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Clinical Trial of Ezogabine (Retigabine) in ALS Subjects

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02450552
Recruitment Status : Completed
First Posted : May 21, 2015
Results First Posted : August 28, 2019
Last Update Posted : August 28, 2019
Sponsor:
Collaborators:
ALS Association
GlaxoSmithKline
Harvard University
Massachusetts General Hospital
Information provided by (Responsible Party):
Brian Wainger, Massachusetts General Hospital

Tracking Information
First Submitted Date  ICMJE May 19, 2015
First Posted Date  ICMJE May 21, 2015
Results First Submitted Date  ICMJE January 8, 2019
Results First Posted Date  ICMJE August 28, 2019
Last Update Posted Date August 28, 2019
Study Start Date  ICMJE June 2015
Actual Primary Completion Date January 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 12, 2019)
Change in Short-interval Intracortical Inhibition (SICI) Measured by Transcranial Magnetic Stimulation (TMS) [ Time Frame: Screening, Baseline, Week 6, Week 8 ]
Short-interval intracortical inhibition (SICI) or paired-pulse SICI is defined as the ratio of the response after a conditioning pulse equal to 80% of resting motor threshold (RMT) is administered 3 ms prior to the signaling pulse divided by motor evoked potential (MEP) amplitude. Transcranial magnetic stimulation (TMS) is a neurophysiologic test for assessing upper motor neuron function. Change in SICI will be assessed by transcranial magnetic stimulation (TMS) after treatment with 900 mg/day or 600 mg/day of ezogabine vs. matched oral placebo.
Original Primary Outcome Measures  ICMJE
 (submitted: May 20, 2015)
Change in Short-interval Intracortical Inhibition (SICI) Measured by Transcranial Magnetic Stimulation (TMS) [ Time Frame: Screening, Baseline, Week 4, Week 6, Week 8, Week 12 ]
Assessed by transcranial magnetic stimulation (TMS) after treatment with 600 mg/day or 900 mg/day of ezogabine vs. matched oral placebo
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 12, 2019)
  • Change in Resting Motor Evoked Potential (MEP) Threshold (Prespecified Secondary Outcome of Primary Importance) [ Time Frame: Screening, Baseline, Week 6, Week 8 ]
    Resting Motor Evoked Potential (MEP) is the magnetic field strength, measured as a percentage of the maximum stimulator output, that produces at least a 0.05 mV response in at least 5 of 10 consecutive trials.Change in resting MEP threshold will be assessed by Transcranial Magnetic Stimulation (TMS).
  • Change in MEP Amplitude [ Time Frame: Screening, Baseline, Week 6, Week 8 ]
    Motor Evoked Potential (MEP) amplitude is defined as the response when a stimulus equal to 120% of Resting Motor Threshold (RMT) is administered. MEP amplitude is calculated as the geometric mean of replicate estimates. Change in MEP will be assessed by Transcranial Magnetic Stimulation (TMS).
  • Change in Duration of Cortical Silent Period [ Time Frame: Screening, Baseline, Week 6, Week 8 ]
    Cortical silent period (CSP) is the suppression of voluntary muscle contraction elicited by stimulation equal to 120% of resting motor threshold (RMT). CSP duration is measured from the time of the muscle activity suppression to return of muscle activity. Change in duration of cortical silent period is assessed by Transcranial Magnetic Stimulation (TMS).
  • Change in Intracortical Facilitation [ Time Frame: Screening, Baseline, Week 6, Week 8 ]
    Paired-pulse Intracortical facilitation (ICF) is defined as the ratio of the response after a conditioning pulse equal to 80% of Resting Motor Threshold (RMT) is administered 15 milliseconds prior to the signaling pulse divided by Motor Evoked Potential (MEP) amplitude. ICF is calculated as the geometric mean of replicate estimates. Change in intracortical facilitation is assessed by Transcranial Magnetic Stimulation (TMS).
  • Change in Electrotonus [ Time Frame: Screening, Baseline, Week 6, Week 8 ]
    Change in depolarizing electrotonus at 90 to 100 milliseconds was assessed by threshold tracking axonal nerve conduction studies (TTNCS). TTNCS is a neurophysiologic test for assessing lower motor neuron function.
  • Change in Strength Duration Time Constant [ Time Frame: Screening, Baseline, Week 6, Week 8 ]
    Assessed by threshold tracking axonal nerve conduction studies (TTNCS).
  • Change in Recovery Cycle [ Time Frame: Screening, Baseline, Week 6, Week 8 ]
    Lower motor neuron excitability can be measured using change in recovery cycle of superexcitability. Change in recovery cycle of superexcitability after first pre-pulse is assessed by threshold tracking axonal nerve conduction studies (TTNCS). Threshold-tracking nerve conduction studies is a neurophysiologic test for assessing lower motor neuron function.
