiovascular events: cardiovascular death [After 3 months and after 3 years for the first and second phases or sequential RCTs respectively]

Incidence of cardiovascular death.

34. Incidence of new adverse event [After 3 months and after 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 v4.0

35. Cost-effectiveness analysis based on the primary outcome and quality adjusted life year (QALY) [After 3 months and after 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 Bayesian approach to calculate the cost-effectiveness plane.

Các biện pháp kết quả khác

1. A composite outcome in adherent vs. non-adherent to PAP therapy subgroups [After 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/year comparing adherent vs. non-adherent to PAP therapy subgroups (lower and higher of a mean of 4 h/day)

2. A composite outcome in adherent vs. non-adherent to PAP therapy subgroups [After 3 years for the second phase or RCT]

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/year comparing adherent vs. non-adherent to PAP therapy subgroups (lower and higher of a mean of 4 h/days)

3. Subgroups according to whether hypercapnia was resolved or not [After 3 months and after 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/year in the subgroups with PaCO2 higher or lower of 45 mmHg at the end of follow-up

4. A composite outcome in subgroups with or without supplemental oxygen at baseline [After 3 months and after 3 years for first and second phases or sequential RCTs respectively]

5. A composite outcome in subgroups of hypercapnia severity at baseline [After 3 months and after 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/year in the subgroups with higher and lower hypercapnia at baseline (above and below of the median PaCO2 measured in mmHg)

6. A composite outcome in subgroups of the apnea-hypopnea index severity at baseline [After 3 months and after 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/year in the subgroups with higher and lower apnea-hypopnea index at baseline (above and below of the median apnea-hypopnea index at baseline)

7. A composite outcome in subgroups with or without hypertension diagnosis at baseline [After 3 months and after 3 years for first and second phases or sequential RCTs respectively]

8. A composite outcome in subgroups with different home care providers [After 3 months and after 3 years for first and second phases or sequential RCTs respectively]

9. Validity analysis of EQ 5D-5L test [After 3 months and after 3 years for first and second phases or sequential RCTs respectively]

To perform a validity analysis of EQ 5D-5L test

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

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