Challenges recruiting to a proof-of-concept pharmaceutical trial for a rare disease: The trigeminal neuralgia experience

Background: 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. Methods: 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. Results: 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. Conclusions: 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. Trial registration: ClinicalTrials.gov, NCT01540630. EudraCT, 2010-023963-16. 07 Aug 2015

Стратегічне планування як основний інструмент ефективності підприємства

Наук. кер.: А.Ю. Жулавськи

Finalised dependability framework and evaluation results

The ambitious aim of CONNECT is to achieve universal interoperability between heterogeneous Networked Systems by means of on-the-fly synthesis of the CONNECTors through which they communicate. The goal of WP5 within CONNECT is to ensure that the non-functional properties required at each side of the connection going to be established are fulfilled, including dependability, performance, security and trust, or, in one overarching term, CONNECTability. To model such properties, we have introduced the CPMM meta-model which establishes the relevant concepts and their relations, and also includes a Complex Event language to express the behaviour associated with the specified properties. Along the four years of project duration, we have developed approaches for assuring CONNECTability both at synthesis time and at run-time. Within CONNECT architecture, these approaches are supported via the following enablers: the Dependability and Performance analysis Enabler, which is implemented in a modular architecture supporting stochastic verification and state-based analysis. Dependability and performance analysis also relies on approaches for incremental verification to adjust CONNECTor parameters at run-time; the Security Enabler, which implements a Security-by-Contract-with-Trust framework to guarantee the expected security policies and enforce them accordingly to the level of trust; the Trust Manager that implements a model-based approach to mediate between different trust models and ensure interoperable trust management. The enablers have been integrated within the CONNECT architecture, and in particular can interact with the CONNECT event-based monitoring enabler (GLIMPSE Enabler released within WP4) for run-time analysis and verification. To support a Model-driven approach in the interaction with the monitor, we have developed a CPMM editor and a translator from CPMM to the GLIMPSE native language (Drools). In this document that is the final deliverable from WP5 we first present the latest advances in the fourth year concerning CPMM, Dependability&Performance Analysis, Incremental Verification and Security. Then, we make an overall summary of main achievements for the whole project lifecycle. In appendix we also include some relevant articles specifically focussing on CONNECTability that have been prepared in the last period

Final CONNECT Architecture

Interoperability remains a fundamental challenge when connecting heterogeneous systems which encounter and spontaneously communicate with one another in pervasive computing environments. This challenge is exasperated by the highly heterogeneous technologies employed by each of the interacting parties, i.e., in terms of hardware, operating system, middleware protocols, and application protocols. The key aim of the CONNECT project is to drop this heterogeneity barrier and achieve universal interoperability. Here we report on the revised CONNECT architecture, highlighting the integration of the work carried out to integrate the CONNECT enablers developed by the different partners; in particular, we present the progress of this work towards a finalised concrete architecture. In the third year this architecture has been enhanced to: i) produce concrete CONNECTors, ii) match networked systems based upon their goals and intent, and iii) use learning technologies to find the affordance of a system. We also report on the application of the CONNECT approach to streaming based systems, further considering exploitation of CONNECT in the mobile environment

Consolidated dependability framework

The aim of CONNECT is to achieve universal interoperability between heterogeneous Networked Systems. For this, the non-functional properties required at each side of the connection going to be established, which we refer to by the one inclusive term "CONNECTability", must be fulfilled. In Deliverable D5.1 we conceived the conceptual models at the foundation of CONNECTability. In D5.2 we then presented a first version of the approaches and of their respective enablers that we developed for assuring CONNECTability both at synthesis time and at run-time. In this deliverables, we present the advancements and contributions achieved in the third year, which include: - a refinement of the CONNECT Property Meta-Model, with a preliminary implementation of a Model-to-Code translator; - an enhanced implementation of the Dependability&Performance analysis Enabler, supporting stochastic verification and state-based analysis, that is enriched with mechanisms for providing feedback to the Synthesis enabler based on monitor's run-time observations; - a fully running version of the Security Enabler, following the Security-by-Contract-with-Trust methodology, for the monitoring and enforcement of CONNECT related security policies; - a complete (XML) definition of the Trust Model Description Language, an editor and the corresponding implementation of supporting tools to be integrated into the Trust Management Enabler

Palatal sclerotherapy for the treatment of intermittent dorsal displacement of the soft palate in 51 standardbred racehorses.