  • Muscle Cramping Frequency [ Time Frame: Week 1 through Week 10 ]
    Frequency of muscle cramping and maximum pain from muscle cramping was collected by subjects via self-report using a daily muscle cramping diary.
  • Hand Held Dynamometry Force Measurement for Abductor Pollicis Brevis [ Time Frame: Screening, Baseline, Week 4, Week 6, Week 8, Week 12 ]
    Hand held dynamometry (HHD) will be used as a quantitative measure of muscle strength of the abductor pollicis brevis (APB) muscle. HHD will be self-report by study participants using a daily muscle cramping diary.
  • Proportion of Days With Fasciculations [ Time Frame: Week 1 through Week 10 ]
    For the purpose of this study, a fasciculation is a brief, spontaneous contraction affecting a small number of muscle fibers, often causing a flicker of movement under the skin. Defining interference with daily activities may be different for each subject and defining daily activities will be different for each subject. Subjects will self report by diary, days with fasciculations.
  • Number of Participants Who Tolerate Study Drug [ Time Frame: 10 weeks ]
    Participants will be judged tolerant of study drug if they reached their target dose and remain on study drug until planned discontinuation. Tolerability will be summarized as the proportion of participants in a treatment group who are tolerant of study drug.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 20, 2015)
  • Change in Resting Motor Evoked Potential (MEP) Threshold (Prespecified Secondary Outcome of Primary Importance) [ Time Frame: Screening, Baseline, Week 4, Week 6, Week 8, Week 12 ]
    Assessed by TMS
  • Change in MEP Amplitude [ Time Frame: Screening, Baseline, Week 4, Week 6, Week 8, Week 12 ]
    Assessed by TMS
  • Change in MEP latency [ Time Frame: Screening, Baseline, Week 4, Week 6, Week 8, Week 12 ]
    Assessed by TMS
  • Change in Duration of Cortical Silent Period [ Time Frame: Screening, Baseline, Week 4, Week 6, Week 8, Week 12 ]
    Assessed by TMS
  • Change in input/output curve amplitude, slope, midpoint of activation [ Time Frame: Screening, Baseline, Week 4, Week 6, Week 8, Week 12 ]
    Assessed by TMS
  • Change in Intracortical Facilitation [ Time Frame: Screening, Baseline, Week 4, Week 6, Week 8, Week 12 ]
    Assessed by TMS
  • Change in Electrotonus [ Time Frame: Screening, Baseline, Week 4, Week 6, Week 8, Week 12 ]
    Assessed by threshold tracking axonal nerve conduction studies (TTNCS).
  • Change in Strength Duration Time Constant [ Time Frame: Screening, Baseline, Week 4, Week 6, Week 8, Week 12 ]
    Assessed by threshold tracking axonal nerve conduction studies (TTNCS)
  • Change in Recovery Cycle [ Time Frame: Screening, Baseline, Week 4, Week 6, Week 8, Week 12 ]
    Assessed by threshold tracking axonal nerve conduction studies (TTNCS).
  • Change in the safety and tolerability of ezogabine at 2 doses (600 milligrams ezogabine and 900 milligrams ezogabine) as assessed by the number of adverse events experienced over time. [ Time Frame: Screening, Baseline, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12, Week 14, and at the Final Safety Visit, if a subject discontinues study drug early ]
    Information on adverse effects of ezogabine will be determined at each visit by direct questioning of the subjects, clinical examination, review of concomitant medications, vital signs and laboratory test results. Tolerability is defined as the proportion of participants able to reach their target dose and remain on study drug until planned discontinuation.
  • Random cerebral spinal fluid concentration of ezogabine [ Time Frame: Week 6 Visit ]
    Subjects will have a single lumbar puncture done to assess ezogabine concentrations at the Week 6 Visit
  • Random serum concentration of ezogabine [ Time Frame: Week 6 Visit ]
    Blood draw at the Week 6 Visit.
  • Muscle Cramping [ Time Frame: Recorded Screening through Week 14 ]
    self-report, by daily muscle cramping diary
  • Hand Held Dynamometry [ Time Frame: Recorded Screening through Week 14 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: May 20, 2015)
in vitro motor neuron firing and EC50 for ezogabine [ Time Frame: week 4 visit ]
Subject induced pluripotent stem cells will be derived from patient blood samples and differentiated into motor neurons. Motor neuron spontaneous firing rate and EC50 for retigabine on spontaneous firing will be measured.
 
