Stride Velocity at the 95th Centile (SV95C) is a novel clinical outcome measure that is captured during normal daily living using wearable technology and represents the maximum ambulatory ability of ...a patient. SV95C is qualified by the European Medicines agency (EMA) for use as a secondary endpoint in pivotal studies in DMD, and is an important real-world functional endpoint complementary to the traditional in-clinic assessments such as the North Star Ambulatory Assessment scale and the Six Meter Walk Test. The Context of Use of SV95C as defined by EMA states that SV95C should be measured for at least 50h during normal daily living to yield an outcome variability that would render SV95C suitable for regulatory decision-making. Considering the increasing use of SV95C in drug development for DMD, it is critical to understand the most common drivers of endpoint variability. Using data from ActiLiège-NEXT, a prospective natural history study in ambulant patients with DMD designed to longitudinally characterise functional disease progression using multiple outcome measures, we evaluated the impact of the time of day, the day of the week as well as seasonal changes on the measurement variability of SV95C in ambulant patients with DMD. Specifically, SV95C will be computed for morning only (8am-12pm) and afternoon recording periods (2pm-6pm) and compared. A similar sensitivity analysis will be done for SV95C computed on weekdays (Monday-Friday) and weekend (Saturday-Sunday). The seasonal impact on the compliance and SV95C will be conducted on longitudinal data and adjusted by the geographical location of the patients, restricting to countries where the maximal temperature difference over the year exceeds 15° and maximal temperature does not exceed 30°C. This data provides important context to the factors that impact the measurement variability of SV95C and will be useful to inform clinical trial design in DMD, when using SV95C as an outcome measure of efficacy.
Duchenne muscular dystrophy is a muscle disease characterized by severe and rapidly progressive muscle weakness. One of the key challenges in treating this condition is identifying objective, ...reliable, and sensitive outcome measures to measure the effects of drug. For this purpose, the ActiMyo® (Sysnav, France), a magneto-inertial wearable device, was developed. Among the assessments with performed by this wearable device, the 95th centile stride velocity (SV95C) was qualified as the 2nd endpoint in 2019 by the European Medical Agency, representing the most rapid 5% of strides during real-life activities. The ActiLiège study is a multicentre clinical study with the aim of gathering data issued from a magneto-inertial wearable. Ambulant patients with DMD and healthy controls were included and will be followed up for three years. The patients wore the ActiMyo® on their ankle and wrist during the first 3 months after the inclusion and afterwards for one month every 3 months. Controls wear the device for a period of one month every 12 months. Digital outputs from the wearable sensors are compared to gold standard assessments. We enrolled seventy-six ambulant DMD patients aged between 4 and 20 years in 7 centres (Belgium, Poland, Hungary, Romania, Czech Republic, Slovenia, and Egypt). Thirty-five of them completed at least 1 year of follow-up. All ambulant patients were either on a 6-month stable course of steroids or started steroids at baseline. The baseline data of the patients and controls will be presented, along with longitudinal data that may provide an indication of sensitivity to change in comparison with other commonly performed outcomes.
In daily practice as well as in clinical trials, patients with spinal muscular atrophy (SMA) treated by a disease-modifying therapy (DMT) are classified as responders (R) or non-responders (NR) ...according to the fact that they reach or do not reach a specific level of improvement on validated functional scales. However, small functional improvements or even stabilization not captured by current outcome measures may appear inexistant or non-significant, although they can have a significant impact on a patient's daily life. The aim of this international multicenter study is to investigate the treatment benefit after 15 months of Spinraza in post-symptomatically treated patients measured by current functional scales compared with individualised aspects of patients’ perception that are not measured in the functional scales. We included patients with SMA type I, II and III and established an order of priority for the functional scales according to each SMA type and age at treatment initiation based on the literature (i.e., patients with SMA II from 24 months: HFMSE-MFM-RULM). Patients were divided into three groups whether they did show clinically significant improvement (i.e., > 4 points on the CHOP Intend), non-clinically significant improvement (i.e., < 4 points on the CHOP Intend) or no improvement (i.e., 0 points or loss on the CHOP Intend) 15 months after treatment initiation. Finally, we designed and conducted a scoring system based on the Clinical Global Impression-Improvement scale, which uses 7 ratings scored from very much improved to very much worse on 22 questions targeting important aspects and tasks in daily life of patients with SMA (i.e., balance, fatigability, swallowing) and which allows the patient to estimate whether a change is perceived after 12 months of stable treatment. This quantification of approximately 100 patients’ impressions across the different groups collected from 7 sites based in Europe and USA will be presented.
Manferdelli, Giorgio, Benjamin J. Narang, Mathias Poussel, Damjan Osredkar, Grégoire P. Millet, and Tadej Debevec. Long-term effects of prematurity on resting ventilatory response to hypercapnia.
. ...22:420-425, 2021.
This study investigated the resting ventilatory response to hypercapnia in prematurely born adults.
Seventeen preterm and fourteen full-term adults were exposed to normoxic hypercapnia (two 5-minute periods at 3% and 6% carbon dioxide CO
interspersed by 5-minute in normoxia). Pulmonary ventilation (Formula: see text) and end-tidal partial pressure of CO
(Petco
) were measured continuously.
