Rasagiline for amyotrophic lateral sclerosis: A randomized,controlled trial

Introduction: Rasagiline is a monoamine oxidase B (MAO-B) inhibitor with possible neuroprotective effects in patients with amyotrophic lateral sclerosis (ALS). Methods: We performed a randomized, double-blind, placebo-controlled trial of 80 ALS participants with enrichment of the placebo group with historical controls (n = 177) at 10 centers in the United States. Participants were randomized in a 3:1 ratio to 2 mg/day rasagiline or placebo. The primary outcome was average slope of decline on the ALS Functional Rating Scale—Revised (ALSFRS-R). Secondary measures included slow vital capacity, survival, mitochondrial and molecular biomarkers, and adverse-event reporting. Results: There was no difference in the average 12-month ALSFRS-R slope between rasagiline and the mixed placebo and historical control cohorts. Rasagiline did not show signs of drug-target engagement in urine and blood biomarkers. Rasagiline was well tolerated with no serious adverse events. Discussion: Rasagiline did not alter disease progression compared with controls over 12 months of treatment. Muscle Nerve 59 :201–207, 2019     

A randomized,double-blind,placebo-controlled phase 2 study to assess safety,tolerability, and efficacy of RT001 in patients with amyotrophic lateral sclerosis

Background and purpose

RT001 is a deuterated synthetic homologue of linoleic acid, which makes membrane polyunsaturated fatty acids resistant to lipid peroxidation, a process involved in motor neuron degeneration in amyotrophic lateral sclerosis (ALS).

Methods

We conducted a randomized, multicenter, placebo-controlled clinical trial. Patients with ALS were randomly allocated to receive either RT001 or placebo for 24 weeks. After the double-blind period, all patients received RT001 during an open-label phase for 24 weeks. The primary outcome measures were safety and tolerability. Key efficacy outcomes included the ALS Functional Rating Scale (ALSFRS-R), percent predicted slow vital capacity, and plasma neurofilament light chain concentration.

Results

In total, 43 patients (RT001 = 21; placebo = 22) were randomized. RT001 was well tolerated; one patient required dose reduction due to adverse events (AEs). Numerically, there were more AEs in the RT001 group compared to the placebo group (71% versus 55%, p = 0.35), with gastrointestinal symptoms being the most common (43% in RT001, 27% in placebo, p = 0.35). Two patients in the RT001 group experienced a serious AE, though unrelated to treatment. The least-squares mean difference in ALSFRS-R total score at week 24 of treatment was 1.90 (95% confidence interval = −1.39 to 5.19) in favor of RT001 (p = 0.25). The directions of other efficacy outcomes favored RT001 compared to placebo, although no inferential statistics were performed.

Conclusions

Initial data indicate that RT001 is safe and well tolerated. Given the exploratory nature of the study, a larger clinical trial is required to evaluate its efficacy.     

Liquid formulation of pentoxifylline is a poorly tolerated treatment for duchenne dystrophy

Introduction: In this study we performed an open‐label, pilot study of an orally administered liquid formulation of immediate‐release pentoxifylline (PTX) on patients with Duchenne muscular dystrophy (DMD). Treatment efficacy, safety, and tolerability were assessed. Methods: The tolerability and safety of PTX and measures of muscle strength and function were evaluated during 12 months of treatment. Results: Seventeen boys with DMD, between 4 and 8 years of age, were enrolled at one of five Cooperative International Neuromuscular Research Group (CINRG) centers. Only 9 were able to complete the 12‐month PTX treatment phase; the primary reason for discontinuation was adverse events. Intolerable gastrointestinal side effects were experienced by 65% of participants. Two participants had severe leukopenia that resolved with medication withdrawal. Conclusions: Open‐label treatment with a liquid formulation of immediate‐release PTX resulted in a high incidence of adverse events in boys with DMD. Poor tolerability of this PTX formulation precluded adequate assessment of efficacy. Muscle Nerve, 2011     

