Safety and Efficacy of Metabolic Surgery in Patients with Type 2 Diabetes in the Middle East and North Africa Region: An Analysis of Primary Roux-en-Y Gastric Bypass and Sleeve Gastrectomy Outcomes.

INTRODUCTION: Type 2 diabetes (T2D) is a chronic medical condition that results in significant health implications and reduced life expectancy. The International Diabetes Federation (IDF) estimated that in 2021, 51.8% of all deaths of people under 60 years old in the Middle East and North Africa (MENA) region were related to diabetes. Bariatric surgery has been demonstrated to be a safe and effective treatment for T2D in different populations worldwide, though few specific data exist on outcomes of procedures in the MENA region. The aim of this study was to compare the safety and postoperative outcomes between patients with and without T2D undergoing primary bariatric surgery at a tertiary referral academic medical center in the United Arab Emirates. METHODS: All patients who underwent primary metabolic surgery between September 2015 and July 2020 were retrospectively reviewed from a prospective database. Group 1 included patients with T2D, and Group 2 included patients without T2D. Patients undergoing revisional or correctional operations were excluded. The procedure performed was based on surgeon discretion in discussion with a multidisciplinary team and the patient. Demographics as well as perioperative and postoperative results were examined. RESULTS: Our study included 542 patients, 160 (29.5%) with T2D and 382 (70.5%) with non-T2D. Mean age was 44.5 years (range 16-70) in the T2D group and 33.3 years (range 15-63) in the non-T2D group; median BMI was 41.8 ± 7.3 and 43.2 ± 7.2, respectively. The T2D group was 37.5% male and 62.5% female, and the non-T2D group was 38.7% male and 61.3% female. There were no significant differences in comorbidities. In the T2D group, 45.6% of patients underwent Roux-en-Y gastric bypass and 54.4% sleeve gastrectomy. In the non-TD2 group, 42.7% of patients received Roux-en-Y gastric bypass and 57.3% sleeve gastrectomy. There were no statistically significant differences in postoperative ED visits (21.8% vs. 24.3%, p = 0.21), minor complications within 30 days (4.3% vs. 5.2%, p = 0.67), readmission rates (5.6% vs. 4.9%, p = 0.77), re-operation rates (3.7% vs. 1.5%, p = 0.11), median hospital stay (2.0 days vs. 3.0, p = 0.05), or complications after 30 days (6.2% vs. 11.2%, p = 0.07). There were no deaths either group. CONCLUSIONS: In this cohort of patients from the MENA region, bariatric surgery in T2D patients is safe and effective, with perioperative outcomes comparable to those of non-T2D patients. To the best of our knowledge, our postoperative findings, which are the first report in the MENA region, are consistent with studies published in North America and Europe.

Pathway to a land-neutral expansion of Brazilian renewable fuel production.

Biofuels are currently the only available bulk renewable fuel. They have, however, limited expansion potential due to high land requirements and associated risks for biodiversity, food security, and land conflicts. We therefore propose to increase output from ethanol refineries in a land-neutral methanol pathway: surplus CO2-streams from fermentation are combined with H2 from renewably powered electrolysis to synthesize methanol. We illustrate this pathway with the Brazilian sugarcane ethanol industry using a spatio-temporal model. The fuel output of existing ethanol generation facilities can be increased by 43%-49% or ~100 TWh without using additional land. This amount is sufficient to cover projected growth in Brazilian biofuel demand in 2030. We identify a trade-off between renewable energy generation technologies: wind power requires the least amount of land whereas a mix of wind and solar costs the least. In the cheapest scenario, green methanol is competitive to fossil methanol at an average carbon price of 95€ tCO2-1.

Real-time intraoperative functioning lumen imaging probe during endoscopic per-oral pyloromyotomy (pop).

