A Study of Oral Dosing of Gabapentin Enacarbil in Japanese Restless Legs Syndrome Patients

Gabapentin Enacarbil Post-marketing Clinical Study A Randomized, Double-blind, Placebo-controlled, Parallel-group Study in Subjects With Restless Legs Syndrome.

The objective of this study was to assess the efficacy of once-daily oral administration of gabapentin enacarbil versus placebo, based on the change in International Restless Legs Syndrome Rating Scale (IRLS) score in participants with moderate-to-severe idiopathic restless legs syndrome. This study also assessed the safety of Gabapentin enacarbil.

Study Overview

• Status: Completed
• Conditions: Restless Legs Syndrome (RLS)
• Intervention / Treatment: Drug: Placebo; Drug: Gabapentin enacarbil

Detailed Description

After 1 week run in period with single-blind placebo, participants meeting the inclusion and none of the exclusion criteria were randomized to receive double-blind treatment with either gabapentin enacarbil 600 mg or placebo for 12 weeks treatment period. After then, single-blind placebo was given for 1 week for follow-up observation.

• Study Type: Interventional
• Enrollment (Actual): 375
• Phase: Phase 4

Contacts and Locations

Study Locations

• Japan
  • Chiba, Japan
    • Site JP00031
  • Fukuoka, Japan
    • Site JP00036
  • Kyoto, Japan
    • Site JP00020
  • Kyoto, Japan
    • Site JP00035
  • Osaka, Japan
    • Site JP00047
  • Osaka, Japan
    • Site JP00010
  • Osaka, Japan
    • Site JP00026
  • Osaka, Japan
    • Site JP00037
  • Osaka, Japan
    • Site JP00039
  • Saitama, Japan
    • Site JP00030
  • Saitama, Japan
    • Site JP00044
  • Aichi
    • Nagoya, Aichi, Japan
      • Site JP00025
    • Nagoya, Aichi, Japan
      • Site JP00029
    • Nagoya, Aichi, Japan
      • Site JP00040
  • Fukuoka
    • Kitakyushu, Fukuoka, Japan
      • Site JP00006
    • Kitakyushu, Fukuoka, Japan
      • Site JP00022
  • Hokkaido
    • Sapporo, Hokkaido, Japan
      • Site JP00002
    • Sapporo, Hokkaido, Japan
      • Site JP00003
    • Sapporo, Hokkaido, Japan
      • Site JP00004
    • Sapporo, Hokkaido, Japan
      • Site JP00023
  • Hyogo
    • Kawanishi, Hyogo, Japan
      • Site JP00041
    • Kobe, Hyogo, Japan
      • Site JP00005
  • Kanagawa
    • Kawasaki, Kanagawa, Japan
      • Site JP00038
    • Yokohama, Kanagawa, Japan
      • Site JP00007
    • Yokohama, Kanagawa, Japan
      • Site JP00017
    • Yokohama, Kanagawa, Japan
      • Site JP00049
    • Yokohama, Kanagawa, Japan
      • Site JP00050
    • Yokosuka, Kanagawa, Japan
      • Site JP00009
  • Osaka
    • Sakai, Osaka, Japan
      • Site JP00032
  • Saitama
    • Tokorozawa, Saitama, Japan
      • Site JP00043
  • Tokyo
    • Arakawa, Tokyo, Japan
      • Site JP00012
    • Chofu, Tokyo, Japan
      • Site JP00001
    • Chofu, Tokyo, Japan
      • Site JP00028
    • Chuo, Tokyo, Japan
      • Site JP00018
    • Chuo, Tokyo, Japan
      • Site JP00024
    • Meguro, Tokyo, Japan
      • Site JP00048
    • Musashino, Tokyo, Japan
      • Site JP00034
    • Nakano, Tokyo, Japan
      • Site JP00046
    • Ota, Tokyo, Japan
      • Site JP00019
    • Shibuya, Tokyo, Japan
      • Site JP00011
    • Shinagawa, Tokyo, Japan
      • Site JP00013
    • Shinagawa, Tokyo, Japan
      • Site JP00015
    • Shinagawa, Tokyo, Japan
      • Site JP00016
    • Shinjuku, Tokyo, Japan
      • Site JP00008
    • Shinjuku, Tokyo, Japan
      • Site JP00014
    • Shinjuku, Tokyo, Japan
      • Site JP00021

