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Efficacy and safety of memantine in children with autism spectrum disorder: Results from three phase 2 multicenter studies.
Hardan, AY, Hendren, RL, Aman, MG, Robb, A, Melmed, RD, Andersen, KA, Luchini, R, Rahman, R, Ali, S, Jia, XD, et al
Autism : the international journal of research and practice. 2019;(8):2096-2111
Abstract
Three phase 2 trials were conducted to assess the efficacy and long-term safety of weight-based memantine extended release (ER) treatment in children with autism spectrum disorder. MEM-MD-91, a 50-week open-label trial, identified memantine extended-release treatment responders for enrollment into MEM-MD-68, a 12-week randomized, double-blind, placebo-controlled withdrawal trial. MEM-MD-69 was an open-label extension trial in which participants from MEM-MD-68, MEM-MD-91, and open-label trial MEM-MD-67 were treated ⩽48 weeks with memantine extended release. In MEM-MD-91, 517 (59.6%) participants were confirmed Social Responsiveness Scale responders at week 12; mean Social Responsiveness Scale total raw scores improved two to three times a minimal clinically important difference of 10 points. In MEM-MD-68, there was no difference between memantine and placebo on the primary efficacy parameter, the proportion of patients with a loss of therapeutic response (defined as ⩾10-point increase from baseline in Social Responsiveness Scale total raw score). MEM-MD-69 exploratory analyses revealed mean standard deviation improvement in Social Responsiveness Scale total raw score of 32.4 (26.4) from baseline of the first lead-in study. No new safety concerns were evident. While the a priori-defined efficacy results of the double-blind trial were not achieved, the considerable improvements in mean Social Responsiveness Scale scores from baseline in the open-label trials were presumed to be clinically important.
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Stage at which riluzole treatment prolongs survival in patients with amyotrophic lateral sclerosis: a retrospective analysis of data from a dose-ranging study.
Fang, T, Al Khleifat, A, Meurgey, JH, Jones, A, Leigh, PN, Bensimon, G, Al-Chalabi, A
The Lancet. Neurology. 2018;(5):416-422
Abstract
BACKGROUND Riluzole is the only drug to prolong survival for amyotrophic lateral sclerosis (ALS) and, at a dose of 100 mg, was associated with a 35% reduction in mortality in a clinical trial. A key question is whether the survival benefit occurs at an early stage of disease, late stage, or is spread throughout the course of the disease. To address this question, we used the King's clinical staging system to do a retrospective analysis of data from the original dose-ranging clinical trial of riluzole. METHODS In the original dose-ranging trial, patients were enrolled between December, 1992, and November, 1993, in Belgium, France, Germany, Spain, Canada, the USA, and the UK if they had probable or definite ALS as defined by the El Escorial criteria. The censor date for the riluzole survival data was set as the original study end date of Dec 31, 1994. For this analysis, King's clinical ALS stage was estimated from the electronic case record data of the modified Norris scale, UK Medical Research Council score for muscle strength, El Escorial category, vital capacity, and gastrostomy insertion data. The lowest allocated stage was 2 because the original trial only included patients with probable or definite ALS. We used a χ2 test to assess the independence of stage at trial enrolment and treatment group, Kaplan-Meier product limit distribution to test the transition from each stage to subsequent stages, and Cox regression to confirm an effect of treatment group on time in stage, controlling for covariates. We did sensitivity analyses by combining treatment groups, using alternative strategies to stage, stratifying by stage at trial enrolment, and using multistate outcome analysis of treatments (MOAT). FINDINGS We analysed the case records of all 959 participants from the original dose-ranging trial, 237 assigned to 50 mg/day riluzole, 236 to 100 mg/day, 244 to 200 mg/day, and 242 to daily placebo. Clinical stage at enrolment did not significantly differ between treatment groups (p=0·22). Time in stage 4 was longer for patients receiving 100 mg/day riluzole than for those receiving placebo (hazard ratio [HR] 0·55, 95% CI 0·36-0·83; log-rank p=0·037). Combining treatment groups and stratifying by stage at enrolment showed a similar result (HR 0·638, 95% CI 0·464-0·878; p=0·006), as did analysis with MOAT where the mean number of days spent in stage 4 was numerically higher for patients given riluzole at higher doses compared with patients receiving placebo. Time from stages 2 or 3 to subsequent stages or death did not differ between riluzole treatment groups and placebo (p=0·83 for stage 2 and 0·88 for stage 3). INTERPRETATION We showed that riluzole prolongs survival in the last clinical stage of ALS; this finding needs to be confirmed in a prospective study, and treatment effects at stage 1 still need to be analysed. The ALS stage at which benefit occurs is important for counselling of patients before starting treatment. Staging should be used in future ALS clinical trials to assess the stage at which survival benefit occurs, and a similar approach could be used for other neurodegenerative diseases. FUNDING NIHR Maudsley Biomedical Research Centre, The European Union Joint Programme on Neurodegeneration, and the King's Summer Undergraduate Studentship.
