Adaptive trial designs for spinal cord injury clinical trials directed to the central nervous system.

STUDY DESIGN: Narrative review. PURPOSE: To provide an overview of adaptive trial designs, and describe how adaptive methods can address persistent challenges encountered by randomized controlled trials of people with spinal cord injury (SCI). RESULTS: With few exceptions, adaptive methodologies have not been incorporated into clinical trial designs of people with SCI. Adaptive methods provide an opportunity to address high study costs, slow recruitment, and excessive amount of time needed to carry out the trial. The availability of existing SCI registries are well poised to support modeling and simulation, both of which are used extensively in adaptive trial designs. Eight initiatives for immediate advancement of adaptive methods in SCI were identified. CONCLUSION: Although successfully applied in other fields, adaptive clinical trial designs in SCI clinical trial programs have been narrow in scope and few in number. Immediate application of several adaptive methods offers opportunity to improve efficiency of SCI trials. Concerted effort is needed by all stakeholders to advance adaptive clinical trial design methodology in SCI.

The challenge of recruitment for neurotherapeutic clinical trials in spinal cord injury.

STUDY DESIGN: Narrative review by individuals experienced in the recruitment of participants to neurotherapeutic clinical trials in spinal cord injury (SCI). OBJECTIVES: To identify key problems of recruitment and explore potential approaches to overcoming them. METHODS: Published quantitative experience with recruitment of large-scale, experimental neurotherapeutic clinical studies targeting central nervous system and using primary outcome assessments validated for SCI over the last 3 decades was summarized. Based on this experience, potential approaches to improving recruitment were elicited from the authors. RESULTS: The rate of recruitment has varied between studies, depending on protocol design and other factors, but particularly inclusion/exclusion criteria. The recruitment rate also ranged over an order of magnitude between individual centers in a given study. In older multicenter studies, average recruitment rate was approximately one person per study center per month. More recent trials experienced lower rates of recruitment and potential reasons for this trend were examined. The current roles and potential of various stakeholder organizations in addressing problems of recruitment were explored. In addition, recent developments in methodology may help reduce the number of subjects required for well-powered studies. CONCLUSIONS: Several approaches are emerging to improve clinical trial design, efficacy outcome measures, and quantifiable surrogate markers, all of which should reduce the number of participants required for adequate statistical power. There is a growing sense of cooperation between various stakeholders but more should be done to bring together consumer and provider groups to improve recruitment and the effectiveness and relevance of neurotherapeutic clinical trials.

Diverse effects of invasive ecosystem engineers on marine biodiversity and ecosystem functions: A global review and meta-analysis.

Invasive ecosystem engineers (IEE) are potentially one of the most influential types of biological invaders. They are expected to have extensive ecological impacts by altering the physical-chemical structure of ecosystems, thereby changing the rules of existence for a broad range of resident biota. To test the generality of this expectation, we used a global systematic review and meta-analysis to examine IEE effects on the abundance of individual species and communities, biodiversity (using several indices) and ecosystem functions, focusing on marine and estuarine environments. We found that IEE had a significant effect (positive and negative) in most studies testing impacts on individual species, but the overall (cumulative) effect size was small and negative. Many individual studies showed strong IEE effects on community abundance and diversity, but the direction of effects was variable, leading to statistically non-significant overall effects in most categories. In contrast, there was a strong overall effect on most ecosystem functions we examined. IEE negatively affected metabolic functions and primary production, but positively affected nutrient flux, sedimentation and decomposition. We use the results to develop a conceptual model by highlighting pathways whereby IEE impact communities and ecosystem functions, and identify several sources of research bias in the IEE-related invasion literature. Only a few of the studies simultaneously quantified IEE effects on community/diversity and ecosystem functions. Therefore, understanding how IEE may alter biodiversity-ecosystem function relationships should be a primary focus of future studies of invasion biology. Moreover, the clear effects of IEE on ecosystem functions detected in our study suggest that scientists and environmental managers ought to examine how the effects of IEE might be manifested in the services that marine ecosystems provide to humans.

Lower extremity outcome measures: considerations for clinical trials in spinal cord injury.