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subject has Restless Legs Syndrome (RLS), based on the International Restless Legs Syndrome Study Group (IRLSSG) Diagnostic Criteria.
• Subject has reported history of RLS symptoms for at least 15 days in the month prior to the first dosing; if on treatment, this frequency of symptoms was started before treatment.
• Subject with International Restless Legs Syndrome Rating Scale (IRLS) score ≥ 15.
• Subject has discontinued dopamine agonists, and/or gabapentin at least 1 week prior to the first dosing.
• Subject has discontinued other treatments for RLS at least 2 weeks prior to the first dosing.
• Female subject must either:

Be of non-childbearing potential:

• Post-menopausal (defined as at least 1 year without any menses) prior to Screening, or
• documented surgically sterile

Or, if of childbearing potential:

• Agree not to try to become pregnant during the study and for 28 days after the final study drug administration
• And have a negative urine pregnancy test at Screening

• And, if heterosexually active, agree to consistently use two forms of highly effective birth control starting at Screening and throughout the study period and for 28 days after the final study drug administration.

  • Female subject must agree not to breastfeed starting at Screening and throughout the study period, and for 28 days after the final study drug administration.
  • Female subject must not donate ova starting at Screening and throughout the study period, and for 28 days after the final study drug administration.
  • Subject agrees not to participate in another interventional study while on treatment.
  • Subject with a Body Mass Index of ≥ 18.5 and < 30.
  • Subject with estimated creatinine clearance of ≥ 60 mL/min.

Exclusion Criteria:

• Subject has a sleep disorder that may significantly affect the assessment of RLS.
• Subject has a history of RLS symptom augmentation or end-of-dose rebound with previous dopamine agonist treatment.
• Subject has neurologic disease or movement disorder.
• Subject has poorly controlled diabetes, iron deficiency anemia, or are currently taking any sedative/hypnotic.
• Subject has a history of suicide attempt within 6 months prior to informed consent.
• Subject has a high level of Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST).
• Subject is currently suffering from moderate or severe depression.
• Subject has a history of alcohol dependence or drug abuse, or subject had alcohol or drug abuse or dependence in the last 1 year.
• Subject is a shift worker, professional driver, or operator of dangerous machinery.
• Subject has clinically significant or unstable medical conditions.
• Subject has a history of hypersensitivity reaction to gabapentin.
• Subject has previously taken pregabalin, gabapentin enacarbil, or the study drug of Gabapentin enacarbil.
• Subject has participated in a clinical study for another investigational drug or medical device or post-marketing clinical study within 12 weeks (84 days) prior to the first dosing, or is currently participating in any of these studies.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo was administered orally once daily after the evening meal.	Drug: Placebo; Oral administration
Experimental: Gabapentin enacarbil; Gabapentin enacarbil was administered orally once daily after the evening meal. Participants with an estimated creatinine clearance of ≥ 60 mL/min to < 90 mL/min at the start of the run-in period were administrated gabapentin enacarbil 300 mg for 1 week followed by gabapentin enacarbil 600 mg for 11 weeks.	Drug: Gabapentin enacarbil; Oral administration; Other Names: Regnite