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Effect of concomitant use of memantine on mortality and efficacy outcomes of galantamine-treated patients with Alzheimer's disease: post-hoc analysis of a randomized placebo-controlled study.
Hager, K, Baseman, AS, Nye, JS, Brashear, HR, Han, J, Sano, M, Davis, B, Richards, HM
Alzheimer's research & therapy. 2016;(1):47
Abstract
BACKGROUND A large, prospective, 2-year, randomized study in patients with mild-to-moderate Alzheimer's disease or mixed dementia demonstrated reductions in mortality and cognitive/functional decline in galantamine-treated patients. A post-hoc analysis was conducted to study the effect of (the presence or absence of) concomitant memantine use on treatment outcome. METHODS Randomized patients (N = 2045) were divided into subgroups based on memantine use. Analyses included demographic and clinical characteristics (age, nursing home placement, Mini-Mental State Examination (MMSE) and Disability Assessment for Dementia (DAD) scores) and mortality endpoints. RESULTS Overall, 496 (24.3 %) patients were memantine users and were older (mean (SD), 74.0 (8.76) vs 72.8 (8.76), p = 0.008), with lower MMSE scores (18.2 (4.16) vs 19.2 (4.02), p < 0.0001) and DAD scores (58.0 (23.49) vs 62.5 (20.52), p < 0.0001) than nonusers. Mortality rates (per 100 patient-years) in memantine nonusers (n = 1549) were lower for galantamine (1.39) vs placebo-treated patients (4.15). In memantine users, mortality rates were similar for placebo-treated (4.49) and galantamine-treated patients (5.57). In memantine nonusers at 24 months, the decline in MMSE scores (effect size (95 % CI) 0.25 (0.14; 0.36)) and DAD scores (0.17 (0.06; 0.28)) from baseline was lower in galantamine patients vs placebo patients. The absence of these benefits in memantine users could not be explained by baseline age, MMSE, or DAD scores. CONCLUSION This post-hoc analysis shows that the beneficial effects of galantamine at 2 years post treatment were not observed in patients who had been placed on background memantine. The reasons for memantine treatment and the possibility of interaction between memantine and galantamine merit further investigation. TRIAL REGISTRATION ClinicalTrials.gov NCT00679627 . Registered 15 May 2008.
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Study protocol for the randomised controlled trial: Ketamine augmentation of ECT to improve outcomes in depression (Ketamine-ECT study).