No difference in lung function was observed between preterm and full-term adults. Petco
was lower in preterm than in full-term adults (
< 0.05) during normoxia. During exposure to 3% CO
, both Formula: see text and Petco
increased in a similar way in preterm and full-term adults. However, at the end of the 6% CO
period, there was a significantly higher Formula: see text in preterm compared with full-term adults (30.2 ± 7.5 vs. 23.7 ± 4.5 L/min,
< 0.0001), whereas no difference was observed for Petco
(46.9 ± 2.1 vs. 50.6 ± 2.1 L/min,
= 0.99). Breath frequency was higher in preterm than in full-term adults (17.9 ± 4.0 vs. 12.8 ± 3.5 b/min,
< 0.01) during 6% CO
exposure.
Although data suggest that prematurity results in resting hypocapnia, the exact underlying mechanisms remain to be elucidated. Moreover, preterm adults seem to have increased chemosensitivity to hypercapnia.
The progressive nature of functional loss in Duchenne Muscular Dystrophy (DMD) is well established and routinely characterised in clinic using assessments such as the North Star Ambulatory Assessment ...and the Six Meter Walk Test. The trajectory of functional loss depends on the patient's age and baseline functional ability. There is a need to better characterise the trajectory of disease progression in order to try to predict disease evolution and optimise patient care. Stride Velocity at the 95th Centile (SV95C) is a novel clinical outcome measure that is captured during normal daily living using wearable technology and represents the maximum ambulatory ability of a patient. SV95C is qualified by the European Medicines agency (EMA) for use as a secondary endpoint in pivotal studies in DMD and is an important real-world functional endpoint complementing the traditional in-clinic assessments. SV95C declines by approximately 7% per year in ambulant patients with DMD who are on a stable dose of steroids. In other functional endpoints such as the NSAA and 6MWT the decline is dependent on the patient's age and baseline ambulatory abilities. This study aims to investigate how yearly change of SV95C is also dependent upon age and baseline function. We will analyse how the evolution of SV95C can be predicted by the baseline value of SV95C and age, using non-linear and linear multiparametric regression models. This analysis will be conducted on data from ActiLiège-NEXT, a prospective natural history study in ambulant patients with DMD. This study was designed to characterise longitudinal functional disease progression using multiple outcome measures, including SV95C. It includes patients with DMD between 4 and 20 years old studied over 1 year. SV95C was measured daily using ActiMyo®, a class I CE medical device with two sensors worn on the ankles. These data will advance our understanding of the importance of SV95C as an outcome measure for functional disease progression in DMD.
Background
Fibromyalgia (FM) has been understudied in the elderly population, a group with particular vulnerabilities to pain, reduced mobility, and sleep disruption.
Aims
To characterize FM symptoms ...and treatments in a cohort of older subjects examined over time to determine the extent to which current, community-based treatment for older FM patients is in accord with published guidelines, and effective in reducing symptoms.
Methods
A longitudinal, observational study of 51 subjects with FM (range 55–95 years) and 81 control subjects (58–95 years) performed at Banner Sun Health Research Institute in Sun City, AZ, USA. Serial history and examination data were obtained over a 6-year period. FM data included medical history, medications, physical examination, tender point examination, neuropsychological testing, sleep and pain ratings, the Physical Function Subscale of the Fibromyalgia Impact Questionnaire, and other standardized scales to evaluate depression and other psychiatric symptoms, and cognitive and functional impairment.
Results
Pain and stiffness that interfered with physical activity, sleep, and mood were reported by 80 % or more of subjects. Over time, pain involved an increasing number of body areas. Over half of subjects were treated with NSAIDs, one-quarter with opioids, and one-quarter with estrogen. Few were treated with dual-acting antidepressants or pregabalin.
Discussion
In this cohort of elders with suboptimally treated FM, substantial persistence of symptoms was seen over time. In general, recommended treatments were either not used or not tolerated.
Conclusions
Age-appropriate treatments as well as education of primary care providers are needed to improve treatment of FM in the older population.
The novel naphtoxazine derivative and preferential D
3 vs D
2 receptor agonist, S32504, restores perturbed motor function in rodent and primate models of antiparkinsonian activity with a potency ...superior to those of two further, preferential D
3 receptor agonists, pramipexole and ropinirole. However, potential neuroprotective properties of S32054 have not, to date, been evaluated. Herein, employing several measures of cellular integrity, we demonstrate that S32504 robustly, concentration-dependently and completely protects terminally differentiated SH-SY5Y cells against 1-methyl-4-phenylpyridinium (MPP+)-induced cell death in vitro. Further, S32504 was substantially more potent than pramipexole and ropinirole, the latter of which was neurotoxic at high concentrations. In vivo, subchronic treatment with low (0.25 mg/kg) and high (2.5 mg/kg) doses of S32504 prior to and during treatment of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP, provided complete protection against MPTP-induced tyrosine hydroxylase immunoreactive (TH-IR) neuronal death in the substantia nigra pars compacta and ventral tegmental area. A high dose of ropinirole (2.5 mg/kg) provided some protection but statistical significance was not attained, and a low dose (0.25 mg/kg) was ineffective. Neither drug afforded protection against the MPTP-induced loss of DA fibers in the striatum, as measured by TH-IR and dopamine transporter immunoreactive fiber counts. In conclusion, the novel naphotoxazine and dopaminergic agonist, S32504, robustly protects dopaminergic neurones against the neurotoxic effects of MPP
+ and MPTP in in vitro and in vivo models, respectively. The underlying mechanisms and therapeutic pertinence of these actions will be of interest to further evaluate in view of its potent actions in behavioral models of antiparkinson activity.
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