Cultivating Patient Preferences in ALS Clinical Trials: Reliability and Prognostic Value of the Patient-Ranked Order of Function

BACKGROUND AND OBJECTIVES: The Patient-Ranked Order of Function (PROOF) is a novel approach to account for patient-reported preferences in the evaluation of treatments of amyotrophic lateral sclerosis (ALS). In this study, we assess the reliability and prognostic value of different sets of patient-reported preferences that can be used for the PROOF end point. METHODS: Data were obtained through online surveys over the course of 12 months using the population-based registry of the Netherlands. Patients were asked to score functional domains of the ALS Functional Rating Scale (ALSFRS-R) and rank the order of importance of each domain. Two weeks after the initial invite, the questionnaire was repeated to evaluate test-retest reliability. Vital status was extracted from the municipal population register. RESULTS: In total, 611 patients with ALS were followed up for survival and 382 patients were included in the test-retest reliability study. All versions of PROOF, using different sets of preferences, resulted in excellent reliability (intraclass correlation coefficients ranged from 0.89 [95% CI 0.87-0.91] to 0.97 [95% CI 0.97-0.98], all p 0.20). Preferences about future events were more variable than preferences about current symptoms. All versions of PROOF strongly predicted overall survival (hazard ratios per 10th rank percentile ranged from 0.80 to 0.83 [95% CI range 0.76-0.87], all p < 0.001) and had a more even separation of survival curves between rank-stratified subgroups compared with the ALSFRS-R total score. DISCUSSION: In a large cohort of patients, we show how patient-reported preferences can be measured and integrated reliably with the ALSFRS-R without leading to systematic bias. Patient preferences may provide unique prognostic information in addition to what is already measured conventionally. This could provide a more comprehensive understanding of how medical interventions effectively address the patient's concerns and improve what matters most to them

Comparing methods to combine functional loss and mortality in clinical trials for amyotrophic lateral sclerosis

Objective: Amyotrophic lateral sclerosis (ALS) clinical trials based on single end points only partially capture the full treatment effect when both function and mortality are affected, and may falsely dismiss efficacious drugs as futile. We aimed to investigate the statistical properties of several strategies for the simultaneous analysis of function and mortality in ALS clinical trials. Methods: Based on the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, we simulated longitudinal patterns of functional decline, defined by the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) and conditional survival time. Different treatment scenarios with varying effect sizes were simulated with follow-up ranging from 12 to 18 months. We considered the following analytical strategies: 1) Cox model; 2) linear mixed effects (LME) model; 3) omnibus test based on Cox and LME models; 4) composite time-to-6-point decrease or death; 5) combined assessment of function and survival (CAFS); and 6) test based on joint modeling framework. For each analytical strategy, we calculated the empirical power and sample size. Results: Both Cox and LME models have increased false-negative rates when treatment exclusively affects either function or survival. The joint model has superior power compared to other strategies. The composite end point increases false-negative rates among all treatment scenarios. To detect a 15% reduction in ALSFRS-R decline and 34% decline in hazard with 80% power after 18 months, the Cox model requires 524 patients, the LME model 794 patients, the omnibus test 526 patients, the composite end poi

Remote monitoring of amyotrophic lateral sclerosis using wearable sensors detects differences in disease progression and survival: a prospective cohort study

Background: There is an urgent need for objective and sensitive measures to quantify clinical disease progression and gauge the response to treatment in clinical trials for amyotrophic lateral sclerosis (ALS). Here, we evaluate the ability of an accelerometer-derived outcome to detect differential clinical disease progression and assess its longitudinal associations with overall survival in patients with ALS. Methods: Patients with ALS wore an accelerometer on the hip for 3–7 days, every 2–3 months during a multi-year observation period. An accelerometer-derived outcome, the Vertical Movement Index (VMI), was calculated, together with predicted disease progression rates, and jointly analysed with overall survival. The clinical utility of VMI was evaluated using comparisons to patient-reported functionality, while the impact of various monitoring schemes on empirical power was explored through simulations. Findings: In total, 97 patients (70.1% male) wore the accelerometer for 1995 days, for a total of 27,701 h. The VMI was highly discriminatory for predicted disease progression rates, revealing faster rates of decline in patients with a worse predicted prognosis compared to those with a better predicted prognosis (p < 0.0001). The VMI was strongly associated with the hazard for death (HR 0.20, 95% CI: 0.09–0.44, p < 0.0001), where a decrease of 0.19–0.41 unit was associated with reduced ambulatory status. Recommendations for future studies using accelerometery are provided. Interpretation: The results serve as motivation to incorporate accelerometer-derived outcomes in clinical trials, which is essential for further validation of these markers to meaningful endpoints. Funding: Stichting ALS Nederland (TRICALS-Reactive-II)

