Restless Legs Syndrome (RLS)
Conditions
Keywords
Restless Legs Syndrome, ASP8825, Gabapentin enacarbil
Brief summary
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.
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.
Interventions
DRUGPlacebo
Oral administration
Oral administration
Sponsors
Astellas Pharma Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to 80 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in International Restless Legs Syndrome Rating Scale (IRLS) Score at Week 12 | Baseline and 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With an Investigator-rated Clinical Global Impression (ICGI) Response | EoT (week 12) | ICGI was assessed by 7-point ordinate scale. Participants who were Very much improved or Much improved were defined as responders. |
| Percentage of Participants With a Patient-rated Clinical Global Impression (PCGI) Response | EoT (week 12) | PCGI was assessed by 7-point ordinate scale. Participants who were Very much improved or Much improved were defined as responders. |
| Change From Baseline in Pittsburgh Sleep Quality Index Total Score (PSQI) | Baseline and EoT (week 12) | 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. |
| Change From Baseline in IRLS Score at Each Time Point | Baseline and weeks 1, 2, 4, 6, 8, 10, 12 and EoT (week 12) | ANCOVA model with the baseline value as a covariate was used. |
| Change From Baseline in Restless Legs Syndrome (RLS) Pain Score | Baseline and EoT (week 12) | 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. |
| Change From Baseline in Health Status Score of EuroQol-5 Dimension-5 Level (EQ-5D-5L) | Baseline and EoT (week 12) | Health status was assessed by general visual analog scale (VAS). The VAS ranges from 0 (worst health status) and 100 (best health status). |
| Number of Participants With Adverse Events | From first dose of study drug up to week 13 | 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. |
| Change From Baseline in Athens Insomnia Scale | Baseline and EoT (week 12) | 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. |
Countries
Japan
Participant flow
Recruitment details
Participants with moderate to severe idiopathic restless legs syndrome were enrolled in 51 study sites in Japan.
Pre-assignment details
Participants received single-blind placebo for 1 week (run-in period). Subsequently, eligible participants were randomized to receive gabapentin enacarbil or placebo orally once daily after dinner for 12 weeks (treatment period).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo was administered orally once daily after the evening meal. | 186 |
| 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 (upward titration period) followed by gabapentin enacarbil 600 mg for 11 weeks. | 189 |
| Total | 375 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 4 |
| Overall Study | Lack of Efficacy | 1 | 3 |
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Miscellaneous | 0 | 1 |
| Overall Study | Protocol Deviation | 3 | 3 |
| Overall Study | Withdrawal by Subject | 3 | 2 |
| Overall Study | Worsening of the target disease | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Gabapentin Enacarbil | Total |
|---|---|---|---|
| Age, Continuous | 52.2 year STANDARD_DEVIATION 12.4 | 51.1 year STANDARD_DEVIATION 13.5 | 51.6 year STANDARD_DEVIATION 13 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 186 Participants | 189 Participants | 375 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| International Restless Legs Syndrome Rating Scale (IRLS) score | 23.8 units on a scale STANDARD_DEVIATION 5.4 | 23.7 units on a scale STANDARD_DEVIATION 5.2 | 23.7 units on a scale STANDARD_DEVIATION 5.3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 186 Participants | 189 Participants | 375 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 79 Participants | 90 Participants | 169 Participants |
| Sex: Female, Male Male | 107 Participants | 99 Participants | 206 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 186 | 0 / 189 |
| other Total, other adverse events | 32 / 186 | 59 / 189 |
| serious Total, serious adverse events | 0 / 186 | 3 / 189 |
Outcome results
Primary
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.
Time frame: Baseline and week 12
Population: Full Analysis Set (FAS) consisted of all participants who received the study drug for the treatment period and were evaluated for at least one efficacy (either primary or secondary) endpoint during the treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline in International Restless Legs Syndrome Rating Scale (IRLS) Score at Week 12 | -10.5 units on a scale |
| Gabapentin Enacarbil | Change From Baseline in International Restless Legs Syndrome Rating Scale (IRLS) Score at Week 12 | -11.7 units on a scale |
Comparison: MMRM with compound symmetry as the 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.p-value: 0.08895% CI: [-2.6, 0.2]Mixed Model of Repeated Measurements
Secondary
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.
