scholarly journals Transplantation of Mesenchymal Stromal Cells in Patients with Amyotrophic Lateral Sclerosis: Results of Phase I/IIa Clinical Trial

2017 ◽  
Vol 26 (4) ◽  
pp. 647-658 ◽  
Author(s):  
Eva Syková ◽  
Petr Rychmach ◽  
Ivana Drahorádová ◽  
ŠImona Konrádová ◽  
Kateřina Růžičková ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Amyotrophic Lateral Sclerosis ◽  
Phase I ◽  
Lumbar Puncture ◽  
Stromal Cells ◽  
Adverse Reactions ◽  
Rating Scale ◽  
Neurodegenerative Disorder ◽  
Safe Procedure ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive untreatable neurodegenerative disorder, leading to the death of the cortical and spinal motoneurons (MNs). Bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) may represent a new approach to slowing down the progression of ALS by providing neurotrophic support to host MNs and by having an anti-inflammatory effect. We have designed a prospective, nonrandomized, open-label clinical trial (phase I/IIa, EudraCT No. 2011-000362-35) to assess the safety and efficacy of autologous multipotent BM-MSCs in ALS treatment. Autologous BM-MSCs were isolated and expanded under GMP conditions. Patients received 15 ± 4.5 × 106 of BM-MSCs via lumbar puncture into the cerebrospinal fluid. Patients were monitored for 6 months before treatment and then for an 18-month follow-up period. Potential adverse reactions were assessed, and the clinical outcome was evaluated by the ALS functional rating scale (ALSFRS), forced vital capacity (FVC), and weakness scales (WSs) to assess muscle strength on the lower and upper extremities. In total, 26 patients were enrolled in the study and were assessed for safety; 23 patients were suitable for efficacy evaluation. After intrathecal BM-MSC application, about 30% of the patients experienced a mild to moderate headache, resembling the headaches after a standard lumbar puncture. No suspected serious adverse reactions (SUSAR) were observed. We found a reduction in ALSFRS decline at 3 months after application ( p < 0.02) that, in some cases, persisted for 6 months ( p < 0.05). In about 80% of the patients, FVC values remained stable or above 70% for a time period of 9 months. Values of WS were stable in 75% of patients at 3 months after application. Our results demonstrate that the intrathecal application of BM-MSCs in ALS patients is a safe procedure and that it can slow down progression of the disease.

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

BMJ Open ◽  
2019 ◽  
Vol 9 (5) ◽  
pp. e028486 ◽  
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.

scholarly journals Utility of phrenic nerve ultrasound in amyotrophic lateral sclerosis

2020 ◽  
Author(s):  
Cezar Thomas Suratos ◽  
Naoko Takamatsu ◽  
Hiroki Yamazaki ◽  
Yusuke Osaki ◽  
Tatsuya Fukumoto ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Phrenic Nerve ◽  
Rating Scale ◽  
Neurodegenerative Disorder ◽  
Pulmonary Function Tests ◽  
Cross Sectional ◽  
The Right ◽  
Als Patients ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting the upper and lower motor neurons causing progressive weakness. It eventually involves the diaphragm which leads to respiratory paralysis and subsequently death. Phrenic nerve (PN) conduction studies and diaphragm ultrasound has been studied and correlated with pulmonary function tests in ALS patients. However, PN ultrasonography has not been employed in ALS. This study aims to sonographically evaluate the morphologic appearance of the PN of ALS patients. Thirty-eight ALS patients and 28 normal controls referred to the neurophysiology laboratory of two institutions were retrospectively included in the study. Baseline demographic and clinical variables such as disease duration, ALS Functional Rating Scale-Revised score, and ALS region of onset were collected. Ultrasound was used to evaluate the PN cross-sectional area (CSA) of ALS and control subjects. The mean PN CSA of ALS patients were 1.08 ± 0.39 mm on the right and 1.02 ± 0.34 mm on the left. The PN CSA of ALS patients were significantly decreased compared to controls (p value < 0.00001). The PN CSA of ALS patients was not correlated to any of the demographic and clinical parameters tested. This study demonstrates that ALS patients have a smaller PN size compared to controls using ultrasonography.

scholarly journals γ' Fibrinogen as a Predictor of Survival in Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 8 ◽  
Author(s):  
Ana Catarina Pronto-Laborinho ◽  
Catarina S. Lopes ◽  
Vasco A. Conceição ◽  
Marta Gromicho ◽  
Nuno C. Santos ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Rating Scale ◽  
Neurodegenerative Disorder ◽  
Positive Impact ◽  
Enzyme Linked Immunosorbent Assay ◽  
Fibrinogen Concentration ◽  
Respiratory Impairment ◽  
Increased Risk ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is an aggressive neurodegenerative disorder related to neuroinflammation that is associated with increased risk of thrombosis. We aimed to evaluate γ' fibrinogen plasma level (an in vivo variant of fibrinogen) as a biomarker in ALS, and to test its role as a predictor of disease progression and survival. Sixty-seven consecutive patients with ALS were followed and the results were compared with those from 82 healthy blood donors. Patients were clinically evaluated at the time of blood sampling and on follow-up (every 3 months for the beginning of the follow-up until death) by applying the revised ALS Functional Rating Scale. Human plasma γ' fibrinogen concentration was quantified using a specific two-site sandwich kit enzyme-linked immunosorbent assay. We found, for the first time, a positive association between γ' fibrinogen concentration and survival in ALS patients: patients with higher γ' fibrinogen plasma levels survived longer, and this finding was not influenced by confounders such as age, gender, respiratory impairment, or functionality (ALSFRS-R score). Since increased levels have a positive impact on outcome, this novel biomarker should be further investigated in ALS.

