The effectiveness of Sodium Oxybate Oral Solution in the treatment of excessive daytime sleepiness in patients with narcolepsy was established in two randomized, double-blind, placebo-controlled trials (Trials N3 and N4) (see Tables 6 to 8). Seventy-eight percent of patients in Trial N3 were also being treated with CNS stimulants.

Trial N3 was a multicenter randomized, double-blind, placebo-controlled, parallel-group trial that evaluated 228 patients with moderate to severe symptoms at entry into the study including a median Epworth Sleepiness Scale (see below) score of 18, and a Maintenance of Wakefulness Test (see below) score of 8.3 minutes. Patients were randomized to one of 4 treatment groups: placebo, Sodium Oxybate Oral Solution 4.5 g per night, Sodium Oxybate Oral Solution 6 g per night, or Sodium Oxybate Oral Solution 9 g per night. The period of double-blind treatment in this trial was 8 weeks. Antidepressants were withdrawn prior to randomization; stimulants were continued at stable doses.

The primary efficacy measures in Trial N3 were the Epworth Sleepiness Scale and the Clinical Global Impression of Change. The Epworth Sleepiness Scale is intended to evaluate the extent of sleepiness in everyday situations by asking the patient a series of questions. In these questions, patients were asked to rate their chances of dozing during each of 8 activities on a scale from 0-3 (0=never; 1=slight; 2=moderate; 3=high). Higher total scores indicate a greater tendency to sleepiness. The Clinical Global Impression of Change is evaluated on a 7‑point scale, centered at No Change, and ranging from Very Much Worse to Very Much Improved. In Trial N3, patients were rated by evaluators who based their assessments on the severity of narcolepsy at baseline.

In Trial N3, statistically significant improvements were seen on the Epworth Sleepiness Scale score at Week 8 and on the Clinical Global Impression of Change score at Week 8 with the 6 g and 9 g per night doses of Sodium Oxybate Oral Solution compared to the placebo group.

Table 6  
Change from Baseline in Daytime Sleepiness Score (Epworth Sleepiness Scale) at Week 8 in Trial N3 (Range 0-24)

Table 7  
Proportion of Patients with a Very Much or Much Improved Clinical Global Impression of Change in Daytime and Nighttime Symptoms in Trial N3

Trial N4 was a multicenter randomized, double-blind, placebo-controlled, parallel-group trial that evaluated 222 patients with moderate to severe symptoms at entry into the study including a median Epworth Sleepiness Scale score of 15, and a Maintenance of Wakefulness Test (see below) score of 10.3 minutes. At entry, patients had to be taking modafinil at stable doses of 200 mg, 400 mg, or 600 mg daily for at least 1 month prior to randomization. The patients enrolled in the study were randomized to one of 4 treatment groups: placebo, Sodium Oxybate Oral Solution, modafinil, or Sodium Oxybate Oral Solution plus modafinil. Sodium Oxybate Oral Solution was administered in a dose of 6 g per night for 4 weeks, followed by 9 g per night for 4 weeks. Modafinil was continued in the modafinil alone and the Sodium Oxybate Oral Solution plus modafinil treatment groups at the patient’s prior dose. Trial N4 was not designed to compare the effects of Sodium Oxybate Oral Solution to modafinil because patients receiving modafinil were not titrated to a maximal dose. Patients randomized to placebo or to Sodium Oxybate Oral Solution treatment were withdrawn from their stable dose of modafinil. Patients taking antidepressants could continue these medications at stable doses.

The primary efficacy measure in Trial N4 was the Maintenance of Wakefulness Test. The Maintenance of Wakefulness Test measures latency to sleep onset (in minutes) averaged over 4 sessions at 2-hour intervals following nocturnal polysomnography. For each test session, the subject was asked to remain awake without using extraordinary measures. Each test session is terminated after 20 minutes if no sleep occurs, or after 10 minutes, if sleep occurs. The overall score is the mean sleep latency for the 4 sessions.

In Trial N4, a statistically significant improvement in the change in the Maintenance of Wakefulness Test score from baseline at Week 8 was seen in the Sodium Oxybate Oral Solution and Sodium Oxybate Oral Solution plus modafinil groups compared to the placebo group.

This trial was not designed to compare the effects of Sodium Oxybate Oral Solution to modafinil, because patients receiving modafinil were not titrated to a maximally effective dose.

Table 8  
Change in Baseline in the Maintenance of Wakefulness Test Score (in minutes) at Week 8 in Trial N4