Descriptive Information
Brief Title  ICMJE Clinical Trial of Ezogabine (Retigabine) in ALS Subjects
Official Title  ICMJE A Phase 2 Pharmacodynamic Trial of Ezogabine (Retigabine) on Neuronal Excitability in Amyotrophic Lateral Sclerosis
Brief Summary This study evaluates the effect of retigabine (600 mg/day, 900 mg/day, or placebo) on motor neuron activity in people with Amyotrophic Lateral Sclerosis (ALS). The total study duration is approximately 14 weeks. ALS subjects will take study drug for approximately 10 weeks.
Detailed Description

One of the major disease features of ALS is the progressive death of motor neurons. Human, rodent and stem cell-based model studies support the hypothesis that neuronal hyperexcitability may contribute to neurodegeneration in both sporadic and familial ALS. The investigators are doing this research study to find out whether retigabine will reduce motor neuron excitability in people with ALS. the investigators will also determine whether the drug is tolerable and safe for patients with ALS.

The proposed study will determine how the potassium channel opener ezogabine (retigabine) affects neurophysiological measures of upper and lower motor neuron excitability in ALS patients as assessed by transcranial magnetic stimulation (TMS) and threshold tracking nerve conduction studies (TTNCS), respectively. The study will include the recruitment of approximately 60 unmatched healthy control subjects for analysis of variability of the neurophysiological tests prior to recruitment of ALS subjects. There will also be 12 matched healthy control subjects, recruited at the same time as ALS subjects.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Amyotrophic Lateral Sclerosis
Intervention  ICMJE
  • Drug: Ezogabine
    Potiga is FDA-approved for adjunctive treatment of partial-onset seizures in patients aged 18 years and older who have responded inadequately to several alternative treatments.
    Other Names:
    • Potiga
    • Retigabine
  • Drug: Placebo
    Matched placebo
Study Arms  ICMJE
  • Experimental: Oral ezogabine 600 mg/day
    Intervention: Drug: Ezogabine
  • Experimental: Oral ezogabine 900 mg/day
    Intervention: Drug: Ezogabine
  • Placebo Comparator: Placebo
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 26, 2018)
65
Original Estimated Enrollment  ICMJE
 (submitted: May 20, 2015)
192
Actual Study Completion Date  ICMJE February 2018
Actual Primary Completion Date January 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

ALS Subject Inclusion Criteria:

  • Male or female, aged 18 to 80.
  • Sporadic or familial ALS diagnosed as possible, laboratory-supported probable, probable, or definite as defined by revised El Escorial criteria.
  • Slow vital capacity (SVC) measure ≥ 50% of predicted for gender, height and age at the Screening Visit,OR in the opinion of the SI, ability to perform and safely complete all study visit procedures.
  • Subjects must not have taken riluzole for at least 30 days, or be on a stable dose of riluzole for at least 30 days prior to the Screening Visit and continue on the stable dose throughout the course of the study (riluzole-naïve subjects are permitted in the study).
  • Subjects must be able to swallow oral medication at the Screening Visit and expected to be able to swallow tablets throughout the course of the study.
  • Capable of providing informed consent and following trial procedures.
  • Geographically accessible to the site.
  • Women must not be able to become pregnant (e.g., post menopausal, surgically sterile, or using adequate birth control methods) for the duration of the study and three months after study completion. Adequate contraception includes: abstinence, hormonal contraception (oral contraception, implanted contraception, injected contraception or other hormonal contraception, for example patch or contraceptive ring), intrauterine device (IUD) in place for ≥ 3 months, barrier method in conjunction with spermicide, or another adequate method.
  • Use of medications known to affect the neurophysiology measures in the study must be scheduled, not as needed (pro re nata, PRN). A subject must have been on a fixed dose for 30 days prior to the Screening Visit, and there must be no reason to believe that a subsequent change would be necessary during the course of the study. These medications include: benzodiazepines, muscle relaxants, tricyclic antidepressants, selective serotonin reuptake inhibitors, non-selective serotonin reuptake inhibitors, hypnotics (including anti-histamines) and anti-cholinergics.
  • TMS shows sufficient MEP amplitude and/or NCS studies show sufficient CMAP amplitude.