Trevithick, L, McAllister-Williams, RH, Blamire, A, Branton, T, Clark, R, Downey, D, Dunn, G, Easton, A, Elliott, R, Ellwell, C, et al
BMC psychiatry. 2015;:257
Abstract
BACKGROUND There is a robust empirical evidence base supporting the acute efficacy of electroconvulsive therapy (ECT) for severe and treatment resistant depression. However, a major limitation, probably contributing to its declining use, is that ECT is associated with impairment in cognition, notably in anterograde and retrograde memory and executive function. Preclinical and preliminary human data suggests that ketamine, used either as the sole anaesthetic agent or in addition to other anaesthetics, may reduce or prevent cognitive impairment following ECT. A putative hypothesis is that ketamine, through antagonising glutamate receptors, protects from excess excitatory neurotransmitter stimulation during ECT. The primary aim of the ketamine-ECT study is to investigate whether adjunctive ketamine can attenuate the cognitive impairment caused by ECT. Its secondary aim is to examine if ketamine increases the speed of clinical improvement with ECT. METHODS/DESIGN The ketamine ECT study is a multi-site randomised, placebo-controlled, double blind trial. It was originally planned to recruit 160 moderately to severely depressed patients who had been clinically prescribed ECT. This recruitment target was subsequently revised to 100 patients due to recruitment difficulties. Patients will be randomly allocated on a 1:1 basis to receive either adjunctive ketamine or saline in addition to standard anaesthesia for ECT. The primary neuropsychological outcome measure is anterograde verbal memory (Hopkins Verbal Learning Test-Revised delayed recall task) after 4 ECT treatments. Secondary cognitive outcomes include verbal fluency, autobiographical memory, visuospatial memory and digit span. Efficacy is assessed using observer and self-report efficacy measures of depressive symptomatology. The effects of ECT and ketamine on cortical activity during cognitive tasks will be studied in a sub-sample using functional near-infrared spectroscopy (fNIRS). DISCUSSION The ketamine-ECT study aims to establish whether or not adjunctive ketamine used together with standard anaesthesia for ECT will significantly reduce the adverse cognitive effects observed after ECT. Potential efficacy benefits of increased speed of symptom improvement and a reduction in the number of ECT treatments required will also be assessed, as will safety and tolerability of adjunctive ketamine. This study will provide important evidence as to whether adjunctive ketamine is routinely indicated for ECT given for depression in routine NHS clinical practice. TRIAL REGISTRATION Current Controlled Trials: ISRCTN14689382 (assigned 30/07/2012); EudraCT Number: 2011-005476-41.
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The Effect of Memantine on Cognitive Function and Behavioral and Psychological Symptoms in Mild-to-Moderate Alzheimer's Disease Patients.
Zhang, N, Wei, C, Du, H, Shi, FD, Cheng, Y
Dementia and geriatric cognitive disorders. 2015;(1-2):85-93
Abstract
BACKGROUND/AIMS: Memantine has been approved by the Food and Drug Administration for the treatment of moderate-to-severe Alzheimer's disease (AD). However, the effect of memantine on patients with mild-to-moderate AD is unclear. METHODS This study is a post hoc analysis of a double-blind clinical trial. Donepezil was used as the standard control treatment. Outcomes included score changes from baseline to week 24 on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog), a modified 20-item Activities of Daily Living Scale (ADL), the Neuropsychiatric Inventory (NPI), and the Mini-Mental State Examination (MMSE) as well as the score of the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-Plus). RESULTS One hundred sixty-seven AD patients with an MMSE score of 10-24 were analyzed. No significant differences in the score changes from baseline to week 24 on all outcomes or the four subscales of the ADAS-cog were observed between the two treatment groups. Donepezil resulted in an improved score for naming ability on the ADAS-cog compared to memantine (p = 0.036), whereas memantine more effectively reduced agitation as measured by the NPI compared to donepezil (p = 0.039). CONCLUSION These findings support the efficacy of memantine for the treatment of mild-to-moderate AD, especially in patients with agitation.
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Memantine improves attention and episodic memory in Parkinson's disease dementia and dementia with Lewy bodies.
Wesnes, KA, Aarsland, D, Ballard, C, Londos, E
International journal of geriatric psychiatry. 2015;(1):46-54
Abstract
OBJECTIVE In both dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), attentional dysfunction is a core clinical feature together with disrupted episodic memory. This study evaluated the cognitive effects of memantine in DLB and PDD using automated tests of attention and episodic memory. METHODS A randomised double-blind, placebo-controlled, 24-week three centre trial of memantine (20 mg/day) was conducted in which tests of attention (simple and choice reaction time) and word recognition (immediate and delayed) from the CDR System were administered prior to dosing and again at 12 and 24 weeks. Although other results from this study have been published, the data from the CDR System tests were not included and are presented here for the first time. RESULTS Data were available for 51 patients (21 DLB and 30 PDD). In both populations, memantine produced statistically significant medium to large effect sized improvements to choice reaction time, immediate and delayed word recognition. CONCLUSIONS These are the first substantial improvements on cognitive tests of attention and episodic recognition memory identified with memantine in either DLB or PDD.
