Development and Evaluation of a Simulation-Based Algorithm to Optimize the Planning of Interim Analyses for Clinical Trials in ALS

BACKGROUND AND OBJECTIVES: Late-phase clinical trials for neurodegenerative diseases have a low probability of success. In this study, we introduce an algorithm that optimizes the planning of interim analyses for clinical trials in amyotrophic lateral sclerosis (ALS) to better use the time and resources available and minimize the exposure of patients to ineffective or harmful drugs. METHODS: A simulation-based algorithm was developed to determine the optimal interim analysis scheme by integrating prior knowledge about the success rate of ALS clinical trials with drug-specific information obtained in early-phase studies. Interim analysis schemes were optimized by varying the number and timing of interim analyses, together with their decision rules about when to stop a trial. The algorithm was applied retrospectively to 3 clinical trials that investigated the efficacy of diaphragm pacing or ceftriaxone on survival in patients with ALS. Outcomes were additionally compared with conventional interim designs. RESULTS: We evaluated 183-1,351 unique interim analysis schemes for each trial. Application of the optimal designs correctly established lack of efficacy, would have concluded all studies 1.2-19.4 months earlier (reduction of 4.6%-57.7% in trial duration), and could have reduced the number of randomized patients by 1.7%-58.1%. By means of simulation, we illustrate the efficiency for other treatment scenarios. The optimized interim analysis schemes outperformed conventional interim designs in most scenarios. DISCUSSION: Our algorithm uses prior knowledge to determine the uncertainty of the expected treatment effect in ALS clinical trials and optimizes the planning of interim analyses. Improving futility monitoring in ALS could minimize the exposure of patients to ineffective or harmful treatments and result in significant ethical and efficiency gains

The need to research refractory breathlessness

High-quality research is needed to improve quality of life for people with chronic refractory breathlessness in COP

Mise en jeu des contrôles inhibiteurs descendants par l'activation d'afférences amyéliniques en réponse à l'application d'une charge inspiratoire génératrice de dyspnée chez l'homme sain (approche neurophysiologique de l'analogie dyspnée-douleur viscérale)

PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

NIV in amyotrophic lateral sclerosis: The ‘when’ and ‘how’ of the matter

International audienceNon-invasive ventilation (NIV) has become an essential part of the treatment of amyotrophic lateral sclerosis (ALS) since 2006. NIV very significantly improves survival, quality of life and cognitive performances. The initial NIV settings are simple, but progression of the disease, ventilator dependence and upper airway involvement sometimes make long-term adjustment of NIV more difficult, with a major impact on survival. Unique data concerning the long-term adjustment of NIV in ALS show that correction of leaks, management of obstructive apnoea and adaptation to the patient's degree of ventilator dependence improve the prognosis. Non-ventilatory factors also impact the efficacy of NIV and various solutions have been described and must be applied, including cough assist techniques, control of excess salivation and renutrition. NIV in ALS has been considerably improved as a result of application of all of these measures, avoiding the need for tracheostomy in the very great majority of cases. More advanced use of NIV also requires pulmonologists to master the associated end-of-life palliative care, as well as the modalities of discontinuing ventilation when it becomes unreasonable

Effects of non-fatiguing respiratory muscle loading induced by expiratory flow limitation during strenuous incremental cycle exercise on metabolic stress and circulating natural killer cells

International audienceExercise induces release of cytokines and increase of circulating natural killers (NK) lymphocyte during strong activation of respiratory muscles. We hypothesised that non-fatiguing respiratory muscle loading during exercise causes an increase in NK cells and in metabolic stress indices. Heart rate (HR), ventilation (VE), oesophageal pressure (Pes), oxygen consumption (VO2), dyspnoea and leg effort were measured in eight healthy humans (five men and three women, average age of 31 ± 4 years and body weight of 68 ± 10 kg), performing an incremental exercise testing on a cycle ergometer under control condition and expiratory flow limitation (FL) achieved by putting a Starling resistor. Blood samples were obtained at baseline, at peak of exercise and at iso-workload corresponding to that reached at the peak of FL exercise during control exercise. Diaphragmatic fatigue was evaluated by measuring the tension time index of the diaphragm. Respiratory muscle overloading caused an earlier interruption of exercise. Diaphragmatic fatigue did not occur in the two conditions. At peak of flow-limited exercise compared to iso-workload, HR, peak inspiratory and expiratory Pes, NK cells and norepinephrine were significantly higher. The number of NK cells was significantly related to ΔPes (i.e. difference between the most and the less negative Pes) and plasmatic catecholamines. Loading of respiratory muscles is able to cause an increase of NK cells provided that activation of respiratory muscles is intense enough to induce a significant metabolic stress

