Transcutaneous electrical diaphragmatic stimulation in mechanically ventilated patients: a randomised study.

BACKGROUND: Few specific methods are available to reduce the risk of diaphragmatic dysfunction for patients under mechanical ventilation. The number of studies involving transcutaneous electrical stimulation of the diaphragm (TEDS) is increasing but none report results for diaphragmatic measurements, and they lack power. We hypothesised that the use of TEDS would decrease diaphragmatic dysfunction and improve respiratory muscle strength in patients in ICU. METHODS: We conducted a controlled trial to assess the impact of daily active electrical stimulation versus sham stimulation on the prevention of diaphragm dysfunction during the weaning process from mechanical ventilation. The evaluation was based on ultrasound measurements of diaphragm thickening fraction during spontaneous breathing trials. We also measured maximal inspiratory muscle pressure (MIP), peak cough flow (PEF) and extubation failure. RESULTS: Sixty-six patients were included and randomised using a 1:1 ratio. The mean number of days of mechanical ventilation was 10 ± 6.8. Diaphragm thickening fraction was > 30% at the SBT for 67% of participants in the TEDS group and 54% of the Sham group (OR1.55, 95% CI 0.47-5.1; p = 0.47). MIP and PEF were similar in the TEDS and Sham groups (respectively 35.5 ± 11.9 vs 29.7 ± 11.7 cmH20; p = 0.469 and 83.2 ± 39.5 vs. 75.3 ± 34.08 L/min; p = 0.83). Rate of extubation failure was not different between groups. CONCLUSION: TEDS did not prevent diaphragm dysfunction or improve inspiratory muscle strength in mechanically ventilated patients. TRIAL REGISTRATION: Prospectively registered on the 20th November 2019 on ClinicalTrials.gov Identifier NCT04171024.

Riociguat real-world use in patients with chronic thromboembolic pulmonary hypertension: A retrospective, observational cohort study in France.

BACKGROUND: Riociguat is the first approved treatment for inoperable and persistent/recurrent post-surgery chronic thromboembolic pulmonary hypertension (CTEPH). The RetrospectIve Adempas® stuDy (RiAD) aimed to describe the real-world utilization of riociguat in France. METHODS: In this retrospective multicentric study in patients initiating riociguat, dosing regimen, co-treatments and clinical characteristics were collected over a 2-year follow-up period. RESULTS: A total of 173 patients (mean age, 71.4 years; female, 63.0%; NYHA II-III, 80.3%) were included from January 2015 to December 2016 in 18 centers. All patients were diagnosed with CTEPH (75.7% inoperable and 20.8% with persistent/recurrent pulmonary hypertension [pH] after surgery) with mean (SD) right atrial pressure 7.6 (4.2) mmHg, mean pulmonary artery pressure 43.0 (11.4) mmHg and mean cardiac output 4.1 (1.1) L/min. Before riociguat initiation, 32.4% of patients previously received at least one pH-specific therapy. At initiation, 93.1% of patients were receiving anticoagulants and 83.2% were not receiving pH-specific co-treatments. Riociguat was initiated at 1 mg three times daily (t.i.d.) in 85.5% of patients and 82.1% were receiving 2.5 mg dose t.i.d. at 24 months. The maximal daily dose of 7.5 mg was never exceeded. At 24 months, the estimated rate of patients still taking riociguat was 78.8% with an estimated mean (SD) time on treatment of 20.1 (0.5) months per patient. No new safety signals were recorded. CONCLUSIONS: The results of this real-world study show that riociguat is used in France in accordance with its therapeutic indication in patients with inoperable or persistent/recurrent post-operative CTEPH and confirm its long-term safety.

Enoxaparin versus Placebo to Prevent Symptomatic Venous Thromboembolism in Hospitalized Older Adult Medical Patients.