Time frame: Baseline and EoT (week 12)
Population: FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline in Athens Insomnia Scale | -2.5 units on a scale |
| Gabapentin Enacarbil | Change From Baseline in Athens Insomnia Scale | -2.5 units on a scale |
Comparison: LSM difference (gabapentin enacarbil group minus placebo group) of the changes in total score of Athens insomnia scale from baseline was calculated by visit, using the ANCOVA model with the baseline value as a covariate.p-value: 0.97595% CI: [-0.7, 0.7]ANCOVA
Secondary
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).
Time frame: Baseline and EoT (week 12)
Population: FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Health Status Score of EuroQol-5 Dimension-5 Level (EQ-5D-5L) | 2.7 units on a scale | Standard Deviation 16.7 |
| Gabapentin Enacarbil | Change From Baseline in Health Status Score of EuroQol-5 Dimension-5 Level (EQ-5D-5L) | 4.2 units on a scale | Standard Deviation 15.3 |
Secondary
Change From Baseline in IRLS Score at Each Time Point
ANCOVA model with the baseline value as a covariate was used.
Time frame: Baseline and weeks 1, 2, 4, 6, 8, 10, 12 and EoT (week 12)
Population: FAS.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo | Change From Baseline in IRLS Score at Each Time Point | Week 1 | -3.1 units on a scale |
| Placebo | Change From Baseline in IRLS Score at Each Time Point | Week 2 | -4.3 units on a scale |
| Placebo | Change From Baseline in IRLS Score at Each Time Point | Week 4 | -6.0 units on a scale |
| Placebo | Change From Baseline in IRLS Score at Each Time Point | Week 6 | -7.4 units on a scale |
| Placebo | Change From Baseline in IRLS Score at Each Time Point | Week 8 | -8.8 units on a scale |
| Placebo | Change From Baseline in IRLS Score at Each Time Point | Week 10 | -9.6 units on a scale |
| Placebo | Change From Baseline in IRLS Score at Each Time Point | Week 12 | -10.5 units on a scale |
| Placebo | Change From Baseline in IRLS Score at Each Time Point | EoT | -10.2 units on a scale |
| Gabapentin Enacarbil | Change From Baseline in IRLS Score at Each Time Point | EoT | -11.1 units on a scale |
| Gabapentin Enacarbil | Change From Baseline in IRLS Score at Each Time Point | Week 1 | -4.2 units on a scale |
| Gabapentin Enacarbil | Change From Baseline in IRLS Score at Each Time Point | Week 8 | -9.8 units on a scale |
| Gabapentin Enacarbil | Change From Baseline in IRLS Score at Each Time Point | Week 2 | -5.8 units on a scale |
| Gabapentin Enacarbil | Change From Baseline in IRLS Score at Each Time Point | Week 12 | -11.9 units on a scale |
| Gabapentin Enacarbil | Change From Baseline in IRLS Score at Each Time Point | Week 4 | -7.5 units on a scale |
| Gabapentin Enacarbil | Change From Baseline in IRLS Score at Each Time Point | Week 10 | -11.2 units on a scale |
| Gabapentin Enacarbil | Change From Baseline in IRLS Score at Each Time Point | Week 6 | -8.8 units on a scale |
Comparison: LMS difference (gabapentin enacarbil group minus placebo group) of the changes in IRLS score from baseline was calculated by visit, using ANCOVA model with the baseline value as a covariate.p-value: 0.05195% CI: [-2.2, 0]ANCOVA
Comparison: LMS difference (gabapentin enacarbil group minus placebo group) of the changes in IRLS score from baseline was calculated by visit, using ANCOVA model with the baseline value as a covariate.p-value: 0.0295% CI: [-2.8, -0.2]ANCOVA
Comparison: LMS difference (gabapentin enacarbil group minus placebo group) of the changes in IRLS score from baseline was calculated by visit, using ANCOVA model with the baseline value as a covariate.p-value: 0.02895% CI: [-2.9, -0.2]ANCOVA
Comparison: LMS difference (gabapentin enacarbil group minus placebo group) of the changes in IRLS score from baseline was calculated by visit, using ANCOVA model with the baseline value as a covariate.p-value: 0.04395% CI: [-2.9, 0]ANCOVA
Comparison: LMS difference (gabapentin enacarbil group minus placebo group) of the changes in IRLS score from baseline was calculated by visit, using ANCOVA model with the baseline value as a covariate.p-value: 0.18495% CI: [-2.4, 0.5]ANCOVA
Comparison: LMS difference (gabapentin enacarbil group minus placebo group) of the changes in IRLS score from baseline was calculated by visit, using ANCOVA model with the baseline value as a covariate.p-value: 0.02795% CI: [-3.1, -0.2]ANCOVA
Comparison: LMS difference (gabapentin enacarbil group minus placebo group) of the changes in IRLS score from baseline was calculated by visit, using ANCOVA model with the baseline value as a covariate.p-value: 0.08795% CI: [-3, 0.2]ANCOVA
Comparison: LMS difference (gabapentin enacarbil group minus placebo group) of the changes in IRLS score from baseline was calculated by visit, using ANCOVA model with the baseline value as a covariate.p-value: 0.31295% CI: [-2.4, 0.8]ANCOVA
Secondary
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.
