Partial failure of CPAP treatment for sleep apnoea: Analysis of the French national sleep database.

BACKGROUND AND OBJECTIVE: Continuous positive airway pressure (CPAP) is the first-line therapy for obstructive sleep apnoea (OSA). Residual apnoea and/or hypopnoea events, that is an apnoea-hypopnoea index (AHI) > 5, during CPAP contribute to treatment drop-out. The clinical scenarios triggering residual events during CPAP use are poorly described. Underlying co-morbidities, especially cardiovascular diseases, lifestyle factors, OSA characteristics at diagnosis and type of mask have been suggested as potential contributors. METHODS: Patients from the prospective French sleep apnoea registry diagnosed with OSA (AHI ≥ 15 events/h) treated with CPAP were included. Logistic regression analysis identified factors associated with a risk of residual AHI > 5 events/h on CPAP. RESULTS: The 12 285 OSA patients were predominantly men (n = 8715, 70.9%), middle-aged (58.2 (49.8; 66.1) years) and obese (median body mass index: 31.3 (27.7; 35.6) kg/m2 ). Most had an AHI ≤ 5 events/h (n = 9573, 77.9%) versus 22.1% with AHI > 5/h. The latter were less CPAP adherent (5.75 (4.01; 7.00) vs 6.00 (4.53; 7.00) h/night). In multivariable analysis, factors associated with residual AHI >5/h were male sex, age, sedentary lifestyle, OSA severity, cardiovascular co-morbidities (heart failure and arrhythmia) and type of interface (orofacial mask versus nasal mask: OR = 2.15 (95%CI: 1.95; 2.37)). A subgroup analysis found that patients using pressures above 10 cm H2 O were 1.43 (95% CI: 1.3; 1.57) times more likely to have residual AHI > 5/h. CONCLUSION: Knowing about risk factors for residual apnoeic-hypopnoeic events may assist in the timely provision of personalized care including the type of PAP therapy, attention to co-morbidities and choice of interface.

Contribution of obstructive sleep apnoea to arterial stiffness: a meta-analysis using individual patient data.

BACKGROUND: Arterial stiffness, measured by pulse wave velocity (PWV), is a strong independent predictor of late cardiovascular events and mortality. It is recognised that obstructive sleep apnoea (OSA) is associated with cardiovascular comorbidities and mortality. Although previous meta-analyses concluded that PWV is elevated in OSA, we feel that an individual patient data analysis from nine relatively homogeneous studies could help answer: to what extent does OSA drive arterial stiffness? METHODS: Individual data from well-characterised patients referred for suspicion of OSA, included in nine studies in which carotid-femoral PWV was measured using a Complior device, were merged for an individual patient data meta-analysis. RESULTS: 893 subjects were included (age: 56±11 (mean±SD), 72% men, 84% with confirmed OSA). Body Mass Index varied from 15 to 81 kg/m2 (30±7 kg/m2). PWV ranged from 5.3 to 20.5 m/s (10.4±2.3 m/s). In univariate analysis, log(PWV) was strongly related to age, gender, systolic blood pressure, presence of type 2 diabetes (all p<0.01) as well as to dyslipidaemia (p=0.03) and an Epworth Sleepiness Scale score ≥9 (p=0.04), whereas it was not related to obesity (p=0.54), a severe Apnoea-Hypopnoea Index (p=0.14), mean nocturnal saturation (p=0.33) or sleep time with oxygen saturation below 90% (p=0.47). In multivariable analysis, PWV was independently associated with age, systolic blood pressure and diabetes (all p<0.01), whereas severe OSA was not significantly associated with PWV. CONCLUSION: Our individual patient meta-analysis showed that elevated arterial stiffness in patients with OSA is driven by conventional cardiovascular risk factors rather than apnoea parameters.

Nonalcoholic fatty liver disease in chronic obstructive pulmonary disease.