BACKGROUND: Admission to the hospital is a major risk factor for the development of venous thromboembolism (VTE). Whether thromboprophylaxis with low-molecular-weight heparin prevents symptomatic VTE in medically ill, hospitalized older adults remains debated. METHODS: In a prospective, randomized, placebo-controlled, double-blind, multicenter trial, older adults (>70 years of age) hospitalized for acute medical conditions were randomly assigned to receive 40 mg a day of low-molecular-weight heparin (enoxaparin) or placebo for 6 to 14 days. The primary efficacy outcome was the cumulative incidence of symptomatic VTE (distal or proximal deep vein thrombosis, fatal or nonfatal pulmonary embolism) at 30 days. The primary safety outcome was major bleeding. Secondary outcomes included efficacy and safety outcomes at 90 days. RESULTS: The trial was prematurely discontinued in September 2020, 5 years after enrollment began, because of drug supply issues. By the time of trial discontinuation, 2559 patients had been randomly assigned at 47 centers. Median age was 82 years and 60% of patients were female. In the intention-to-treat population, the primary efficacy outcome occurred in 22 out of 1278 (cumulative incidence, 1.8%) patients in the enoxaparin group and in 27 out of 1263 (cumulative incidence, 2.2%) patients in the placebo group (cumulative incidence difference, −0.4 percentage points; 95% confidence interval, −1.5 to 0.7), with no significant difference in time to VTE (P=0.46). The incidence of major bleeding was 0.9% in the enoxaparin group and 1.0% in the placebo group. At 90 days there were 14 symptomatic pulmonary emboli in the enoxaparin group and 25 in the placebo group; all 39 pulmonary embolism events resulted in hospital readmission and/or death, with 5 deaths from pulmonary embolism in the enoxaparin group and 11 deaths in the placebo group. CONCLUSIONS: This trial of thromboprophylaxis in medically ill, hospitalized older adults did not demonstrate that enoxaparin reduced the risk of symptomatic VTE after 1 month. Because the trial was prematurely discontinued, larger trials are needed to definitively address this question. (Funded by the French Ministry of Health Programme Hospitalier de Recherche Clinique, grant number PHRC-N-13-0283; ClinicalTrials.gov number, NCT02379806.)

Oxygen uptake kinetics during treadmill walking in adolescents with clinically stable cystic fibrosis.

BACKGROUND: Oxygen uptake (V̇O2) kinetics have been shown to be slowed in adolescents with cystic fibrosis (CF) during heavy-intensity cycling and maximal exercise testing. OBJECTIVES: This study investigated V̇O2 kinetics in adolescents with CF compared to control adolescents (CON) during a treadmill-walking exercise. METHODS: Eight adolescents with CF and mild-to-moderate pulmonary obstruction (5 girls; 13.1 ± 2.5 years; FEV1 67.8 ± 21.4%) and 18 CON adolescents (10 girls; 13.8 ± 1.8 years) were recruited. Pulmonary gas exchange and ventilation were measured during a single transition of 10 min of treadmill walking and a 5 min seated recovery period. Participant's walking speed was determined during a one-minute self-paced walking task along a 50-m corridor. A six-parameter, non-linear regression model was used to describe the changes in V̇O2 function during the treadmill walking and recovery, with monoexponential curve fitting used to describe the mean response time (MRT1) at the onset of exercise, and the half-life (T1/2V̇O2) at the offset of exercise. V̇O2 baseline and amplitude, minute ventilation and respiratory equivalents were recorded. RESULTS: V̇O2 kinetics were slower in CF group compared to CON group during the treadmill walking with a greater MRT1 (32 ± 14 s vs 21 ± 16 s; p = .04, effect size = 0.75). The T1/2V̇O2 was prolonged during recovery in CF group compared to CON group (86 ± 24 s vs 56 ± 22 s; p = .04, effect size = 1.31). The mean VE/V̇CO2 during exercise was the only parameter significantly greater in CF group compared to CON group (32.9 ± 2.3 vs 29.0 ± 2.4; p < .01, effect size = 1.66). CONCLUSION: V̇O2 kinetics were found to be slowed in adolescents with CF during treadmill walking.

Nasal High-Flow Therapy during Exercise in Patients with Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis.