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An open-label multicenter study to assess the safety of dextromethorphan/quinidine in patients with pseudobulbar affect associated with a range of underlying neurological conditions.
Pattee, GL, Wymer, JP, Lomen-Hoerth, C, Appel, SH, Formella, AE, Pope, LE
Current medical research and opinion. 2014;(11):2255-65
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Abstract
BACKGROUND Pseudobulbar affect (PBA) is associated with neurological disorders or injury affecting the brain, and characterized by frequent, uncontrollable episodes of crying and/or laughing that are exaggerated or unrelated to the patient's emotional state. Clinical trials establishing dextromethorphan and quinidine (DM/Q) as PBA treatment were conducted in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). This trial evaluated DM/Q safety in patients with PBA secondary to any neurological condition affecting the brain. OBJECTIVE To evaluate the safety and tolerability of DM/Q during long-term administration to patients with PBA associated with multiple neurological conditions. METHODS Fifty-two-week open-label study of DM/Q 30/30 mg twice daily. Safety measures included adverse events (AEs), laboratory tests, electrocardiograms (ECGs), vital signs, and physical examinations. CLINICAL TRIAL REGISTRATION #NCT00056524. RESULTS A total of 553 PBA patients with >30 different neurological conditions enrolled; 296 (53.5%) completed. The most frequently reported treatment-related AEs (TRAEs) were nausea (11.8%), dizziness (10.5%), headache (9.9%), somnolence (7.2%), fatigue (7.1%), diarrhea (6.5%), and dry mouth (5.1%). TRAEs were mostly mild/moderate, generally transient, and consistent with previous controlled trials. Serious AEs (SAEs) were reported in 126 patients (22.8%), including 47 deaths, mostly due to ALS progression and respiratory failure. No SAEs were deemed related to DM/Q treatment by investigators. ECG results suggested no clinically meaningful effect of DM/Q on myocardial repolarization. Differences in AEs across neurological disease groups appeared consistent with the known morbidity of the primary neurological conditions. Study interpretation is limited by the small size of some disease groups, the lack of a specific efficacy measure and the use of a DM/Q dose higher than the eventually approved dose. CONCLUSIONS DM/Q was generally well tolerated over this 52 week trial in patients with PBA associated with a wide range of neurological conditions.
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Vitamin E and memantine in Alzheimer's disease: clinical trial methods and baseline data.
Dysken, MW, Guarino, PD, Vertrees, JE, Asthana, S, Sano, M, Llorente, M, Pallaki, M, Love, S, Schellenberg, GD, McCarten, JR, et al
Alzheimer's & dementia : the journal of the Alzheimer's Association. 2014;(1):36-44
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BACKGROUND Alzheimer's disease (AD) has been associated with both oxidative stress and excessive glutamate activity. A clinical trial was designed to compare the effectiveness of (i) alpha-tocopherol, a vitamin E antioxidant; (ii) memantine (Namenda), an N-methyl-D-aspartate antagonist; (iii) their combination; and (iv) placebo in delaying clinical progression in AD. METHODS The Veterans Affairs Cooperative Studies Program initiated a multicenter, randomized, double-blind, placebo-controlled trial in August 2007, with enrollment through March 2012 and follow-up continuing through September 2012. Participants with mild-to-moderate AD who were taking an acetylcholinesterase inhibitor were assigned randomly to 2000 IU/day of alpha-tocopherol, 20 mg/day memantine, 2000 IU/day alpha-tocopherol plus 20 mg/day memantine, or placebo. The primary outcome for the study is the Alzheimer's Disease Cooperative Study/Activities of Daily Living Inventory. Secondary outcome measures include the Mini-Mental State Examination; the Alzheimer's Disease Assessment Scale, cognitive portion; the Dependence Scale; the Neuropsychiatric Inventory; and the Caregiver Activity Survey. Patient follow-up ranged from 6 months to 4 years. RESULTS A total of 613 participants were randomized. The majority of the patients were male (97%) and white (86%), with a mean age of 79 years. The mean Alzheimer's Disease Cooperative Study/Activities of Daily Living Inventory score at entry was 57 and the mean Mini-Mental State Examination score at entry was 21. CONCLUSION This large multicenter trial will address the unanswered question of the long-term safety and effectiveness of alpha-tocopherol, memantine, and their combination in patients with mild-to-moderate AD taking an acetylcholinesterase inhibitor. The results are expected in early 2013.