ALS Subject Exclusion Criteria:

  • Medical condition, laboratory finding, or physical exam finding that precludes participation.
  • Serum AST and ALT value >2.0 times the upper normal limit
  • Clinically significant conduction abnormalities on electrocardiogram or a known history of cardiac arrhythmia, myocardial infarction within the past 24 months, or congestive heart failure.
  • Estimated glomerular filtration rate < 50 mL/min at Screening Visit.
  • Concomitant digoxin treatment.
  • Known allergic reactions to components of the study product(s).
  • Exposure to any other agent currently under investigation for the treatment of patients with ALS (off-label use or investigational) within 30 days of the Screening Visit including ezogabine, exposure to cell replacement therapy within six months of the Screening Visit or any prior intraparenchymal cell replacement injection within the spinal cord or brain at anytime in the past.
  • Presence of tracheostomy at the Screening Visit.
  • History of clinically significant urinary retention, , or current use of medications to treat urinary retention.
  • History of drug and or alcohol abuse within 12 months of the Screening Visit.
  • The presence of unstable psychiatric disease, cognitive impairment, or dementia that would impair ability of the subject to provide informed consent, according to SI judgment.
  • Clinically significant history of unstable or severe cardiac, oncologic, hepatic, or renal disease, or other uncontrolled medical condition.
  • Presence of feeding tube.
  • Current use of antipsychotic, antiepileptic (except benzodiazepines, gabapentin, pregabalin) or class 1 (e.g. flecainide) or class 3 (e.g. amiodarone) antiarrhythmic medications. Quinidine or a quinidine-containing drug is allowed if the quinidine dose is not greater than 20 mg/day (for a full list of medications, please reference the study MOP).
  • Inability to perform either TMS or NCS studies due to insufficient MEP or CMAP amplitude.
  • Pregnant women or women currently breastfeeding.
  • Contraindication to TMS studies including ferromagnetic metal in the head or neck (potentially found in aneurysm clips, implanted medication pumps, implanted brain stimulators, pacemakers, cochlear implants), or history of epilepsy. Dental fillings are permitted.
  • Anything else that, in the opinion of the SI, would place the subject at increased risk or preclude the subject's full compliance with or completion of the study.

Healthy Control Subject Inclusion Criteria:

  • Male or female, aged 18 to 80.
  • Absence of a known neurological disorder.
  • Capable of providing informed consent and following trial procedures.
  • Geographically accessible to the site.
  • Age (+/- 10 years and site-matched to a ALS participant within 6 months of their Baseline visit).[Matched controls only]
  • TMS shows sufficient MEP amplitude and/or NCS studies show sufficient CMAP amplitude (amplitudes defined in MOP).
  • Use of medications known to affect the neurophysiology measures in the study must be scheduled, not as needed (pro re nata, PRN). A subject must have been on a fixed dose for 30 days prior to the Screening Visit, and there must be no reason to believe that a subsequent change would be necessary during the course of the study. These medications include: benzodiazepines, muscle relaxants, tricyclic antidepressants, selective serotonin reuptake inhibitors, non-selective serotonin reuptake inhibitors, hypnotics (including anti-histamines) and anti-cholinergics.

Healthy Control Subject Exclusion Criteria:

  • History of ALS or other neurodegenerative disease.
  • Presence of positive family history of ALS.
  • Current use of an antipsychotic or antiarrhythmic medication
  • Definitely or possibly pregnant.
  • Contraindication to TMS studies including ferromagnetic metal in the head or neck ( potentially found in aneurysm clips, implanted medication pumps, implanted brain stimulators, pacemakers, cochlear implants), or history of epilepsy. Dental fillings are permitted.
  • Anything that, in the opinion of the SI, would place the subject at increased risk or preclude the subject's full compliance with or completion of the study.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02450552
Other Study ID Numbers  ICMJE 2014D002776
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Brian Wainger, Massachusetts General Hospital
Study Sponsor  ICMJE Brian Wainger
Collaborators  ICMJE
  • ALS Association
  • GlaxoSmithKline
  • Harvard University
  • Massachusetts General Hospital
Investigators  ICMJE
Principal Investigator: Brian Wainger, MD, PhD Massachusetts General Hospital
PRS Account Massachusetts General Hospital
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP