Summary Background Current standard of care for trigeminal neuralgia is treatment with the sodium channel blockers carbamazepine and oxcarbazepine, which although effective are associated with poor ...tolerability and the need for titration. BIIB074, a Nav1.7-selective, state-dependent sodium-channel blocker, can be administered at therapeutic doses without titration, and has shown good tolerability in healthy individuals in phase 1 studies. We therefore assessed the safety and efficacy of BIIB074 in patients with trigeminal neuralgia in a phase 2a study. Methods We did a double-blind, multicentre, placebo-controlled, randomised withdrawal phase 2a trial in 25 secondary care centres in Denmark, Estonia, France, Germany, Italy, Latvia, Lithuania, Romania, South Africa, Spain, Switzerland, and the UK. After a 7-day run-in phase, eligible patients aged 18–80 years with confirmed trigeminal neuralgia received open-label, BIIB074 150 mg three times per day, orally, for 21 days. Patients who met at least one response criteria were then randomly assigned (1:1) to BIIB074 or placebo for up to 28 days in a double-blind phase. We used an interactive web response system to assign patients with a computer-generated schedule, with stratification (presence or absence of existing pain medication). Patients, clinicians, and assessors were masked to treatment allocation. The primary endpoint was the difference between groups in the number of patients classified as treatment failure during the double blind phase assessed in the modified intention-to-treat population. We assessed safety in all patients who received one or more doses of BIIB074. This study is registered with ClinicalTrials.gov ( NCT01540630 ) and EudraCT (2010-023963-16). Findings The first patient was enrolled on April 23, 2012, and the last patient completed the study on February 26, 2014. We enrolled 67 patients into the open-label phase; 44 completed open-label treatment, and 29 were randomly assigned to double-blind treatment (15 to BIIB074 and 14 to placebo). During the double-blind phase, five (33%) patients assigned to BIIB074 versus nine (64%) assigned to placebo were classified as treatment failures (p=0·0974). BIIB074 was well tolerated, with similar adverse events in the double-blind phase to placebo. Headache was the most common adverse event with BIIB074 in the open-label phase (in 13 19% of 67 patients), followed by dizziness (in six 9% patients). In the double-blind phase, headache, pyrexia, nasopharyngitis, sleep disorder, and tremor were the most frequent adverse events in patients assigned to BIIB074 (in one 7% of 15 patients for each event), and headache, dizziness, diarrhoea, and vomiting were the most frequent adverse events in patients assigned to placebo (in one 7% of 14 patients for each event). No severe or serious adverse events were reported in the BIIB074 group during the double-blind phase. One patient assigned to placebo reported intestinal adhesions with obstruction as a severe and serious adverse event, which was considered as unrelated to study medication. Interpretation The primary endpoint of treatment failure was not significantly lower in the BIIB074 group than in the placebo group. However, our findings provide a basis for continued investigation of BIIB074 in patients with trigeminal neuralgia in future clinical trials. Funding Convergence Pharmaceuticals.
Abstract Current treatments of neuropathic pain arising from conditions such as nerve injury/compression are only partially effective, and limited in their use by side-effects. p38 mitogen-activated ...protein kinase (MAPK) is involved in the regulation and synthesis of inflammatory mediators, and is the target for a novel class of cytokine-suppressive anti-inflammatory drugs. p38 inhibitors may reduce neuronal sensitisation in preclinical models of neuropathic pain, particularly where there is a substantial inflammatory component. An exploratory, multicentre, double-blind, placebo-controlled, two-period, cross-over trial was undertaken to evaluate the effect of dilmapimod (SB-681323), a selective p38 MAPK inhibitor, on neuropathic pain symptoms and signs. Fifty patients with nerve trauma, radiculopathy or carpal tunnel syndrome were randomised; 43 patients completed the study. Eligible patients received oral dilmapimod and placebo twice daily for 2 weeks, with an intervening washout period of 2–4 weeks. Subjects attended weekly for efficacy and safety assessments, which included evaluation of daily and current pain intensity using an 11-point numerical rating scale (NRS), quantitative sensory testing, allodynia and global impression of change. There was a statistically significant reduction in the primary endpoint of average daily pain score during the second week of treatment among patients treated with dilmapimod (15 mg/day) compared to placebo using NRS 0.80; 95% CI (0.28, 1.33); p = 0.0034. A similar trend for effect was seen in some secondary endpoints. Dilmapimod was well tolerated, with no clinically relevant safety findings. p38 MAPK inhibitors merit further evaluation for neuropathic pain in larger clinical trials, particularly for clinically meaningful analgesic effect size.