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in International Restless Legs Syndrome Rating Scale (IRLS) Score at Week 12	The IRLS consisted of 10-item scale for assessing severity of restless legs syndrome (RLS) with each item ranging from 0 (no symptoms) to 4 (very severe symptoms). The total IRLS score ranges from 0 to 40. Higher IRLS score indicated greater disease activity. Mixed Model of Repeated Measurements (MMRM) model with compound symmetry as a covariance structure was used. The explanatory variables of the model included treatment group, IRLS score at baseline, age category, estimated creatinine clearance category, time point, and interaction of treatment group and time point.	Baseline and week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in IRLS Score at Each Time Point	ANCOVA model with the baseline value as a covariate was used.	Baseline and weeks 1, 2, 4, 6, 8, 10, 12 and EoT (week 12)
Percentage of Participants With an Investigator-rated Clinical Global Impression (ICGI) Response	ICGI was assessed by 7-point ordinate scale. Participants who were "Very much improved" or "Much improved" were defined as responders.	EoT (week 12)
Percentage of Participants With a Patient-rated Clinical Global Impression (PCGI) Response	PCGI was assessed by 7-point ordinate scale. Participants who were "Very much improved" or "Much improved" were defined as responders.	EoT (week 12)
Change From Baseline in Pittsburgh Sleep Quality Index Total Score (PSQI)	The self-rated items of the PSQI generate seven component scores (range of subscale scores, 0-3). The sum of these seven component scores yielded one global score of subjective sleep quality (range, 0-21). Higher scores represent poorer subjective sleep. ANCOVA model with the baseline value as a covariate was used.	Baseline and EoT (week 12)
Change From Baseline in Athens Insomnia Scale	Athens Insomnia Scale consisted of 8-item scale (range of subscale scores, 0-3). The scale range of Athens Insomnia was 0-24. Higher scores represent poorer sleep quality. ANCOVA model with the baseline value as a covariate was used.	Baseline and EoT (week 12)
Change From Baseline in Restless Legs Syndrome (RLS) Pain Score	The scale range of RLS pain score was 0-10. Higher scores represent greater RLS pain intensity. ANCOVA model with the baseline value as a covariate was used.	Baseline and EoT (week 12)
Change From Baseline in Health Status Score of EuroQol-5 Dimension-5 Level (EQ-5D-5L)	Health status was assessed by general visual analog scale (VAS). The VAS ranges from 0 (worst health status) and 100 (best health status).	Baseline and EoT (week 12)
Number of Participants With Adverse Events	Treatment-emergent adverse events (TEAE) was defined as an adverse event (AE) with onset after the start of the run-in period. A drug-related TEAE was a TEAE with at least a possible relationship to the study drug as assessed by the investigator. Serious TEAE was an AE considered serious.	From first dose of study drug up to week 13

Collaborators and Investigators

• Sponsor: Astellas Pharma Inc

Publications and helpful links

Helpful Links

• Link to results on the Astellas Clinical Study Results website

Study record dates

Study Major Dates

• Study Start (Actual): March 30, 2017
• Primary Completion (Actual): June 25, 2018
• Study Completion (Actual): June 25, 2018

Study Registration Dates

• First Submitted: February 12, 2017
• First Submitted That Met QC Criteria: February 12, 2017
• First Posted (Actual): February 15, 2017

Study Record Updates

• Last Update Posted (Actual): October 29, 2019
• Last Update Submitted That Met QC Criteria: October 15, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: Restless Legs Syndrome; ASP8825; Gabapentin enacarbil
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Nervous System Diseases; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Neurologic Manifestations; Neurobehavioral Manifestations; Disease; Dyskinesias; Psychomotor Disorders; Parasomnias; Syndrome; Psychomotor Agitation; Restless Legs Syndrome; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Tranquilizing Agents; Psychotropic Drugs; Anti-Anxiety Agents; Anticonvulsants; Antimanic Agents; Gabapentin
• Other Study ID Numbers: 8825-CL-0101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Access to anonymized individual participant level data will not be provided for this trial as it meets one or more of the exceptions described on www.clinicalstudydatarequest.com under "Sponsor Specific Details for Astellas."

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes