Ropinirole hydrochloride for amyotrophic lateral sclerosis: A single-center, randomized feasibility, double-blind, placebo-controlled trial

ABSTRACTBackgroundWe previously used an induced pluripotent stem cell-based drug repurposing approach to demonstrate that ropinirole hydrochloride (ropinirole) attenuated amyotrophic lateral sclerosis (ALS)-specific pathological phenotypes. Here, we assessed the safety and feasibility of ropinirole in ALS patients to verify its efficacy.MethodsWe conducted a randomized feasibility trial of ALS. Twenty participants with ALSFRS-R scores greater than 2 points were randomly assigned using dynamic allocation to receive ropinirole or placebo for 24 weeks in the double-blind period. Upon completion, participants could choose to participate in the following 24-week open-label active extension period. The primary outcomes were safety and tolerability. The secondary outcomes for the feasibility trial objective were the change in the ALS Functional Rating Scale-Revised (ALSFRS-R) score, composite functional endpoint, combined assessment of function and survival, event-free survival, and time to ≤50% forced vital capacity (blinded outcome assessment). This study is registered with the UMIN Clinical Trials Registry, UMIN000034954.FindingsTwenty-one participants were randomized into two groups (ropinirole group; n=14) and received ropinirole (n=13) or placebo (n=7) and the data of all participants were analysed using mixed-effects models for repeated measures together. Overall, the incidences of adverse events, most of which had been reported previously, were similar within both groups. Notably, the incidence of gastrointestinal disorders (mainly, temporary mild nausea and diarrhoea) was high at 76·9% in the ropinirole group (14·3% in the placebo group). Regarding the feasibility of verifying efficacy, there were no significant differences in the ALSFRS-R score and combined assessment of function and survival scores during the double-blind period for 6 months, while the participants in the ropinirole group had lived an additional 27·9 weeks without disease progression events compared with the placebo group (log-rank test, 95% confidence interval, 4·3–37·4) at 12 months (secondary outcome).InterpretationRopinirole is safe and tolerable for patients with ALS and this trial indicates feasibility for a subsequent large-scale trial.FundingThis study was funded by The Japan Agency for Medical Research and Development and K Pharma Inc.

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Ropinirole hydrochloride remedy for amyotrophic lateral sclerosis - Protocol for a randomized, double-blind, placebo-controlled, single-center, and open-label continuation phase I/IIa clinical trial (ROPALS trial)

10.21203/rs.2.207/v1 ◽

2019 ◽

Author(s):

Satoru Morimoto ◽

Shinichi Takahashi ◽

Komei Fukushima ◽

Hideyuki Saya ◽

Norihiro Suzuki ◽

...

Keyword(s):

Clinical Trial ◽

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Rating Scale ◽

Secondary Outcome ◽

Single Center ◽

Double Blind ◽

Human Spinal Cord ◽

Ropinirole Hydrochloride ◽

Lateral Sclerosis

Abstract Background: Amyotrophic lateral sclerosis (ALS) is one of intractable neurological diseases, which is an incurable disease. ALS is a progressive disease characterized by muscle atrophy and weakness caused by selective vulnerability of upper and lower motor neurons. In the disease research ever conducted, it has been common to use mouse models carrying mutations in responsible genes for familial ALS as pathological models of ALS. However, there is no model that has reproduced the actual conditions of human spinal cord pathology. Thus, we developed a method of producing human spinal motor neurons using human induced pluripotent stem cells (iPSCs) and an innovative experimental technique for drug screening. As a result, ropinirole hydrochloride was eventually discovered after considering preferable transitivity in the brain, tolerability including adverse reactions, and others. Therefore, we explore the safety, tolerability and efficacy of ropinirole hydrochloride to ALS in this clinical trial. Methods/Design: ROPALS trial is a single-center double-blind randomized parallel group-controlled trial of the safety, tolerability, and efficacy of ropinirole hydrochloride extended-release tablet (Requip CR) at 2mg - 16mg doses in patients with ALS. 20 patients will be recruited as active drug and placebo group. All patients will be able to be on the standard treatment for ALS of riluzole if not changed the dosage. The primary outcome will be safety and tolerability at 24 weeks defined from the date of randomization. Secondary outcome will be the efficacy including the change of ALS Functional Rating Scale-Revised (ALSFRS-R), the change in Combined Assessment of Function and Survival (CAFS), and composite endpoint as a sum of Z-transformed scores on the various clinical items. Noteworthy, we will perform explorative search for drug effect evaluation by using the patients-derived iPSCs to prove this trial concept. Eligible patients will have El Escorial Possible, clinically possible and laboratory-supported, clinically probable, or clinically definite amyotrophic lateral sclerosis with disease duration less than 60 months (inclusive), ALSFRS-R score ≥2 points on all items and age from 20 to 80 years. Discussion: Patient recruitment began in December 2018 and the last patient is expected to complete the trial protocol in November 2020. Trial registration: Current controlled trials UMIN000034954 Protocol version: version 1.1 (Date; 7/Nov/2018) Keywords: Amyotrophic Lateral Sclerosis, Ropinirole hydrochloride, Requip CR, iPSC-drug discovery