Analgesic effects of dyspnoea: "Air hunger" does not inhibit the spinal nociception reflex in humans

Dyspnoea has distinct sensory modalities, including air hunger and the sensation of excessive breathing "work/effort". Both have analgesic properties. In the case of work/effort, spinal mechanisms have been documented (inhibitory effect on the spinal nociceptive flexor reflex, RIII). This mechanism involves C-fibres. As C-fibres are unlikely to play a major role in air hunger, we hypothesised that inducing this type of dyspnoea would not result in RIII inhibition. Eight healthy volunteers were exposed to a hypercapnic hyperoxic gas mixture (5% CO2 and 95% O2) and asked to voluntarily fight the corresponding ventilatory reflex response by reducing tidal volume below its spontaneous level. Ventilatory variables and dyspnoea intensity (ordinal scale) were measured. Electromyography of the biceps femoris was used to record the amplitude of RIII in response to painful electrical sural nerve stimulation. Air hunger failed to inhibit the RIII reflex. We conclude that the mechanisms of air hunger induced analgesia do not include a spinal contribution and are therefore mostly central

Scalene muscle activity during progressive inspiratory loading under pressure support ventilation in normal humans

We hypothesized that (1) in healthy humans subjected to intermittent positive pressure non-invasive ventilation, changes in the ventilator trigger sensitivity would be associated with increased scalene activity, (2) if properly processed - through inspiratory phase-locked averaging - surface electromyograms (EMG) of the scalenes would reliably detect and quantify this, (3) there would be a correlation between dyspnea and scalene EMG. Surface and intramuscular EMG activity of scalene muscles were measured in 10 subjects. They breathed quietly through a face mask for 10 min and then were connected to a mechanical ventilator. Recordings were performed during three 15-min epochs where the subjects breathed against an increasingly negative pressure trigger (-5%, -10% and -15% of maximal inspiratory pressure). With increasing values of the inspiratory trigger, inspiratory efforts, dyspnea and the scalene activity increased significantly. The scalene EMG activity level was correlated with the esophageal pressure time product and with dyspnea intensity. Inspiration-adjusted surface EMG averaging could be useful to detect small increases of the scalene muscles activity during mechanical ventilation

Relieving dyspnoea by non-invasive ventilation decreases pain thresholds in amyotrophic lateral sclerosis

International audienceBackground: Dyspnoea is a threatening sensation of respiratory discomfort that presents many similarities with pain. Experimental dyspnoea in healthy subjects induces analgesia. This 'dyspnoea-pain counter-irritation' could, in reverse, imply that relieving dyspnoea in patients with chronic respiratory diseases would lower their pain thresholds.Methods: We first determined pressure pain thresholds in 25 healthy volunteers (22-31 years; 13 men; handheld algometer), during unloaded breathing (BASELINE) and during inspiratory threshold loading (ITL). Two levels of loading were used, adjusted to induce dyspnoea self-rated at 60% or 80% of a 10 cm visual analogue scale (ITL6 and ITL8). 18 patients with chronic respiratory failure due to amyotrophic lateral sclerosis (ALS) were then studied during unassisted breathing and after 30 and 60 min of non-invasive ventilation-NIV30 and NIV60-(same dyspnoea evaluation).Results: In healthy volunteers, pressure pain thresholds increased significantly in the deltoid during ITL6 (p<0.05) and ITL8 (p<0.05) and in the trapezius during ITL8 (p<0.05), validating the use of pressure pain thresholds to study dyspnoea-pain counter-irritation. In patients with ALS, the pressure pain thresholds measured in the deltoid during unassisted breathing decreased by a median of 24.5%-33.0% of baseline during NIV30 and NIV60 (p<0.05).Conclusion: Relieving dyspnoea by NIV in patients with ALS having respiratory failure is associated with decreased pressure pain thresholds. Clinical implications have yet to be determined, but this observation suggests that patients with ALS could become more susceptible to pain after the institution of NIV, hence the need for reinforced attention towards potentially painful diagnostic and therapeutic interventions

