Ignite Creation Date:
2024-05-06 @ 1:50 AM
Last Modification Date:
2024-10-26 @ 11:10 AM
Study NCT ID:
NCT01911975
Status:
COMPLETED
Last Update Posted:
2018-01-10
First Post:
2013-07-13
Brief Title:
Safety and Tolerability of Lacosamide in Patients With Gain-of-function Nav17 Mutations Related Small Fiber Neuropathy
Sponsor:
Academisch Ziekenhuis Maastricht
Organization:
Academisch Ziekenhuis Maastricht
Study Overview
Official Title:
Efficacy Safety and Tolerability of Lacosamide in Patients With Gain-of-function Nav17 Mutations Related Small Fiber Neuropathy a Randomized Double-blind Placebo Controlled Crossover Trial
Status:
COMPLETED
Status Verified Date:
2018-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Lacosamide is a functionalized amino acid with antinociceptive properties in inflammatory and neuropathic pain and displays a unique mechanism it enhances slow inactivation of Nav13 Nav17 and Nav18
Nav17 is expressed predominantly in nociceptive and sympathetic neurons Gain-of-function mutations have been described in Nav17 that result in extreme pain disorders such as SCN9A-associated small fiber neuropathy In the disease states genetically linked to a gain-of-function of Nav17 the sodium channel is mutated to increase the sodium influx resulting in a hyperexcitable sensory neuron and a resultant sensation of pain
The objective of the study is to determine the efficacy and safety of lacosamide a sodium channel blocker in patients with pain due to SCN9A-associated small fiber neuropathy
Nav17 is expressed predominantly in nociceptive and sympathetic neurons Gain-of-function mutations have been described in Nav17 that result in extreme pain disorders such as SCN9A-associated small fiber neuropathy In the disease states genetically linked to a gain-of-function of Nav17 the sodium channel is mutated to increase the sodium influx resulting in a hyperexcitable sensory neuron and a resultant sensation of pain
The objective of the study is to determine the efficacy and safety of lacosamide a sodium channel blocker in patients with pain due to SCN9A-associated small fiber neuropathy
Detailed Description:
Indication Lacosamide is a functionalized amino acid with antinociceptive properties in inflammatory and neuropathic pain and displays a unique mechanism it enhances slow inactivation of Nav13 Nav17 and Nav18
Rationale A significant body of evidence implicates sodium channels in mediating the pathophysiological components of both neuropathic and nociceptive pain This is supported by clinical evidence suggesting that local anaesthetics anticonvulsants and tricyclic compounds that block voltage-gated sodium channels may act as useful therapeutics for managing and treating pain The use of these sodium channel blockers has however been limited by the lack of selectivity for different sodium channel subtypes with often additional central nervous system CNS and cardiovascular side effects Therefore a key to improvement on the limitations of most existing sodium channel blockers is to selectively target those that are involved in pain mechanisms whilst sparing those channels involved in cardiovascular function
Nav17 is expressed predominantly in nociceptive and sympathetic neurons The role of this channel in nociceptive neurons has been characterized by human genetics which indicates an essential and non-redundant role in pain transduction and conduction following noxious stimuli Gain-of-function mutations have been described in Nav17 that result in extreme pain disorders such as inherited erythromelalgia IEM paroxysmal extreme pain disorder PEPD and SCN9A-associated small fiber neuropathy In the disease states genetically linked to a gain-of-function of Nav17 the channel is mutated to increase the sodium influx resulting in a hyperexcitable sensory neuron and a resultant sensation of pain
Lacosamide is a functionalized aminoacid that was synthesized during the development of anticonvulsant drug candidates and has displayed antinociceptive properties in inflammatory and neuropathic pain Lacosamide displays a unique mechanism of action in that it seemingly selectively stabilizes channels into the slow- inactivated state Lacosamide inhibited currents from Nav13 Nav17 and Nav18 but only after prolonged depolarizations consistent with an enhancement in slow-inactivation with no effect on fast inactivation Furthermore lacosamide was better able to discriminate between resting and inactivated channels compared to lidocaine or carbamazepine thus likely allowing for improved selectivity over neurons with a depolarized membrane potential with little tonic block