Background: Several studies have evaluated the effect of nasal high-flow (NHF) therapy to enhance exercise performance and tolerance in patients with chronic obstructive pulmonary disease (COPD); however, results are disparate. Objective: The aim of this systematic review and meta-analysis was to assess the effect of NHF therapy as an adjuvant to exercise training on functional exercise capacity in patients with COPD. Data Sources: An electronic search was performed in the following databases: PubMed, the Cochrane Central Register of Controlled Trials, the Physiotherapy Evidence Database, ScienceDirect, the Web of Science, OpenGrey, ClinicalTrials.gov, and European Respiratory Society and American Thoracic Society databases. Data Extraction: Two authors independently selected relevant randomized trials (parallel-group or crossover design), extracted data, assessed the risk of bias, and rated the quality of the evidence. Synthesis: Eleven studies were included, involving 408 participants (eight full papers and three conference abstracts). Most studies had a high risk of bias or other methodological limitations. The use of NHF therapy during a single session increased functional exercise capacity (standardized mean difference, 0.36 [95% confidence interval (CI), 0.03 to 0.69]; P = 0.03, heterogeneity [I2 = 83%]). When conference abstracts were included in the pooled analysis, the estimated effect did not change (P = 0.006). The use of NHF therapy throughout a pulmonary rehabilitation program (parallel-group randomized controlled trials) increased functional exercise capacity at 4-12 weeks compared with training without NHF therapy (standardized mean difference, 0.34 [95% CI, 0.00-0.68]; P = 0.05, heterogeneity [I2 = 18%]). Conclusions: There is very-low-quality to low-quality evidence that NHF therapy improves functional exercise capacity. Patient responses to NHF therapy were highly variable and heterogeneous, with benefits ranging from clinically trivial to worthwhile.

Short-term effects of menthol on walking dyspnoea in patients with COPD: a randomised, single blinded, cross-over study.

Chewing menthol gum prior to exercise is a safe, easy-to-implement, low-cost, non-pharmacologic intervention that provides a reduction in dyspnoea in a third of patients and decreases the perception of discomfort during exercise in two-thirds of patients https://bit.ly/3FoFHp1.

Severe pulmonary hypertension associated with chronic obstructive pulmonary disease: A prospective French multicenter cohort.

BACKGROUND: A small proportion of patients with chronic obstructive pulmonary disease (COPD) patients present severe pulmonary hypertension (PH), defined by mean pulmonary artery pressure (mPAP) ≥35 mm Hg measured by right heart catheterization. Little is known about the characteristics of severe PH-COPD. The aim of the study based on a national registry was to describe this phenotype. METHODS: We prospectively included and followed patients with incident PH-COPD. Clinical, functional, hemodynamic data at inclusion and follow-up were retrieved. Survival assessed by Kaplan-Meier analysis was the primary end-point. RESULTS: From 2012 to 2016, 99 patients from 13 French centers were included in the study (82 males; median age 66.0 years [interquartile range 62.0-72.0]). At inclusion, most patients had marked dyspnea (55.6% and 22.2% New York Heart Association class III and IV, respectively). During 12 months before inclusion, 42.9% had an exacerbation requiring a hospitalization. Pulmonary function tests showed a moderate obstructive pattern with median (interquartile range) FEV1 50.0 [35.0-63.0] % predicted and low diffusing capacity for carbon monoxide, median 20.0 [16.5-30.6] % predicted. The median values for PaO2 and PaCO2 on room air were 50.0 [44.8-62.0] and 36.0 [31.1-43.0] mm Hg. Median values of mPAP, pulmonary artery occlusion pressure, cardiac index and pulmonary vascular resistance were 42.0 [37.0-48.0] mm Hg, 11.0 [9.0-14.0] mm Hg, 3.0 [2.4-3.6] L/min/m2, and 6.3 [4.2-7.9] WU, respectively. Mean restricted survival was 15.0 [13.9-16.0] months. CONCLUSIONS: Severe PH-COPD is characterized by moderate airway obstruction but marked dyspnea and marked hypoxemia, low DLCO and high mPAP. This phenotype is associated with poor prognosis.

Role of Non-Invasive Respiratory Supports in COVID-19 Acute Respiratory Failure Patients with Do Not Intubate Orders.

The current gold-standard treatment for COVID-19-related hypoxemic respiratory failure is invasive mechanical ventilation. However, do not intubate orders (DNI), prevent the use of this treatment in some cases. The aim of this study was to evaluate if non-invasive ventilatory supports can provide a good therapeutic alternative to invasive ventilation in patients with severe COVID-19 infection and a DNI. Data were collected from four centres in three European countries. Patients with severe COVID-19 infection were included. We emulated a hypothetical target trial in which outcomes were compared in patients with a DNI order treated exclusively by non-invasive respiratory support with patients who could be intubated if necessary. We set up a propensity score and an inverse probability of treatment weighting to remove confounding by indication. Four-hundred patients were included: 270 were eligible for intubation and 130 had a DNI order. The adjusted risk ratio for death among patients eligible for intubation was 0.81 (95% CI 0.46 to 1.42). The median length of stay in acute care for survivors was similar between groups (18 (10-31) vs. (19 (13-23.5); p = 0.76). The use of non-invasive respiratory support is a good compromise for patients with severe COVID-19 and a do not intubate order.