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Efficacy of memantine in the treatment of fibromyalgia: A double-blind, randomised, controlled trial with 6-month follow-up.
Olivan-Blázquez, B, Herrera-Mercadal, P, Puebla-Guedea, M, Pérez-Yus, MC, Andrés, E, Fayed, N, López-Del-Hoyo, Y, Magallon, R, Roca, M, Garcia-Campayo, J
Pain. 2014;(12):2517-2525
Abstract
Fibromyalgia (FM) is a prevalent and disabling chronic disease. Recent studies have found elevated levels of glutamate in several brain regions, leading to hypotheses about the usefulness of glutamate-blocking drugs such as memantine in the treatment of FM. The aim of this study was to evaluate the efficacy of memantine in the treatment of pain and other clinical variables (global function, clinical impression, depression, anxiety, quality of life) in FM patients. A double-blind, parallel randomised controlled trial was developed. A total of 63 patients diagnosed with FM were recruited from primary health care centres in Zaragoza, Spain. Memantine was administered at doses of 20mg/d after 1 month of titration. Assessments were carried out at baseline, posttreatment, and 3- and 6-month follow-up. Compared with a placebo group, memantine significantly decreased ratings on a pain visual analogue scale (Cohen's d=1.43 at 6 months) and pain measured with a sphygmomanometer (d=1.05). All other secondary outcomes except anxiety also improved, with moderate-to-large effect sizes at 6 months. Compared with placebo, the absolute risk reduction obtained with memantine was 16.13% (95% confidence interval=2.0% to 32.6%), and the number needed to treat was 6.2 (95% confidence interval=3 to 47). Tolerance was good, with dizziness (8 patients) and headache (4 patients) being the most frequent side effects of memantine. Although additional studies with larger sample sizes and longer follow-up times are needed, this study provides preliminary evidence of the utility of memantine for the treatment of FM.
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Memantine in patients with frontotemporal lobar degeneration: a multicentre, randomised, double-blind, placebo-controlled trial.
Boxer, AL, Knopman, DS, Kaufer, DI, Grossman, M, Onyike, C, Graf-Radford, N, Mendez, M, Kerwin, D, Lerner, A, Wu, CK, et al
The Lancet. Neurology. 2013;(2):149-56
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BACKGROUND Memantine has been used off-label to treat frontotemporal lobar degeneration (FTD). A previous 26-week open-label study suggested a transient, modest benefit on neuropsychiatric symptoms as measured by the neuropsychiatric inventory (NPI). We aimed to determine whether memantine is an effective treatment for FTD. METHODS We did a randomised, parallel group, double-blind, placebo-controlled trial of 20 mg memantine taken orally daily for 26 weeks in patients with FTD. Participants met Neary criteria for behavioural variant FTD (bvFTD) or semantic dementia and had characteristic brain atrophy. Use of acetylcholinesterase inhibitors was prohibited. Individuals were randomly assigned to receive either memantine or matched placebo tablets (1:1) in blocks of two and four patients. All patients and study personnel were masked to treatment assignment. Primary endpoints were the change in total NPI score and clinical global impression of change (CGIC) score after 26 weeks and were analysed by intention to treat. This study is registered with Clinicaltrials.gov, number NCT00545974. FINDINGS Of 100 patients screened, 81 were randomly assigned to receive memantine (39 patients) or placebo (42 patients). Five (6%) patients discontinued, and 76 completed the 26-week treatment. Enrolment numbers were lower than planned because of many patients' preference to take memantine or cholinesterase inhibitors off-label rather than participate in a clinical trial. Memantine treatment had no effect on either the NPI (mean difference 2·2, 95% CI -3·9 to 8·3, p=0·47) or CGIC (mean difference 0·0, -0·4 to 0·4, p=0·90) after 26 weeks of treatment. Memantine was generally well tolerated; however, patients in the memantine group had more frequent cognitive adverse events (six patients) than those in the placebo group (one). INTERPRETATION Memantine treatment showed no benefit in patients with FTD. These data do not support memantine use in FTD. FUNDING Forest Research Institute.