Nonalcoholic fatty liver disease (NAFLD) is independently linked to cardiometabolic morbidity and mortality. Low-grade inflammation, oxidative stress and ectopic fat, common features of chronic obstructive pulmonary disease (COPD), might contribute to the development of NAFLD.We aimed to investigate the prevalence of NAFLD and to evaluate the relationship between various types of liver damage and COPD severity, comorbidities and circulating inflammatory cytokines. Validated noninvasive tests (FibroMax: SteatoTest, NashTest and FibroTest) were used to assess steatosis, nonalcoholic steatohepatitis (NASH) and liver fibrosis. Patients underwent an objective assessment of COPD comorbidities, including sleep studies. Biological parameters included a complete lipid profile and inflammatory markers.In COPD patients the prevalence of steatosis, NASH and fibrosis were 41.4%, 36.9% and 61.3%, respectively. In multivariate analysis, SteatoTest and FibroTest were significantly associated with sex, body mass index (BMI), untreated sleep apnoea and insulin resistance, and, in addition, COPD Global Initiative for Chronic Obstructive Lung Disease stage for SteatoTest. Patients with steatosis had higher tumour necrosis factor-α levels and those with NASH or a combination of liver damage types had raised leptin levels after adjustment for age, sex and BMI.We concluded that NAFLD is highly prevalent in COPD and might contribute to cardiometabolic comorbidities.

Impact of concomitant medications on obstructive sleep apnoea.

Obstructive sleep apnoea (OSA) is characterized by repeated episodes of apnoea and hypopnoea during sleep. Little is known about the potential impact of therapy drugs on the underlying respiratory disorder. Any influence should be taken into account and appropriate action taken, including drug withdrawal if necessary. Here, we review drugs in terms of their possible impact on OSA; drugs which (1) may worsen OSA; (2) are unlikely to have an impact on OSA; (3) those for which data are scarce or contradictory; and (4) drugs with a potentially improving effect. The level of evidence is ranked according to three grades: A - randomized controlled trials (RCTs) with high statistical power; B - RCTs with lower power, non-randomized comparative studies and observational studies; C - retrospective studies and case reports. Our review enabled us to propose clinical recommendations. Briefly, agents worsening OSA or inducing weight gain, that must be avoided, are clearly identified. Drugs such as 'Z drugs' and sodium oxybate should be used with caution as the literature contains conflicting results. Finally, larger trials are needed to clarify the potential positive impact of certain drugs on OSA. In the meantime, some, such as diuretics or other antihypertensive medications, are helpful in reducing OSA-associated cardiovascular morbidity.

Prevalence of obesity hypoventilation syndrome in ambulatory obese patients attending pathology laboratories.

BACKGROUND AND OBJECTIVE: The prevalence of obesity hypoventilation syndrome (OHS) in the unselected obese is unknown. Our objectives were: (i) to determine the prevalence of OHS in ambulatory obese patients not previously referred to a pulmonologist for suspicion of sleep breathing disorders and (ii) to assess whether venous bicarbonate concentration [HCO3-v ] can be used to detect OHS. METHODS: In this prospective multicentric study, we measured [HCO3-v ] in consenting obese patients attending pathology analysis laboratories. Patients with [HCO3-v ] ≥ 27 mmol/L were referred to a pulmonologist for comprehensive sleep and respiratory evaluations. Those with [HCO3-v ] < 27 mmol/L were randomized to either referral to a pulmonologist or ended the study. RESULTS: For the 1004 screened patients, the [HCO3-v ] was ≥27 mmol/L in 24.6% and <27 mmol/L in 45.9%. A total of 29.5% who had previously consulted a pulmonologist were excluded. A population of 241 obese patients underwent sleep and respiratory assessments. The prevalence of OHS in this population was 1.10 (95% CI = 0.51; 2.27). In multivariate analysis, PaCO2 , forced expiratory volume in 1 s (FEV1 ), apnoea-hypopnoea index (AHI), BMI, use of ≥3 anti-hypertensive drugs, anti-diabetics, proton pump inhibitors and/or paracetamol were related to raised [HCO3-v ]. CONCLUSION: The prevalence of OHS in our obese population was lower than previous estimations based on hospitalized patients or clinical cohorts with sleep breathing disorders. Apart from hypercapnia, increased [HCO3-v ] may also reflect multimorbidity and polypharmacy, which should be taken into account when using [HCO3-v ] to screen for OHS.

Intermittent hypoxia in obese Zucker rats: cardiometabolic and inflammatory effects.

NEW FINDINGS: What is the central question of this study? This study addresses the relative impact of obesity and intermittent hypoxia in the pathophysiological process of obstructive sleep apnoea by investigating the metabolic, inflammatory and cardiovascular consequences of intermittent hypoxia in lean and obese Zucker rats. What is the main finding and its importance? We found that obesity and intermittent hypoxia have mainly distinct consequences on the investigated inflammatory and cardiometabolic parameters in Zucker rats. This suggests that, for a given severity of sleep apnea, the association of obesity and obstructive sleep apnoea may not necessarily be deleterious. Obstructive sleep apnoea is associated with obesity with a high prevalence, and both co-morbidities are independent cardiovascular risk factors. Intermittent hypoxia (IH) is thought to be the main factor responsible for the obstructive sleep apnoea-related cardiometabolic alterations. The aim of this study was to assess the respective impact of obesity and IH on the inflammatory and cardiometabolic state in rats. Lean and obese Zucker rats were exposed to normoxia or chronic IH, and we assessed metabolic and inflammatory parameters, such as plasma lipids and glucose, serum leptin and adiponectin, liver cytokines, nuclear factor-κB activity and cardiac endothelin-1 levels. Myocardial infarct size was also evaluated following in vitro ischaemia-reperfusion. Circulating lipids, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), leptin and adiponectin levels were higher in obese versus lean rats. Chronic IH did not have a significant impact on metabolic parameters in lean rats. In obese rats, IH increased glycaemia and HOMA-IR. Liver interleukin-6 and tumour necrosis factor-α levels were elevated in lean rats exposed to IH; obesity prevented the increase in interleukin-6 but not in tumour necrosis factor-α. Finally, IH exposure enhanced myocardial sensitivity to infarction in both lean and obese rats and increased cardiac endothelin-1 in lean but not obese rats. In conclusion, this study shows that the dyslipidaemia and insulin resistance induced by obesity of genetic origin does not enhance the deleterious cardiovascular response to IH and may even partly protect against IH-induced inflammation.

Impact of effective versus sham continuous positive airway pressure on liver injury in obstructive sleep apnoea: Data from randomized trials.

BACKGROUND AND OBJECTIVE: Obstructive sleep apnoea (OSA) could be an independent risk factor for non-alcoholic fatty liver disease (NAFLD) occurrence and progression. The impact of continuous positive airway pressure (CPAP) treatment on non-invasive markers of NAFLD has not been studied. The aim of this study was to evaluate the effect of 6-12 weeks of effective CPAP on the FibroMax test (comprising components including the SteatoTest, NashTest and FibroTest) through three randomized sham controlled studies. METHODS: The FibroMax test was performed in 103 obstructive sleep apnoea patients (apnoea + hypopnoea index > 15/h) enrolled in a randomized study comparing sham versus effective CPAP. RESULTS: At baseline, 40.4% of patients in the sham CPAP group and 45.5% in the CPAP group exhibited liver steatosis. Furthermore, 39.6% of patients in the sham CPAP group and 58.4% in the CPAP group displayed borderline or possible non-alcoholic steatohepatitis (NASH). Six to twelve weeks of effective CPAP did not demonstrate any impact on reducing steatosis, NASH or liver fibrosis even after adjustment for gender, BMI, baseline apnoea + hypopnoea index and severity of liver injury. CONCLUSION: A number of non-invasive markers of liver damage are increased in untreated obstructive sleep apnoea patients, potentially contributing to cardiometabolic risk, but they do not improve after 6-12 weeks of effective CPAP treatment. CLINICAL TRIAL REGISTRATION: NCT01196845 (ADISAS), NCT00464659 (MneSAS) and NCT00669695 (StatinflaSAS) at ClinicalTrials.gov.

Comparison of continuous positive airway pressure and bosentan effect in mildly hypertensive patients with obstructive sleep apnoea: A randomized controlled pilot study.