Muscle weakness, functional capacities and recovery for COVID-19 ICU survivors.

BACKGROUND: Few studies have evaluated muscle strength in COVID-19 ICU survivors. We aimed to report the incidence of limb and respiratory muscle weakness in COVID-19 ICU survivors. METHOD: We performed a cross sectional study in two ICU tertiary Hospital Settings. COVID-19 ICU survivors were screened and respiratory and limb muscle strength were measured at the time of extubation. An ICU mobility scale was performed at ICU discharge and walking capacity was self-evaluated by patients 30 days after weaning from mechanical ventilation. RESULTS: Twenty-three patients were included. Sixteen (69%) had limb muscle weakness and 6 (26%) had overlap limb and respiratory muscle weakness. Amount of physiotherapy was not associated with muscle strength. 44% of patients with limb weakness were unable to walk 100 m 30 days after weaning. CONCLUSION: The large majority of COVID-19 ICU survivors developed ICU acquired limb muscle weakness. 44% of patients with limb weakness still had severely limited function one-month post weaning.

Measurement properties of the one-minute sit-to-stand test in children and adolescents with cystic fibrosis: A multicenter randomized cross-over trial.

BACKGROUND: Functional exercise capacity assessment is recommended in children with cystic fibrosis (CF). The six-minute walk test (6MWT) is a valid evaluation of exercise capacity but can be technically complex. Inversely, the sit-to-stand test (STST) is a simple method to evaluate exercise capacity, and is validated in healthy children and adults with CF. This study aimed to evaluate STST measurement properties in children and adolescents with CF. METHODS: In this multicenter study, children with CF (6 to 18 years) performed two iterations of both the STST and the 6MWT in a randomized order. Criterion validity was determined by assessing correlations between STST repetitions and 6MWT distance (6MWD). Intra-rater reliability, test-retest repeatability, mean bias and limits of agreement were also assessed. Relationships with other outcomes (i.e. respiratory and quadriceps muscle strength) and cardio-respiratory responses were analysed for both tests. RESULTS: Thirty-six children with CF were included (mean age 12.0 ±3.5 years and FEV1 95.8 ±25.0%). On average, 39.6 ±10.5 repetitions were performed during the STST and mean 6MWD was 596.0 ±102.6 meters. STST number of repetitions was significantly correlated with 6MWD (r = 0.48; p<0.01). Both tests had very good intra-rater reliability (ICCSTST = 0.91 (95%CI 0.76-0.96) and ICC6MWT = 0.94 (95%CI 0.85-0.97)), and a significant test-retest learning effect. The number of STST repetitions was not correlated with quadriceps or respiratory muscle strength test, and the STST induced fewer cardio-respiratory responses than the 6MWT. CONCLUSIONS: The STST is an easy-to-use functional test with moderate criterion validity when compared to the 6MWT in children with CF, probably because both tests measure different components of functional exercise capacity. The STST is useful when the 6MWT is unfeasible, however further investigations are required to explore the clinical implications of STST results in children with CF. CLINICAL TRIAL REGISTRATION: NCT03069625.

The relationship between maximal expiratory pressure values and critical outcomes in mechanically ventilated patients: a post hoc analysis of an observational study.