Small fiber neuropathy SFN is a relatively common disorder of peripheral nerves primarily affecting small somatic fibers autonomic fibers or both In a proportion of patients with SFN no underlying cause can be identified these cases are termed idiopathic SFN Gain-of-function mutations in SCN9A have recently been reported to be present in 28 of patients with idiopathic SFN suggesting an underlying genetic basis for a proportion of patients with this disease Electrophysiological analysis demonstrated multiple gain-of-function changes in the mutant channels with each of the mutations resulting in hyperexcitability in dorsal root ganglion DRG neurons Moreover most of these mutations showed impaired slow inactivation of Nav17 a finding that provides a rationale to evaluate the possible pain reduction potential of lacosamide in this condition
Study Rationale and Objectives The objective of the study is to determine the efficacy and safety of lacosamide a sodium channel blocker in patients with pain due to SCN9A-associated SFN The proposed study plans to recruit patients with clinically diagnosed SFN where a mutation in SCN9A has been confirmed genetically and where possible has been demonstrated on functional testing to cause hyperexcitability of DRG neurons This small precision medicine population provides an opportunity to evaluate the efficacy and safety of lacosamide in treatment of pain due to SCN9A-associated SFN
Rationale A significant body of evidence implicates sodium channels in mediating the pathophysiological components of both neuropathic and nociceptive pain This is supported by clinical evidence suggesting that local anaesthetics anticonvulsants and tricyclic compounds that block voltage-gated sodium channels may act as useful therapeutics for managing and treating pain The use of these sodium channel blockers has however been limited by the lack of selectivity for different sodium channel subtypes with often additional central nervous system CNS and cardiovascular side effects Therefore a key to improvement on the limitations of most existing sodium channel blockers is to selectively target those that are involved in pain mechanisms whilst sparing those channels involved in cardiovascular function
Nav17 is expressed predominantly in nociceptive and sympathetic neurons The role of this channel in nociceptive neurons has been characterized by human genetics which indicates an essential and non-redundant role in pain transduction and conduction following noxious stimuli Gain-of-function mutations have been described in Nav17 that result in extreme pain disorders such as inherited erythromelalgia IEM paroxysmal extreme pain disorder PEPD and SCN9A-associated small fiber neuropathy In the disease states genetically linked to a gain-of-function of Nav17 the channel is mutated to increase the sodium influx resulting in a hyperexcitable sensory neuron and a resultant sensation of pain
Lacosamide is a functionalized aminoacid that was synthesized during the development of anticonvulsant drug candidates and has displayed antinociceptive properties in inflammatory and neuropathic pain Lacosamide displays a unique mechanism of action in that it seemingly selectively stabilizes channels into the slow- inactivated state Lacosamide inhibited currents from Nav13 Nav17 and Nav18 but only after prolonged depolarizations consistent with an enhancement in slow-inactivation with no effect on fast inactivation Furthermore lacosamide was better able to discriminate between resting and inactivated channels compared to lidocaine or carbamazepine thus likely allowing for improved selectivity over neurons with a depolarized membrane potential with little tonic block
Small fiber neuropathy SFN is a relatively common disorder of peripheral nerves primarily affecting small somatic fibers autonomic fibers or both In a proportion of patients with SFN no underlying cause can be identified these cases are termed idiopathic SFN Gain-of-function mutations in SCN9A have recently been reported to be present in 28 of patients with idiopathic SFN suggesting an underlying genetic basis for a proportion of patients with this disease Electrophysiological analysis demonstrated multiple gain-of-function changes in the mutant channels with each of the mutations resulting in hyperexcitability in dorsal root ganglion DRG neurons Moreover most of these mutations showed impaired slow inactivation of Nav17 a finding that provides a rationale to evaluate the possible pain reduction potential of lacosamide in this condition
Study Rationale and Objectives The objective of the study is to determine the efficacy and safety of lacosamide a sodium channel blocker in patients with pain due to SCN9A-associated SFN The proposed study plans to recruit patients with clinically diagnosed SFN where a mutation in SCN9A has been confirmed genetically and where possible has been demonstrated on functional testing to cause hyperexcitability of DRG neurons This small precision medicine population provides an opportunity to evaluate the efficacy and safety of lacosamide in treatment of pain due to SCN9A-associated SFN
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2013-001511-70 | EUDRACT_NUMBER | None | None |