Restless Legs Syndrome
Conditions
Brief summary
The objective of the study was to generate the data necessary to determine the gabapentin exposure produced by 4 dose levels of GEn (600 mg, 1200 mg, 1800 mg, and 2400 mg) or placebo, and the corresponding relief of symptoms in subjects with Restless Legs Syndrome (RLS).
Detailed description
This was a multicenter, randomized, double blind, placebo controlled, parallel group study, comparing 4 doses of GEn (XP13512) with placebo given once daily to subjects with RLS. Eligible subjects were randomized in equal numbers into 1 of 5 treatment groups (GEn 600 mg, 1200 mg, 1800 mg, or 2400 mg or placebo) for 12 weeks of treatment. Data from this study will be utilized as part of a larger pharmacokinetic (PK) pharmacodynamic (PD) analysis of data from several studies (XP084/RXP111495) that are part of the GEn RLS clinical development program. Safety and tolerability were also assessed.
Interventions
DRUGGEn (XP13512/GSK1838262)
Double-Blind Treatment Phase: 600 mg GEn (XP13512) orally, once daily for 3 days followed by 600 or 1200 mg on days 4-6, followed by 600 or 1200 or 1800 mg on days 7-9, followed by 600 or 1200 or 1800 or 2400 mg on days 10-84. Double-Blind Taper Phase: 600 or 1200 or 1800 mg GEn (XP13512) orally, once daily on days 85-86, followed by 600 mg or 1200 mg on days 87-88, followed by 600 mg on days 89-91
DRUGPlacebo
Placebo orally once daily
Sponsors
XenoPort, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Men or women at least 18 years of age * RLS, based on the IRLSSG Diagnostic Criteria * History of RLS symptoms occurring at least 15 nights in the month prior to Screening or, if on RLS treatment, this frequency of symptoms must have been applicable prior to start of treatment * Documented RLS symptoms for at least 4 of the 7 consecutive evenings/nights * Total RLS severity score of 15 or greater on the IRLS Rating Scale * If taking dopamine agonists, gabapentin, or other treatments for RLS (e.g., opioids, benzodiazepines) medications must have been discontinued at least 2 weeks prior to Screening; * If taking any prescription medication, therapy must have been stabilized for at least 3 months prior to Screening with no anticipated changes for the duration of the study; * Body Mass Index (BMI) of 34 or below * estimated creatinine clearance of at least 60 mL/min
Exclusion criteria
* a sleep disorder (e.g., sleep apnea) that may significantly affect the assessment of RLS * history of RLS symptom augmentation or end of dose rebound with previous dopamine agonist treatment * neurologic disease or movement disorder (e.g., diabetic neuropathy, Parkinson's disease, multiple sclerosis, dyskinesias, and dystonias); * other clinically significant or unstable medical condition or conditions which could affect RLS treatment efficacy assessments * serum ferritin level below 20 ng/mL * currently suffering from moderate or severe depression using the Diagnostic and Statistical Manual of Mental Disorders and Treatment IV (DSM IV TR)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Css, Max and Css, Min | Weeks 4 and 12 | Css, max is defined as the maximum or peak concentration of a drug observed after multiple administration, at steady state. Css, max is one of the parameters of particular use in estimating the bioavailability of drugs, by measuring the total amount of drug absorbed. Css, min is defined as the minimum concentration of a drug observed after its administration, in steady state. ng, nanograms; PK, pharmacokinetic; W, week; BLQ, below limit of quantitation. |
| Mean Tmax and T1/2 | Weeks 4 and 12 | Tmax is defined as the time to the maximum or peak concentration of a drug observed after multiple administration. T1/2 is defined as the time to when half of the total amount of a particular substance is eliminated from the body. |
| Mean AUCss | Weeks 4 and 12 | The area under the plot of plasma concentration of drug against time after drug administration is defined as the area under the curve (AUC). The AUCss is the area under the curve during the steady-state period. The AUCss is of particular use in estimating the bioavailability of drugs, by measuring the extent of absorption. AUCss used concentration data from 0 to 24 hours at steady-state for Weeks 4 and 12. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| GEn Placebo Oral placebo tablet taken once daily. Days 1 to 3: one placebo tablet. Days 4 to 6: two placebo tablets. Days 7 to 9: three placebo tablets. Days 10 to 84: four placebo tablets. On Day 85, participants entered a 7-day Taper Period. Days 85 to 86: three placebo tablets. Days 87 to 88: two placebo tablets. Days 89 to 91: one placebo tablet. | 41 |
| GEn 600 mg Gabapentin enacarbil (GEn) (XP13512/GSK1838262) 600 milligrams (mg) taken orally once a day for 12 weeks. Days 1 to 3: one extended release (ER) tablet (600 mg GEn). Days 4 to 6: one ER tablet (600 mg GEn) and one placebo tablet. Days 8 to 10: one ER tablet (600 mg GEn) and two placebo tablets. Days 10 to 84: one ER tablet (600 mg GEn) and three placebo tablets. On Day 85, participants entered a 7-day Taper Period. Days 85 to 86: three placebo tablets. Days 87 to 88: two placebo tablets. Days 89 to 91: one placebo tablet. | 48 |
| GEn 1200 mg Oral GEn 1200 mg taken once daily. Days 1 to 3: one ER tablet (600 mg GEn). Days 4 to 6: two ER tablets (1200 mg GEn). Days 8 to 10: two ER tablets (1200 mg GEn) and one placebo tablet. Days 10 to 84: two ER tablets (1200 mg GEn) and two placebo tablets. On Day 85, participants entered a 7-day Taper Period. Days 85 to 86: one ER tablet (600 mg GEn) and two placebo tablets. Days 87 to 88: two placebo tablets. Days 89 to 91: one placebo tablet. | 45 |
| GEn 1800 mg Oral GEn 1800 mg taken once daily. Days 1 to 3: one ER tablet (600 mg GEn). Days 4 to 6: two ER tablets (1200 mg GEn). Days 8 to 10: three ER tablets (1800 mg GEn). Days 10 to 84: three ER tablets (1800 mg GEn) and one placebo tablet. On Day 85, participants entered a 7-day Taper Period. Days 85 to 86: two ER tablets (1200 mg GEn) and one placebo tablet. Days 87 to 88: one ER tablet (600 mg) and one placebo tablet. Days 89 to 91: one placebo tablet. | 38 |
| GEn 2400 mg Oral GEn 1200 mg taken once daily. Days 1 to 3: one ER tablet (600 mg GEn). Days 4 to 6: two ER tablets (1200 mg GEn). Days 8 to 10: three ER tablets (1800 mg GEn). Days 10 to 84: four ER tablets (2400 mg GEn). On Day 85, participants entered a 7-day Taper Period. Days 85 to 86: three ER tablets (1800 mg GEn). Days 87 to 88: two ER tablets (1200 mg). Days 89 to 91: one ER (600 mg) tablet. | 45 |
| Total | 217 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 4 | 6 | 3 | 5 |
| Overall Study | Lost to Follow-up | 0 | 2 | 3 | 2 | 3 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 2 | 1 | 0 | 3 |
| Overall Study | Treatment Failure | 1 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Sponsor | 1 | 0 | 0 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 5 | 4 | 1 | 0 |
Baseline characteristics
| Characteristic | GEn Placebo | GEn 600 mg | GEn 1200 mg | GEn 1800 mg | GEn 2400 mg | Total |
|---|---|---|---|---|---|---|
| Age Continuous | 47.1 Years STANDARD_DEVIATION 11.16 | 47.3 Years STANDARD_DEVIATION 12.78 | 49.8 Years STANDARD_DEVIATION 11.51 | 50.2 Years STANDARD_DEVIATION 13.79 | 45.9 Years STANDARD_DEVIATION 13.93 | 48.0 Years STANDARD_DEVIATION 12.67 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 participants | 0 participants | 0 participants | 0 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Asian | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Black or African American | 1 participants | 0 participants | 1 participants | 2 participants | 2 participants | 6 participants |
| Race/Ethnicity, Customized White or Caucasian | 39 participants | 48 participants | 44 participants | 35 participants | 42 participants | 208 participants |
| Sex: Female, Male Female | 29 Participants | 31 Participants | 23 Participants | 27 Participants | 29 Participants | 139 Participants |
| Sex: Female, Male Male | 12 Participants | 17 Participants | 22 Participants | 11 Participants | 16 Participants | 78 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 21 / 41 | 24 / 48 | 33 / 45 | 25 / 38 | 42 / 45 |
| serious Total, serious adverse events | 1 / 41 | 0 / 48 | 1 / 45 | 0 / 38 | 1 / 45 |
Outcome results
Primary
Mean AUCss
The area under the plot of plasma concentration of drug against time after drug administration is defined as the area under the curve (AUC). The AUCss is the area under the curve during the steady-state period. The AUCss is of particular use in estimating the bioavailability of drugs, by measuring the extent of absorption. AUCss used concentration data from 0 to 24 hours at steady-state for Weeks 4 and 12.