BACKGROUND: Endoscopic per-oral pyloromyotomy (POP) has emerged as a safe and effective first line option in medically refractory gastroparesis. Determining the appropriate extent of the pyloromyotomy continues to present a challenge as there are no standardized tools for measuring changes in pyloric distensibility during the procedure. The objective of this study was to evaluate the utility of using impedance planimetry with endoscopic functional luminal imaging probe (FLIP) to measure changes in pyloric distensibility after POP, and to compare these changes with improvement in symptoms and objective gastric emptying. METHODS: Patients with medically refractory gastroparesis underwent POP with FLIP measurements of the pylorus (EndoFLIP®, Medtronic, Fridley MN). FLIP measurements, as well as changes in symptoms measured by the validated gastroparesis cardinal symptom index (GCSI) and scintigraphic gastric emptying studies (GES), were evaluated before and after POP. RESULTS: A total of 14 patients underwent measurement with FLIP during POP, 12 of whom had pre- and post-POP measurements. Mean pyloric diameter increased by 1.4 mm, from 13.9 mm to 15.3 mm (p = 0.0012). Mean distensibility index increased from 6.2 mm2/mmHg to 9.1 mm2/mmHg (p = 0.0074). Successful division of the pylorus was achieved in 100% of patients with a mean operative time of 36 min and no perioperative complications. The mean length of stay was 0.7 days (0-3 days). Post-POP mean GCSI score improved from 2.97 to 2.28 at a mean follow-up time of 27 days (p < 0.001). Objective improvement in gastric emptying was observed in 80% of patients with scintigraphic GES, with mean four-hour retention decreasing from 46.3% to 32.4% (p < 0.007). CONCLUSIONS: FLIP is a safe and feasible tool to provide objective measurements during POP. Larger cohorts with longer follow-up are required to determine if measured improvements in pyloric diameter and distensibility are predictive of sustained improvements in GCSI and GES.

Gastroparesis with concomitant gastrointestinal dysmotility is not a contraindication for per-oral pyloromyotomy (POP).

INTRODUCTION: Per-oral pyloromyotomy (POP or G-POEM) provides significant short-term improvements in symptoms and objective emptying for patients with medically refractory gastroparesis, but it is unclear if patients with gastroparesis and co-existing dysmotility (small bowel or colonic delay) also benefit. In this study, we used wireless motility capsule (WMC) data to measure outcomes in patients with isolated gastroparesis (GP) and gastroparesis with co-existing dysmotility (GP + Dys) who underwent POP. METHODS: We retrospectively analyzed patients who had POP and completed WMC data during their evaluation of intestinal dysmotility. WMC data were reviewed to identify patients who demonstrated isolated GP or GP + Dys. Each patient's pre-op and post-op Gastroparesis Cardinal Symptom Index (GCSI) and 4-h solid-phase scintigraphy gastric emptying studies (GES) scores were compared to evaluate improvement. RESULTS: Of the entire cohort (n = 73), 89% were female with a mean age of 47.0 ± 15.0 years old. Gastroparesis etiologies were divided among idiopathic (54.8%), diabetic (26%), postsurgical (8.2%), autoimmune (5.5%), and multifactorial (5.5%). Forty-one patients (56%) had GP and 32 patients (44%) had GP + Dys. GCSI improved after POP whether the patient had isolated GP (- 12.31, p < 0.001) or GP + Dys (- 9.58, p < 0.001); however, there was no significant difference in total GCSI improvement between the two groups. A subset of patients had postoperative GES available (n = 47). In the isolated GP and GP + Dys cohorts, 15/28 (54%) and 12/19 (63%) patients had normal post-op 4-h GES, respectively, but no statistical difference between the two groups. CONCLUSION: Patients with medically refractory gastroparesis with and without concomitant gastrointestinal dysmotility show short-term subjective and objective improvement after POP. Concomitant small bowel or colonic dysmotility should not deter physicians from offering POP in carefully selected patients with gastroparesis.

Conversion of Sleeve Gastrectomy to Roux-en-Y Gastric Bypass to Enhance Weight Loss: Single Enterprise Mid-Term Outcomes and Literature Review.

Background: Suboptimal weight loss (SWL) occurs up to 30% after sleeve gastrectomy (SG). Conversion to Roux-en-Y gastric bypass (cRYGB) has shown heterogeneous results in terms of additional weight loss and resolution of weight-related comorbidities. We aim to evaluate mid-term outcomes of cRYGB specifically for SWL after SG. Methods: All patients who underwent cRYGB for SWL from April 2010 to June 2019 from prospective registries at three affiliated tertiary care centers were retrospectively reviewed. Patients who underwent revision or conversion for complications were excluded. Mixed-effects and polynomial regression models were used to evaluate weight loss results after conversion. Results: Thirty-two patients underwent cRYGB from SG. About 68.7% were women with mean age of 46.6 years. Mean body mass index (BMI) before SG was 55.3 kg/m2. Before conversion, mean BMI was 44.5 kg/m2 with 17.3% total weight loss (TWL). All procedures were completed laparoscopically in a median surgical time of 183 min. Three major complications occurred (9.3%), one gastrojejunal (GJ) leak and two reoperations. Four cases (12.5%) of GJ stenosis were diagnosed. No mortality was registered. Mean follow-up time was 24 months and patients had 36 kg/m2 mean BMI, 17.4% TWL, 27.2% had BMI >35 kg/m2. Conclusions: cRYGB after SG for SWL showed good mid-term results, better than those reported in literature.

