| 1. |
- Benatar, Michael, et al.
(author)
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Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01) : a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial
- 2024
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In: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 23:7, s. 687-699
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Journal article (peer-reviewed)abstract
- Background: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis.Methods: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed.Findings: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI –0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]).Interpretation: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated.Funding: Orphazyme.
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| 2. |
- Finsel, Julia, et al.
(author)
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Determining impairment in the Swedish, Polish and German ECAS : the importance of adjusting for age and education
- 2023
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In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : Taylor & Francis. - 2167-8421 .- 2167-9223. ; 24:5-6, s. 475-484
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Journal article (peer-reviewed)abstract
- Objective: Age and years of education are strong predictors of cognitive performance in several versions of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) and cutoffs for the Swedish and Polish versions are not established yet. Here we evaluated the performance of healthy subjects on the national versions of the Swedish and Polish ECAS and compared cognitive performance on three European translations of the ECAS.Methods: The ECAS performances of healthy subjects from Sweden (n = 111), Poland (n = 124) and Germany (n = 86) were compared. Based on the test results on the national versions of ECAS, age- and education-adjusted cutoffs were compared for the German, Swedish and Polish versions, respectively.Results: Age and years of education correlated with performance in the ECAS. Swedish subjects under the age of 60 years and Swedish subjects with low education level scored significantly higher in memory than the respective German and Polish subgroups. German and Polish subjects over 60 years of age performed significantly better in language than the respective Swedish subgroup. The Polish cohort in total had lower executive scores compared to the Swedish cohort, and lower than the German subjects in the higher education subgroup.Conclusions: The results highlight the importance of establishing age- and education-adjusted ECAS cutoffs not only in general, but also for seemingly similar populations of different origins. The results should be taken into account when comparing cognition data across patient populations including in drug trials where an ECAS test result is being used as an inclusion criterium or outcome measure.
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| 3. |
- Forsberg, Karin, et al.
(author)
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Precisionsmedicinsk genterapi har bromsat utveckling av ALS : [SOD1 gene therapy delays ALS disease progression]
- 2024
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In: Läkartidningen. - : Läkartidningen Förlag AB. - 0023-7205 .- 1652-7518. ; 121
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Journal article (peer-reviewed)abstract
- We present a patient with familial amyotrophic lateral sclerosis caused by an aggressive A4S mutation in the SOD1 gene. In 2020, the patient was enrolled in the VALOR SOD1 gene therapy phase-3 trial. At screening, the ALSFRS-R score was 41 (48 is normal) and the level of CSF-neurofilament L (an indicator of ongoing neuronal damage) was 11 000 ng/L (ref <650 ng/L). In the four years following enrollment, the patient received monthly intrathecal treatment with tofersen, an antisense oligonucleotide compound that inhibits SOD1 protein expression and hence lowers the synthesis of toxic SOD1 protein species. Side effects have been minimal and mostly attributed to the spinal taps. The patient remains ambulatory with an active social lifestyle. The ALSFRS-R score has in the past 18 months stabilized around 35-37, CSF-NfL is 1 290 ng/L and plasma-NfL is 12 (reference <13). This is the first documented arresting intervention in a patient with ALS in Sweden.
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| 4. |
- Foucher, Juliette, et al.
(author)
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Validity and reliability measures of the Swedish Karolinska version of the Edinburgh Cognitive and Behavioral ALS Screen (SK-ECAS)
- 2023
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In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : Taylor & Francis. - 2167-8421 .- 2167-9223. ; 24:7-8, s. 713-718
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Journal article (peer-reviewed)abstract
- Objective: Cognitive and behavioral impairment is observed in up to 50% of patients with amyotrophic lateral sclerosis (ALS). The Edinburgh Cognitive and Behavioral ALS Screen (ECAS) is a 5-domain screening tool customized for quick cognitive screening in patients with ALS. Although the ECAS is available in Swedish at the Karolinska University Hospital (SK-ECAS), it has not yet been validated in Sweden stressing the need to assess validity and reliability of the SK-ECAS Version A.Methods: The study included 176 patients with ALS or other motor neuron disease diagnosed between September 2017 and October 2021 at the Karolinska ALS Clinical Research Center in Stockholm, Sweden, and 35 age-matched healthy control subjects. SK-ECAS was validated against the Montreal Cognitive Assessment (MoCA) and optimal cutoffs, receiver operating characteristic (ROC) curve and area under the curve (AUC) were calculated.Results: We identified an optimal cutoff of 108 for the SK-ECAS total score and 82 for the SK-ECAS ALS-specific score to detect cognitive impairment. The SK-ECAS showed good performance in indicating abnormal cognition with an AUC of 0.73 for SK-ECAS ALS-specific score and 0.77 for SK-ECAS total score. There was good internal consistency with a Cronbach’s alpha of 0.79.Conclusions: This study demonstrates good validity and reliability indices for SK-ECAS Version A for the detection of cognitive impairment in newly diagnosed ALS patients.
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| 5. |
- Lulé, Dorothée E., et al.
(author)
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Deficits in verbal fluency in presymptomatic C9orf72 mutation gene carriers-a developmental disorder
- 2020
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In: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ Publishing Group Ltd. - 0022-3050 .- 1468-330X. ; 91:11, s. 1195-1200
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Journal article (peer-reviewed)abstract
- Background: A mutation in C9orf72 constitute a cross-link between amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD). At clinical manifestation, both patient groups may present with either cognitive impairment of predominantly behaviour or language (in FTD) or motor dysfunctions (in ALS).Methods: In total, 36 non-symptomatic mutation carriers from ALS or FTD families were examined, including 21 subjects with C9orf72 and 15 with SOD1 mutations. Data were compared with 91 age-matched, education-matched and gender-matched healthy subjects (56 were first-degree relatives from ALS or FTD families, 35 with no known family history of ALS/FTD). MRI scanning for diffusion tensor imaging was performed to map fractional anisotropy (FA). Subjects performed an extensive neuropsychological assessment to address verbal fluency, language, executive, memory and visuospatial function. Measurements were repeated after 12 months.Results: C9orf72 expansion carriers performed significantly worse in verbal fluency and non-verbal memory and presented with distinct alterations in structural white matter integrity indicated by lower FA values in inferior and orbitofrontal cortical areas compared with carriers of SOD1 mutations or healthy subjects. Loss of structural integrity was associated with decreased verbal fluency performance. White matter alterations and cognitive performance showed no changes over 12 months in all subjects.Discussion: Reduced verbal fluency performance seems to be a distinct clinical feature of C9orf72 carriers before symptomatic disease onset without evidence for change over time in our cohort. The results support the emerging hypothesis of a general disorder in development in addition to neurodegeneration in C9orf72 carriers.
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