BACKGROUND AND OBJECTIVE: Randomized controlled trials (RCT) have shown that continuous positive airway pressure (CPAP) has only limited impact on blood pressure (BP). Alternative strategies for obstructive sleep apnoea (OSA)-associated hypertension are therefore needed. Endothelin-1 has been demonstrated a key player in the deleterious cardiovascular consequences of OSA. In OSA, CPAP treatment has never been compared with endothelin receptor antagonist medications. Thus, we assessed the respective efficacy of CPAP and bosentan in reducing 24-h diastolic BP (DBP) in patients with OSA never treated by either therapy. METHODS: In a crossover pilot study, 16 mildly hypertensive patients (office systolic BP (SBP)/DBP: 142 ± 7/85 ± 8 mm Hg) with severe OSA (55 ± 8 years; body mass index, 29.6 ± 4.2 kg/m(2) ; apnoea-hypopnoea index, 40.8 ± 20.2/h) were randomized to either CPAP (n = 7) or bosentan (125 mg/day, n = 9) first for 4 weeks. After 2-weeks of washout, the second 4-week period consisted of the alternative treatment (in crossover). The primary outcome was the 24-h mean DBP change after treatment. RESULTS: In intention-to-treat analysis, the mean difference in 24-h DBP measurements between treatments was -3.1 (-6.9/0.7) mm Hg (median, 25th/75th percentiles) (P = 0.101) with bosentan having a greater effect. CONCLUSION: In this RCT, in mildly hypertensive patients with OSA, bosentan did not modify 24-h DBP but only reduced office BP suggesting that Endothelin-1 blockade does not play a major role in treatment of OSA-related hypertension.

Response to statin therapy in obstructive sleep apnea syndrome: a multicenter randomized controlled trial.

RATIONALE: Accumulated evidence implicates sympathetic activation as inducing oxidative stress and systemic inflammation, which in turn lead to hypertension, endothelial dysfunction, and atherosclerosis in obstructive sleep apnea (OSA). Statins through their pleiotropic properties may modify inflammation, lipid profile, and cardiovascular outcomes in OSA. METHODS: This multicenter, randomized, double-blind study compared the effects of atorvastatin 40 mg/day versus placebo over 12 weeks on endothelial function (the primary endpoint) measured by peripheral arterial tone (PAT). Secondary endpoints included office blood pressure (BP), early carotid atherosclerosis, arterial stiffness measured by pulse wave velocity (PWV), and metabolic parameters. RESULTS: 51 severe OSA patients were randomized. Key demographics for the study population were age 54 ± 11 years, 21.6% female, and BMI 28.5 ± 4.5 kg/m(2). In intention to treat analysis, mean PAT difference between atorvastatin and placebo groups was 0.008 (-0.29; 0.28), P = 0.979. Total and LDL cholesterol significantly improved with atorvastatin. Systolic BP significantly decreased with atorvastatin (mean difference: -6.34 mmHg (-12.68; -0.01), P = 0.050) whereas carotid atherosclerosis and PWV were unchanged compared to the placebo group. CONCLUSION: In OSA patients, 3 months of atorvastatin neither improved endothelial function nor reduced early signs of atherosclerosis although it lowered blood pressure and improved lipid profile. This trial is registered with NCT00669695.

Long-term incident severe outcomes in a prospective cohort of non-obese obstructive sleep apnoea patients free of comorbidities at inclusion.

In a prospective cohort of OSA patients without comorbidities at inclusion, age, mean blood pressure, mean oxygen saturation and minimum oxygen saturation were associated with long-term incidence of severe health events https://bit.ly/3VyYEzC.

Multidimensional phenotyping to distinguish among distinct obstructive sleep apnea, chronic obstructive pulmonary disease, and overlap syndrome phenotypes.

OBJECTIVE/BACKGROUND: Chronic obstructive pulmonary disease (COPD), obstructive sleep apnea (OSA) and their comorbid association called Overlap Syndrome (OS) are frequent chronic diseases with high individual and societal burdens. Precise descriptions of the respective symptoms, comorbidities, and medications associated with these three conditions are lacking. We used a multidimensional phenotyping approach to identify relevant phenotypes characterizing these 3 disorders. PATIENTS/METHODS: 308 patients with OSA, COPD and OS were prospectively assessed using a combination of body shape measurements and multidimensional questionnaires evaluating sleep, fatigue, depression and respiratory symptoms. Comorbidities and medications were confirmed by physicians. Patients made home blood pressure self-measurements using a connected wearable device to identify undiagnosed or uncontrolled hypertension. RESULTS: Three distinct relevant phenotypes were identified. OSA patients were round in shape with a balanced waist-to-hip ratio, frequent witnessed apneas, nocturia, daytime sleepiness, depression, and high diastolic blood pressure. COPD patients had a thinner body shape with a high waist-to-hip ratio, complained mainly of fatigue, and exhibited a higher resting heart rate. OS patients were round in shape with a balanced waist-to-hip ratio, reported little sleepiness and depression, but had impaired sleep and the highest rate of cardio-metabolic comorbidities. Diminished fitness-to-drive was most apparent in patients with OSA and OS. Home blood pressure measurements identified undiagnosed hypertension in 80 % of patients and in nearly 80 % of those with hypertension it was uncontrolled by their current medications. CONCLUSIONS: Our systematic multidimensional phenotyping approach identified distinct body shapes, symptoms, and comorbidity profiles among patients with OSA, COPD, and OS.

