An Efficacy and Safety Evaluation of HORIZANT in Adolescents 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.

• HORIZANT 300 mg (Drug), also known as Gabapentin Enacarbil Extended-Release Tablets: HORIZANT 300 mg once daily
• HORIZANT 600 mg (Drug), also known as Gabapentin Enacarbil Extended-Release Tablets: HORIZANT 600 mg once daily
• Placebo (Drug): Placebo once daily

Primary outcomes

• the change on the IRLS rating scale from baseline to Week 12 [12 weeks]: IRLS rating change
• the proportion of patients who are responders, assessed on the CGI-I scale as "much improved" or "very much improved" (CGI-I rating of 1 or 2, respectively) at Week 12 [12 weeks]: CGI-I scale

Secondary outcomes

• IRLS total score, change from baseline to Weeks 4 and 8 [4, 8 weeks]: IRLS change
• CGI-I score at Weeks 4 and 8 [4, 8 weeks]: CGI-I score
• Proportions of patients by sleep parameters collected on the Post-Sleep questionnaire at baseline and Week 12 [Baseline to 12 weeks]: sleep parameters on Post-Sleep questionnaire
• Proportions of patients by sleep parameters collected on the ESS-CHAD© total score and change from baseline to Week 12 [Baseline to 12 weeks]: sleep parameters by ESS-CHAD© total score and change
• Proportions of patients with AEs, fatal serious adverse events (SAEs), non-fatal SAEs, and discontinuations due to AEs at all post-dose time points; and proportion of patients with neuropsychiatric AEs [12 weeks]: Adverse event proporations

Sex: All, ages: 13 Years to 17 Years

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.

• Steven Caras, MD, Study director, Xenoport/Arbor Pharmaceuticals, LLC