The Rilutek ® (riluzole) Global Early Access Programme: An open-label safety evaluation in the treatment of amyotrophic lateral sclerosis

Abstract We studied the feasibility, safety, tolerability and pharmacokinetics of intracerebroventricular delivery of recombinant human vascular endothelial growth factor in patients with amyotrophic lateral sclerosis. In this phase I study in patients with amyotrophic lateral sclerosis, the study drug was delivered using an implantable programmable pump connected to a catheter inserted in the frontal horn of the lateral cerebral ventricle. A first cohort received open label vascular endothelial growth factor (0.2, 0.8 and 2 µg/day), a second cohort received placebo, 0.8 or 2 µg/day of study dug. After the 3-month study period, all patients could participate in an open label extension study. In total, 18 patients with amyotrophic lateral sclerosis, seen at the University Hospitals in Leuven were included. The surgical procedure was well tolerated in most patients. One patient had transient postoperative seizures, due to an ischemic lesion along the catheter tract. The first 3-month study period was completed by 15/18 patients. Administration of 2 µg/day vascular endothelial growth factor resulted in sustained detectable levels in cerebrospinal fluid. A pulmonary embolus occurred in 3 patients, in 1 patient in the first 3-month study, and in 2 patients during the open label extension study. The study drug was well tolerated in the other patients, for up to 6 years in the open label extension study. Our study shows that intracerebroventricular administration of 2 µg/day of vascular endothelial growth factor to patients with amyotrophic lateral sclerosis is feasible, results in detectable cerebrospinal fluid levels and is well tolerated in most patients. The most common serious adverse event was a pulmonary embolus.

Download Full-text

Plasma exchange with albumin replacement and disease progression in amyotrophic lateral sclerosis: a pilot study

Neurological Sciences ◽

10.1007/s10072-021-05723-z ◽

2021 ◽

Author(s):

Mónica Povedano ◽

Andrés Paipa ◽

Miquel Barceló ◽

Michael K. Woodward ◽

Sandra Ortega ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Pilot Study ◽

Disease Progression ◽

Plasma Exchange ◽

Rating Scale ◽

Open Label ◽

Primary Endpoints ◽

Rate Of Decline ◽

Post Hoc ◽

Lateral Sclerosis

Abstract Background Plasma exchange (PE) is used to treat a range of neurological disorders. Based on results demonstrated in Alzheimer’s disease, we theorized that PE with albumin replacement (PE-A) might alter the metabolic profile of plasma and cerebrospinal fluid in patients with amyotrophic lateral sclerosis (ALS) by removing disease-inducing molecules. The aim of this study was to evaluate the effect of PE-A on disease progression in ALS. Methods In this open-label, non-controlled, single-arm, prospective pilot study, 13 adults with ALS had 6 months’ treatment with PE-A 5% and 6 months’ follow-up. Primary endpoints were changes from baseline in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score and forced vital capacity (FVC) through 48 weeks. A post hoc analysis compared individual patient data with the expected ALSFRS-R progression slope. Results The median ALSFRS-R score declined throughout the study, although the rate of decline was slower than expected in seven patients at treatment end and in five patients at study end. Six patients remained in the same baseline slope progression category, and four patients improved their slope category at treatment end. Median FVC decreased significantly during the study. Treatment was well tolerated. Of 330 PE-A procedures, 0.9% were associated with potentially related adverse events. Conclusion Although functional impairment progressed, about two-thirds of patients showed a slower than expected rate of decline at treatment end. Most patients had unaltered (54.5%) or reduced (36.4%) ALSFRS-R slope progression at treatment end. Further evaluation of PE-A in controlled studies involving more patients is warranted. EudraCT number 2013-004842-40. Trial registration ClinicalTrials.gov identifier: NCT02479802.

Download Full-text

Oral levosimendan in amyotrophic lateral sclerosis: a phase II multicentre, randomised, double-blind, placebo-controlled trial

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2018-320288 ◽

2019 ◽

Vol 90 (10) ◽

pp. 1165-1170 ◽

Cited By ~ 7

Author(s):

Ammar Al-Chalabi ◽

Pamela Shaw ◽

P Nigel Leigh ◽

Leonard van den Berg ◽

Orla Hardiman ◽

...

Keyword(s):

Heart Rate ◽

Amyotrophic Lateral Sclerosis ◽

Phase Ii ◽

Primary Endpoint ◽

Phase Iii ◽

Open Label ◽

Double Blind ◽

Double Blind Placebo ◽

Lateral Sclerosis

ObjectiveTo evaluate the efficacy and safety of oral levosimendan in patients with amyotrophic lateral sclerosis (ALS). This phase II, randomised, double-blind, placebo-controlled, crossover, three-period study with 6 months open-label follow-up enrolled adults with ALS and sitting slow vital capacity (SVC) 60%–90 % of predicted from 11 sites in four countries.MethodsPatients received levosimendan 1 mg daily, 1 mg two times a day or placebo during three 14-day crossover periods and levosimendan 1–2 mg daily during open-label follow-up. Primary endpoint was sitting SVC; secondary endpoints included supine SVC, ALS Functional Rating Scale-Revised (ALSFRS-R), tolerability and safety.ResultsOf 66 patients randomised, 59 contributed to the double-blind results and 50 entered open-label follow-up. Sitting SVC was not significantly different between the treatments. In post hoc analysis using period-wise baselines, supine SVC favoured levosimendan over placebo, estimated mean differences from baseline being −3.62% on placebo, +0.77% on levosimendan 1 mg daily (p=0.018) and +2.38% on 1 mg two times a day (p=0.001). Headache occurred in 16.7% of patients during levosimendan 1 mg daily (p=0.030), 28.6% during 1 mg two times a day (p=0.002) and 3.3% during placebo. The respective frequencies for increased heart rate were 5.1% (p=0.337), 18.5% (p=0.018) and 1.7%. No significant differences between the treatments were seen for other adverse events.ConclusionsLevosimendan did not achieve the primary endpoint of improving sitting SVC in ALS. Headache and increased heart rate were increased on levosimendan, although it was otherwise well tolerated. A phase III study to evaluate the longer term effects of oral levosimendan in ALS is ongoing.