Randomized,double‐blind,pilot evaluation of intravenous glutathione in Parkinson's disease

The objective of this study was to evaluate the safety, tolerability, and preliminary efficacy of intravenous glutathione in Parkinson's disease (PD) patients. This was a randomized, placebo‐controlled, double‐blind, pilot trial in subjects with PD whose motor symptoms were not adequately controlled with their current medication regimen. Subjects were randomly assigned to receive intravenous glutathione 1,400 mg or placebo administered three times a week for 4 weeks. Twenty‐one subjects were randomly assigned, 11 to glutathione and 10 to placebo. One subject who was assigned to glutathione withdrew from the study for personal reasons prior to undergoing any postrandomization efficacy assessments. Glutathione was well tolerated and there were no withdrawals because of adverse events in either group. Reported adverse events were similar in the two groups. There were no significant differences in changes in Unified Parkinson's Disease Rating Scale (UPDRS) scores. Over the 4 weeks of study medication administration, UPDRS ADL + motor scores improved by a mean of 2.8 units more in the glutathione group (P = 0.32), and over the subsequent 8 weeks worsened by a mean of 3.5 units more in the glutathione group (P = 0.54). Glutathione was well tolerated and no safety concerns were identified. Preliminary efficacy data suggest the possibility of a mild symptomatic effect, but this remains to be evaluated in a larger study. © 2009 Movement Disorder Society     

Beneficial effects of intrathecal IGF-1 administration in patients with amyotrophic lateral sclerosis

Abstract

Objectives: There is currently no effective pharmacological treatment for amyotrophic lateral sclerosis (ALS). In a transgenic mouse model of ALS, intrathecal infusion of insulin-like growth factor (IGF)-1 showed a promising increase in survival. We performed a double-blind clinical trial to assess the effect of intrathecal administration of IGF-1 on disease progression in patients with ALS.

Methods: Nine patients with ALS were randomly assigned to receive either a high dose (3 μg/kg of body weight) or low dose (0.5 μg/kg of body weight) of IGF-1 every 2 weeks for 40 weeks. The outcome measurements were the rate of decline of bulbar and limb functions (Norris scales) and forced vital capacity.

Results: The high-dose treatment slowed a decline of motor functions of the ALS patients in total Norris and limb Norris scales, but not in bulbar Norris or vital capacity. The intrathecal administration of IGF-1 had a modest but significant beneficial effect in ALS patients without any serious adverse effects.

Discussion: Intrathecal IGF-1 treatment could provide an effective choice for ALS although further studies in more patients are needed to confirm its efficacy and optimize dosages of IGF-1.     

A trial of buspirone for anxiety in Parkinson's disease: Safety and tolerability

IntroductionIn Parkinson's disease (PD), anxiety is common, associated with lower health-related quality of life, and undertreated. The primary objective of this study was to determine the tolerability of buspirone for the treatment of anxiety in PD.MethodsIndividuals with PD and clinically significant anxiety were randomized 4:1 to flexible dosage buspirone or placebo for 12 weeks. Treatment was initiated at 7.5 mg twice daily and titrated based on response and tolerability to an optimal dosage (maximum 30 mg twice daily). The primary outcome was the proportion of participants who failed to complete the study on study drug. Secondary outcomes included adverse events, dosage reductions, motor function, dyskinesias, and anxiety.ResultsA total of 21 participants enrolled, 4 were randomized to placebo and 17 to buspirone (mean (SD) age 65.5 (9.8), 76.5% male, 88% on concomitant antidepressant or anxiolytic). In the buspirone group, 7 (41%) failed to complete the study on drug, 5 due to intolerability. The median buspirone dosage was 7.5 mg twice daily. No serious adverse events occurred. A total of 9 (53%) buspirone participants experienced adverse events consistent with worsened motor function. In the buspirone group, mean (SD) improvement from baseline to week 12 in Hamilton Anxiety Rating Scale was −3.9 (3.8) and Parkinson Anxiety Scale −7.1 (6.4).ConclusionTolerability concerns do not support moving immediately forward with a large-scale efficacy trial. However, concomitant anxiolytics may have affected tolerability and a signal of efficacy was seen suggesting that future studies of buspirone monotherapy be considered.     