Intermittent claudication (IC) is the most common symptom of peripheral arterial disease, which significantly affects walking ability, functional capacity and quality of life. Supervised exercise ...programs (SEP) are recommended as first-line treatment, but recruitment and adherence rates are poor. The time required to complete a SEP is the most common barrier to participation cited by patients who decline. High-intensity interval training (HIIT) is more time efficient than current SEPs and therefore has the potential to overcome this barrier. We conducted a systematic review to appraise the evidence for HIIT programs for IC.
MEDLINE, Embase, and CENTRAL databases were searched for terms related to HIIT and IC. Randomized and nonrandomized trials that investigated HIIT for the treatment of IC were included, with no exclusions based on exercise modality, protocol, or use of a comparator arm. Outcome measures were walking distances, peak oxygen uptake, recruitment and adherence rates, and quality of life. The risk of bias was assessed using the Cochrane tool and study quality using a modified Physiotherapy Evidence Database scale.
Nine articles reporting eight studies were included in the review. HIIT seems to improve walking distances and oxygen uptake in relation to controls, with improvements attainable in just 6 weeks. When HIIT was compared with low-intensity exercise, it seemed that longer low-intensity programs were required to obtain similar benefits to those from short-term HIIT.
Initial evidence suggests that HIIT may provide benefits for patients with IC. Initially, pilot studies of low-volume, short-term HIIT vs usual SEPs are required. This strategy will allow for larger randomized, controlled trials to be appropriately designed and adequately powered to further explore the potential benefits of HIIT in IC.
Neuropathic pain affects ~ 6.9–10% of the general population and leads to loss of function, anxiety, depression, sleep disturbance, and impaired cognition. Here, we report the safety, tolerability, ...and pharmacokinetics of a voltage‐dependent and use‐dependent sodium channel blocker, vixotrigine, currently under investigation for the treatment of neuropathic pain conditions. The randomized, placebo‐controlled, phase I clinical trials were split into single ascending dose (SAD) and multiple ascending dose (MAD) studies. Healthy volunteers received oral vixotrigine as either single doses followed by a ≥ 7‐day washout period for up to 5 dosing sessions (SAD, n = 30), or repeat doses (once or twice daily) for 14 and 28 days (MAD, n = 51). Adverse events (AEs), maximum observed vixotrigine plasma concentration (Cmax), area under the concentration‐time curve from predose to 24 hours postdose (AUC0–24), time to Cmax (Tmax), and terminal half‐life (t1/2), among others, were assessed. Drug‐related AEs were reported in 47% and 53% of volunteers in the SAD and MAD studies, respectively, with dizziness as the most commonly reported drug‐related AE. SAD results showed that Cmax and AUC increased with dose, Tmax was 1–2 hours, and t1/2 was ~ 11 hours. A twofold increase in accumulation was observed when vixotrigine was taken twice vs. once daily (MAD). Steady‐state was achieved from day 5 onward. These data indicate that oral vixotrigine is well‐tolerated when administered as single doses up to 825 mg and multiple doses up to 450 mg twice daily.
AIM To determine if patients can localise dysphagia level determined endoscopically or radiologically and association of gender, age, level and pathology.METHODS Retrospective review of consecutive ...patients presenting to dysphagia hotline between March 2004 and March 2015 was carried out. Demographics, clinical history and investigation findings were recorded including patient perception of obstruction level (pharyngeal, mid sternal or low sternal) was documented and the actual level of obstruction found on endoscopic or radiological examination (if any) was noted. All patients with evidence of obstruction including oesophagealcarcinoma, peptic stricture, Schatzki ring, oesophageal pouch and cricopharyngeal hypertrophy were included in the study who had given a perceived level of dysphagia. The upper GI endoscopy reports (barium study where upper GI endoscopy was not performed) were reviewed to confirm the distance of obstructing lesion from central incisors. A previously described anatomical classification of oesophagus was used to define the level of obstruction to be upper, middle or lower oesophagus and this was compared with patient perceived level.RESULTS Three thousand six hundred and sixty-eight patients were included, 42.0% of who were female, mean age 70.7 ± 12.8 years old. Of those with obstructing lesions, 726 gave a perceived level of dysphagia: 37.2% had oesophageal cancer, 36.0% peptic stricture, 13.1% pharyngeal pouches, 10.3% Schatzki rings and 3.3% achalasia. Twenty-seven point five percent of patients reported pharyngeal level (upper) dysphagia, 36.9% mid sternal dysphagia and 25.9% lower sternal dysphagia (9.5% reported multiple levels). The level of obstructing lesion seen on diagnostic testing was upper (17.2%), mid (19.4%) or lower (62.9%) or combined (0.3%). When patients localised their level of dysphagia to a single level, the kappa statistic was 0.245 (P < 0.001), indicating fair agreement. 48% of patients reporting a single level of dysphagia were accurate in localising the obstructing pathology. With respect to pathology, patients with pharyngeal pouches were most accurate localising their level of dysphagia(P < 0.001). With respect to level of dysphagia, those with pharyngeal level lesions were best able to identify the level of dysphagia accurately (P < 0.001). No association (P > 0.05) was found between gender, patient age or clinical symptoms with their ability to detect the level of dysphagia.CONCLUSION Patient perceived level of dysphagia is unreliable in determining actual level of obstructing pathology and should not be used to tailor investigations.
