Safety and Tolerability of Lacosamide in Patients With Gain-of-function Nav1.7 Mutations Related Small Fiber Neuropathy

NCT01911975 | Completed Phase 3 DMC

• 2 other identifiers: SFN-Lacosamide2013-001511-70
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

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 Nav1.3, Nav1.7, and Nav1.8. Nav1.7 is expressed predominantly in nociceptive and sympathetic neurons. Gain-of-function mutations have been described in Nav1.7 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 Nav1.7, 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.

Conditions

Small Fiber Neuropathy

Keywords

Small Fiber Neuropathy; Painful Neuropathy; NAV1.7 Voltage-Gated Sodium Channel; SCN9A

Outcome Measures

Primary Outcomes (1)

• Pain Intensity Numerical Rating Scale

  mean daily pain intensity is assesed twice a day, during a period of 33 weeks

Secondary Outcomes (6)

• Daily Sleep Interference Scale

  Daily sleep interference will be assesed once daily, during a period of 33 weeks

• • Adverse Events, Laboratory Safety Tests (Hematology, Clinical Chemistry, Urinalysis), Blood Pressure, Pulse Rate, ECG.

  At start of the study and 5 times during 33 weeks

• Small Fiber Neuropathy Symptoms Inventory Questionnaire (SFN-SIQ).

  SFN-SIQ will be assesed 13 times during 33 weeks

• Patient Global Impression of Change (PGIC).

  Global impression of change will be assesed 12 times during 33 weeks

• Neuropathic Pain Scale (NPS).

  Neuropathic pain will be assesed 13 times during 33 weeks.

Study Arms (2)

Placebo

PLACEBO COMPARATOR

Patients with gain-of-function Nav 1.7 related small fiber neuropathy in this arm will receive placebo.

Drug: Placebo

Lacosamide

EXPERIMENTAL

Patients with gain-of-function Nav 1.7 related small fiber neuropathy in this arm will receive lacosamide.

Drug: Lacosamide

Interventions

Lacosamide DRUG

comparison between lacosamide 200mg twice daily and microcrystalline cellulose (placebo) 200mg twice daily.

Also known as: Vimpat

Lacosamide

Placebo DRUG

comparison between microcrystalline cellulose (placebo) 200mg twice daily and lacosamide 200mg twice daily.

Also known as: Microcrystalline cellulose

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male and/or female subjects between the ages of 18 and 80 years.
• Presence of a clinical diagnosis of Small Fiber Neuropathy (SFN), with at least 2 of the following clinical symptoms:
• Burning feet.
• Allodynia.
• Diminished pain and/or temperature sensation.
• Dry eyes or mouth.
• Orthostatic dizziness.
• Bowel disturbances (constipation, diarrhea, gastroparesis).
• Urinary disturbances.
• Sweat changes (hyper-/hypohidrosis).
• Visual accommodation problems and/or blurred vision.
• Hot flashes/palpitations.
• Impotence, diminished ejaculation or lubrication.
• In addition to the clinical diagnosis of SFN, presence of confirmed abnormality on intra-epidermal nerve fiber density evaluation (IENFD) and/or Quantitative Sensory Testing (QST) and a mutation in the SCN9A gene, confirmed by sequencing. Where possible, in vitro confirmation of the functionality of the mutation should have been performed and documented.
• Presence of pain due to SFN for at least 3 months prior to Screening and an average self-reported pain score of at least 3 during this time.

You may not qualify if:

• Subjects with predominantly signs of large nerve fiber involvement, clinically significant abnormal nerve conduction studies.
• History or presence of illnesses known to cause SFN (excluding diabetes mellitus).
• Subjects with other severe pain conditions which may impair the self-assessment of pain due to SFN.
• Any condition possibly affecting drug intake and absorption.
• History of known alcohol, analgesic or illicit drug abuse within 12 months of Screening.
• Subjects taking medications with activity at sodium channels. These medications are prohibited until the end of the study period and require a washout period of at least 5 half lives (90 days for capsaicin patches) prior to the Screening visit.
• lead ECG demonstrating QTcF (Fridericia's correction) \>450 or a QRS interval \>120 msec at Screening. If QTcF exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be repeated two more times and the average of the three QTcF values should be used to determine the subject's eligibility.
• Severe renal impairment (creatinine clearance ≤ 30 mL/min).
• Treatment with an investigational drug within 30 days or 5 half-lives preceding the first dose of study medication.
• Participation in other studies during the period of current study participation, or has planned surgery during the course of the study.
• Pregnant females; breastfeeding females; females of childbearing potential not using effective contraception or not agreeing to continue effective contraception for at least 28 days after the last dose of investigational product.
• Other clinically significant or unstable, or severe acute or chronic medical or psychiatric/psychological condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study.
• In the case of incidental findings the patient and his/her treating physician will be informed and asked to undertake action if necessary. If a patient does not want to be informed about possible incidental findings, nor wants his treating physician to be informed, he or she cannot participate in this study.

Sponsors & Collaborators

• Academisch Ziekenhuis Maastricht: lead

Study Sites (1)

Maastricht University Medical Center

Maastricht, Netherlands

Location

Related Publications (3)

• Faber CG, Hoeijmakers JG, Ahn HS, Cheng X, Han C, Choi JS, Estacion M, Lauria G, Vanhoutte EK, Gerrits MM, Dib-Hajj S, Drenth JP, Waxman SG, Merkies IS. Gain of function Nanu1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol. 2012 Jan;71(1):26-39. doi: 10.1002/ana.22485. Epub 2011 Jun 22.

  PMID: 21698661 BACKGROUND

• de Greef BTA, Hoeijmakers JGJ, Geerts M, Oakes M, Church TJE, Waxman SG, Dib-Hajj SD, Faber CG, Merkies ISJ. Lacosamide in patients with Nav1.7 mutations-related small fibre neuropathy: a randomized controlled trial. Brain. 2019 Feb 1;142(2):263-275. doi: 10.1093/brain/awy329.

  PMID: 30649227 DERIVED

• de Greef BT, Merkies IS, Geerts M, Faber CG, Hoeijmakers JG. Efficacy, safety, and tolerability of lacosamide in patients with gain-of-function Nav1.7 mutation-related small fiber neuropathy: study protocol of a randomized controlled trial-the LENSS study. Trials. 2016 Jun 30;17(1):306. doi: 10.1186/s13063-016-1430-1.

  PMID: 27363506 DERIVED

MeSH Terms

Conditions

Small Fiber Neuropathy; Neuropathy, Painful

Interventions

Lacosamide; microcrystalline cellulose

Condition Hierarchy (Ancestors)

Peripheral Nervous System Diseases; Neuromuscular Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Acetamides; Amides; Organic Chemicals; Acetates; Acids, Acyclic; Carboxylic Acids

Study Officials

• Catharina G Faber, MD, PhD

  Academisch Ziekenhuis Maastricht

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD

Study Record Dates

• First Submitted: July 13, 2013
• First Posted: July 30, 2013
• Study Start: September 1, 2014
• Primary Completion: May 1, 2017
• Study Completion: May 1, 2017
• Last Updated: January 10, 2018

Record last verified: 2018-01

Locations

NL (1)