Natural history of lung function over one year in patients with Parkinson's disease.

BACKGROUND: Little is known about decline in lung function in Parkinson's disease (PD). To assess these changes, we assessed the changes in lung function that occurred over 12 months in patients on standard PD therapy as part of the observational cohort of an open-label study of inhaled levodopa (CVT-301) in PD. METHODS: PD patients on stable oral PD therapy and no chronic respiratory disease had spirometry and diffusing capacity of the lungs for carbon monoxide (DLCO) measured at 3, 6, 9, and 12 months. RESULTS: 106 patients (81.5%) in the observational cohort on no investigational therapy completed the study. Mean FEV1 declined at 12 months from 2.88L at baseline with a mean change of -0.11L, greater than the -0.030-0.045L/year observed in healthy, non-smokers aged 60-70 years. FVC declined from 3.77L (mean change -0.19L); FEV1/FVC ratio remained relatively constant. DLCO mean change was -0.48 mL/min/mmHg from a baseline of 24.24 mL/min/mmHg. This change in DLCO, while not significant, was similar to that seen in non-smokers aged 60-70 years (DLCO -0.42-0.63 mL/min/mmHg/year). Decreases in alveolar volume (VA) and inspiratory vital capacity (IVC) rather than the transfer coefficient (DLCO/VA) were observed. CONCLUSIONS: PD patients had greater declines in FEV1, and FVC, but not in DLCO, compared to healthy non-smokers of similar age. Declines in FEV1 and FVC with little change in FEV1/FVC, and decline in VA and IVC with little change in DLCO/VA, suggest these changes were due to decreases in lung volume and are compatible with progressive PD-associated respiratory muscle weakness. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02352363 Registered January 26, 2015 [https://clinicaltrials.gov/ct2/show/NCT02352363]) and EudraCT (2014-003799-22).

Endoscopic Balloon Therapy.

Intragastric balloon therapy is an endoluminal treatment of obesity that is indicated for patients with moderate obesity (body mass index, 30-35 kg/m2) who have failed to lose weight with lifestyle and medical management. Treatment duration ranges from 4 to 12 months, and percent total body weight loss ranges from 6% to 15% at the time of balloon removal. Adverse events, such as bowel obstruction or gastric perforation, are rare, and early balloon removal because of intolerance is the most common complication. Long-term data are lacking, although weight regain after balloon removal seems to be common.

Efficacy of Virtual Case-Based General Surgery Clerkship Curriculum During COVID-19 Distancing.

OBJECTIVE: The COVID-19 pandemic created a paradigm shift in medical education with a reliance upon alternative teaching methods to deliver meaningful surgery clerkship content. This study examines the efficacy of a novel, case-based virtual surgery clerkship curriculum to determine its impact on student experience during quarantine. STUDY DESIGN: Sixteen third-year medical students enrolled in the General Surgery clerkship between April through June 2020 during COVID-19 distancing at a quaternary medical center (Cleveland Clinic, Cleveland, OH) participated in this study. Course surveys, including a 10-question curriculum-based multiple-choice assessment, were administered before and after the clerkship. Analyses include student self-perception of readiness to see a surgical consult independently, students' interest in pursuing a General Surgery residency, and improvement of surgical knowledge. RESULTS AND CONCLUSION: On a 5-point Likert scale, students felt significantly more assured in their ability to independently assess a surgical consult by the end of the course. Five (31%) students reported an influence of the curriculum on their personal interest in a career in General Surgery. Mean scores on the curriculum-based knowledge assessment increased. These findings highlight that a virtual platform can be a reliable alternative adjunct that delivers surgical content and positively impacts student experience. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40670-020-01126-5.

Endoscopic mucosal incision and muscle interruption (MIMI) for the treatment of Zenker's diverticulum.