Time frame: Baseline and EoT (week 12)
Population: FAS
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline in Pittsburgh Sleep Quality Index Total Score (PSQI) | -1.7 units on a scale |
| Gabapentin Enacarbil | Change From Baseline in Pittsburgh Sleep Quality Index Total Score (PSQI) | -1.7 units on a scale |
Comparison: LMS difference (gabapentin enacarbil group minus placebo group) of the changes in PSQI component and global scores from baseline was calculated by visit, using the ANCOVA model with the baseline value as a covariate.p-value: 0.87795% CI: [-0.5, 0.5]ANCOVA
Secondary
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.
Time frame: Baseline and EoT (week 12)
Population: FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline in Restless Legs Syndrome (RLS) Pain Score | -0.9 units on a scale |
| Gabapentin Enacarbil | Change From Baseline in Restless Legs Syndrome (RLS) Pain Score | -1.0 units on a scale |
Comparison: LSM difference (gabapentin enacarbil group minus placebo group) of the changes in RLS pain score from baseline was calculated by visit, using the ANCOVA model with the baseline value as a covariate.p-value: 0.83895% CI: [-0.4, 0.3]ANCOVA
Secondary
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.
Time frame: From first dose of study drug up to week 13
Population: Safety Analysis Set (SAF) consisted of all participants given at least one dose of the study drug for the treatment period.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Adverse Events | TEAEs leading to death | 0 Participants |
| Placebo | Number of Participants With Adverse Events | Drug-related serious TEAEs | 0 Participants |
| Placebo | Number of Participants With Adverse Events | Drug-related TEAEs | 36 Participants |
| Placebo | Number of Participants With Adverse Events | TEAEs leading to discontinuation of study drug | 4 Participants |
| Placebo | Number of Participants With Adverse Events | Serious TEAEs | 0 Participants |
| Placebo | Number of Participants With Adverse Events | Drug-related TEAEs leading to disc. of study drug | 3 Participants |
| Placebo | Number of Participants With Adverse Events | Any TEAEs | 71 Participants |
| Gabapentin Enacarbil | Number of Participants With Adverse Events | Drug-related TEAEs leading to disc. of study drug | 4 Participants |
| Gabapentin Enacarbil | Number of Participants With Adverse Events | Any TEAEs | 94 Participants |
| Gabapentin Enacarbil | Number of Participants With Adverse Events | Drug-related TEAEs | 60 Participants |
| Gabapentin Enacarbil | Number of Participants With Adverse Events | TEAEs leading to death | 0 Participants |
| Gabapentin Enacarbil | Number of Participants With Adverse Events | Serious TEAEs | 3 Participants |
| Gabapentin Enacarbil | Number of Participants With Adverse Events | Drug-related serious TEAEs | 0 Participants |
| Gabapentin Enacarbil | Number of Participants With Adverse Events | TEAEs leading to discontinuation of study drug | 4 Participants |
Secondary
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.
Time frame: EoT (week 12)
Population: FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With an Investigator-rated Clinical Global Impression (ICGI) Response | 53.2 percentage of participants |
| Gabapentin Enacarbil | Percentage of Participants With an Investigator-rated Clinical Global Impression (ICGI) Response | 57.4 percentage of participants |
p-value: 0.46795% CI: [-6.4, 14.8]Fisher Exact
Secondary
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.
Time frame: EoT (week 12)
Population: FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With a Patient-rated Clinical Global Impression (PCGI) Response | 50.5 percentage of participants |
| Gabapentin Enacarbil | Percentage of Participants With a Patient-rated Clinical Global Impression (PCGI) Response | 56.4 percentage of participants |
p-value: 0.395% CI: [-4.8, 16.5]Fisher Exact