The effectiveness of XYWAV in pediatric patients is based upon a clinical study in patients treated with Xyrem, as described below, and additional pharmacokinetic information [see Use in Specific Populations (8.4)].

The effectiveness of Xyrem in the treatment of cataplexy and excessive daytime sleepiness in pediatric patients 7 years of age and older with narcolepsy was established in a double-blind, placebo-controlled, randomized-withdrawal study (NCT02221869). The study was conducted in 106 pediatric patients (median age: 12 years; range: 7 to 17 years) with a baseline history of at least 14 cataplexy attacks in a typical 2-week period prior to any treatment for narcolepsy symptoms. Of the 106 patients, 2 did not receive study drug and 63 patients were randomized 1:1 either to continued treatment with Xyrem or to placebo. Randomization to placebo was stopped early as the efficacy criterion was met at the pre-planned interim analysis. 

Patients entered the study either taking a stable dosage of Xyrem or were Xyrem-naïve. CNS stimulants were allowed at entry, and approximately 50% of patients continued taking a stable dose of stimulant throughout the stable-dose and double-blind periods. Xyrem-naïve patients were initiated and titrated based on body weight over a period of up to 10 weeks. The total nightly dose was administered in two divided doses, with the first dose given at nighttime and the second given 2.5 to 4 hours later [see Dosage and Administration (2.2)]. Once a stable dosage of Xyrem had been achieved, these patients entered the 2-week stable-dose period; patients on a stable dosage of Xyrem at study entry remained on this dosage for 3 weeks prior to randomization. Efficacy was established at dosages ranging from 3 g to 9 g of Xyrem per night.

The primary efficacy measure was the change in frequency of cataplexy attacks. In addition, change in cataplexy severity was evaluated with the Clinical Global Impression of Change for cataplexy severity. The efficacy of Xyrem in the treatment of excessive daytime sleepiness in pediatric patients with narcolepsy was evaluated with the change in the Epworth Sleepiness Scale (Child and Adolescent) score. The Epworth Sleepiness Scale (Child and Adolescent) is a modified version of the scale used in the adult clinical trial described above. The overall change in narcolepsy condition was assessed by the Clinical Global Impression of Change for narcolepsy overall. Efficacy was assessed during or at the end of the 2-week double-blind treatment period, relative to the last 2 weeks or end of the stable-dose period (see Tables 7 and 8).

Pediatric patients taking stable dosages of Xyrem who discontinued Xyrem treatment and were randomized to placebo during the double-blind treatment period experienced a statistically significant increase in weekly cataplexy attacks compared with patients who were randomized to continue treatment with Xyrem. Patients randomized to receive placebo during the double-blind treatment period experienced a statistically significant worsening of EDS compared with patients randomized to continue receiving Xyrem (see Table 7).

* For weekly number of cataplexy attacks, baseline value is calculated from the last 14 days of the stable-dose period.   
† For Epworth Sleepiness Scale score, baseline value is collected at the end of stable-dose period.  
‡ Weekly number of cataplexy attacks is calculated from all days within the double-blind treatment period.  
§ For Epworth Sleepiness Scale, value is collected at the end of the double-blind treatment period.  
¶ P-value from rank-based analysis of covariance (ANCOVA) with treatment as a factor and rank baseline value as a covariate.  
** One patient in each of the treatment groups did not have baseline ESS score available and were not included in this analysis.  


Patients randomized to receive placebo during the double-blind treatment period experienced a statistically significant worsening of cataplexy severity and narcolepsy overall according to the clinician’s assessment compared with patients randomized to continue receiving Xyrem (see Table 8).

* Responses indicate change of severity or symptoms relative to receiving Xyrem treatment at baseline.  
† Percentages based on total number of observed values.  
‡ Two patients randomized to Xyrem did not have the CGIc assessments completed and were excluded from the analysis.  
§ P-value from Pearson’s chi-square test.