BACKGROUND: In peroral endoscopic myotomy for Zenker's diverticulum (Z-POEM), the cricopharyngeus muscle is divided within a submucosal tunnel started in the hypopharynx. We aimed to evaluate the safety and preliminary outcomes in patients who underwent a modified version of the Z-POEM where the tunnel is made directly overlying the cricopharyngeus, the mucosal incision and muscular interruption (MIMI) approach, and to compare these with patients who underwent a non-tunneled flexible endoscopic approach. METHODS: All patients with ZD who were treated by flexible endoscopy at our institution between January 2015 and February 2020 were identified by a retrospective chart review. Dysphagia symptoms were assessed using a validated scoring system. RESULTS: Nineteen patients with ZD underwent MIMI (mean age 76.1 years, 68.1% male) and seven patients underwent non-tunneled flexible endoscopic approach (mean age 64.4 years, 85.7% male) during the study period. Mean ZD size was 2.8 cm in the MIMI group and 1.9 cm in the non-tunneled group (p = 0.03). Clinical success was achieved in 17/19(89.5%) MIMI patients and 7/7(100%) of non-tunneled flexible endoscopic patients (p = 0.101). Dysphagia scores improved in both groups, although this difference was only significant in the MIMI group (p ≤ 0.001). Recurrence occurred in 2/17(11.7%) MIMI patients and 3/7(42.9%) non-tunneled flexible endoscopic patients (p = 0.096). There were 4 complications, including one pharyngeal perforation requiring open surgical repair in a patient with a small ZD with an associated cricopharyngeal bar in the MIMI group. Median length of follow-up was 290 [142; 465] days in the MIMI group and 1056 [258; 1206] days in the non-tunneled group (p = 0.094). CONCLUSIONS: MIMI is a technically feasible and effective treatment for ZD. Care should be taken in patients with a cricopharyngeal bar and small ZD, as this may increase the risk of perforation. Larger studies with long-term follow-up are needed to determine if MIMI reduces the risk of symptom recurrence when compared to non-tunneled flexible endoscopic approaches.

A 12-month, dose-level blinded safety and efficacy study of levodopa inhalation powder (CVT-301, Inbrija) in patients with Parkinson's disease.

INTRODUCTION: CVT-301 (Inbrija®) is a levodopa inhalation powder for on-demand treatment of OFF episodes in Parkinson's disease patients treated with carbidopa/levodopa. Safety and efficacy results of a 12-month, dose-level blinded extension study of a phase 3 trial (SPAN℠-PD) of CVT-301 are presented. METHODS: Patients were receiving oral carbidopa/levodopa and adjunctive CVT-301 treatment, blinded to dose (60 mg or 84 mg, N = 325). Study visits occurred every 3 months. Pulmonary function was assessed by spirometry. Other safety assessments included dyskinesia and adverse events (AEs). Secondary objectives of the study included maintenance of improvement assessments for occurrence of an ON state during the 60-min post-dose period, change in total daily OFF time, and Patient Global Impression of Change (PGIC). RESULTS: Most frequent AEs (≥5%) were cough (15.4%), fall (13.1%), upper respiratory tract infection (7.1%), and dyskinesia (5.1%). Severe AEs (>1 event) were cough (1.9%) and dyskinesia (0.6%). Twelve-month mean changes from baseline for FEV1, FVC, and DLCO were -0.092 L, -0.097 L, and -0.922 mL/min/mmHg, respectively. At 12 months, 73.0% of patients on 84 mg achieved an ON state within 60 min. Total daily OFF time was reduced by 0.55 h (month 1) and 0.88 h (month 12) for the 84 mg dose. Percentage of patients self-reported as improved by PGIC was 65.5-91.9% over 12 months. CONCLUSION: CVT-301 was generally well-tolerated. Twelve-month decline in pulmonary function was consistent with a prior PD control group. Exploratory efficacy results showed CVT-301 maintained improvement at achieving ON states in patients experiencing OFF episodes, decreasing daily OFF time, and maintaining improvement in PGIC.

The Effect of Fasting during Ramadan on Outcomes after Bariatric Surgery at an Academic Medical Center in the Middle East.

