A systematic review of non-motor symptom evaluation in clinical trials for amyotrophic lateral sclerosis

Abstract

Background Amyotrophic lateral sclerosis (ALS) is increasingly recognised as a multi-system disorder, presenting with common and impactful non-motor symptoms, such as neuropsychiatric symtpoms, cognitive and behavioural changes, pain, disordered sleep, fatigue and problematic saliva. Aim/hypothesis We aimed to systematically review 25 years of ALS clinical trials data to identify if non-motor features were evaluated, in addition to the traditional measures of motor functioning and survival, and where evaluated to describe the instruments used to assess. We hypothesised that assessment of non-motor symptoms has been largely neglected in trial design and not evaluated with ALS-suitable instruments. Methods We reviewed clinical trials of investigative medicinal products in ALS, since the licensing of riluzole in 1994. Trial registry databases including WHO International Trials Registry, European Clinical Trials Register, clinicaltrials.gov, and PubMed were systematically searched for Phase II, III or IV trials registered, completed or published between 01/01/1994 and 16/09/2020. No language restrictions were applied. Results 237 clinical trials, including over 29,222 participants, were investigated for their use of non-motor outcome measures. These trials evaluated neuropsychiatric symptoms (75, 32%), cognitive impairment (16, 6.8%), behavioural change (34, 14%), pain (55, 23%), sleep disturbances (12, 5%) and fatigue (18, 8%). Problematic saliva was assessed as part of composite ALS-FRS(R) scores in 184 trials (78%) but with no focus on this as an isolated symptom. 31 (13%) trials including 3585 participants did not include any assessment of non-motor symptoms. Conclusions Non-motor symptoms such as neuropsychiatric, cognitive and behavioural changes, pain, disordered sleep, fatigue, and problematic saliva have not been consistently evaluated in trials for people with ALS. Where evaluated, non-symptoms were primarily assessed using instruments and impairment thresholds that are not adapted for people with ALS. Future trials should include non-motor symptom assessments to evaluate the additional potential therapeutic benefit of candidate drugs. PROPSERO registration CRD42020223648.

ALS Cognitive Behavioral Screen-Phone Version (ALS-CBS™-PhV): norms, psychometrics, and diagnostics in an Italian population sample

“…From an experimental standpoint, the ALS-CBS™-PhV may allow large-scale epidemiological studies on FT disorders in MND patients [23] and facilitate follow-ups in clinical trials [4], specifically when combined with the available, self-administered ALS Functional Rating Scale -Revised [28]. By assessing executive functioning, the ALS-CBS™-PhV can furthermore be feasible for testing patients with frontotemporal dementias or other motor diseases possibly presenting with a dysexecutive profile (e.g., extra-pyramidal disorders) -as shown for another MND-specific I-level neuropsychological tool, the Edinburgh Cognitive and Behavioral ALS Screen [20,32].…”

Thick Mucus in ALS: A Mixed-Method Study on Associated Factors and Its Impact on Quality of Life of Patients and Caregivers

“…We conclude from our data that mucus accumulation in ALS patients results mainly from impaired airway clearance by weakened cough. When considering this mechanism, thick mucus could also be labelled as a motor sign, rather than a non-motor sign in ALS, whereby the approach of whether this is classified as a motor or non-motor sign is inconsistent in recent reviews [ 22 , 23 ].…”

Amyotrophic Lateral Sclerosis—The Complex Phenotype—From an Epidemiological Perspective: A Focus on Extrapyramidal and Non-Motor Features

“…People with ALS experiencing greater frequency of non-motor symptoms report lower quality of life than those who indicate more severe motor symptoms, suggesting that the impact of these non-motor symptoms on the daily lives of people with ALS is at least comparable to the impact of motor symptoms [ 38 , 39 ]. However, non-motor symptoms have not been consistently evaluated in trials for people with ALS, and when evaluated, non-motor symptoms were primarily assessed using instruments and impairment cut-offs that are not adapted for people with ALS [ 40 ].…”