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A Randomized, Double-blind, Placebo-controlled Trial of DL-3-n-butylphthalide in Amyotrophic Lateral Sclerosis Patients

10.21203/rs.3.rs-1142455/v1 ◽

2021 ◽

Author(s):

Mingsheng Liu ◽

Xiaoli Yao ◽

Xusheng Huang ◽

Huifang Shang ◽

Dongsheng Fan ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Placebo Group ◽

Clinical Global Impression ◽

Rating Scale ◽

Controlled Trial ◽

Controlled Clinical Trial ◽

Double Blind ◽

Double Blind Placebo ◽

Significant Difference ◽

Lateral Sclerosis

Abstract Background: To determine the efficacy and safety of DL-3-n-butylphthalide (NBP) for the treatment of amyotrophic lateral sclerosis (ALS).Methods: A randomized, double-blind, placebo-controlled trial was performed at 19 ALS clinical centers of the Chinese ALS Association. Patients with definite or probable ALS were randomly treated with NBP or placebo for 12 months. The Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score was the primary endpoint and was evaluated every 3 months. Secondary endpoints included survival and tracheotomy incidence, total Medical Research Council (MRC) score, percentage of predicted forced vital capacity (FVC), and clinical global impression scale score assessed using the visual analog scale. Results: Between November 23, 2015 and November 22, 2017, 312 ALS patients were enrolled and randomly allocated to either the NBP group (156 patients) or placebo group (156 patients). Ninety-three patients in the NBP group and 92 patients in the placebo group were included in the primary end point analysis. There was no significant difference in the ALSFRS-R score, total MRC score, or clinical global impression between the two groups after treatment. The NBP group exhibited a mild trend of less decrease in the percentage of predicted FVC between baseline and the 12-month visit than the placebo group (least-squares mean change from baseline ± standard error: -7.34±4.28, 95％CI(-15.24,0.56), p=0.0335). Adverse events were reported in 56.5% of patients in the placebo group and 68.8% of patients in the NBP group (χ2=2.99, P=0.0838). No serious adverse event related to treatment occurred.Conclusion: we found no evidence that NBP improved the ALSFRS-R score in patients with ALS. The results suggest a mild trend in the percentage of predicted FVC decreased slowly in the NBP treatment group than in the placebo group.Trial registration: A Multi-center, Randomized, Double Blinding, Placebo-Controlled Clinical Trial of Dl-3-Butylphthalide in the Treatment of Amyotrophic Lateral Sclerosis, ChiCTR-IPR-15007365, Registered 1 November 2015, http://www.chictr.org.cn/showproj.aspx?proj=12354

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Proteostasis and ALS: protocol for a phase II, randomised, double-blind, placebo-controlled, multicentre clinical trial for colchicine in ALS (Co-ALS)

BMJ Open ◽

10.1136/bmjopen-2018-028486 ◽

2019 ◽

Vol 9 (5) ◽

pp. e028486 ◽

Cited By ~ 11

Author(s):

Jessica Mandrioli ◽

Valeria Crippa ◽

Cristina Cereda ◽

Valentina Bonetto ◽

Elisabetta Zucchi ◽

...