STUDY DESIGN: This is a focused review article. OBJECTIVES: To identify important concepts in lower extremity (LE) assessment with a focus on locomotor outcomes and provide guidance on how existing outcome measurement tools may be best used to assess experimental therapies in spinal cord injury (SCI). The emphasis lies on LE outcomes in individuals with complete and incomplete SCI in Phase II-III trials. METHODS: This review includes a summary of topics discussed during a workshop focusing on LE function in SCI, conceptual discussion of corresponding outcome measures and additional focused literature review. RESULTS: There are a number of sensitive, accurate, and responsive outcome tools measuring both quantitative and qualitative aspects of LE function. However, in trials with individuals with very acute injuries, a baseline assessment of the primary (or secondary) LE outcome measure is often not feasible. CONCLUSION: There is no single outcome measure to assess all individuals with SCI that can be used to monitor changes in LE function regardless of severity and level of injury. Surrogate markers have to be used to assess LE function in individuals with severe SCI. However, it is generally agreed that a direct measurement of the performance for an appropriate functional activity supersedes any surrogate marker. LE assessments have to be refined so they can be used across all time points after SCI, regardless of the level or severity of spinal injury. SPONSORS: Craig H. Neilsen Foundation, Spinal Cord Outcomes Partnership Endeavor.

Considerations and recommendations for selection and utilization of upper extremity clinical outcome assessments in human spinal cord injury trials.

STUDY DESIGN: This is a focused review article. OBJECTIVES: This review presents important features of clinical outcomes assessments (COAs) in human spinal cord injury research. Considerations for COAs by trial phase and International Classification of Functioning, Disability and Health are presented as well as strengths and recommendations for upper extremity COAs for research. Clinical trial tools and designs to address recruitment challenges are identified. METHODS: The methods include a summary of topics discussed during a two-day workshop, conceptual discussion of upper extremity COAs and additional focused literature review. RESULTS: COAs must be appropriate to trial phase and particularly in mid-late-phase trials, should reflect recovery vs. compensation, as well as being clinically meaningful. The impact and extent of upper vs. lower motoneuron disease should be considered, as this may affect how an individual may respond to a given therapeutic. For trials with broad inclusion criteria, the content of COAs should cover all severities and levels of SCI. Specific measures to assess upper extremity function as well as more comprehensive COAs are under development. In addition to appropriate use of COAs, methods to increase recruitment, such as adaptive trial designs and prognostic modeling to prospectively stratify heterogeneous populations into appropriate cohorts should be considered. CONCLUSIONS: With an increasing number of clinical trials focusing on improving upper extremity function, it is essential to consider a range of factors when choosing a COA. SPONSORS: Craig H. Neilsen Foundation, Spinal Cord Outcomes Partnership Endeavor.

Long-term safety and efficacy of dalfampridine for walking impairment in patients with multiple sclerosis: Results of open-label extensions of two Phase 3 clinical trials.

BACKGROUND: In Phase 3 double-blind trials (MS-F203 and MS-F204), dalfampridine extended release tablets 10 mg twice daily (dalfampridine-ER; prolonged-release fampridine in Europe; fampridine modified or sustained release elsewhere) improved walking speed relative to placebo in patients with multiple sclerosis (MS). OBJECTIVES: Evaluation of long-term safety and efficacy of dalfampridine-ER in open-label extensions (MS-F203EXT, MS-F204EXT). METHODS: Patients received dalfampridine-ER 10 mg twice daily; and had Timed 25-Foot Walk (T25FW) assessments at 2, 14 and 26 weeks, and then every 6 months. Subjects were categorized as dalfampridine-ER responders or non-responders, based on their treatment response in the double-blind parent trials that assessed T25FW. RESULTS: We had 269 patients enter MS-F203EXT and 154 patients complete it; for a maximum exposure of 5 years. We had 214 patients enter MS-F204EXT and 146 complete it; for a maximum exposure of 3.3 years. No new safety signals emerged and dalfampridine-ER tolerability was consistent with the double-blind phase. Improvements in walking speed were lost after dalfampridine-ER was discontinued in the parent trial, but returned by the 2-week assessment after re-initiation of the drug. Throughout the extensions, mean improvement in walking speed declined, but remained improved, among the double-blind responders as compared with non-responders. CONCLUSIONS: The dalfamipridine-ER safety profile was consistent with the parent trials. Although walking speed decreased over time, dalfampridine-ER responders continued to show improved walking speed, which was sustained compared with non-responders.