Vixotrigine (BIIB074) is a voltage- and use-dependent sodium channel blocker. These studies will evaluate the efficacy and safety of vixotrigine in treating pain experienced by patients with ...trigeminal neuralgia (TN) using enriched enrollment randomized withdrawal trial designs.
Two double-blind randomized withdrawal studies are planned to evaluate the efficacy and safety of vixotrigine compared with placebo in participants with TN (NCT03070132 and NCT03637387). Participant criteria include ≥18 years old who have classical, purely paroxysmal TN diagnosed ≥3 months prior to study entry, who experience ≥3 paroxysms of pain/day. The two studies will include a screening period, 7-day run-in period, a 4- or 6-week single-dose-blind dose-optimization period (Study 1) or 4-week open-label period (Study 2), and 14-week double-blind period. Participants will receive vixotrigine 150 mg orally three times daily in the dose-optimization and open-label periods. The primary endpoint of both studies is the proportion of participants classified as responders at Week 12 of the double-blind period. Secondary endpoints include safety measures, quality of life, and evaluation of vixotrigine population pharmacokinetics.
There is a need for an effective, well-tolerated, noninvasive treatment for the neuropathic pain associated with TN. The proposed studies will evaluate the efficacy and safety of vixotrigine in treating pain experienced by patients with TN.
This study aimed to describe recruitment challenges encountered during a phase IIa study of vixotrigine, a state and use-dependent Nav1.7 channel blocker, in individuals with trigeminal neuralgia.
...This was an international, multicenter, placebo-controlled, randomized withdrawal study that included a 7-day run-in period, a 21-day open-label phase, and a 28-day double-blind phase in which patients (planned n = 30) were randomized to vixotrigine or placebo. Before recruitment, all antiepileptic drugs had to be stopped, except for gabapentin or pregabalin. After the trial, patients returned to their original medications. Patient recruitment was expanded beyond the original five planned (core) centers in order to meet target enrollment (total recruiting sites N = 25). Core sites contributed data related to patient identification for study participation (prescreening data). Data related to screening failures and study withdrawal were also analyzed using descriptive statistics.
Approximately half (322/636; 50.6%) of the patients who were prescreened at core sites were considered eligible for the study and 56/322 (17.4%) were screened. Of those considered eligible, 26/322 (8.1%) enrolled in the study and 6/322 (1.9%) completed the study. In total, 125 patients were screened across all study sites and 67/125 (53.6%) were enrolled. At prescreening, reasons for noneligibility varied by site and were most commonly diagnosis change (78/314; 24.8%), age > 80 years (75/314; 23.9%), language/distance/mobility (61/314; 19.4%), and noncardiac medical problems (53/314; 16.9%). At screening, frequently cited reasons for noneligibility included failure based on electrocardiogram, insufficient pain, and diagnosis change.
Factors contributing to recruitment challenges encountered in this study included diagnosis changes, anxiety over treatment changes, and issues relating to distance, language, and mobility. Wherever possible, future studies should be designed to address these challenges.
ClinicalTrials.gov, NCT01540630 . EudraCT, 2010-023963-16. 07 Aug 2015.