Keyword(s):

Clinical Trial ◽

Amyotrophic Lateral Sclerosis ◽

Disease Progression ◽

Phase Ii ◽

Mononuclear Cells ◽

Rating Scale ◽

Double Blind ◽

Peripheral Blood Mononuclear ◽

Double Blind Placebo ◽

Lateral Sclerosis

IntroductionDisruptions of proteasome and autophagy systems are central events in amyotrophic lateral sclerosis (ALS) and support the urgent need to find therapeutic compounds targeting these processes. The heat shock protein B8 (HSPB8) recognises and promotes the autophagy-mediated removal of misfolded mutant SOD1 and TDP-43 fragments from ALS motor neurons (MNs), as well as aggregating species of dipeptides produced in C9ORF72-related diseases. In ALS-SOD1 mice and in human ALS autopsy specimens, HSPB8 is highly expressed in spinal cord MNs that survive at the end stage of disease. Moreover, the HSPB8–BAG3–HSP70 complex maintains granulostasis, which avoids conversion of dynamic stress granules (SGs) into aggregation-prone assemblies. We will perform a randomised clinical trial (RCT) with colchicine, which enhances the expression of HSPB8 and of several autophagy players, blocking TDP-43 accumulation and exerting crucial activities for MNs function.Methods and analysisColchicine in amyotrophic lateral sclerosis (Co-ALS) is a double-blind, placebo-controlled, multicentre, phase II RCT. ALS patients will be enrolled in three groups (placebo, colchicine 0.01 mg/day and colchicine 0.005 mg/day) of 18 subjects treated with riluzole; treatment will last 30 weeks, and follow-up will last 24 weeks. The primary aim is to assess whether colchicine decreases disease progression as measured by ALS Functional Rating Scale - Revised (ALSFRS-R) at baseline and at treatment end. Secondary aims include assessment of (1) safety and tolerability of Colchicine in patiets with ALS; (2) changes in cellular activity (autophagy, protein aggregation, and SG and exosome secretion) and in biomarkers of disease progression (neurofilaments); (3) survival and respiratory function and (4) quality of life. Preclinical studies with a full assessment of autophagy and neuroinflammation biomarkers in fibroblasts, peripheral blood mononuclear cells and lymphoblasts will be conducted in parallel with clinic assessment to optimise time and resources.Ethics and disseminationThe study protocol was approved by the Ethics Committee of Area Vasta Emilia Nord and by Agenzia Italiana del Farmaco (EUDRACT N.2017-004459-21) based on the Declaration of Helsinki. This research protocol was written without patient involvement. Patients’ association will be involved in disseminating the study design and results. Results will be presented during scientific symposia or published in scientific journals.Trial registration numberEUDRACT 2017-004459-21;NCT03693781; Pre-results.

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MERIDIAN: A phase 2, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of pegcetacoplan in patients with amyotrophic lateral sclerosis

10.5327/1516-3180.744 ◽

2021 ◽

Author(s):

Frederico Mennucci de Haidar Jorge ◽

Angela Genge ◽

Ammar Al- Chalabi ◽

Orla Hardiman ◽

Alice Shen ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Rating Scale ◽

Phase 2 ◽

Efficacy And Safety ◽

Open Label ◽

Double Blind ◽

Double Blind Placebo ◽

Sporadic Als ◽

The Difference ◽

Lateral Sclerosis

Introduction: Inflammation underlies the pathogenesis of numerous neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). In ALS, the complement system has been implicated in the neuropathology of disease and disease progression. Pegcetacoplan, a subcutaneously administered C3 complement inhibitor, is being investigated in hematology, nephrology, and neurology. The current clinical study (NCT04579666) is investigating whether pegcetacoplan can improve survival and function in people diagnosed with apparent sporadic ALS. Objectives and Methodology: Evaluate the efficacy and safety of pegcetacoplan compared to placebo among people diagnosed with ALS in a global, multicenter, randomized, double-blind, placebo-controlled, phase 2 study. Approximately 228 patients diagnosed with apparent sporadic ALS, ≥18 years of age and with an ALS Functional Rating Scale-Revised (ALSFRS-R) score ≥30, slow vital capacity (SVC) ≥60% of the predicted value at screening, and with symptom onset within 72 weeks before screening, are eligible for enrollment. After screening, patients will be randomized 2:1 to treatment groups receiving either subcutaneous pegcetacoplan (1080 mg) or placebo twice weekly for a duration of 52 weeks. The primary efficacy endpoint is the difference in the Combined Assessment of Function and Survival (CAFS) ranked score at 52 weeks after treatment initiation. Additional, secondary functional efficacy (ALSFRS-R, percent SVC, muscle strength, quality of life, and caregiver burden) and safety endpoints will be analyzed at 52 weeks. After the placebo-controlled period, all patients will have the option to receive pegcetacoplan in an open-label period for an additional 52 weeks. Results: This ongoing study is currently enrolling participants. Conclusions: Results of this study will determine the role of complement and C3 inhibition in patients with ALS.