BACKGROUND: Little interest has been paid to expiratory muscle strength, and the impact of expiratory muscle weakness on critical outcomes is not known. Very few studies assessed the relationship between maximal expiratory pressure (MEP) and critical outcomes. The aim of this study was to investigate the relationship between MEP and critical outcomes. METHODS: This work was a secondary analysis of a prospective, observational study of adult patients who required mechanical ventilation for ≥ 24 h in an 18-bed ICU. MEP was assessed before extubation after a successful, spontaneous breathing trial. The relationships between MEP and extubation failure, and short-term (30 days) mortality, were investigated. Univariate logistic regressions were computed to investigate the relationship between MEP values and critical outcomes. Two multivariate analyses, with and without maximal inspiratory pressure (MIP), both adjusted using principal component analysis, were undertaken. Unadjusted and adjusted ROC curves were computed to compare the respective ability of MEP, MIP and the combination of both measures to discriminate patients with and without extubation failure or premature death. RESULTS: One hundred and twenty-four patients were included. Median age was 66 years (IQR 18) and median mechanical ventilation duration was 7 days (IQR 6). Extubation failure rate was 15% (18/124 patients) and the rate for 30-day mortality was 11% (14/124 patient). Higher MEP values were significantly associated with a lower risk of extubation failure in the univariate analysis [OR 0.96 95% CI (0.93-0.98)], but not with short-term mortality. MEP was independently linked with extubation failure when MIP was not included in the multivariate model, but not when it was included, despite limited collinearity between these variables. This study was not able to differentiate the respective abilities of MEP, MIP, and their combination to discriminate patients with extubation failure or premature death (adjusted AUC for the combination of MEP and MIP: 0.825 and 0.650 for extubation failure and premature death, respectively). CONCLUSIONS: MEP is related to extubation failure. But, the results did not support its use as a substitute for MIP, since the relationship between MEP and critical outcomes was no longer significant when MIP was included. The use of MIP and MEP measurements combined did not reach higher discriminative capacities for critical outcomes that MEP or MIP alone. Trial Registration This study was retrospectively registered at https://clinicaltrials.gov/ct2/show/NCT02363231?cond=NCT02363231&draw=2&rank=1 (NCT02363231) in 13 February 2015.

Evaluation of Humoral Immunity to SARS-CoV-2: Diagnostic Value of a New Multiplex Addressable Laser Bead Immunoassay.

Despite efforts to develop anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody (Ab) immunoassays, reliable serological methods are still needed. We developed a multiplex addressable laser bead immunoassay (ALBIA) to detect and quantify anti-Spike S1 and nucleocapsid N Abs. Recombinant S1 and N proteins were bound to fluorescent beads (ALBIA-IgG-S1/N). Abs were revealed using class-specific anti-human Ig Abs. The performances of the test were analyzed on 575 serum samples including 192 from SARS-CoV-2 polymerase chain reaction-confirmed patients, 13 from seasonal coronaviruses, 70 from different inflammatory/autoimmune diseases, and 300 from healthy donors. Anti-S1 IgM were detected by monoplex ALBIA-IgM-S1. Comparison with chemiluminescent assays or enzyme-linked immunosorbent assays was performed using commercial tests. Multiplex ALBIA-IgG-S1/N was effective in detecting and quantifying anti-SARS-CoV-2 IgG Abs. Two weeks after first symptoms, sensitivity and specificity were 97.7 and 98.0% (anti-S1), and 100 and 98.7% (anti-N), respectively. Agreement with commercial tests was good to excellent, with a higher sensitivity of ALBIA. ALBIA-IgG-S1/N was positive in 53% of patients up to day 7, and in 75% between days 7 and 13. For ALBIA-IgM-S1, sensitivity and specificity were 74.4 and 98.7%, respectively. Patients in intensive care units had higher IgG Ab levels (Mann-Whitney test, p < 0.05). ALBIA provides a robust method for exploring humoral immunity to SARS-CoV-2. Serology should be performed after 2 weeks following first symptoms, when all COVID-19 (coronavirus disease 2019) patients had at least one anti-S1 or anti-N IgG Ab, illustrating the interest of a multiplex test.

Mid-Term Effects of Pulmonary Rehabilitation on Cognitive Function in People with Severe Chronic Obstructive Pulmonary Disease.

