An Efficacy and Safety Evaluation of HORIZANT in Adolescents With Moderate-to-Severe Primary RLS

The primary objective of the trial is to evaluate the efficacy of HORIZANT 300 mg and 600 mg, compared to placebo, at 12 weeks of treatment, for the treatment of Restless Legs Syndrome (RLS) in adolescents (13 to 17 years of age) diagnosed with moderate-to-severe primary RLS.

This is a multicenter, double-blind, placebo-controlled, 3 arm, parallel group study of HORIZANT in adolescents (13 to 17 years of age) diagnosed with moderate-to-severe primary RLS. Eligible patients enter a 7-day screening period during which safety assessments are performed. Eligible patients are randomized in a 1:1:1 ratio to HORIZANT 300 mg or 600 mg, or matching placebo, followed by a 12-week treatment period. Patients take the study drug once daily at approximately 5 PM with food. Patients will visit the clinical site on 5 or 6 different occasions.

Eligibility Criteria:
Inclusion Criteria:

1. Male and female adolescent patients, aged 13 to 17 years, diagnosed with RLS based on the IRLSSG consensus criteria (Allen RP 2014) (Appendix 2).
2. Total RLS severity score of 15 or greater on the IRLS rating scale at Visit 1 (screening) and at Visit 2 (baseline) (Appendix 8).
3. RLS symptoms for at least 4 of 7 consecutive evenings/nights during the screening period.
4. Body weight greater than 33.4 kg and a healthy weight using age-based body mass index (BMI) range 5th-95th percentile at screening and baseline.
5. Negative pregnancy test for all females at screening and baseline. Sexually active patients must agree to use 2 medically accepted methods of contraception, 1 of which is a highly effective method (e.g., hormonal or intrauterine device \[IUD\]) \[the second may be a barrier method (e.g., male condom, female condom, diaphragm or cervical cap)\], during the course of the study treatment and for 4 weeks after the last dose of study treatment. For patients using hormonal contraceptives as one of the methods, the contraceptive should be stabilized for at least 3 months prior to screening.

   Female patients who normally abstain from sexual activity may be recruited, providing they remain abstinent during the study, or if they become sexually active, they must agree to use 2 effective methods of birth control as described above.
6. Male patients must agree to use a barrier method (male condom, female condom, diaphragm, or cervical cap) with spermicide for at least 30 days prior to dosing and throughout the study, if sexually active. Male patients who normally abstain from sexual activity may be recruited, providing they remain abstinent during the study, or if they become sexually active, they must agree to use a barrier method as described above.
7. Estimated creatinine clearance of at least 60 mL/min (using the Cockcroft-Gault equation) at screening only.
8. Appropriate cognitive and communication skills, as judged by the clinician, needed to complete study assessments.
9. Signed patient and parent Institutional Review Board (IRB)-approved informed consent/assent form (as applicable) before any study-related procedures are performed.
10. Willing and able to follow the study procedures.

Exclusion Criteria:

1. History of a primary sleep disorder other than RLS that may significantly affect the symptoms of RLS.
2. Serum ferritin level \< 20 ng/mL at screening.
3. History of allergy, hypersensitivity, or intolerance to HORIZANT or any other gabapentin products (e.g., Neurontin®, Gralise®).
4. Suffering from an isolated periodic limb movement disorder without RLS.
5. Currently meet Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) criteria for substance use disorder, or history thereof, within 12 months before dosing.
6. Current or past history of any significant psychiatric disorder including, but not limited to, depression (treatment with antidepressants), bipolar disorder, or schizophrenia.
7. Diagnosis of ADHD is allowed, provided the patient is not receiving medication(s) known to affect the assessment of RLS.
8. History of suicidal behavior or suicidal ideation as indicated by the C-SSRS, administered at screening, and as per investigator's judgment.
9. Patients with a history of epilepsy, subjects currently prescribed treatments for epilepsy, or subjects with a history of seizure in the last 5 years.
10. Medical condition or disorder that would interfere with the action, absorption, distribution, metabolism, or excretion of gabapentin enacarbil, or, in the Principal Investigator's judgment is considered to be clinically significant and may pose a safety concern, or, could interfere with the accurate assessment of safety or efficacy, or could potentially affect a patient's safety or study outcome.
11. In the judgement of the Principal Investigator, clinically significant, abnormal laboratory result or physical examination finding not resolved by the time of baseline assessments.
12. Positive test for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, human immunodeficiency virus (HIV) antibody at screening.
13. Uncontrolled hypertension defined as blood pressure (BP) ≥ 95 percentile adjusted for age, height, and sex, according to the tables published by the US Department of Health and Human Services 2005, at screening and before dosing. Appendix 5 contains the tables that can be consulted.
14. Participated in an investigational drug trial within the 4 weeks before dosing or plans to participate in another study at any time during this study.
15. Received an investigational product within 6 months prior to dosing.