Trial Participation in Neurodegenerative Diseases: Barriers and Facilitators: A Systematic Review and Meta-Analysis

BACKGROUND AND OBJECTIVES: Clinical trials in neurodegenerative diseases often encounter selective enrollment and under-representation of certain patient populations. This delays drug development and substantially limits the generalizability of clinical trial results. To inform recruitment and retention strategies, and to better understand the generalizability of clinical trial populations, we investigated which factors drive participation. METHODS: We reviewed the literature systematically to identify barriers to and facilitators of trial participation in 4 major neurodegenerative disease areas: Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and Huntington disease. Inclusion criteria included original research articles published in a peer-reviewed journal and evaluating barriers to and/or facilitators of participation in a clinical trial with a drug therapy (either symptomatic or disease-modifying). The Critical Appraisal Skills Program checklist for qualitative studies was used to assess and ensure the quality of the studies. Qualitative thematic analyses were employed to identify key enablers of trial participation. Subsequently, we pooled quantitative data of each enabler using meta-analytical models. RESULTS: Overall, we identified 36 studies, enrolling a cumulative sample size of 5,269 patients, caregivers, and health care professionals. In total, the thematic analysis resulted in 31 unique enablers of trial participation; the key factors were patient-related (own health benefit and altruism), study-related (treatment and study burden), and health care professional-related (information availability and patient-physician relationship). When meta-analyzed across studies, responders reported that the reason to participate was mainly driven by (1) the relationship with clinical staff (70% of the respondents; 95% CI 53%-83%), (2) the availability of study information (67%, 95% CI 38%-87%), and (3) the use or absence of a placebo or sham-control arm (53% 95% CI 32%-72%). There was, however, significant heterogeneity between studies (all p < 0.001). DISCUSSION: We have provided a comprehensive list of reasons why patients participate in clinical trials for neurodegenerative diseases. These results may help to increase participation rates, better inform patients, and facilitate patient-centric approaches, thereby potentially reducing selection mechanisms and improving generalizability of trial results

A qualitative evaluation of the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) by the patient community: a web-based cross-sectional survey

Objective: The revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) is the most commonly used outcome measure in ALS studies. The aim of this study was to identify potential limitations of the ALSFRS-R from the perspective of people living with ALS and their caregivers. Methods: A web-based survey was developed by investigators, people living with ALS, and their caregivers, and shared across social media. For each item, participants were asked, “Can you think of a situation where you might not be able to answer this item accurately or that your answer might not reflect your abilities?” Responses were divided into two categories: criticisms that could be addressed in a manual or issues with the items/responses that would require measure modification. Results: 57 participants (72% participants with ALS, 28% caregivers) responded to at least one item question, of which 71.9% expressed concern about at least one item. The most frequently identified items were speech, walking, and cutting food. Common criticisms were: language used is of a medical literacy level too high; item is situational; difficult to distinguish the difference between response choices; and the structure and/or underlying assumptions of the item makes it difficult to answer. Conclusions: Several items of the ALSFRS-R were considered to inaccurately reflect the abilities of patients with ALS. The ALSFRS-R may need a revision to address these issues, preferably in co-development with people living with ALS and their caregivers, and/or alternate outcome measures should be considered for patients with ALS

The Effects of a Blended Care Intervention in Partners of Patients With Acquired Brain Injury - Results of the CARE4Carer Randomized Controlled Trial