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Study protocol for a randomised, double-blind, placebo-controlled study evaluating the Efficacy of cannabis-based Medicine Extract in slowing the disease pRogression of Amyotrophic Lateral sclerosis or motor neurone Disease: the EMERALD trial

BMJ Open ◽

10.1136/bmjopen-2019-029449 ◽

2019 ◽

Vol 9 (11) ◽

pp. e029449 ◽

Cited By ~ 4

Author(s):

Berzenn Urbi ◽

Simon Broadley ◽

Richard Bedlack ◽

Ethan Russo ◽

Arman Sabet

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Disease Progression ◽

Rating Scale ◽

Numeric Rating Scale ◽

Motor Neurone ◽

Double Blind ◽

Based Medicine ◽

Numeric Rating ◽

Lateral Sclerosis

IntroductionAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no known cure and with an average life expectancy of 3–5 years post diagnosis. The use of complementary medicine such as medicinal cannabis in search for a potential treatment or cure is common in ALS. Preclinical studies have demonstrated the efficacy of cannabinoids in extending the survival and slowing of disease progression in animal models with ALS. There are anecdotal reports of cannabis slowing disease progression in persons with ALS (pALS) and that cannabis alleviated the symptoms of spasticity and pain. However, a clinical trial in pALS with these objectives has not been conducted.Methods and analysisThe Efficacy of cannabis-based Medicine Extract in slowing the disease pRogression of Amyotrophic Lateral sclerosis or motor neurone Disease trial is a randomised, double-blind, placebo-controlled cannabis trial in pALS conducted at the Gold Coast University Hospital, Australia. The investigational product will be a cannabis-based medicine extract (CBME) supplied by CannTrust Inc., Canada, with a high-cannabidiol-low-tetrahydrocannabinol concentration. A total of 30 pALS with probable or definite ALS diagnosis based on the El Escorial criteria, with a symptom duration of <2 years, age between 25 and 75years and with at least 70% forced vital capacity (FVC) will be treated for 6 months. The primary objective of the study is to evaluate the efficacy of CBME compared with placebo in slowing the disease progression measured by differences in mean ALS Functional Rating Scale-Revised and FVC score between the groups at the end of treatment. The secondary objectives are to evaluate the safety and tolerability of CBME by summarising adverse events, the effects of CBME on spasticity, pain, weight loss and quality of life assessed by the differences in mean Numeric Rating Scale for spasticity and Numeric Rating Scale for pain, percentage of total weight loss and ALS specific quality of life-Revised questionnaire.Ethics and disseminationThe study has been approved by the local Institutional Review Board. The results of this study will be published in a peer-reviewed journal.Trial registration numberNCT03690791

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Randomized phase 2 study of perampanel for sporadic amyotrophic lateral sclerosis

Journal of Neurology ◽

10.1007/s00415-021-10670-y ◽

2021 ◽

Author(s):

Hitoshi Aizawa ◽

Haruhisa Kato ◽

Koji Oba ◽

Takuya Kawahara ◽

Yoshihiko Okubo ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Rating Scale ◽