Purpose: Cognitive dysfunction is a common impairment associated with COPD. However, little is known about 1) its prevalence among those subjects referred for pulmonary rehabilitation (PR), 2) how it may affect the benefit of PR, 3) whether PR improves cognitive function and 4) whether cognitive dysfunction affects the usability of telehealth technology usually used to deliver in-home PR. Patients and Methods: Fifty-six subjects with stable COPD (54% females, mean age 62 years (SD 9) and median FEV1 0.9 L (IQR 0.7 to 1.1)) participated in this multicenter observational study and performed 24 sessions of PR. The Montreal Cognitive Assessment tool (MoCA) was used to assess the occurrence of mild cognitive dysfunction (using a screening cutoff <26) at baseline, completion of PR and 3 months of follow-up. Results: Mild cognitive dysfunction was found in 41 subjects (73% [95% CI: 60 to 83%]). The MoCA score significantly improved following PR for those people with baseline mild cognitive dysfunction (p<0.01). There was no significant difference in clinical outcomes between those people with or without mild cognitive dysfunction following PR nor in the proportion of subjects who were autonomous in using the telemonitoring system (83% compared with 71%, p=0.60). Conclusion: Mild cognitive dysfunction is highly prevalent among those people with COPD referred for PR but does not affect the benefits of PR nor the usability of a telemonitoring system. PR may improve short- and mid-term cognitive function for those people who experience mild cognitive dysfunction at the time they are referred to PR.

Clinimetric evaluation of muscle function tests for individuals with cystic fibrosis: A systematic review.

Accurate testing of muscle function is essential in individuals with cystic fibrosis (CF). A literature search was conducted in MEDLINE, CENTRAL, CINAHL, PEDro, ScienceDirect and Web of Science according to PRISMA and COSMIN guidelines from inception to September 2019 to investigate the clinimetric properties of muscle tests in individuals with CF. The search identified 37 studies (1310 individuals) and 34 different muscle tests. Maximal inspiratory pressure, inspiratory work capacity and quadriceps strength measured by computerised dynamometry were identified as reliable tests of muscle function. The one-minute sit-to-stand test was found to have high reliability but its validity to measure quadriceps strength is unknown. The clinimetric properties of other routinely used tests have not been reported in people with CF. Very different measurement procedures were identified. Inspiratory muscle and quadriceps testing can be considered as reliable but high-quality studies evaluating tests of other muscles function (e.g. muscle endurance) are lacking.

ICU outcomes can be predicted by noninvasive muscle evaluation: a meta-analysis.

BACKGROUND: The relationship between muscle function in critically ill patients assessed using bedside techniques and clinical outcomes has not been systematically described. We aimed to evaluate the association between muscle weakness assessed by bedside evaluation and mortality or weaning from mechanical ventilation, and the capacity of each evaluation tool to predict outcomes. METHODS: Five databases (PubMed, Embase, CINAHL, Cochrane Library, Science Direct) were searched from January 2000 to December 2018. Data were extracted and random effects meta-analyses were performed. RESULTS: 60 studies were analysed, including 4382 patients. Intensive care unit (ICU)-related muscle weakness was associated with an increase in overall mortality with odds ratios ranging from 1.2 (95% CI 0.60-2.40) to 4.48 (95% CI 1.49-13.42). Transdiaphragmatic twitch pressure had the highest predictive capacity for overall mortality, with a sensitivity of 0.87 (95% CI 0.76-0.93) and a specificity of 0.36 (95% CI 0.27-0.43). The area under the curve (AUC) was 0.74 (95% CI 0.70-0.78). Muscle weakness was associated with an increase in mechanical ventilation weaning failure rate with an odds ratio ranging from 2.64 (95% CI 0.72-9.64) to 19.07 (95% CI 9.35-38.9). Diaphragm thickening fraction had the highest predictive capacity for weaning failure with a sensitivity of 0.76 (95% CI 0.67-0.83) and a specificity of 0.86 (95% CI 0.78-0.92). The AUC was 0.86 (95% CI 0.83-0.89). CONCLUSION: ICU-related muscle weakness detected by bedside techniques is a serious issue associated with a high risk of death or prolonged mechanical ventilation. Evaluating diaphragm function should be a clinical priority in the ICU.

Energy conservation technique improves dyspnoea when patients with severe COPD climb stairs: a randomised crossover study.

In this randomised, crossover trial, 22 patients with severe chronic obstructive pulmonary disease climbed six flights of stairs (108 steps) twice, under two test conditions: (1) energy conservation technique (ECT): participants were asked to rest for at least 5 seconds every three steps and (2) control condition: participants climbed the stairs at their own pace. Significant lower dyspnoea (primary outcome), leg discomfort, minute ventilation and capillary blood lactate under the ECT condition were found, with no change in total task time. CLINICAL TRIAL REGISTRATION: NCT03564028.