Macroalgal blooms alter community structure and primary productivity in marine ecosystems.

Eutrophication, coupled with loss of herbivory due to habitat degradation and overharvesting, has increased the frequency and severity of macroalgal blooms worldwide. Macroalgal blooms interfere with human activities in coastal areas, and sometimes necessitate costly algal removal programmes. They also have many detrimental effects on marine and estuarine ecosystems, including induction of hypoxia, release of toxic hydrogen sulphide into the sediments and atmosphere, and the loss of ecologically and economically important species. However, macroalgal blooms can also increase habitat complexity, provide organisms with food and shelter, and reduce other problems associated with eutrophication. These contrasting effects make their overall ecological impacts unclear. We conducted a systematic review and meta-analysis to estimate the overall effects of macroalgal blooms on several key measures of ecosystem structure and functioning in marine ecosystems. We also evaluated some of the ecological and methodological factors that might explain the highly variable effects observed in different studies. Averaged across all studies, macroalgal blooms had negative effects on the abundance and species richness of marine organisms, but blooms by different algal taxa had different consequences, ranging from strong negative to strong positive effects. Blooms' effects on species richness also depended on the habitat where they occurred, with the strongest negative effects seen in sandy or muddy subtidal habitats and in the rocky intertidal. Invertebrate communities also appeared to be particularly sensitive to blooms, suffering reductions in their abundance, species richness, and diversity. The total net primary productivity, gross primary productivity, and respiration of benthic ecosystems were higher during macroalgal blooms, but blooms had negative effects on the productivity and respiration of other organisms. These results suggest that, in addition to their direct social and economic costs, macroalgal blooms have ecological effects that may alter their capacity to deliver important ecosystem services.

Dalfampridine improves sensorimotor function in rats with chronic deficits after middle cerebral artery occlusion.

BACKGROUND AND PURPOSE: Stroke survivors often have permanent deficits that are only partially addressed by physical therapy. This study evaluated the effects of dalfampridine, a potassium channel blocker, on persistent sensorimotor deficits in rats with treatment initiated 4 or 8 weeks after stroke. METHODS: Rats underwent permanent middle cerebral artery occlusion. Sensorimotor function was measured using limb-placing and body-swing symmetry tests, which normally show a partial recovery from initial deficits that plateaus ≈4 weeks after permanent middle cerebral artery occlusion. Dalfampridine was administered starting at 4 or 8 weeks after permanent middle cerebral artery occlusion in 2 blinded, vehicle-controlled studies. Plasma samples were collected and brain tissue was processed for histologic assessment. RESULTS: Dalfampridine treatment (0.5-2.0 mg/kg) improved forelimb- and hindlimb-placing responses and body-swing symmetry in a reversible and dose-dependent manner. Plasma dalfampridine concentrations correlated with dose. Brain infarct volumes showed no differences between treatment groups. CONCLUSIONS: Dalfampridine improves sensorimotor function in the rat permanent middle cerebral artery occlusion model. Dalfampridine extended-release tablets (prolonged release fampridine outside the United States) are used to improve walking in patients with multiple sclerosis, and these preclinical data provide a strong rationale for examining the potential of dalfampridine to treat chronic stable deficits in stroke patients. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01605825.

Biological-physical interactions are fundamental to understanding and managing coastal dynamics.

There is an urgent need to address coastal dynamics as a fundamental interaction between physical and biological processes, particularly when trying to predict future biological-physical linkages under anticipated changes in environmental forcing. More integrated modelling, support for observational networks and the use of management interventions as controlled experimental exercises should now be vigorously pursued.

The response of microphytobenthos to physical disturbance, herbicide, and titanium dioxide nanoparticle exposure.

The microphytobenthos that form transient biofilms are important primary producers in intertidal, depositional habitats, yet we have only a limited understanding of how they respond to the cumulative impacts of the growing range of anthropogenic stressors to which they are exposed. We know even less about how the temporal alignment of exposure - such as duration and exposure sequence - may affect the response. Estuarine biofilms were cultured in mesocosms and exposed to the herbicide glyphosate and titanium dioxide (TiO2) nanoparticles in different sequences (glyphosate-first or TiO2-first), as well as in the presence and absence of physical disturbance. We found that at environmentally realistic chemical concentrations, the order of exposure was less important than the total stressor scenario in terms of impacts on key functional attributes and diatom community structure. Physical disturbance did not have an impact on functional attributes, regardless of exposure sequence.