Sporadic Amyotrophic Lateral Sclerosis ◽

Phase 2 ◽

Double Blind ◽

Efficacy Outcome ◽

Phase 2 Study ◽

Significant Difference ◽

To Receive ◽

Lateral Sclerosis

Abstract Objective To evaluate the efficacy and safety of perampanel in patients with sporadic amyotrophic lateral sclerosis (SALS). Methods This randomized, double-blind, placebo-controlled, multicenter, phase 2 clinical study was conducted at 12 sites. Patients with probable or definite ALS as defined by revised El Escorial criteria were enrolled. Sixty-six patients were randomly assigned (1:1:1) to receive placebo, 4 mg perampanel, or 8 mg perampanel daily for 48 weeks. Adverse events (AEs) were recorded throughout the trial period. The primary efficacy outcome was the change in Amyotrophic Lateral Sclerosis Rating Scale-Revised (ALSFRS-R) score after 48 weeks of treatment. Results One patient withdrew before starting the treatment. Of 65 patients included, 18 of 22 patients randomized to placebo (82%), 14 of 22 patients randomized to 4 mg perampanel (64%), and 7 of 21 patients randomized to 8 mg perampanel (33%) completed the trial. There was a significant difference in the change of ALSFRS-R scores [− 8.4 (95% CI − 13.9 to − 2.9); p = 0.015] between the placebo and the perampanel 8 mg group, primarily due to worsening of the bulbar subscore in the perampanel 8 mg group. Serious AEs were more frequent in the perampanel 8 mg group than in the placebo group (p = 0.0483). Conclusions Perampanel was associated with a significant decline in ALSFRS-R score and was linked to worsening of the bulbar subscore in the 8 mg group.

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The effect of levetiracetam on tremor severity and functionality in patients with multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458508099142 ◽

2009 ◽

Vol 15 (3) ◽

pp. 371-378 ◽

Cited By ~ 23

Author(s):

P Feys ◽

G Nagels ◽

WF Helsen ◽

Keyword(s):

Multiple Sclerosis ◽

Repeated Measures ◽

Rating Scale ◽

Secondary Outcome ◽

Life Questionnaire ◽

Maximal Dose ◽

Intention Tremor ◽

Double Blind ◽

Drawing Task ◽

Spiral Drawing

Background Multiple sclerosis (MS) intention tremor is a disabling symptom, which is difficult to treat. Objectives To investigate the effects of levetiracetam, an antiepileptic drug, on tremor severity and related functionality in MS. Methods A randomized, double-blind, placebo-controlled, cross-over study examined the effects of 6 weeks of oral levetiracetam administration (starting dose = 250 mg/day, maximal dose = 2000 mg/day) in 18 MS patients with disabling intention tremor. Primary outcome was Fahn’s Tremor Rating Scale (FTRS) A&B. Secondary outcome measures were the nine-hole peg test, patient’s opinion rated with the visual analog scale, FTRS C, and an activities of daily life questionnaire and validated tremor indexes derived during the performance of a digitized spiral drawing task and a wrist step-tracking task. Repeated measures analysis of variance and Friedman tests were applied. Results In all, 14 patients completed the trial. Maximal dose intake ranged from 1000 to most commonly 2000 mg, depending on patients’ tolerance level. No significant effects of levetiracetam were found for any outcome measure. Further analyses on subgroups with different tremor severity showed no differential effects. Eight patients reported adverse events such as fatigue and stomach ache. Conclusions Levetiracetam intake of 2000 mg/day did not affect tremor severity or functionality in patients with MS.

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G-CSF (filgrastim) treatment for amyotrophic lateral sclerosis: protocol for a phase II randomised, double-blind, placebo-controlled, parallel group, multicentre clinical study (STEMALS-II trial)

BMJ Open ◽

10.1136/bmjopen-2019-034049 ◽

2020 ◽

Vol 10 (3) ◽

pp. e034049

Author(s):

Paolina Salamone ◽

Giuseppe Fuda ◽

Federico Casale ◽

Giuseppe Marrali ◽

Christian Lunetta ◽

...

Keyword(s):