AIM：To determine which features of history and demographics predict a diagnosis of malignancy or peptic stricture in patients presenting with dysphagia.METHODS：A prospective case-control study of ...2000 consecutive referrals（1031 female,age range：17-103 years） to a rapid access service for dysphagia,based in a teaching hospital within the United Kingdom,over 7 years.The service consists of a nurse-led telephone triage followed by investigation（barium swallow or gastroscopy）,if appropriate,within 2 wk.Logistic regression analysis of demographic and clinical variables was performed.This includes age,sex,duration of dysphagia,whether to liquids or solids,and whether there are associated features（reflux,odynophagia,weight loss,regurgitation）.We determined odds ratio（OR） for these variables for the diagnoses of malignancy and peptic stricture.We determined the value of the Edinburgh Dysphagia Score（EDS） in predicting cancer in our cohort.Multivariate logistic regression was performed and P 〈 0.05 considered significant.The local ethics committee confirmed ethics approval was not required（audit）.RESULTS：The commonest diagnosis is gastro-esophageal reflux disease（41.3%）.Malignancy（11.0%） and peptic stricture（10.0%） were also relatively common.Malignancies were diagnosed by histology（97%） or on radiological criteria,either sequential barium swallows showing progression of disease or unequivocal evidence of malignancy on computed tomography.The majority of malignancies were esophago-gastric in origin but ear,nose and throat tumors,pancreatic cancer and extrinsic compression from lung or mediastinal metastatic cancer were also found.Malignancy was statistically more frequent in older patients（aged 〉73 years,OR 1.1-3.3,age 〈 60 years 6.5%,60-73 years 11.2%,〉 73 years 11.8%,P 〈 0.05）,males（OR 2.2-4.8,males 14.5%,females 5.6%,P 〈 0.0005）,short duration of dysphagia（≤ 8 wk,OR 4.5-20.7,16.6%,8-26 wk 14.5%,〉 26 wk 2.5%,P 〈 0.0005）,progressive symptoms（OR 1.3-2.6：progressive 14.8%,intermittent 9.3%,P 〈 0.001）,with weight loss of ≥ 2 kg（OR 2.5-5.1,weight loss 22.1%,without weight loss 6.4%,P 〈 0.0005） and without reflux（OR 1.2-2.5,reflux 7.2%,no reflux 15.5%,P 〈 0.0005）.The likelihood of malignancy was greater in those who described true dysphagia（food or drink sticking within 5 s of swallowing than those who did not（15.1%vs 5.2% respectively,P 〈 0.001）.The sensitivity,specificity,positive predictive value and negative predictive value of the EDS were 98.4%,9.3%,11.8% and 98.0% respectively.Three patients with an EDS of 3（high risk EDS ≥ 3.5） had malignancy.Unlike the original validation cohort,there was no difference in likelihood of malignancy based on level of dysphagia（pharyngeal level dysphagia 11.9% vs mid sternal or lower sternal dysphagia 12.4%）.Peptic stricture was statistically more frequent in those with longer duration of symptoms（〉 6 mo,OR 1.2-2.9,≤ 8 wk 9.8%,8-26 wk 10.6%,〉 26 wk 15.7%,P 〈 0.05） and over 60 s（OR 1.2-3.0,age 〈 60 years 6.2%,60-73 years 10.2%,〉 73 years 10.6%,P 〈 0.05）.CONCLUSION：Malignancy and peptic stricture are frequent findings in those referred with dysphagia.The predictive value for associated features could help determine need for fast track investigation whilst reducing service pressures.
Objectives.—Previous research using transcranial magnetic stimulation has produced equivocal findings concerning thresholds for the generation of visual phosphenes in migraine with aura. These ...studies were methodologically varied and did not systematically address cortical excitability in migraine without aura. We therefore studied magnetophosphene thresholds in both migraine with aura and migraine without aura compared with headache‐free controls.
Methods.—Sixteen subjects with migraine with aura and 12 subjects with migraine without aura were studied and compared with 16 sex‐ and age‐matched controls. Using a standardized transcranial magnetic stimulation protocol of the occipital cortex, we assessed the threshold stimulation intensity at which subjects just perceived phosphenes via a method of alternating course and fine‐tuning of stimulator output.
Results.—There were no significant differences across groups in the proportion of subjects seeing phosphenes. However, the mean threshold at which phosphenes were reported was significantly lower in both migraine groups (migraine with aura=47%, migraine without aura=46%) than in controls (66%). Moreover, there was no significant correlation between individual phosphene threshold and the time interval to the closest migraine attack.
Conclusion.—Our findings confirm that the occipital cortex is hyperexcitable in the migraine interictum, both in migraine with and without aura.
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