Randomized controlled trial of memantine in dementia associated with Parkinson's disease

The objective of this study is to investigate the safety and tolerability of memantine, a glutamatergic modulator, in patients suffering from dementia associated with Parkinson's disease (PDD), an increasingly common complication of PD. This was a 22‐week trial of 25 participants with a DSM‐IV diagnosis of PDD who were randomized to either placebo or 20 mg/day of memantine. Memantine was well tolerated by participants at 20 mg/day dosing. No participant was withdrawn due to memantine‐related adverse events. Six weeks after drug withdrawal, a significantly greater proportion (P = 0.04) of memantine‐treated participants deteriorated globally compared with those treated with placebo. These findings suggest that continued treatment with memantine may be needed to maintain global level of functioning over time. Based on the findings of this pilot study, memantine is safe and very well‐tolerated in PDD. © 2009 Movement Disorder Society     

Significant CMAP decrement by repetitive nerve stimulation is more frequent in median than ulnar nerves of patients with amyotrophic lateral sclerosis

Introduction: Several studies have shown a significant amplitude decrement in compound muscle action potentials (CMAPs) on repetitive nerve stimulation (RNS) of muscles involved in amyotrophic lateral sclerosis (ALS).In ALS, muscle wasting preferentially affects the thenar muscles (APB) rather than the hypothenar muscles (ADM). Methods: We performed RNS studies in the APB and ADM muscles of 32 ALS patients to determine whether the effect of RNS differs between the median and ulnar nerves. Results: The decremental responses to RNS were greater in the APB than in the ADM. Reduced CMAP amplitude was negatively correlated with CMAP decrement in median but not in ulnar nerves. Conclusions: The greater CMAP decrement in median nerve is attributable to preferential involvement of the APB in the pathophysiology of ALS or some underlying difference in the biology of the two muscles/nerves. Further investigations will better our understanding of the pathophysiology of ALS. Muscle Nerve, 2012     

Tolerability and feasibility of at-home remotely supervised transcranial direct current stimulation (RS-tDCS): Single-center evidence from 6,779 sessions

IntroductionThe ability to deploy transcranial direct current stimulation (tDCS) at home is a key usability advantage to support scaling for pivotal clinical trials. We have established a home-based tDCS protocol for use in clinical trials termed remotely supervised (RS)-tDCS.ObjectiveTo report the tolerability and feasibility of tDCS sessions completed to date using RS-tDCS in clinical trials.MethodsWe analyzed tolerability (i.e., adverse events, AEs) reported in six Class I/II/III trials using RS-tDCS to study symptom outcomes over 10 to 60 daily applications. Across the six clinical trials, 308 participants (18–78 years old) completed an average of 23 sessions for a total of 6779 RS-tDCS administrations. The majority of participants were diagnosed with multiple sclerosis, and open-label trials included those diagnosed with a range of other conditions (e.g., Parkinson's disease, post-stroke aphasia, traumatic brain injury, cerebellar ataxia), with minimum-to-severe neurologic disability. Clinical trial feasibility (i.e., treatment fidelity and blinding integrity) was examined using two Class I randomized controlled trials (RCTs).ResultsNo serious AEs occurred. Across administrations, three sessions (0.04%) were aborted due to discomfort, but no participant discontinued due to tolerability. The AEs most commonly reported by participants were tingling (68%), itching (41%) and warmth sensation (42%) at the electrode site, and these were equally reported in active and sham tDCS conditions. The two Class I RCTs resulted in rapid enrollment, high fidelity to treatment completion, and blinding integrity.ConclusionsAt-home RS-tDCS is tolerable, including when used over extended periods of time. Home-based RS-tDCS is feasible and can enable Class I tDCS clinical trial designs.     