INTRODUCTION: Ramadan is characterized by a month of fasting between dawn and sunset. Cleveland Clinic Abu Dhabi is located in the United Arab Emirates, where the majority of our patients observe Ramadan. In many practices, bariatric surgery has been delayed until after Ramadan in order to avoid postoperative complications. However, there are no studies that evaluate this theory. OBJECTIVES: Our study aimed to evaluate perioperative outcomes between bariatric surgeries performed before/during Ramadan and at times distant to Ramadan. METHODS: All patients who underwent primary bariatric surgery at Cleveland Clinic Abu Dhabi between September 2015 and July 2019 were retrospectively reviewed. The Pre-Ramadan (PR) cohort included patients that underwent surgery during the month of Ramadan and up to 3 months before Ramadan. The Non-Ramadan (NR) cohort included patients from the remainder 8 months. RESULTS: Our study included 542 patients: 185 patients in the PR cohort and 357 patients in the NR cohort. Baseline characteristics were similar. There were no statistically significant differences in perioperative outcomes, including emergency department (ED) visits (23.2% PR vs. 24.4% NR, p = .77), readmission rates (2.2% PR vs. 4.5% NR, p = .17), reoperation (1.1% PR vs. 3.6% NR, p = .09), and complications within 30 days (3.8% PR vs. 7.0% NR, p = .13). CONCLUSIONS: There is no difference among patients who undergo surgery before/during Ramadan and at times distant to Ramadan. Based on this data, there does not appear to be an increased risk of performing bariatric surgery prior to or during Ramadan in a comprehensive, multi-disciplinary program.

Quality of Information About Bariatric Surgery on the Internet: A Two-Continent Comparison of Website Content.

BACKGROUND: Many patients considering bariatric surgery will obtain medical information through the Internet. The type and quality of information patients access may vary significantly by geographic region. METHODS: Searches were performed using commercial search engines in both the United States of America (USA) and United Arab Emirates (UAE) using search terms "bariatric surgery" and "weight loss surgery." Quality was assessed using the scoring systems previously published by DISCERN (United Kingdom (UK)), the Journal of the American Medical Association Benchmark (JAMA; USA), and Expanded Ensuring Quality Information for Patients (EQIP) (UK). RESULTS: Website types were more evenly distributed in UAE, though physician websites were also the most common (n = 25, 25%). Within the USA, most websites analyzed were from physicians (n = 32, 32%), followed by academic sources (n = 26, 26%). Academic websites were the highest average quality in the USA (p < .00001). The overall mean DISCERN scores for all websites in the UAE group and US group had no statistically significance differences (p = .950). The overall mean JAMA Benchmark for all websites in the UAE group and USA had no statistically significance differences (p = 0.202). There were no major differences between the USA and UAE in Expanded EQIP scores. CONCLUSIONS: The overall quality of information regarding bariatric surgery is poor to fair in both the USA and UAE. Additionally, there are differences in the types of sites retrieved by the most commonly used search engines in each region. The lack of high-quality, evidence-based, information regarding bariatric surgery online is a potential target to improve public education.

Assessment of volume preservation performed before or after partial nephrectomy accurately predicts postoperative renal function: Results from a prospective multicenter study.

PURPOSE: Partial nephrectomy (PN) is standard for small renal masses, improving renal function by preserving renal parenchyma compared with radical nephrectomy. Recent work demonstrated that postoperative surgeon assessment of volume preservation (SAVP) and 3D imaging measurements agree and correlate with postoperative function. We hypothesize preoperative assessment of volume preservation (PAVP) with PN based on preoperative imaging will reliably indicate postoperative renal function. MATERIALS AND METHODS: Data were collected from 336 patients undergoing PN for suspected renal cancer by 40 surgeons at 12 centers in Europe and the United States within the Surface-Intermediate-Base International Consortium. Surgeons recorded PAVP and SAVP for individual patients; pre- and postoperative glomerular filtration rate (GFR) was estimated by Chronic Kidney Disease Epidemiology Collaboration equations. Correlations between PAVP, SAVP, and postoperative GFR were assessed with linear regression models. Bland-Altman analysis was used to assess agreement between PAVP and SAVP with a significant cutoff of 5%. RESULTS: Median PAVP was 90% (interquartile range [IQR] 85%-100%) and SAVP was 90% (IQR: 80%-94%). PAVP and SAVP were moderately correlated (R2 = 0.67, P < 0.0001) and deemed "interchangeable" by Bland-Altman analysis at a 5% acceptable rate of difference (95% CI: -5.4, -3.1). Median postoperative GFR was 77.3 (IQR: 56.2, 92.0). Both PAVP (R2 = 0.82, P < 0.0001) and SAVP (R2 = 0.83, P < 0.0001) were correlated with postoperative GFR. Multivariable models utilizing volume-adjusted GFR based on PAVP or SAVP significantly and similarly predicted postoperative GFR (R2 = 0.72 for each). CONCLUSION: Renal function is closely linked to the amount of parenchymal volume preservation, whether estimated prior to surgery (PAVP) or afterward (SAVP). PAVP provides reasonably accurate information for decision-making in patients considering PN.