A phase 3 trial of extended release oral dalfampridine in multiple sclerosis.

OBJECTIVE: A previous phase 3 study showed significant improvement in walking ability in multiple sclerosis (MS) patients treated with oral, extended-release dalfampridine (4-aminopyridine) 10mg twice daily. The current study was designed to confirm efficacy and further define safety and pharmacodynamics. METHODS: This was a 39-center, double-blind trial in patients with definite MS of any course type. Participants were randomized to 9 weeks of treatment with dalfampridine (10mg twice daily; n = 120) or placebo (n = 119). Response was defined as consistent improvement on the Timed 25-Foot Walk, with percentage of timed walk responders (TWRs) in each treatment group as the primary outcome. The last on-treatment visit provided data from 8 to 12 hours postdose, to examine maintenance of effect. RESULTS: One patient from each group was excluded from the modified Intention to Treat population. The proportion of TWRs was higher in the dalfampridine group (51/119 or 42.9%) compared to the placebo group (11/118 or 9.3%, p < 0.0001). The average improvement in walking speed among dalfampridine-treated TWRs during the 8-week efficacy evaluation period was 24.7% from baseline (95% confidence interval, 21.0-28.4%); the mean improvement at the last on-treatment visit was 25.7%, showing maintenance of effect over the interdosing period. There were no new safety findings. INTERPRETATION: This interventional study provides class 1 evidence that dalfampridine extended-release tablets produce clinically meaningful improvement in walking ability in a subset of people with MS, with the effect maintained between doses.

Ecosystem engineers drive differing microbial community composition in intertidal estuarine sediments.

Intertidal systems are complex and dynamic environments with many interacting factors influencing biochemical characteristics and microbial communities. One key factor are the actions of resident fauna, many of which are regarded as ecosystem engineers because of their bioturbation, bioirrigation and sediment stabilising activities. The purpose of this investigation was to elucidate the evolutionary implications of the ecosystem engineering process by identifying, if any, aspects that act as selection pressures upon microbial communities. A mesocosm study was performed using the well characterised intertidal ecosystem engineers Corophium volutator, Hediste diversicolor, and microphytobenthos, in addition to manual turbation of sediments to compare effects of bioturbation, bioirrigation and stabilisation. A range of sediment functions and biogeochemical gradients were measured in conjunction with 16S rRNA sequencing and diatom taxonomy, with downstream bacterial metagenome function prediction, to identify selection pressures that incited change to microbial community composition and function. Bacterial communities were predominantly Proteobacteria, with the relative abundance of Bacteroidetes, Alphaproteobacteria and Verrucomicrobia being partially displaced by Deltaproteobacteria, Acidobacteria and Chloroflexi as dissolved oxygen concentration and redox potential decreased. Bacterial community composition was driven strongly by biogeochemistry; surface communities were affected by a combination of sediment functions and overlying water turbidity, and subsurface communities by biogeochemical gradients driven by sediment reworking. Diatom communities were dominated by Nitzschia laevis and Achnanthes sp., and assemblage composition was influenced by overlying water turbidity (manual or biogenic) rather than direct infaunal influences such as grazing.

Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial.