This retrospective study evaluated the efficacy and side effects of palatal sclerotherapy in standardbred racehorses suspected to have intermittent dorsal displacement of the soft palate (IDDSP). Fifty-one horses were treated with multiple endoscopically guided injections of 3% sodium tetradecyl sulfate in the soft palate. Two groups were identified: those that had respiratory noises during exercise (n = 27) and those that did not (n = 24). Treatment was well-tolerated. Furthermore, horses significantly reduced their racing times for the last 400 m compared with their times before treatment and even when their times were compared to the mean times for horses in the same race. In conclusion, palatal sclerotherapy appears to be a suitable alternative therapeutic option for horses suspected to have IDDSP

Palatal sclerotherapy for the treatment of intermittent dorsal displacement of the soft palate in 51 standardbred racehorses

This retrospective study evaluated the efficacy and side effects of palatal sclerotherapy in standardbred racehorses suspected to have intermittent dorsal displacement of the soft palate (IDDSP). Fifty-one horses were treated with multiple endoscopically guided injections of 3% sodium tetradecyl sulfate in the soft palate. Two groups were identified: those that had respiratory noises during exercise (n = 27) and those that did not (n = 24). Treatment was well-tolerated. Furthermore, horses significantly reduced their racing times for the last 400 m compared with their times before treatment and even when their times were compared to the mean times for horses in the same race. In conclusion, palatal sclerotherapy appears to be a suitable alternative therapeutic option for horses suspected to have IDDSP

A Gain-of-Function Mutation in Nav1.6 in a Case of Trigeminal Neuralgia

Abstract Idiopathic trigeminal neuralgia (TN) is a debilitating pain disorder characterized by episodic unilateral facial pain along the territory of branches of the trigeminal nerve. Human pain disorders, but not TN, have been linked to gain-of-function mutations in peripheral voltage-gated sodium channels (NaV1.7, NaV1.8 and NaV1.9). Gain-of-function mutations in NaV1.6, which is expressed in myelinated and unmyelinated central nervous system (CNS) and peripheral nervous system neurons and supports neuronal high-frequency firing, have been linked to epilepsy but not to pain. Here, we describe an individual who presented with evoked and spontaneous paroxysmal unilateral facial pain and carried a diagnosis of TN. Magnetic resonance imaging showed unilateral neurovascular compression, consistent with pain in areas innervated by the second branch of the trigeminal nerve. Genetic analysis as part of a phase 2 clinical study in patients with TN conducted by Convergence Pharmaceuticals Ltd revealed a previously undescribed de novo missense mutation in NaV1.6 (c.A406G; p.Met136Val). Whole-cell voltage-clamp recordings show that the Met136Val mutation significantly increases peak current density (1.5-fold) and resurgent current (1.6-fold) without altering gating properties. Current-clamp studies in trigeminal ganglia (TRG) neurons showed that Met136Val increased the fraction of high-firing neurons, lowered the current threshold and increased the frequency of evoked action potentials in response to graded stimuli. Our results demonstrate a novel NaV1.6 mutation in TN, and show that this mutation potentiates transient and resurgent sodium currents and leads to increased excitability in TRG neurons. We suggest that this gain-of-function NaV1.6 mutation may exacerbate the pathophysiology of vascular compression and contribute to TN

Safety and efficacy of a Nav1.7 selective sodium channel blocker in patients with trigeminal neuralgia: a double-blind, placebo-controlled, randomised withdrawal phase 2a trial

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