Long-term outcomes of CPAP-treated sleep apnea patients: Impact of blood-pressure responses after CPAP initiation and of treatment adherence.

BACKGROUND AND OBJECTIVE: In randomized controlled trials, continuous positive airway pressure (CPAP) is reported as lowering blood pressure (BP) with a mean systolic blood pressure effect size of 2.5 mmHg. These trials have a median follow-up of less than 6 months. Whether this initial BP response during the first months of CPAP treatment translates into a reduction in long-term cardiovascular events and mortality is unknown. METHODS: This observational study addressed long-term hard cardiovascular outcomes and all-cause mortality in a well-defined population of 241 patients previously included in the AgirSASadom parallel randomized controlled trial (assessing whether fixed-pressure CPAP was superior to auto-adjusted CPAP in reducing BP (baseline evaluations 2010-2012)). Long-term outcomes were analyzed using a Cox survival model, and a logistic regression analysis was performed for long-term CPAP adherence. RESULTS: Sixty-nine cardiovascular events occurred in 61 patients during a median follow-up of 113 months (interquartile range [102 ; 124]) giving an incidence of 26 for 1000 person-years. Twenty-one (8.7%) patients died. BP values at baseline (i.e., office and 24-h BP) was a strong predictor of incident cardiometabolic events and mortality (p < 0.01) whereas initial BP response after the first four months of CPAP was not related to outcomes. Long-term CPAP adherence above 4 h/night was associated with a reduction in all-cause mortality (Log-rank P = 0.02) but not in the occurrence of long-term cardiovascular events. CONCLUSION: Independently of initial blood pressure response, long-term CPAP adherence is one of the prerequisites for reducing mortality.

Machine learning and geometric morphometrics to predict obstructive sleep apnea from 3D craniofacial scans.

BACKGROUND: Obstructive sleep apnea (OSA) remains massively underdiagnosed, due to limited access to polysomnography (PSG), the highly complex gold standard for diagnosis. Performance scores in predicting OSA are evaluated for machine learning (ML) analysis applied to 3D maxillofacial shapes. METHODS: The 3D maxillofacial shapes were scanned on 280 Caucasian men with suspected OSA. All participants underwent single night in-home or in-laboratory sleep testing with PSG (Nox A1, Resmed, Australia), with concomitant 3D scanning (Sense v2, 3D systems corporation, USA). Anthropometric data, comorbidities, medication, BERLIN, and NoSAS questionnaires were also collected at baseline. The PSG recordings were manually scored at the reference sleep center. The 3D craniofacial scans were processed by geometric morphometrics, and 13 different supervised algorithms, varying from simple to more advanced, were trained and tested. Results for OSAS recognition by ML models were then compared with scores for specificity and sensitivity obtained using BERLIN and NoSAS questionnaires. RESULTS: All valid scans (n = 267) were included in the analysis (patient mean age: 59 ± 9 years; BMI: 27 ± 4 kg/m2). For PSG-derived AHI≥15 events/h, the 56% specificity obtained for ML analysis of 3D craniofacial shapes was higher than for the questionnaires (Berlin: 50%; NoSAS: 40%). A sensitivity of 80% was obtained using ML analysis, compared to nearly 90% for NoSAS and 61% for the BERLIN questionnaire. The auROC score was further improved when 3D geometric morphometrics were combined with patient anthropometrics (auROC = 0.75). CONCLUSION: The combination of 3D geometric morphometrics with ML is proposed as a rapid, efficient, and inexpensive screening tool for OSA. TRIAL REGISTRATION NUMBER: NCT03632382; Date of registration: 15-08-2018.

Implantable cardiac devices in sleep apnoea diagnosis: A systematic review and meta-analysis.

