Novel sublingual low-dose zolpidem tablet reduces latency to sleep onset following spontaneous middle-of-the-night awakening in insomnia in a randomized, double-blind, placebo-controlled, outpatient study

Abstract

Study objectives: To evaluate efficacy and safety of 3.5-mg zolpidem tartrate sublingual tablets (ZST) on latency to sleep onset after middle-of-the-night (MOTN) awakenings in patients with insomnia characterized by difficulty returning to sleep after MOTN awakenings.

Design: Multicenter randomized, double-blind, placebo-controlled, parallel-group.

Setting: Outpatient.

Patients: There were 295 adults (median age 43 y; 68.1% female) with primary insomnia and difficulty returning to sleep after MOTN awakenings (three or more MOTN awakenings/wk during screening).

Interventions: After a 2-wk, single-blind placebo eligibility period, participants were randomized 1:1 to as-needed MOTN dosing with 3.5 mg ZST or placebo for 28 nights. An interactive voice response system determined if the study drug could be taken and recorded sleep/wake efficacy measures.

Results: ZST significantly (P < 0.0001) decreased latency to sleep onset over 4 wk (baseline 68.1 min; ZST 38.2 min) compared with placebo (baseline 69.4 min; placebo 56.4 min). Ratings of morning sleepiness/alertness significantly (P = 0.0041) favored the ZST group on nights medication was taken but not on other nights. Participants in the ZST group took the study drug on 62% of nights during the 4 wk; members of the placebo group took study medication on 64% of nights. Adverse events were generally mild and at the same rate (19.3% of participants) in both groups. There were no treatment-related serious adverse events (SAEs), and one adverse event-related study discontinuation from the placebo group. Dosing/week did not increase across the study.

Conclusions: 3.5 mg ZST used as needed significantly reduced latency to return to sleep in comparison with placebo in these patients with insomnia. Sleep quality was improved, and morning sleepiness/alertness scores also improved. ZST was well tolerated. These data demonstrate the utility of a sleep-promoting agent when used as needed in the MOTN.

Clinical trials registration: NCT00466193: "A Study of Zolpidem Tartrate Tablet in Adult Patients with Insomnia" http://www.clinicaltrials.gov/ct2/show/NCT00466193?spons=%22Transcept+Pharmaceuticals%22&spons_ex=Y&rank=2

Figure 1

Patient disposition. ^aThe safety population includes all randomized patients who took at least one dose of study medication during the double-blind treatment phase of the study. ^bThe efficacy population includes all randomized subjects who took at least 1 dose of study medication and provided at least 1 LSO_MOTN value. LSO_MOTN latency to sleep onset following middle-of-the-night awakening.

Figure 2

LSO_MOTN during the double-blind treatment period. Analysis of covariance model with log-transformed mean LSO_MOTN as response; treatment and pooled site as fixed effects and baseline log-transformed average LSO_MOTN as covariate. P-value shown is for treatment. All values < 0.0001 ZST compared to placebo. LSO_MOTN, latency to sleep onset following middle-of-the-night awakening; ZST, 3.5-mg zolpidem tartrate sublingual tablet.

Figure 3

Change from baseline in TST_MOTN. Baseline TST_MOTN was derived from the average of values collected during the 2-wk placebo run-in period for those nights study medication was taken. Analysis of covariance model with mean TST_MOTN as the response; treatment and pooled site as fixed effects and average TST_MOTN at baseline as a covariate. *P < 0.02; ₊P < 0.05. TST_MOTN, subjective total sleep time following middle-of-the-night awakening; ZST 3.5-mg zolpidem tartrate sublingual tablet.

Figure 4

NAW_MOTN during the run-in and double-blind treatment period. Continuous values obtained by averaging were then categorized as shown. The row mean score statistic was employed for categorized mean NAW_MOTN. (A) Baseline NAW_MOTN is the average of values collected during the 2-wk placebo single-blind screening period for those nights study medication was taken. No statistical difference between groups. (B) Four-wk treatment average. P < 0.001. NAW_MOTN, subjective number of awakenings following middle-of-the-night awakening; ZST, 3.5-mg zolpidem tartrate sublingual tablet.

Figure 5

Mean number of study medication tablets consumed per wk during the single-blind and double-blind periods. There was no statistical difference between groups at either phase.