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

doi:10.1016/S1474-4422(17)30005-4

The Lancet Neurology

Volume 16, Issue 4, April 2017, Pages 291-300

https://doi.org/10.1016/S1474-4422(17)30005-4 Get rights and content

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.

Introduction

Trigeminal neuralgia is a rare, and at times debilitating, orofacial disorder, characterised by unilateral paroxysms of severe pain in the territory innervated by the trigeminal nerve, usually triggered by innocuous stimuli.¹ The only treatment approved by the US Food and Drug Administration (FDA) for trigeminal neuralgia is the voltage-gated sodium-channel (Nav) blocker carbamazepine, which was approved in the 1960s. Carbamazepine and its analogue oxcarbazepine are recommended as first-line treatments for trigeminal neuralgia;² however, although generally considered effective, these treatments are limited by poor tolerability, the need for well managed titration, and potential for pharmacological interactions.2, 3, 4, 5 Other oral drugs (predominantly anticonvulsants) have been investigated in trigeminal neuralgia; however, none have shown a clear benefit.2, 6, 7, 8 Results from Cochrane reviews have highlighted that few high-quality clinical trials of trigeminal neuralgia have been done and, even for carbamazepine, the evidence base is weak.3, 6, 7 Findings from a systematic review⁹ indicated that botulinum toxin is effective in trigeminal neuralgia; however, we have not identified any randomised controlled trials that have assessed the duration of its effect beyond 3 months.

Research in context

Evidence before this study

We searched PubMed with the term ‘trigeminal neuralgia’ for English-language papers published between June 1, 2005, and June 16, 2015, and searched our own publications, and identified five systematic reviews of drug treatments in patients with trigeminal neuralgia. Overall, the scientific literature highlighted the absence of high-quality clinical trials in trigeminal neuralgia. Current standard of care and guideline-recommended first-line treatments are the sodium channel blockers carbamazepine or oxcarbazepine. Carbamazepine is the only medication that has been approved by the US Food and Drug Administration for trigeminal neuralgia. However, even for these drugs, the evidence is weak (third-tier evidence only for carbamazepine and no eligible studies for oxcarbazepine according to Cochrane systematic reviews). Further, these treatments are limited by poor tolerability, need for well-managed titration, and potential for pharmacological interactions.

Added value of this study

Few advances have been made in the treatment of trigeminal neuralgia in recent decades and there is a shortage of high-quality clinical trials in this area. Our study addressed barriers to traditional randomised controlled trials in the trigeminal neuralgia population, by using a randomised withdrawal design that restricts the exposure of patients to placebo in the absence of benefit. The results of our study indicate potential for BIIB074, a Nav1.7-selective sodium channel blocker, to be both effective and well tolerated in patients with trigeminal neuralgia. Notably, by contrast with findings for carbamazepine and oxcarbazepine, treatment with BIIB074 was associated with low rates of cognitive impairment, and could be administered at therapeutic doses without the need for titration.

Implications of all the available evidence

To our knowledge, BIIB074 is unique in that it is being developed for trigeminal neuralgia as the primary indication. Our results provide a basis for the continued investigation of BIIB074 in trigeminal neuralgia in future trials.

Nav1.7 is a sodium channel that is preferentially expressed in peripheral neurons, including trigeminal neurons, and results from functional and genetic studies suggest a link between Nav1.7 and pain signalling in human beings.10, 11, 12 Loss-of-function mutations in Nav1.7 are associated with insensitivity to pain in individuals who are apparently cognitively healthy,¹³ suggesting Nav1.7 as a potential target for pain. The efficacy of carbamazepine (known to block Nav1.7¹⁴) and oxcarbazepine lend further support for Nav1.7 as a target in trigeminal neuralgia.

BIIB074 is a Nav1.7-selective, state-dependent, sodium-channel blocker15, 16 under investigation for the treatment of trigeminal neuralgia. Findings from electrophysiological studies have shown that BIIB074 preferentially inhibits high frequencies of firing in neurons,¹⁷ such as would be expected in the paroxysms of pain in trigeminal neuralgia.18, 19 Results from phase 1 studies have suggested that BIIB074 has good tolerability in healthy individuals and can be administered at therapeutic doses without lengthy titration (unpublished). Thus, if proven efficacious, BIIB074 could fill an unmet need for a trigeminal neuralgia treatment that is both effective and well tolerated, particularly because many patients opt to remain on medications rather than undergo neurosurgical procedures.⁴

We therefore assessed the safety and efficacy of BIIB074 in patients with trigeminal neuralgia in a phase 2a randomised withdrawal trial.²⁰

Section snippets

Study design and participants

We did an international double-blind, multicentre, placebo-controlled, randomised withdrawal phase 2a study (appendix) in 25 secondary care centres with a special interest in headache and facial pain (across Denmark, Estonia, France, Germany, Italy, Latvia, Lithuania, Romania, South Africa, Spain, Switzerland, and the UK). The full study design had been published previously before completion of the study.²⁰ The study protocol, patient information, informed consent forms, and amendments, were

Results

The first patient was enrolled in the study on April 23, 2012, and the last patient completed on Feb 26, 2014. We screened 125 patients, and the diagnostic committee reviewed the trigeminal neuralgia diagnosis for 104 patients (all those not reviewed were deemed as screen failures). 67 patients entered the open-label phase, all of whom had a confirmed diagnosis before entry (figure 1). 44 (66%) of these 67 patients completed the open-label phase. The mITT population included 29 patients who

Discussion

Fewer patients in the BIIB074 group had treatment failures, the primary endpoint of the study, than those in the placebo group in the double-blind phase of the study, but the difference was not significant. We noted significant treatment differences versus placebo in secondary endpoints during the double-blind phase, including time to treatment failure, number of paroxysms, average daily pain score, PGIC, and CGIC. Although robust conclusions about efficacy and safety cannot be drawn from this

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^†: Kevin Gunn was an employee of Convergence Pharmaceuticals at the time of this study and is now retired

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ArticlesSafety 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

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Bioorg Med Chem Lett

Pain

J Pain

Epilepsy Res

Epilepsy Behav

The International Classification of Headache Disorders, 3rd edn (beta version)

Cephalalgia

AAN-EFNS guidelines on trigeminal neuralgia management

Eur J Neurol

Carbamazepine for chronic neuropathic pain and fibromyalgia in adults

Cochrane Database Syst Rev

Natural history and outcome of 200 outpatients with classical trigeminal neuralgia treated with carbamazepine or oxcarbazepine in a tertiary centre for neuropathic pain

J Headache Pain

Comparison of tolerability and adverse symptoms in oxcarbazepine and carbamazepine in the treatment of trigeminal neuralgia and neuralgiform headaches using the Liverpool Adverse Events Profile (AEP)

J Headache Pain

Non-antiepileptic drugs for trigeminal neuralgia

Cochrane Database Syst Rev

Antiepileptic drugs for neuropathic pain and fibromyalgia—an overview of Cochrane reviews

Cochrane Database Syst Rev

Trigeminal neuralgia

BMJ Clin Evid

Botulinum toxin treatment of neuropathic pain

Semin Neurol

The Na(V)1.7 sodium channel: from molecule to man

Nat Rev Neurosci

Articles
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