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Clinical Trial of Ezogabine (Retigabine) in ALS Subjects

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ClinicalTrials.gov Identifier: NCT02450552
Recruitment Status : Active, not recruiting
First Posted : May 21, 2015
Last Update Posted : May 7, 2018
Sponsor:
Collaborators:
ALS Association
GlaxoSmithKline
Harvard University
Massachusetts General Hospital
Information provided by (Responsible Party):
Brian Wainger, Massachusetts General Hospital

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.

Condition or disease Intervention/treatment Phase
Amyotrophic Lateral Sclerosis Drug: Ezogabine Drug: Placebo Phase 2

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 : Interventional  (Clinical Trial)
Estimated Enrollment : 192 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 2 Pharmacodynamic Trial of Ezogabine (Retigabine) on Neuronal Excitability in Amyotrophic Lateral Sclerosis
Study Start Date : June 2015
Actual Primary Completion Date : February 2018
Estimated Study Completion Date : September 2018


Arm Intervention/treatment
Experimental: Oral ezogabine 600 mg/day 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

Experimental: Oral ezogabine 900 mg/day 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

Placebo Comparator: Placebo Drug: Placebo
Matched placebo




Primary Outcome Measures :
  1. Change in short-interval intracortical inhibition (SICI) measured by transcranial magnetic stimulation (TMS) [ Time Frame: Screening, Baseline, Week 6, Week 8 ]
    Assessed by transcranial magnetic stimulation (TMS) after treatment with 600 mg/day or 900 mg/day of ezogabine vs. matched oral placebo


Secondary Outcome Measures :
  1. Change in resting motor evoked potential (MEP) threshold (prespecified secondary outcome of primary importance) [ Time Frame: Screening, Baseline, Week 6, Week 8 ]
    Assessed by TMS

  2. Change in MEP amplitude [ Time Frame: Screening, Baseline, Week 6, Week 8 ]
    Assessed by TMS

  3. Change in MEP latency [ Time Frame: Screening, Baseline, Week 6, Week 8 ]
    Assessed by TMS

  4. Change in duration of cortical silent period [ Time Frame: Screening, Baseline, Week 6, Week 8 ]
    Assessed by TMS

  5. Change in input/output curve amplitude, slope, midpoint of activation [ Time Frame: Screening, Baseline, Week 6, Week 8 ]
    Assessed by TMS

  6. Change in intracortical facilitation [ Time Frame: Screening, Baseline, Week 6, Week 8 ]
    Assessed by TMS

  7. Change in electrotonus [ Time Frame: Screening, Baseline, Week 6, Week 8 ]
    Assessed by threshold tracking axonal nerve conduction studies (TTNCS).

  8. Change in strength duration time constant [ Time Frame: Screening, Baseline, Week 6, Week 8 ]
    Assessed by threshold tracking axonal nerve conduction studies (TTNCS)

  9. Change in recovery cycle [ Time Frame: Screening, Baseline, Week 6, Week 8 ]
    Assessed by threshold tracking axonal nerve conduction studies (TTNCS).

  10. 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.

  11. 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. the LP is OPTIONAL.

  12. Random serum concentration of ezogabine [ Time Frame: Week 6 Visit ]
    Blood draw at the Week 6 Visit.

  13. Muscle Cramping [ Time Frame: Recorded Screening through Week 14 ]
    self-report, by daily muscle cramping diary

  14. Hand Held Dynamometry [ Time Frame: Recorded Screening through Week 14 ]

Other Outcome Measures:
  1. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02450552


Locations
United States, Arizona
Barrow Neuological Institute
Phoenix, Arizona, United States, 85013
United States, California
Cedars-Sinai
Los Angeles, California, United States, 90048
UC Irvine Medical Center
Orange, California, United States, 92868
United States, Florida
Mayo Clinic in Florida
Jacksonville, Florida, United States, 32224
United States, Georgia
Augusta University (Georgia Regents Medical Center)
Augusta, Georgia, United States, 30901
United States, Maryland
Johns Hopkins Hospital
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
United States, New York
Hospital for Special Surgery
New York, New York, United States, 10021
United States, North Carolina
Duke University Hospital
Durham, North Carolina, United States, 27705
United States, Pennsylvania
Penn State College of Medicine Milton S. Hershey Medical Center
Hershey, Pennsylvania, United States, 17033
Sponsors and Collaborators
Brian Wainger
ALS Association
GlaxoSmithKline
Harvard University
Massachusetts General Hospital
Investigators
Principal Investigator: Brian Wainger, MD, PhD Massachusetts General Hospital

Responsible Party: Brian Wainger, Physician, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT02450552     History of Changes
Other Study ID Numbers: 2014D002776
First Posted: May 21, 2015    Key Record Dates
Last Update Posted: May 7, 2018
Last Verified: May 2018

Keywords provided by Brian Wainger, Massachusetts General Hospital:
Amyotrophic Lateral Sclerosis
ALS
Lou Gehrig

Additional relevant MeSH terms:
Sclerosis
Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases
Ezogabine
Anticonvulsants
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action