Time frame: Weeks 4 and 12
Population: Safety Population. Placebo participants were not included in the PK assessments, as they had no exposure to GEn. Of participants who completed the study, some were not included at Week 12 (sample not taken or below limit of quantitation).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GEn 600 mg | Mean AUCss | Week 12, n=0, 32, 30, 30, 30 | 51.4 ng*hour/ml | Standard Deviation 16.5 |
| GEn 600 mg | Mean AUCss | Week 4, n=0, 38, 33, 33, 35 | 49.3 ng*hour/ml | Standard Deviation 14.8 |
| GEn 1200 mg | Mean AUCss | Week 4, n=0, 38, 33, 33, 35 | 96.1 ng*hour/ml | Standard Deviation 30.4 |
| GEn 1200 mg | Mean AUCss | Week 12, n=0, 32, 30, 30, 30 | 95.7 ng*hour/ml | Standard Deviation 38.5 |
| GEn 1800 mg | Mean AUCss | Week 4, n=0, 38, 33, 33, 35 | 141 ng*hour/ml | Standard Deviation 41 |
| GEn 1800 mg | Mean AUCss | Week 12, n=0, 32, 30, 30, 30 | 146 ng*hour/ml | Standard Deviation 41.4 |
| GEn 2400 mg | Mean AUCss | Week 12, n=0, 32, 30, 30, 30 | 173 ng*hour/ml | Standard Deviation 54.4 |
| GEn 2400 mg | Mean AUCss | Week 4, n=0, 38, 33, 33, 35 | 176 ng*hour/ml | Standard Deviation 53.8 |
Primary
Mean Css, Max and Css, Min
Css, max is defined as the maximum or peak concentration of a drug observed after multiple administration, at steady state. Css, max is one of the parameters of particular use in estimating the bioavailability of drugs, by measuring the total amount of drug absorbed. Css, min is defined as the minimum concentration of a drug observed after its administration, in steady state. ng, nanograms; PK, pharmacokinetic; W, week; BLQ, below limit of quantitation.
Time frame: Weeks 4 and 12
Population: Safety Population: all participants (par.) who were randomized and received at least one (or any portion of a) dose of study drug. Population was analyzed as randomized. Placebo par. had no exposure to GEn and were not included in the PK assessments. Of par. who completed the study, some were not included at W12 (sample not taken or BLQ).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GEn 600 mg | Mean Css, Max and Css, Min | Css, max; Week 4, n=0, 39, 33, 33, 36 | 3.86 nanograms per milliliter (ng/ml) | Standard Deviation 1.25 |
| GEn 600 mg | Mean Css, Max and Css, Min | Css, max; Week 12, n=0, 32, 30, 30, 31 | 4.14 nanograms per milliliter (ng/ml) | Standard Deviation 1.19 |
| GEn 600 mg | Mean Css, Max and Css, Min | Css, min; Week 4, n=0, 39, 33, 33, 36 | 0.690 nanograms per milliliter (ng/ml) | Standard Deviation 0.359 |
| GEn 600 mg | Mean Css, Max and Css, Min | Css, min; Week 12, n=0, 32, 30, 30, 31 | 0.600 nanograms per milliliter (ng/ml) | Standard Deviation 0.332 |
| GEn 1200 mg | Mean Css, Max and Css, Min | Css, min; Week 12, n=0, 32, 30, 30, 31 | 1.32 nanograms per milliliter (ng/ml) | Standard Deviation 1.15 |
| GEn 1200 mg | Mean Css, Max and Css, Min | Css, min; Week 4, n=0, 39, 33, 33, 36 | 1.37 nanograms per milliliter (ng/ml) | Standard Deviation 0.894 |
| GEn 1200 mg | Mean Css, Max and Css, Min | Css, max; Week 12, n=0, 32, 30, 30, 31 | 7.15 nanograms per milliliter (ng/ml) | Standard Deviation 2.76 |
| GEn 1200 mg | Mean Css, Max and Css, Min | Css, max; Week 4, n=0, 39, 33, 33, 36 | 7.14 nanograms per milliliter (ng/ml) | Standard Deviation 2.62 |
| GEn 1800 mg | Mean Css, Max and Css, Min | Css, min; Week 4, n=0, 39, 33, 33, 36 | 1.63 nanograms per milliliter (ng/ml) | Standard Deviation 0.967 |
| GEn 1800 mg | Mean Css, Max and Css, Min | Css, min; Week 12, n=0, 32, 30, 30, 31 | 1.60 nanograms per milliliter (ng/ml) | Standard Deviation 0.994 |
| GEn 1800 mg | Mean Css, Max and Css, Min | Css, max; Week 12, n=0, 32, 30, 30, 31 | 12.0 nanograms per milliliter (ng/ml) | Standard Deviation 3.83 |
| GEn 1800 mg | Mean Css, Max and Css, Min | Css, max; Week 4, n=0, 39, 33, 33, 36 | 11.4 nanograms per milliliter (ng/ml) | Standard Deviation 3.54 |
| GEn 2400 mg | Mean Css, Max and Css, Min | Css, min; Week 12, n=0, 32, 30, 30, 31 | 2.41 nanograms per milliliter (ng/ml) | Standard Deviation 1.29 |
| GEn 2400 mg | Mean Css, Max and Css, Min | Css, max; Week 4, n=0, 39, 33, 33, 36 | 14.0 nanograms per milliliter (ng/ml) | Standard Deviation 4.23 |
| GEn 2400 mg | Mean Css, Max and Css, Min | Css, max; Week 12, n=0, 32, 30, 30, 31 | 13.3 nanograms per milliliter (ng/ml) | Standard Deviation 3.83 |
| GEn 2400 mg | Mean Css, Max and Css, Min | Css, min; Week 4, n=0, 39, 33, 33, 36 | 2.34 nanograms per milliliter (ng/ml) | Standard Deviation 1.78 |
Primary
Mean Tmax and T1/2
Tmax is defined as the time to the maximum or peak concentration of a drug observed after multiple administration. T1/2 is defined as the time to when half of the total amount of a particular substance is eliminated from the body.
Time frame: Weeks 4 and 12
Population: Safety Population. Placebo participants (par.) were not included in the PK assessments, as they had no exposure to GEn. At W4, there were two par. excluded from the T1/2, as a result of no sample taken or a PK profile not possible. Of par. who completed the study, some were not included at W12 (sample not taken or below limit of quantitation).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GEn 600 mg | Mean Tmax and T1/2 | Tmax; Week 4, n=0, 39, 33, 33, 36 | 8.76 hours | Standard Deviation 3.81 |
| GEn 600 mg | Mean Tmax and T1/2 | Tmax; Week 12, n=0, 32, 30, 30, 31 | 6.96 hours | Standard Deviation 3.76 |
| GEn 600 mg | Mean Tmax and T1/2 | T1/2; Week 4, n=0, 38, 33, 33, 35 | 5.82 hours | Standard Deviation 1.46 |
| GEn 600 mg | Mean Tmax and T1/2 | T1/2, Week 12, n=0, 32, 30, 30, 30 | 6.27 hours | Standard Deviation 1.77 |
| GEn 1200 mg | Mean Tmax and T1/2 | Tmax; Week 12, n=0, 32, 30, 30, 31 | 8.72 hours | Standard Deviation 3.68 |
| GEn 1200 mg | Mean Tmax and T1/2 | T1/2; Week 4, n=0, 38, 33, 33, 35 | 6.67 hours | Standard Deviation 1.94 |
| GEn 1200 mg | Mean Tmax and T1/2 | T1/2, Week 12, n=0, 32, 30, 30, 30 | 6.63 hours | Standard Deviation 2.23 |
| GEn 1200 mg | Mean Tmax and T1/2 | Tmax; Week 4, n=0, 39, 33, 33, 36 | 8.57 hours | Standard Deviation 3.16 |
| GEn 1800 mg | Mean Tmax and T1/2 | T1/2; Week 4, n=0, 38, 33, 33, 35 | 5.82 hours | Standard Deviation 1.56 |
| GEn 1800 mg | Mean Tmax and T1/2 | Tmax; Week 12, n=0, 32, 30, 30, 31 | 8.00 hours | Standard Deviation 2.58 |
| GEn 1800 mg | Mean Tmax and T1/2 | T1/2, Week 12, n=0, 32, 30, 30, 30 | 5.89 hours | Standard Deviation 1.36 |
| GEn 1800 mg | Mean Tmax and T1/2 | Tmax; Week 4, n=0, 39, 33, 33, 36 | 7.61 hours | Standard Deviation 2.67 |
| GEn 2400 mg | Mean Tmax and T1/2 | T1/2, Week 12, n=0, 32, 30, 30, 30 | 6.09 hours | Standard Deviation 1.28 |
| GEn 2400 mg | Mean Tmax and T1/2 | Tmax; Week 12, n=0, 32, 30, 30, 31 | 8.13 hours | Standard Deviation 3.2 |
| GEn 2400 mg | Mean Tmax and T1/2 | Tmax; Week 4, n=0, 39, 33, 33, 36 | 8.01 hours | Standard Deviation 3.62 |
| GEn 2400 mg | Mean Tmax and T1/2 | T1/2; Week 4, n=0, 38, 33, 33, 35 | 6.05 hours | Standard Deviation 1.11 |