scholarly journals Open Randomized Clinical Trial on JWSJZ Decoction for the Treatment of ALS Patients

2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
Weidong Pan ◽  
Xiaojing Su ◽  
Jie Bao ◽  
Jun Wang ◽  
Jin Zhu ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Amyotrophic Lateral Sclerosis ◽  
Rating Scale ◽  
Control Group ◽  
Efficacy And Safety ◽  
Significant Difference ◽  
Als Patients ◽  
And Control ◽  
Lateral Sclerosis ◽  
Basic Treatment

Objective. To investigate the efficacy and safety of the traditional Chinese medicine Jiawei Sijunzi (JWSJZ) decoction for the treatment of patients with amyotrophic lateral sclerosis (ALS).Methods. Forty-eight patients with ALS were divided into a JWSJZ group (n=24) and a control group (n=24) using a randomized number method. Together with the basic treatment for ALS, JWSJZ decoction was added to the treatment regimen of patients in the JWSJZ group or Riluzole was administered to the control group for 6 months. Neurologists evaluated the treated and control patients using the ALS functional rating scale (ALSFRS) before, 3 and 6 months after starting the additional treatments.Results. The ALSFRS scores in both groups were lower 3 and 6 months after treatment than before. There was a significant difference at 6 months after treatment between the subgroups of patients with ALS whose limbs were the initial site of attack. No serious adverse effects were observed in the JWSJZ group.Conclusion. JWSJZ decoction may be a safe treatment for ALS, and may have delayed the development of ALS, especially in the subgroup of patients in whom the limbs were attacked first when compared with Riluzole treatment.

scholarly journals Monitoring disease progression with plasma creatinine in amyotrophic lateral sclerosis clinical trials

2017 ◽  
Vol 89 (2) ◽  
pp. 156-161 ◽  
Author(s):  
Ruben P A van Eijk ◽  
Marinus J C Eijkemans ◽  
Toby A Ferguson ◽  
Stavros Nikolakopoulos ◽  
Jan H Veldink ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Amyotrophic Lateral Sclerosis ◽  
Muscle Strength ◽  
Sample Size ◽  
Disease Progression ◽  
Rating Scale ◽  
Plasma Creatinine ◽  
Rate Of Decline ◽  
Lateral Sclerosis

ObjectivesPlasma creatinine is a predictor of survival in amyotrophic lateral sclerosis (ALS). It remains, however, to be established whether it can monitor disease progression and serve as surrogate endpoint in clinical trials.MethodsWe used clinical trial data from three cohorts of clinical trial participants in the LITRA, EMPOWER and PROACT studies. Longitudinal associations between functional decline, muscle strength and survival with plasma creatinine were assessed. Results were translated to trial design in terms of sample size and power.ResultsA total of 13 564 measurements were obtained for 1241 patients. The variability between patients in rate of decline was lower in plasma creatinine than in ALS functional rating scale–Revised (ALSFRS-R; p<0.001). The average rate of decline was faster in the ALSFRS-R, with less between-patient variability at baseline (p<0.001). Plasma creatinine had strong longitudinal correlations with the ALSFRS-R (0.43 (0.39–0.46), p<0.001), muscle strength (0.55 (0.51–0.58), p<0.001) and overall mortality (HR 0.88 (0.86–0.91, p<0.001)). Using plasma creatinine as outcome could reduce the sample size in trials by 21.5% at 18 months. For trials up to 10 months, the ALSFRS-R required a lower sample size.ConclusionsPlasma creatinine is an inexpensive and easily accessible biomarker that exhibits less variability between patients with ALS over time and is predictive for the patient’s functional status, muscle strength and mortality risk. Plasma creatinine may, therefore, increase the power to detect treatment effects and could be incorporated in future ALS clinical trials as potential surrogate outcome.

scholarly journals Botulinum toxin for the treatment of lower limb cramp pain in patients with Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 1 (1) ◽  
Author(s):  
Tejas Mehta ◽  
Richard Sommers ◽  
Raghav Govindarajan
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Pain Score ◽  
Lower Limb ◽  
Rating Scale ◽  
Retrospective Chart Review ◽  
Pain Scale ◽  
Wilcoxon Test ◽  
Safe Procedure ◽  
Lateral Sclerosis

Background: Muscle cramps and pain associated with them can be seen in patients with amyotrophic lateral sclerosis (ALS) and are known to reduce the quality of life. Pharmacological treatment may not benefit all patients in treating these cramps. We assess the efficacy of Onabotulinum toxin A (BTX-A) in the treatment of lower limb cramps in patients with ALS. Methods: This retrospective chart review included a total of ten patients with ALS who suffered from pain due to lower limb cramps and were managed with BTX-A. Data including patient demographics, visual analog pain scale at different intervals during follow up, ALS functional rating scale and site of onset of ALS symptoms were documented. The pain score at baseline (before administration), at 3 months follow up and at 6 months follow up were compared using Wilcoxon test to assess BTX-A’s efficacy. Results: A significant improvement in average pain score due to cramps from baseline to the 6-month interval with a change of 3.1±0.7 (p<0.05,95%CI) was seen on the pain scale. No adverse events were noted during administration or post injections. Conclusion: Local BTX-A administration is an efficacious and safe procedure for improving pain associated with cramps in patients with ALS.

scholarly journals 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)

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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