Clinical trial of L‐Carnitine and valproic acid in spinal muscular atrophy type I

Introduction: The aim of this study was to determine the safety and therapeutic potential of L ‐carnitine and valproic acid (VPA) in infants with spinal muscular atrophy (SMA). Methods: Our investigation was an open‐label phase 2 multicenter trial of L ‐carnitine and VPA in infants with SMA type I with retrospective comparison to an untreated, matched cohort. Primary outcomes were: safety and adverse events; secondary outcomes were survival, time to death/>16 hours/day of ventilator support; motor outcomes; and maximum ulnar compound motor action potential amplitude. Results: A total of 245 AEs were observed in 35 of the 37 treated subjects (95%). Respiratory events accounted for 49% of all adverse events, resulting in 14 deaths. Survival was not significantly different between treated and untreated cohorts. Discussion: This trial provides evidence that, in infants with SMA type I, L ‐carnitine/VPA is ineffective at altering survival. The substantial proportion of infants reaching end‐points within 6 months of enrollment underscores the urgent need for pre‐symptomatic treatment in SMA type I. Muscle Nerve 57 : 193–199, 2018     

Intravenous Ketamine for Late-Life Treatment-Resistant Depression: A Pilot Study of Tolerability,Safety, Clinical Benefits,and Effect on Cognition

ObjectiveEvidence-based treatment options for late-life treatment-resistant depression (TRD) are limited. Ketamine is a promising treatment for TRD; however, there is a paucity of data on its safety and efficacy in older adults.MethodsIn this pilot clinical trial, 25 adults aged ≥60 years with TRD received IV ketamine openly twice a week for 4 weeks; partial responders at the end of this acute phase were eligible to receive weekly infusions for 4 more weeks in a continuation phase. Acceptability, tolerability, and safety, including adverse and serious adverse events (AEs and SAEs), blood pressure changes, dissociation, craving, in addition to rates of depression response and remission were evaluated. The NIH Toolbox Cognitive Battery was used to assess specific measures of executive function (EF) and overall fluid cognition.ResultsCompletion rates were 88% for the acute phase and 100% for the continuation phase. No AEs resulted in participant discontinuation, and there were no SAEs. Treatment-emergent elevation of blood pressure, dissociation, and craving were transient and did not result in any participant discontinuation. Depressive symptoms improved significantly and 48% of participants responded. During the acute phase, the EF measures and the fluid cognition composite score improved (Cohen's d = 0.61), and these improvements were sustained in the continuation phase.ConclusionThis pilot study suggests that repeated IV ketamine infusions are well-tolerated and are associated with improvement in depression and EF in older adults with TRD. These promising findings need to be confirmed and extended in a larger randomized controlled trial.     

Autologous mesenchymal stem cells: clinical applications in amyotrophic lateral sclerosis

Abstract

Objectives: Our study was aimed to evaluate the feasibility and safety of intraspinal cord implantation of autologous mesenchymal stem cells (MSCs) in a few well-monitored amyotrophic lateral sclerosis (ALS) patients.

Methods: Seven patients affected by definite ALS were enrolled in the study and two patients were treated for compassionate use and monitored for at least 3 years. Bone marrow was collected from the posterior iliac crest according to the standard procedure and MSCs were expanded ex vivo according to Pittenger's protocol. The cells were suspended in 2 ml autologous cerebrospinal fluid and transplanted into the spinal cord by a micrometric pump injector.

Results: The in vitro expanded MSCs did not show any bacterial o fungal contamination, hemopoietic cell contamination, chromosomic alterations and early cellular senescence. No patient manifested major adverse events such as respiratory failure or death. Minor adverse events were intercostal pain irradiation and leg sensory dysesthesia, both reversible after a mean period of 6 weeks. No modification of the spinal cord volume or other signs of abnormal cell proliferation were observed. A significant slowing down of the linear decline of the forced vital capacity was evident in four patients 36 months after MSCs transplantation.