Health-related quality of life in young adults with congenital central hypoventilation syndrome due to PHOX2B mutations: a cross-sectional study

International audienceBackground: Congenital central hypoventilation syndrome (CCHS) is a rare genetic disease due to PHOX2B mutations. CCHS patients suffer from many autonomic disorders, dominated clinically by defective ventilatory automatisms. From birth, the life of CCHS patients depends on ventilatory support during sleep, involving a high burden of care. Whether or not this impairs the quality of life of these patients during adulthood remains unknown. Methods: We applied the medical outcome study short form-36 (SF-36) to 12 CCHS patients aged 15–33 (9 women) at the time of their passage from pediatric to adult care. Scores for the SF-36 dimensions were compared to the age-and gender-matched French reference population after transformation into standardized Z-scores. The SF-36 physical component summary score (PCS) and mental component summary score (MCS) were compared to American reference values. Results: Median Z-scores were significantly different from zero for PF (physical functioning, p = 0.020) and GH (general health perception, p = 0.0342) and for PCS (p = 0.020). The other physical dimensions (RP, role limitation due to physical function; BP, bodily pain) and the mental dimensions (VT, vitality; SF, social functioning; RE, role limitation due to emotional function; MH, mental health) and MCS were not altered. Conclusions: We conclude that, despite the physical constraints imposed by CCHS and its anxiogenic nature, this disease is associated with an impairment of health-related quality of life in young adults that remains moderate. Whatever the underlying explanations, these results convey hope to parents with a child diagnosed with CCHS and for patients themselves

Dyspnoea-12 and Multidimensional Dyspnea Profile: Systematic Review of Use and Properties

International audienceContext: The Dyspnoea-12 (D-12) and Multidimensional Dyspnea Profile (MDP) were specifically developed for assessment of multiple sensations of breathlessness.Objectives: This systematic review aimed to identify the use and measurement properties of the D-12 and MDP across populations, settings and languages.Methods: Electronic databases were searched for primary studies (2008-2020) reporting use of the D-12 or MDP in adults. Two independent reviewers completed screening and data extraction. Study and participant characteristics, instrument use, reported scores and minimal clinical important differences (MCID) were evaluated. Data on internal consistency (Cronbach's α) and test-retest reliability (intraclass correlation coefficient, ICC) were pooled using random effects models between settings and languages.Results: A total 75 publications reported use of D-12 (n = 35), MDP (n = 37) or both (n = 3), reflecting 16 chronic conditions. Synthesis confirmed two factor structure, internal consistency (Cronbach's α mean, 95% CI: D-12 Total = 0.93, 0.91-0.94; MDP Immediate Perception [IP] = 0.88, 0.85-0.90; MDP Emotional Response [ER] = 0.86, 0.82-0.89) and 14 day test-rest reliability (ICC: D-12 Total = 0.91, 0.88-0.94; MDP IP = 0.85, 0.70-0.93; MDP ER = 0.84, 0.73-0.90) across settings and languages. MCID estimates for clinical interventions ranged between -3 and -6 points (D-12 Total) with small variability in scores over 2 weeks (D-12 Total 2.8 (95% CI: 2.0 to 3.7), MDP-A1 0.8 (0.6 to 1.1) and six months (D-12 Total 2.9 (2.0 to 3.7), MDP-A1 0.8 (0.6 to 1.1)).Conclusion: D-12 and MDP are widely used, reliable, valid and responsive across various chronic conditions, settings and languages, and could be considered standard instruments for measuring dimensions of breathlessness in international trials