Clinical Trial ◽

Amyotrophic Lateral Sclerosis ◽

Phase Ii ◽

Rating Scale ◽

Bone Marrow Cells ◽

Double Blind ◽

Double Blind Placebo ◽

Parallel Group ◽

Als Patients ◽

Lateral Sclerosis

IntroductionAmyotrophic lateral sclerosis (ALS) is a fatal progressive neurological disorder characterised by a selective degeneration of motor neurons (MNs). Stem cell transplantation is considered as a promising strategy in neurological disorders therapy and the possibility of inducing bone marrow cells (BMCs) to circulate in the peripheral blood is suggested to investigate stem cells migration in degenerated ALS nerve tissues where potentially repair MN damage. Granulocyte-colony stimulating factor (G-CSF) is a growth factor which stimulates haematopoietic progenitor cells, mobilises BMCs into injured brain and it is itself a neurotrophic factor for MN. G-CSF safety in humans has been demonstrated and many observations suggest that it may affect neural cells. Therefore, we decided to use G-CSF to mobilise BMCs into the peripheral circulation in patients with ALS, planning a clinical trial to evaluate the effect of G-CSF administration in ALS patients compared with placebo.Methods and analysisSTEMALS-II is a phase II multicentre, randomised double-blind, placebo-controlled, parallel group clinical trial on G-CSF (filgrastim) and mannitol in ALS patients. Specifically, we investigate safety, tolerability and efficacy of four repeated courses of intravenous G-CSF and mannitol administered in 76 ALS patients in comparison with placebo (indistinguishable glucose solution 5%). We determine increase of G-CSF levels in serum and cerebrospinal fluid as CD34+cells and leucocyte count after treatment; reduction in ALS Functional Rating Scale-Revised Score, forced vital capacity, Scale for Testing Muscle Strength Score and quality of life; the adverse events/reactions during the treatment; changes in neuroinflammation biomarkers before and after treatment.Ethics and disseminationThe study protocol was approved by the Ethics Committee of Azienda Ospedaliera Universitaria ‘Città della Salute e della Scienza’, Torino, Italy. Results will be presented during scientific symposia or published in scientific journals.Trial registration numberEudract 2014-002228-28.

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Ropinirole hydrochloride remedy for amyotrophic lateral sclerosis – Protocol for a randomized, double-blind, placebo-controlled, single-center, and open-label continuation phase I/IIa clinical trial (ROPALS trial)

Regenerative Therapy ◽

10.1016/j.reth.2019.07.002 ◽

2019 ◽

Vol 11 ◽

pp. 143-166 ◽

Cited By ~ 6

Author(s):

Satoru Morimoto ◽

Shinichi Takahashi ◽

Komei Fukushima ◽

Hideyuki Saya ◽

Norihiro Suzuki ◽

...

Keyword(s):

Clinical Trial ◽

Amyotrophic Lateral Sclerosis ◽

Phase I ◽

Single Center ◽

Open Label ◽

Double Blind ◽

Continuation Phase ◽

Double Blind Placebo ◽

Ropinirole Hydrochloride ◽

Lateral Sclerosis

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Efficacy and Safety of Bumetanide in Patients with Amyotrophic Lateral Sclerosis: A Randomized Controlled Clinical Trial

10.21203/rs.3.rs-265649/v1 ◽

2021 ◽

Author(s):

Soraya Mehrabi ◽

Mohsen Sedighi ◽

Bahram Haghi Ashtiani ◽

Motahareh Afrakhteh ◽

Elahe Shahriari ◽

...

Keyword(s):

Clinical Trial ◽

Amyotrophic Lateral Sclerosis ◽

Placebo Group ◽

Motor Unit ◽

Rating Scale ◽

Controlled Trial ◽

Controlled Clinical Trial ◽

Cortical Hyperexcitability ◽

Als Patients ◽

Lateral Sclerosis

Abstract Background: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the terminal degenerative disease of the motor units. This clinical trial was aimed to investigate the modulatory effect of bumetanide on physiological symptoms of ALS patients.Methods: This was a double-blind, placebo-controlled trial in which ALS patients were randomized 1:1 to receive bumetanide (2 mg daily) or matching placebo group for up to 4 months. Motor Unit Number Index (MUNIX), motor unit size index (MUSIX), and ALS Functional Rating Scale, revised (ALSFRS-R) was assessed before and after treatment as following bumetanide treatment.Results: 18 patients were allocated to bumetanide and 18 to the placebo group. In final analysis, 16 patients in bumetanide and 15 patients in the placebo group completed the trial. Patients in the placebo group showed a significant decrease in MUNIX value for all examined muscles after treatment, while MUNIX value for trapezius in bumetanide group increased significantly (p˂0.05). MUZIX value for tibialis anterior and trapezius (p˂0.05) improved significantly after bumetanide administration, whereas trapezius (p˂0.05) and abductor pollicis brevis (p˂0.01) in the placebo group showed a significantly decreased value. ALSFRS-R score decreased significantly in the placebo group after treatment (p˂0.001), but ALSFRS-R in bumetanide group improved significantly (p˂0.05). Three adverse effects (polyuria, vertigo, orthostatic hypotension) in bumetanide group were judged to be related to bumetanide.Conclusion: Bumetanide treatment might be effective in modulation of ALS symptoms possibly due to the hyperpolarization of GABA actions and mitigation of cortical hyperexcitability.

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