Download Full-text

Safety and efficacy of diaphragm pacing in patients with respiratory insufficiency due to amyotrophic lateral sclerosis (DiPALS): a multicentre, open-label, randomised controlled trial

The Lancet Neurology ◽

10.1016/s1474-4422(15)00152-0 ◽

2015 ◽

Vol 14 (9) ◽

pp. 883-892 ◽

Cited By ~ 52

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Randomised Controlled Trial ◽

Respiratory Insufficiency ◽

Controlled Trial ◽

Open Label ◽

Diaphragm Pacing ◽

Safety And Efficacy ◽

Randomised Controlled ◽

Lateral Sclerosis

Download Full-text

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.

Download Full-text

Efficacy of thalidomide for the treatment of amyotrophic lateral sclerosis: A phase II open label clinical trial

Amyotrophic Lateral Sclerosis ◽

10.1080/17482960802709416 ◽

2009 ◽

pp. 1-12

Author(s):

Elijah Stommel ◽

Jeffrey Cohen ◽

Camilo Fadul ◽

Christopher Cogbill ◽

David Graber ◽

...

Keyword(s):

Clinical Trial ◽

Amyotrophic Lateral Sclerosis ◽

Phase Ii ◽

Open Label ◽

Lateral Sclerosis

Download Full-text

An open label study of a novel immunosuppression intervention for the treatment of amyotrophic lateral sclerosis

Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration ◽

10.1080/21678421.2017.1421666 ◽

2018 ◽

Vol 19 (3-4) ◽

pp. 242-249 ◽

Cited By ~ 13

Author(s):

Christina N. Fournier ◽

David Schoenfeld ◽

James D. Berry ◽

Merit E. Cudkowicz ◽

James Chan ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Open Label ◽

Open Label Study ◽

Label Study ◽

Lateral Sclerosis

Download Full-text

Nutritional counseling with or without mobile health technology: a randomized open-label standard-of-care-controlled trial in ALS

10.21203/rs.2.108/v1 ◽

2018 ◽

Author(s):

Anne-Marie M Wills ◽

Jamie Garry ◽

Jane Hubbard ◽

Taylor Mezoian ◽

Christopher T Breen ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Mobile Health ◽

Standard Care ◽

Controlled Trial ◽

Standard Of Care ◽

Health Technology ◽

Calorie Intake ◽

Nutritional Counseling ◽

Open Label ◽

Lateral Sclerosis

Abstract Background: Nutritional status is an important prognostic factor in Amyotrophic Lateral Sclerosis (ALS). We wished to study the safety, tolerability and efficacy of nutritional counseling with or without an mHealth application to maintain or increase body weight in ALS, compared to standard care. Methods: In this randomized open-label, standard-of-care-controlled, single-center clinical trial, we randomly assigned adults with ALS to one of three nutritional interventions: counseling by their physician or nurse (“standard care”), counseling by a registered dietitian (RD) (“in-person”), or counseling supported by a mHealth app (“mHealth”). Both intervention arms received tailored nutrition recommendations and recorded dietary intake and weight biweekly (mHealth) or monthly (in-person). The primary outcome of weight and secondary and tertiary outcomes of calorie intake, ALSFRS-R, and quality of life (QOL) were recorded at each clinic visit and analyzed in an ITT mixed model analysis. Results: A total of 88 participants were enrolled of whom 78 were included in this analysis. The three arms were well-balanced except for excess males in the mHealth arm and greater weight lost at baseline in the in-person arm. Participants in the mHealth arm increased their calorie intake at month 3 to an average of 94% (95% CI: 85, 103) of recommended calories, compared to 81% (95% CI: 72, 91, p= 0.06 vs. mHealth) in the standard care arm. After 6 months, calorie intake and change in weight was not different among the three arms. QOL scores in the mHealth arm were stable over three months (0.3 points, 95% CI: -1.7, 2.2) compared to worsening in standard care (-2.1 points, 95% CI: -4.0, -0.2, p = 0.09 vs. mHealth), but all scores declined by six months. ALSFRS-R total scores declined by an average of -2.6 points (95% CI: -5.1, -0.1) over six months in the mHealth arm (p=0.13 vs. standard care) compared to -5.8 points (95% CI: -8.2, -3.4, p=0.74 vs. standard care) in the in-person and -5.2 points (95% CI: -7.6, -2.9) in the standard care arm. Conclusions: Nutritional counseling is safe but did not increase weight compared to standard care in ALS patients. Trial Registration: Clinicaltrials.gov identifier NCT02418546. Registered April 16, 2015. Keywords: Amyotrophic Lateral Sclerosis, ALS, Neurodegenerative disease, mobile health technology, mHealth, nutrition, nutritional counseling, randomized controlled trial

Download Full-text