BACKGROUND: Clinical studies suggested that fampridine (4-aminopyridine) improves motor function in people with multiple sclerosis. This phase III study assessed efficacy and safety of oral, sustained-release fampridine in people with ambulatory deficits due to multiple sclerosis. METHODS: We undertook a randomised, multicentre, double-blind, controlled phase III trial. We randomly assigned 301 patients with any type of multiple sclerosis to 14 weeks of treatment with either fampridine (10 mg twice daily; n=229) or placebo (n=72), using a computer-generated sequence stratified by centre. We used consistent improvement on timed 25-foot walk to define response, with proportion of timed walk responders in each treatment group as the primary outcome. We used the 12-item multiple sclerosis walking scale to validate the clinical significance of the response criterion. Efficacy analyses were based on a modified intention-to-treat population (n=296), which included all patients with any post-treatment efficacy data. The study is registered with ClinicalTrials.gov, number NCT00127530. FINDINGS: The proportion of timed walk responders was higher in the fampridine group (78/224 or 35%) than in the placebo group (6/72 or 8%; p<0.0001). Improvement in walking speed in fampridine-treated timed walk responders, which was maintained throughout the treatment period, was 25.2% (95% CI 21.5% to 28.8%) and 4.7% (1.0% to 8.4%) in the placebo group. Timed walk responders showed greater improvement in 12-item multiple sclerosis walking scale scores (-6.84, 95% CI -9.65 to -4.02) than timed walk non-responders (0.05, -1.48 to 1.57; p=0.0002). Safety data were consistent with previous studies. INTERPRETATION: Fampridine improved walking ability in some people with multiple sclerosis. This improvement was associated with a reduction of patients' reported ambulatory disability, and is a clinically meaningful therapeutic benefit.

Pharmacokinetics of 14C-radioactivity after oral intake of a single dose of 14C-labeled fampridine (4-aminopyridine) in healthy volunteers.

BACKGROUND: Fampridine (4-aminopyridine) is a potassium channel blocker that has been evaluated as a treatment for patients with spinal cord injury and multiple sclerosis. OBJECTIVE: The purpose of this study was to determine the pharmacokinetics of a single dose of an orally administered solution of (14)C-labeled fampridine in healthy volunteers. METHODS: In this open-label, single-dose study conducted in an inpatient setting, healthy adult men were administered an oral solution containing 15 mg of (14)C-labeled fampridine (100 microCi) in a fasted state. In addition to blood sampling for analysis of plasma (14)C-radioactivity at prescribed intervals over 7 days, all urine and feces were collected for analysis of drug recovery and disposition. Urine samples were also analyzed for metabolic profiling. Plasma pharmacokinetic parameters of the (14)C-radiolabeled drug were determined using standard liquid-scintillation techniques. Recovery was calculated to provide the total amount of radioactivity excreted as a proportion of the original dose. Nonhydrolyzed and hydrolyzed urine extracts were analyzed for radioactivity and metabolites using reverse-phase, isocratic high-performance liquid chromatography with spectrophotometric and radioactive detection. Tolerability was assessed through evaluation of vital signs, hematologic and other laboratory parameters, and electrocardiography. RESULTS: The 4 white male subjects had a mean (SD) age of 21 (2) years. No clinically significant abnormalities in vital signs, clinical chemistry, hematology, urinalysis, or electrocardiography were observed either before or during the study. Peak plasma radioactivity was reached at 1 hour after dosing, with a median concentration of 72.9 ng x mL(-1). There was complete disappearance of radioactivity by 24 hours (limit of quantitation, 400 disintegrations/min per peak), and the calculated median t(1/2) was 3.14 hours. Total cumulative recovery of (14)C-radioactivity was 96.36%, with only 0.51% of drug recovered in feces. On chromatography, 2 metabolites accounted for a low proportion of total urinary radioactivity (3% and 6% of total radioactivity in the interval from 0 to 4 hours after dosing; 17% and 9% in the interval from 8 to 12 hours after dosing). Three subjects reported mild and transient dizziness occurring 1 half-hour after dosing; this was considered possibly related to the study drug. CONCLUSION: Fampridine administered as an oral solution was rapidly absorbed and was nearly completely and rapidly eliminated as unchanged drug via urinary excretion, suggesting that it is unlikely to undergo substantial metabolic transformation.

Assessment of Clinically Meaningful Improvements in Self-Reported Walking Ability in Participants with Multiple Sclerosis: Results from the Randomized, Double-Blind, Phase III ENHANCE Trial of Prolonged-Release Fampridine.