Conclusions: Our results demonstrate that direct injection of autologous expanded MSCs into the spinal cord of ALS patients is safe, with no significant acute or late toxicity, and well tolerated. The clinical results seem to be encouraging.     

Clonidine for attention-deficit/hyperactivity disorder: II. ECG changes and adverse events analysis

OBJECTIVE: To examine the safety and tolerability of clonidine used alone or with methylphenidate in children with attention-deficit/hyperactivity disorder (ADHD). METHOD: In a 16-week multicenter, double-blind trial, 122 children with ADHD were randomly assigned to clonidine (n = 31), methylphenidate (n = 29), clonidine and methylphenidate (n = 32), or placebo (n = 30). Doses were flexibly titrated up to 0.6 mg/day for clonidine and 60 mg/day for methylphenidate (both with divided dosing). Groups were compared regarding adverse events and changes from baseline to week 16 in electrocardiograms and vital signs. RESULTS: There were more incidents of bradycardia in subjects treated with clonidine compared with those not treated with clonidine (17.5% versus 3.4%; p =.02), but no other significant group differences regarding electrocardiogram and other cardiovascular outcomes. There were no suggestions of interactions between clonidine and methylphenidate regarding cardiovascular outcomes. Moderate or severe adverse events were more common in subjects on clonidine (79.4% versus 49.2%; p =.0006) but not associated with higher rates of early study withdrawal. Drowsiness was common on clonidine, but generally resolved by 6 to 8 weeks. CONCLUSIONS: Clonidine, used alone or with methylphenidate, appears safe and well tolerated in childhood ADHD. Physicians prescribing clonidine should monitor for bradycardia and advise patients about the high likelihood of initial drowsiness.     

Thalidomide causes sinus bradycardia in ALS

Objective Neuroinflammation contributes to motor neuron degeneration in ALS. Thalidomide (THL) shows potent anti-inflammatory properties and increased the lifespan in ALS transgenic mice. Thalidomide was therefore suggested as atherapeutic intervention for the treatment of ALS.We conducted a pilot, randomized clinical trial of THL in patients with ALS to assess safety, feasibility, and preliminary estimates of treatment efficacy. Methods Patients were randomized to THL in combination with riluzole (n = 18) or riluzole alone (n = 19). THL was initiated at 100 mg per day for 6 weeks. Thereafter, the dose was increased every week by 50 mg until reaching the dose of 400 mg per day and planned to continue for another 12 weeks. Results Within 12 weeks of THL treatment, nine THL patients (50%) developed bradycardia defined as a heart rate below 60 beats per minute (bpm) and ranged from 46 to 59 bpm. Mean heart rate dropped by 17 bpm with THL treatment. Severe symptomatic bradycardia of 30 bpm occurred in one patient. A further patient died from sudden unexpected death. The study was terminated prematurely for safety concerns. The secondary outcome variables showed similar results for both groups. Conclusion Bradycardia was the most common adverse event of THL treatment in ALS. THL-related bradycardia does not appear to be ALS-specific. It is conceivable, however, that the unexpected frequency and severity of THL-induced bradycardia may be related to subclinical involvement of the autonomic nervous system in ALS. The cardiac toxicity discourages further clinical trials and compassionate use of THL in ALS. ClinicalTrials.gov Identifier: NCT00231140. Disclosures Dr. Meyer reports receiving grant support from Pharmion Germany, support for clinical trials through research support by contract to his institution from Eli Lilly, TEVA Pharmaceuticals, Novartis, ONO Pharmaceuticals, and ExonHit, and speaking fees from TEVA Pharmaceuticals, fees for attending advisory board from Celgene, and consulting fees from Merz Pharmaceuticals. Dr. Münch reports receiving support for clinical trials through research support by contract to his institution from Bayer and Genzyme, and fees for consulting and attending advisory board from Genzyme.     