Dalfampridine Effects Beyond Walking Speed in Multiple Sclerosis.

BACKGROUND: Dalfampridine extended release (ER) improves walking in people with multiple sclerosis (MS), as demonstrated by walking speed improvement. This exploratory study evaluated treatment effects of dalfampridine-ER on gait, balance, and walking through treatment withdrawal and reinitiation. METHODS: Dalfampridine-ER responders, based on Timed 25-Foot Walk (T25FW) assessment before study entry, were included in this open-label, three-period, single-center study. Period 1: on-drug evaluations performed at screening and 1 week after screening. Period 2: dalfampridine-ER withdrawal and off-drug evaluations (days 5 and 11). Period 3: dalfampridine-ER reinitiation/final on-drug evaluation (day 15). PRIMARY OUTCOME VARIABLES: NeuroCom composite scores for gait and balance; balance was evaluated if gait changes were significant. Secondary variables: individual NeuroCom scores, walking speed (T25FW) and distance (2-Minute Walk Test [2MWT]), and balance (Berg Balance Scale [BBS]). RESULTS: All 20 patients completed the study: mean age, 53.1 years; mean MS duration, 11.3 years; mean time taking dalfampridine-ER, 315.3 days. NeuroCom gait composite scores worsened during period 2 relative to period 1 and improved during period 3; the mean ± SD difference in gait composite scores on drug was 4.03 ± 1.51 points (P = .015). Balance composite scores did not change significantly. Improvements were observed for off-drug versus on-drug for T25FW (0.36 ft/sec, P < .001), 2MWT (25.4 ft, P = .006), and BBS (1.7 points, P = .003). Safety profile was consistent with previous studies. CONCLUSIONS: Significant improvements in gait, walking speed, distance, and balance were demonstrated by dalfampridine-ER reinitiation after a 10-day withdrawal period.

Effects of Dalfampridine Extended-release Tablets on 6-minute Walk Distance in Patients With Multiple Sclerosis: A Post Hoc Analysis of a Double-blind, Placebo-controlled Trial.

PURPOSE: Dalfampridine extended-release (ER) tablets 10 mg BID have been approved for use in improving walking in people with multiple sclerosis (MS). This subgroup analysis evaluated the effects of dalfampridine ER 5 and 10 mg BID on distance walked, as assessed using the 6-minute walk (6MW) test. METHODS: This analysis of data from a randomized, placebo-controlled, double-blind study (N = 430) included only the 153 patients with 6MW data available. Participants (aged 18-70 years) were randomly assigned in a 1:1:1 ratio to receive dalfampridine ER 5 or 10 mg or placebo, BID for 4 weeks. The 6MW was used for assessing walking distance at baseline and 2 weeks after the start of treatment at the 26 study sites that were able to perform this test. Participants were administered the 12-item MS Walking Scale (MSWS-12), a patient-reported measure of the impact of MS on walking. Post hoc outcomes included the percentages of patients who achieved an increase from baseline in 6MW distance of ≥20% and who achieved a minimal clinically important difference (MCID) from baseline in 6MW distance, defined as ≥+55 m. Changes from baseline in walking speed (MSWS-12) were compared, stratified by subgroup that achieved ≥20% versus <20% improvement on the 6MW. The correlation between change in walking speed over time and subgroup (by change in distance walked) was evaluated. The tolerability of dalfampridine was assessed based on the prevalence of treatment-emergent adverse events (TEAEs). FINDINGS: In the post hoc analysis, the percentage of patients with an improvement in 6MW distance that met or exceeded the MCID was significantly greater with dalfampridine ER 10 mg BID relative to placebo (37.3% vs 12.2%; nominal P = 0.004). Similarly, the percentage with an improvement in 6MW distance of ≥20% was significantly greater with dalfampridine 10 mg BID relative to placebo (45.1% vs 14.3%; nominal P < 0.001). Regardless of treatment allocation, improvement in MSWS-12 was significantly greater in the subgroup that achieved a ≥20% improvement on the 6MW compared with the subgroup with <20% improvement (mean changes, -15.5 vs -7.2; nominal P = 0.041). The prevalences and types of TEAEs were consistent with those reported in previous studies. IMPLICATIONS: Based on the MCID for 6MW, the use of dalfampridine ER 10 mg BID but not 5 mg BID was associated with statistically significant and clinically meaningful improvements in walking relative to placebo. The correlation between improvement on MSWS-12 and the 20% increase in 6MW distance suggests that an improvement on MSWS-12 is clinically relevant. These results, although highlighting a lack of efficacy of dalfampridine ER 5 mg BID, suggest that the 10-mg BID dose is effective for improving walking speed, as observed on short timed-walk tests, and for increasing distance walked over longer timed-walk periods. ClinicalTrials.gov identifier: NCT01328379.