Objective: To assess effects of the CARE4Carer blended care intervention on caregiver mastery and psychosocial functioning compared with usual care in partners of patients with acquired brain injury (ABI). Design: Multicenter randomized controlled trial. Setting: Nine sites for rehabilitation medicine. Participants: 120 partners of outpatients with ABI were randomly allocated to blended care (N=59) or usual care (N=61). Intervention: The blended care intervention (20 weeks) was aimed at improving caregiving skills and consisted of 9 online sessions, combined with 2 face-to-face consultations with a social worker. Main Outcome Measures: Mastery was assessed with the Caregiver Mastery Scale, secondary outcome measures were caregiver strain (Caregiver Strain Index), family functioning (Family Assessment Device), anxiety and depression (Hospital Anxiety and Depression Scale), burden (self-rated), and quality of life (CarerQol). Assessments were performed at baseline, 24, and 40 weeks. Results: The adjusted mean difference in caregiver mastery between intervention and control group at week 24 was 1.31 (SD3.48, 95% confidence interval (CI) -0.12 to 2.74, P=.072) and at week 40 was 1.31 (SD3.69, 95% CI -0.26 to 2.88, P=.100). In the per protocol analysis, the adjusted mean difference in caregiver mastery at week 24 was 1.53 (SD3.38, 95% CI 0.10 to 2.96, P=.036) and at week 40 was 1.57 (SD3.63, 95% CI 0.01 to 3.14, P=.049). Regarding secondary outcomes, caregiver strain was lower in the intervention group in the per protocol analysis at week 40. Family functioning was higher in the intervention group in week 24, whereas anxiety was lower at both timepoints. Conclusions: In the subset of participants who were able to complete the intervention, caregiver mastery and psychosocial functioning improved. Future work should focus on improving adherence as this will optimize beneficial effects of blended care

Enriched enrollment randomized double-blind placebo-controlled cross-over trial with phenytoin cream in painful chronic idiopathic axonal polyneuropathy (EPHENE): a study protocol

Background: Patients with chronic idiopathic axonal polyneuropathy (CIAP) can have neuropathic pain that significantly impacts quality of life. Oral neuropathic pain medication often has insufficient pain relief and side effects. Topical phenytoin cream could circumvent these limitations. The primary objectives of this trial are to evaluate (1) efficacy in pain reduction and (2) safety of phenytoin cream in patients with painful CIAP. The main secondary objective is to explore the usefulness of a double-blind placebo-controlled response test (DOBRET) to identify responders to sustained pain relief with phenytoin cream. Methods: This 6-week, enriched enrollment randomized double-blind, placebo-controlled triple cross-over trial compares phenytoin 20%, 10% and placebo cream in 48 participants with painful CIAP. Enriched enrollment is based on a positive DOBRET in 48 participants who experience within 30 minutes ≥2 points pain reduction on the 11-point numerical rating scale (NRS) in the phenytoin 10% cream applied area and ≥1 point difference in pain reduction on the NRS between phenytoin 10% and placebo cream applied area, in favour of the former. To explore whether DOBRET has predictive value for sustained pain relief, 24 DOBRET-negative participants will be included. An open-label extension phase is offered with phenytoin 20% cream for up to one year, to study long-term safety. The main inclusion criteria are a diagnosis of CIAP and symmetrical neuropathic pain with a mean weekly pain score of ≥4 and <10 on the NRS. The primary outcome is the mean difference between phenytoin 20% versus placebo cream in 7-day average pain intensity, as measured by the NRS, over week 2 in DOBRET positive participants. Key secondary outcomes include the mean difference in pain intensity between phenytoin 10% and phenytoin 20% cream, and between phenytoin 10% and placebo cream. Furthermore, differences between the 3 interventions will be evaluated on the Neuropathic Pain Symptom Inventory, EuroQol EQ5-5D-5L, and evaluation of adverse events. Discussion: This study will provide evidence on the efficacy and safety of phenytoin cream in patients with painful CIAP and will give insight into the usefulness of DOBRET as a way of personalized medicine to identify responders to sustained pain relief with phenytoin cream. Trial registration: ClinicalTrials.gov NCT04647877. Registered on 1 December 2020

The RESISTANT study (Respiratory Muscle Training in Patients with Spinal Muscular Atrophy): study protocol for a randomized controlled trial