BACKGROUND: Walking impairment is a hallmark of multiple sclerosis (MS). It affects > 90% of individuals over time, reducing independence and negatively impacting health-related quality of life, productivity, and daily activities. Walking impairment is consistently reported as one of the most distressing impairments by individuals with MS. Prolonged-release (PR)-fampridine previously has been shown to improve objectively measured walking speed in walking-impaired adults with MS. The impact of PR-fampridine from the perspective of the individual with MS warrants full and detailed examination. OBJECTIVE: The objective of this study was to evaluate whether PR-fampridine has a clinically meaningful effect on self-reported walking ability in walking-impaired participants with MS. METHODS: ENHANCE was a phase III, randomized, double-blind, placebo-controlled study of PR-fampridine 10 mg twice daily in walking-impaired individuals age 18-70 years with either relapsing or progressive forms of MS and an Expanded Disability Status Scale (EDSS) score of 4.0-7.0 at screening. Participants were stratified by EDSS score (≤ 6.0 or 6.5-7.0) at randomization to ensure a balanced level of disability in the treatment groups. The primary endpoint was the proportion of participants with a mean improvement in the 12-item Multiple Sclerosis Walking Scale (MSWS-12) score exceeding the predefined threshold for clinically meaningful improvement (≥ 8 points) over 24 weeks. Secondary endpoints included the proportion with ≥ 15% improvement in Timed Up and Go (TUG) speed, and mean changes in Multiple Sclerosis Impact Scale physical impact subscale (MSIS-29 PHYS), Berg Balance Scale (BBS), and ABILHAND scores over 24 weeks. RESULTS: In total, 636 participants with MS were randomized (PR-fampridine, n = 317; placebo, n = 319; modified intention-to-treat sample: PR-fampridine, n = 315; placebo, n = 318). At baseline in the PR-fampridine and placebo groups, 46% and 51% had a progressive form of MS, median [range] EDSS scores were 6.0 [4.0-7.0] and 5.5 [4.0-7.0], mean [range] MSWS-12 scores were 63.6 [0-100] and 65.4 [0-100], and mean [range] TUG speed was 0.38 [0.0-1.0] and 0.38 [0.0-1.2] feet/s, respectively. A significantly higher percentage of PR-fampridine-treated participants (136/315 [43.2%]) had clinically meaningful improvement in MSWS-12 score over 24 weeks versus placebo (107/318 [33.6%]; odds ratio 1.61 [95% confidence interval 1.15-2.26]; p = 0.006). For PR-fampridine versus placebo, significantly more participants had a ≥ 15% improvement in TUG speed, and there was significantly greater mean improvement in MSIS-29 PHYS score (p < 0.05); numerical improvements that were not statistically significant were observed in BBS/ABILHAND. Adverse events that were more common in the PR-fampridine group than placebo group (difference ≥ 3%) by Medical Dictionary for Regulatory Activities (MedDRA®) Preferred Term were urinary tract infection and insomnia. There were no seizures reported. CONCLUSIONS: PR-fampridine treatment resulted in sustained, clinically meaningful improvements over 24 weeks in self-reported walking and functional ability in walking-disabled participants with MS. CLINICALTRIALS. GOV IDENTIFIER: NCT02219932.

Chondroitinase improves anatomical and functional outcomes after primate spinal cord injury.

Inhibitory extracellular matrices form around mature neurons as perineuronal nets containing chondroitin sulfate proteoglycans that limit axonal sprouting after CNS injury. The enzyme chondroitinase (Chase) degrades inhibitory chondroitin sulfate proteoglycans and improves axonal sprouting and functional recovery after spinal cord injury in rodents. We evaluated the effects of Chase in rhesus monkeys that had undergone C7 spinal cord hemisection. Four weeks after hemisection, we administered multiple intraparenchymal Chase injections below the lesion, targeting spinal cord circuits that control hand function. Hand function improved significantly in Chase-treated monkeys relative to vehicle-injected controls. Moreover, Chase significantly increased corticospinal axon growth and the number of synapses formed by corticospinal terminals in gray matter caudal to the lesion. No detrimental effects were detected. This approach appears to merit clinical translation in spinal cord injury.

Miracles and molecules--progress in spinal cord repair.

Severe spinal cord injury (SCI) leads to devastating loss of neurological function below the level of injury and adversely affects multiple body systems. Most basic research on SCI is designed to find ways to improve the unsatisfactory cellular and molecular responses of spinal cord to injury, which include an array of early processes of autodestruction and a subsequent lack of functional tissue repair. This research has brought us to the threshold of practical application along three lines of approach, derived from animal model studies: acute neuroprotection, enhanced axonal regeneration or plasticity, and treatment of demyelination. There is a growing commercial interest in this previously neglected therapeutic area.