Evaluation of Dalfampridine Extended Release 5 and 10 mg in Multiple Sclerosis: A Randomized Controlled Trial.

BACKGROUND: Dalfampridine extended-release (ER) tablets, 10 mg twice daily, have been shown to improve walking in people with multiple sclerosis. We evaluated the safety and efficacy of dalfampridine-ER 5 mg compared with 10 mg. METHODS: Patients were randomized to double-blind treatment with twice-daily dalfampridine-ER tablets, 5 mg (n = 144) or 10 mg (n = 143), or placebo (n = 143) for 4 weeks. Primary efficacy endpoint was change from baseline walking speed by the Timed 25-Foot Walk 3 to 4 hours after the last dose. At 40% of sites, 2-week change from baseline walking distance was measured by the 6-Minute Walk test. RESULTS: At 4 weeks, walking speed changes from baseline were 0.363, 0.423, and 0.478 ft/s (placebo, dalfampridine-ER 5 mg, and dalfampridine-ER 10 mg, respectively [P = NS]). Post hoc analysis of average changes between pretreatment and on-treatment showed that relative to placebo, only dalfampridine-ER 10 mg demonstrated a significant increase in walking speed (mean ± SE): 0.443 ± 0.042 ft/s versus 0.303 ± 0.038 ft/s (P = .014). Improvement in 6-Minute Walk distance was significantly greater with dalfampridine-ER 10 mg (128.6 ft, P = .014) but not with 5 mg (76.8 ft, P = .308) relative to placebo (41.7 ft). Adverse events were consistent with previous studies. No seizures were reported. CONCLUSIONS: Dalfampridine-ER 5 and 10 mg twice daily did not demonstrate efficacy on the planned endpoint. Post hoc analyses demonstrated significant increases in walking speed relative to placebo with dalfampridine-ER 10 mg. No new safety signals were observed.

A pooled analysis of two phase 3 clinical trials of dalfampridine in patients with multiple sclerosis.

BACKGROUND: Two phase 3 clinical trials demonstrated that dalfampridine extended-release 10-mg tablets (D-ER), twice daily, significantly improved walking relative to placebo in patients with multiple sclerosis (MS). The objective of this study was to evaluate the efficacy and safety of D-ER in patients with MS using pooled data from the two phase 3 trials. METHODS: Data were pooled from the two trials, and D-ER was compared with placebo for timed-walk responder rate, changes in walking speed, and the 12-item Multiple Sclerosis Walking Scale (MSWS-12). Response rates were evaluated with respect to demographic and clinical characteristics. RESULTS: D-ER had a significantly higher proportion of timed-walk responders relative to placebo (37.6% vs. 8.9%; P < .0001). The responder rate was independent of age, gender, race, body-mass index, type of MS, duration of MS, baseline Expanded Disability Status Scale score, baseline walking speed, and concomitant use of immunomodulatory therapies. Significant improvements were observed in walking speed and in MSWS-12 score for the pooled D-ER group compared with placebo. The safety profile was consistent with the individual studies; no new safety or tolerability concerns were identified. CONCLUSIONS: D-ER demonstrated efficacy for the improvement of walking in patients with MS; response was independent of demographic and clinical characteristics.