Vagus nerve stimulation in children with intractable epilepsy: a randomized controlled trial

Aim The aim of this study was to evaluate the effects of vagus nerve stimulation (VNS) in children with intractable epilepsy on seizure frequency and severity and in terms of tolerability and safety. Method In this study, the first randomized active controlled trial of its kind in children, 41 children (23 males; 18 females; mean age at implantation 11y 2mo, SD 4y 2mo, range 3y 10mo–17y 8mo) were included. Thirty‐five participants had localization‐related epilepsy (25 symptomatic; 10 cryptogenic), while six participants had generalized epilepsy (four symptomatic; two idiopathic). During a baseline period of 12 weeks, seizure frequency and severity were recorded using seizure diaries and the adapted Chalfont Seizure Severity Scale (NHS3), after which the participants entered a blinded active controlled phase of 20 weeks. During this phase, half of the participants received high‐output VNS (maximally 1.75mA) and the other half received low‐output stimulation (0.25mA). Finally, all participants received high‐output stimulation for 19 weeks. For both phases, seizure frequency and severity were assessed as during the baseline period. Overall satisfaction and adverse events were assessed by semi‐structured interviews. Results At the end of the randomized controlled blinded phase, seizure frequency reduction of 50% or more occurred in 16% of the high‐output stimulation group and in 21% of the low‐output stimulation group (p=1.00). There was no significant difference in the decrease in seizure severity between participants in the stimulation groups. Overall, VNS reduced seizure frequency by 50% or more in 26% of participants at the end of the add‐on phase The overall seizure severity also improved (p<0.001). Interpretation VNS is a safe and well‐tolerated adjunctive treatment of epilepsy in children. Our results suggest that the effect of VNS on seizure frequency in children is limited. However, the possible reduction in seizure severity and improvement in well‐being makes this treatment worth considering in individual children with intractable epilepsy.     

A Double-Blind,Randomized, Placebo-Controlled Trial of Ursodeoxycholic Acid (UDCA) in Parkinson's Disease

Background

Rescue of mitochondrial function is a promising neuroprotective strategy for Parkinson's disease (PD). Ursodeoxycholic acid (UDCA) has shown considerable promise as a mitochondrial rescue agent across a range of preclinical in vitro and in vivo models of PD.

Objectives

To investigate the safety and tolerability of high-dose UDCA in PD and determine midbrain target engagement.

Methods

The UP (UDCA in PD) study was a phase II, randomized, double-blind, placebo-controlled trial of UDCA (30 mg/kg daily, 2:1 randomization UDCA vs. placebo) in 30 participants with PD for 48 weeks. The primary outcome was safety and tolerability. Secondary outcomes included 31-phosphorus magnetic resonance spectroscopy (³¹P-MRS) to explore target engagement of UDCA in PD midbrain and assessment of motor progression, applying both the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) and objective, motion sensor-based quantification of gait impairment.

Results

UDCA was safe and well tolerated, and only mild transient gastrointestinal adverse events were more frequent in the UDCA treatment group. Midbrain ³¹P-MRS demonstrated an increase in both Gibbs free energy and inorganic phosphate levels in the UDCA treatment group compared to placebo, reflecting improved ATP hydrolysis. Sensor-based gait analysis indicated a possible improvement of cadence (steps per minute) and other gait parameters in the UDCA group compared to placebo. In contrast, subjective assessment applying the MDS-UPDRS-III failed to detect a difference between treatment groups.