BACKGROUND: A particularly high burden of sleep apnoea is reported in patients treated with cardiac implants such as pacemakers and defibrillators. Sleep apnoea diagnosis remains a complex procedure mainly based on sleep and respiratory indices captured by polysomnography (PSG) or respiratory polygraphy (PG). AIM: We aimed to evaluate the performance of implantable cardiac devices for sleep apnoea diagnosis compared to reference methods. METHOD: Systematic structured literature searches were performed in PubMed, Embase and. Cochrane Library was performed to identify relevant studies. Quantitative characteristics of the studies were summarized and a qualitative synthesis was performed by a randomized bivariate meta-analysis and completed by pre-specified sensitivity analyses for different implant types and brands. RESULTS: 16 studies involving 999 patients met inclusion criteria and were included in the meta-analysis. The majority of patients were men, of mean age of 64 ± 4.6 years. Sensitivity of cardiac implants for sleep apnoea diagnosis ranged from 60 to 100%, specificity from 50 to 100% with a prevalence of sleep apnoea varying from 22 to 91%. For an apnoea-hypopnoea index threshold ≥30 events/h during polysomnography (corresponding to severe sleep apnoea), the overall performance of the implants was relevant with a sensitivity of 78% and a specificity of 79%. Subgroup analyses on implant type and brand provided no additional information owing to the small number of studies. CONCLUSION: The respiratory disturbance index provided by cardiac implants is clinically relevant and might improve access to sleep apnoea diagnosis in at-risk cardiovascular populations. PROSPERO Registration number: CRD42020181656.

Diagnosis of Sleep Apnoea Using a Mandibular Monitor and Machine Learning Analysis: One-Night Agreement Compared to in-Home Polysomnography.

Background: The capacity to diagnose obstructive sleep apnoea (OSA) must be expanded to meet an estimated disease burden of nearly one billion people worldwide. Validated alternatives to the gold standard polysomnography (PSG) will improve access to testing and treatment. This study aimed to evaluate the diagnosis of OSA, using measurements of mandibular movement (MM) combined with automated machine learning analysis, compared to in-home PSG. Methods: 40 suspected OSA patients underwent single overnight in-home sleep testing with PSG (Nox A1, ResMed, Australia) and simultaneous MM monitoring (Sunrise, Sunrise SA, Belgium). PSG recordings were manually analysed by two expert sleep centres (Grenoble and London); MM analysis was automated. The Obstructive Respiratory Disturbance Index calculated from the MM monitoring (MM-ORDI) was compared to the PSG (PSG-ORDI) using intraclass correlation coefficient and Bland-Altman analysis. Receiver operating characteristic curves (ROC) were constructed to optimise the diagnostic performance of the MM monitor at different PSG-ORDI thresholds (5, 15, and 30 events/hour). Results: 31 patients were included in the analysis (58% men; mean (SD) age: 48 (15) years; BMI: 30.4 (7.6) kg/m2). Good agreement was observed between MM-ORDI and PSG-ORDI (median bias 0.00; 95% CI -23.25 to + 9.73 events/hour). However, for 15 patients with no or mild OSA, MM monitoring overestimated disease severity (PSG-ORDI < 5: MM-ORDI mean overestimation + 5.58 (95% CI + 2.03 to + 7.46) events/hour; PSG-ORDI > 5-15: MM-ORDI overestimation + 3.70 (95% CI -0.53 to + 18.32) events/hour). In 16 patients with moderate-severe OSA (n = 9 with PSG-ORDI 15-30 events/h and n = 7 with a PSG-ORD > 30 events/h), there was an underestimation (PSG-ORDI > 15: MM-ORDI underestimation -8.70 (95% CI -28.46 to + 4.01) events/hour). ROC optimal cut-off values for PSG-ORDI thresholds of 5, 15, 30 events/hour were: 9.53, 12.65 and 24.81 events/hour, respectively. These cut-off values yielded a sensitivity of 88, 100 and 79%, and a specificity of 100, 75, 96%. The positive predictive values were: 100, 80, 95% and the negative predictive values 89, 100, 82%, respectively. Conclusion: The diagnosis of OSA, using MM with machine learning analysis, is comparable to manually scored in-home PSG. Therefore, this novel monitor could be a convenient diagnostic tool that can easily be used in the patients' own home. Clinical Trial Registration: https://clinicaltrials.gov, identifier NCT04262557.