Background: Spinal Muscular Atrophy (SMA) is characterized by progressive and predominantly proximal and axial muscle atrophy and weakness. Respiratory muscle weakness results in impaired cough with recurrent respiratory tract infections, nocturnal hypoventilation, and may ultimately lead to fatal respiratory failure in the most severely affected patients. Treatment strategies to either slow down the decline or improve respiratory muscle function are wanting. Objective: The aim of this study is to assess the feasibility and efficacy of respiratory muscle training (RMT) in patients with SMA and respiratory muscle weakness. Methods: The effect of RMT in patients with SMA, aged ≥ 8 years with respiratory muscle weakness (maximum inspiratory mouth pressure [PImax] ≤ 80 Centimeters of Water Column [cmH2O]), will be investigated with a single blinded randomized sham-controlled trial consisting of a 4-month training period followed by an 8-month open label extension phase. Intervention: The RMT program will consist of a home-based, individualized training program involving 30-breathing cycles through an inspiratory and expiratory muscle training device. Patients will be instructed to perform 10 training sessions over 5–7 days per week. In the active training group, the inspiratory and expiratory threshold will be adjusted to perceived exertion (measured on a Borg scale). The sham-control group will initially receive RMT at the same frequency but against a constant, non-therapeutic resistance. After four months the sham-control group will undergo the same intervention as the active training group (i.e., delayed intervention). Individual adherence to the RMT protocol will be reviewed every two weeks by telephone/video call with a physiotherapist. Main study parameters/endpoints: We hypothesize that the RMT program will be feasible (good adherence and good acceptability) and improve inspiratory muscle strength (primary outcome measure) and expiratory muscle strength (key secondary outcome measure) as well as lung function, patient reported breathing difficulties, respiratory infections, and health related quality of life (additional secondary outcome measures, respectively) in patients with SMA. Discussion: RMT is expected to have positive effects on respiratory muscle strength in patients with SMA. Integrating RMT with recently introduced genetic therapies for SMA may improve respiratory muscle strength in this patient population. Trial registration: Retrospectively registered at clinicaltrial.gov: NCT05632666

A comparison between bioelectrical impedance analysis and air-displacement plethysmography in assessing fat-free mass in patients with motor neurone diseases: a cross-sectional study

Aim: To determine the validity of bioelectrical impedance analysis (BIA) in quantifying fat-free mass (FFM) compared to air-displacement plethysmography (ADP) in patients with a motor neurone disease (MND). Methods: FFM of 140 patients diagnosed with MND was determined by ADP using the BodPod (i.e. the gold standard), and by BIA using the whole-body Bodystat. FFM values were translated to predicted resting energy expenditure (REE); the actual REE was measured using indirect calorimetry, resulting in a metabolic index. Validity of the BIA compared to the ADP was assessed using Bland-Altman analysis and Pearson’s r. To assess the clinical relevance of differences, we evaluated changes in metabolic index and in individualized protein demand. Results: Despite the high correlation between ADP and BIA (r = 0.93), averaged across patients, the assessed mean fat-free mass was 51.7 kg (± 0.9) using ADP and 54.2 kg (± 1.0) using BIA. Hence, BIA overestimated fat-free mass by 2.5 kg (95% CI 1.8–3.2, p < 0.001). Clinically, an increased metabolic index would be more often underdiagnosed in patients with MND using BIA (31.4% according to BIA versus 44.2% according to ADP, p = 0.048). A clinically relevant overestimation of ≥ 15 g in protein demand was observed for 4 (2.9%) patients using BIA. Conclusions: BIA systematically overestimates FFM in patients with MND. Although the differences are limited with ADP, underscoring the utility of BIA for research, overestimation of fat-free mass may have consequences for clinical decision-making, especially when interest lies in determining the metabolic index

Association Between Serum Lipids and Survival in Patients With Amyotrophic Lateral Sclerosis: A Meta-analysis and Population-Based Study

Background and ObjectiveTo explore the association between lipids, polygenic profile scores (PPS) for biomarkers of lipid metabolism, markers of disease severity, and survival in patients with amyotrophic lateral sclerosis (ALS).MethodsWe meta-analyzed the current literature on the prognostic value of lipids in patients with ALS. Subsequently, we evaluated the relationship between lipid levels at diagnosis, clinical disease stage, and survival in all consecutive patients diagnosed in the Netherlands. We determined the hazard ratio (HR) of each lipid for overall survival, defined as death from any cause. A subset of patients was matched to a previous genome-wide association study; data were used to calculate PPS for biomarkers of lipid metabolism and to determine the association between observed lipid levels at diagnosis and survival.ResultsMeta-analysis of 4 studies indicated that none of the biomarkers of the lipid metabolism were statistically significantly associated with overall survival; there was, however, considerable heterogeneity between study results. Using individual patient data (N = 1,324), we found that increased high-density lipoprotein (HDL) cholesterol was associated with poorer survival (HR of 1.33 (95% CI 1.14-1.55, p 0.50).DiscussionLipids may contain valuable information about disease severity and prognosis, but their main value may be driven as a consequence of disease progression. Our results underscore that gaining further insight into lipid metabolism and longitudinal data on serum concentrations of the lipid profile could improve the monitoring of patients and potentially further disentangle ALS pathogenesis