Conclusions

High-dose UDCA is safe and well tolerated in early PD. Larger trials are needed to further evaluate the disease-modifying effect of UDCA in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

An open-label, dose-titration tolerability study of atomoxetine hydrochloride in Japanese adults with attention-deficit/hyperactivity disorder

Aims: The main purpose of this first atomoxetine study in Japanese adults with attention‐deficit/hyperactivity disorder (ADHD) was to investigate the tolerability of an 8‐week treatment regimen. Methods: This was an open‐label, dose escalation study conducted in 45 Japanese patients aged at least 18 years with DSM‐IV‐defined ADHD. Patients received atomoxetine orally for 8 weeks. Atomoxetine administration was started at 40 mg/day (7 days), and subsequently increased to a maximum dose of 120 mg/day. Tolerability was assessed by discontinuation rate due to adverse events. Adverse events, laboratory tests, vital signs and electrocardiograms were collected. In addition, ADHD symptoms were assessed by using the Japanese version of the Conners' Adult ADHD Rating Scale‐Investigator Rated: Screening Version (CAARS‐Inv:SV) scores. Results: Thirty‐nine patients completed the study period. Atomoxetine was well tolerated with a 6.7% (3/45) discontinuation rate due to nausea, malaise and anorexia. The most commonly reported adverse events were nausea, nasopharyngitis and headache; there were no unexpected safety concerns. No deaths or serious adverse events were reported. Mean CAARS‐Inv:SV‐J total ADHD symptom scores decreased in a time‐dependent manner; the mean change from baseline to endpoint was ?15.0 (P < 0.001). Conclusions: This study showed that atomoxetine was well tolerated in these patients and suggested that atomoxetine at a maximum dose of 120 mg/day would be safe in Japanese ADHD patients.     

Pre‐morbid type 2 diabetes mellitus is not a prognostic factor in amyotrophic lateral sclerosis

Introduction: The aim of this study was to determine whether a history of pre‐morbid type 2 diabetes mellitus (DM2) is a prognostic factor in amyotrophic lateral sclerosis (ALS). Methods: The relationship between DM2 and survival was analyzed in a study population consisting of 1,322 participants from 6 clinical trials. Results: Survival did not differ by diabetes status (log‐rank test, P = 0.98), but did differ by body mass index (BMI) (log‐rank test, P = 0.008). In multivariate analysis, there was no significant association between diabetes and survival (P = 0.18), but the risk of reaching a survival endpoint decreased by 4% for each unit increase in baseline BMI (HR 0.96, 95% CI 0.94–0.99, P = 0.001). DM2 was less prevalent among ALS clinical trial participants than predicted. Conclusions: A history of pre‐morbid DM2 is not an independent prognostic factor in ALS clinical trial databases. The low DM2 prevalence rate should be examined in a large, prospective study to determine whether DM2 affects ALS risk. Muscle Nerve 52:339–343, 2015     

Intravenous lacosamide as replacement for oral lacosamide in patients with partial-onset seizures

PURPOSE: This multicenter, double-blind, double-dummy, randomized, inpatient trial evaluated the safety, tolerability, and pharmacokinetics of intravenous lacosamide as replacement for oral lacosamide in patients with partial-onset seizures. METHODS: Patients were enrolled from an ongoing open-label extension trial of oral lacosamide and randomized (2:1) to either intravenous lacosamide and oral placebo or intravenous placebo and oral lacosamide. During the 2-day inpatient treatment period, patients received twice-daily doses of lacosamide equivalent to their current daily dose of oral lacosamide. The first 30 patients enrolled received infusions with 60-min durations and the next 30 received infusions with 30-min durations. RESULTS: Of 60 patients randomized, 59 completed the trial. Treatment-emergent adverse events (AEs) were reported by 16 patients and included dizziness, headache, back pain, somnolence, and injection site pain. The tolerability profile of intravenous lacosamide was consistent with that of oral lacosamide. All AEs were considered mild or moderate in intensity, and no serious AEs or AEs leading to withdrawal were reported. CONCLUSIONS: Intravenous lacosamide, administered as 60- or 30-min twice-daily infusions, showed a similar safety and tolerability profile to oral lacosamide when used as replacement therapy. Results from this trial support further investigation of intravenous lacosamide at shorter infusion durations.