Clinical Trial of Ezogabine (Retigabine) in ALS Subjects

NCT02450552 | Completed Phase 2 Results DMC

• 1 other identifier: 2014D002776
• Study Type: interventional
• Target: 65
• Locations: 1 country
• Sites: 12

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.

Conditions

Amyotrophic Lateral Sclerosis

Keywords

Amyotrophic Lateral Sclerosis; ALS; Lou Gehrig

Outcome Measures

Primary Outcomes (1)

• Change in Short-interval Intracortical Inhibition (SICI) Measured by Transcranial Magnetic Stimulation (TMS)

  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.

  Screening, Baseline, Week 6, Week 8

Secondary Outcomes (11)

• Change in Resting Motor Evoked Potential (MEP) Threshold (Prespecified Secondary Outcome of Primary Importance)

  Screening, Baseline, Week 6, Week 8

• Change in MEP Amplitude

  Screening, Baseline, Week 6, Week 8

• Change in Duration of Cortical Silent Period

  Screening, Baseline, Week 6, Week 8

• Change in Intracortical Facilitation

  Screening, Baseline, Week 6, Week 8

• Change in Electrotonus

  Screening, Baseline, Week 6, Week 8

Study Arms (3)

Oral ezogabine 600 mg/day

EXPERIMENTAL

Drug: Ezogabine

Oral ezogabine 900 mg/day

EXPERIMENTAL

Drug: Ezogabine

Placebo

PLACEBO COMPARATOR

Drug: Placebo

Interventions

Ezogabine DRUG

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.

Also known as: Potiga, Retigabine

Oral ezogabine 600 mg/day; Oral ezogabine 900 mg/day

Placebo DRUG

Matched placebo

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Brian Wainger: lead
• ALS Association: collaborator
• GlaxoSmithKline: collaborator
• Harvard University: collaborator
• Massachusetts General Hospital: collaborator

Study Sites (12)

Barrow Neuological Institute

Phoenix, Arizona, 85013, United States

Location

Cedars-Sinai

Los Angeles, California, 90048, United States

Location

UC Irvine Medical Center

Orange, California, 92868, United States

Location

Mayo Clinic in Florida

Jacksonville, Florida, 32224, United States

Location

Augusta University (Georgia Regents Medical Center)

Augusta, Georgia, 30901, United States

Location

Johns Hopkins Hospital

Baltimore, Maryland, 21287, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Hospital for Special Surgery

New York, New York, 10021, United States

Location

Duke University Hospital

Durham, North Carolina, 27705, United States

Location

Penn State College of Medicine Milton S. Hershey Medical Center

Hershey, Pennsylvania, 17033, United States

Location

Related Publications (1)

• Wainger BJ, Macklin EA, Vucic S, McIlduff CE, Paganoni S, Maragakis NJ, Bedlack R, Goyal NA, Rutkove SB, Lange DJ, Rivner MH, Goutman SA, Ladha SS, Mauricio EA, Baloh RH, Simmons Z, Pothier L, Kassis SB, La T, Hall M, Evora A, Klements D, Hurtado A, Pereira JD, Koh J, Celnik PA, Chaudhry V, Gable K, Juel VC, Phielipp N, Marei A, Rosenquist P, Meehan S, Oskarsson B, Lewis RA, Kaur D, Kiskinis E, Woolf CJ, Eggan K, Weiss MD, Berry JD, David WS, Davila-Perez P, Camprodon JA, Pascual-Leone A, Kiernan MC, Shefner JM, Atassi N, Cudkowicz ME. Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial. JAMA Neurol. 2021 Feb 1;78(2):186-196. doi: 10.1001/jamaneurol.2020.4300.

  PMID: 33226425 DERIVED

MeSH Terms

Conditions

Amyotrophic Lateral Sclerosis

Interventions

ezogabine

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; TDP-43 Proteinopathies; Neuromuscular Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Results Point of Contact

• Title: Protocol Investigator
• Organization: Massachusetts General Hospital - Neurological Clinical Research Institute

Brian.Wainger@MGH.HARVARD.EDU

617-726-2000

Study Officials

• Brian Wainger, MD, PhD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Physician

Study Record Dates

• First Submitted: May 19, 2015
• First Posted: May 21, 2015
• Study Start: June 1, 2015
• Primary Completion: January 1, 2018
• Study Completion: February 1, 2018
• Last Updated: August 28, 2019
• Results First Posted: August 28, 2019

Record last verified: 2019-08

Locations

US (12)