Melatonin agonist tasimelteon (HETLIOZ®) improves sleep in patients with primary insomnia: A multicenter, randomized, double-blind, placebo-controlled trial

1. Tasimelteon significantly reduced sleep onset latency from the first night, with improvements maintained over 4 weeks in patients with chronic sleep onset insomnia.

2. The drug was well tolerated, with only mild adverse events reported and no evidence of next-day residual effects, rebound insomnia, or withdrawal

Evidence Rating Level: 1 (Excellent)

Study Rundown: This randomized, double-blind, placebo-controlled Phase III trial evaluated tasimelteon, a dual melatonin MT1/MT2 receptor agonist, in 322 adults with primary insomnia characterized by difficulty falling asleep. Patients received 20 mg, 50 mg, or placebo nightly for five weeks, with polysomnography conducted at multiple intervals. Tasimelteon significantly reduced latency to persistent sleep (LPS), with improvements of 45–46 minutes at weeks 1–2 compared to 28 minutes with placebo (p < 0.001), and sustained benefit through week 4. Subjective sleep latency also improved. Modest gains in total sleep time and sleep efficiency were observed, while effects on sleep maintenance were limited. Tasimelteon was well tolerated, with no evidence of next-day impairment, rebound insomnia, or withdrawal symptoms. The most frequent adverse events were mild (e.g., headache, nasopharyngitis). These findings indicate tasimelteon provides rapid, durable, and safe improvement in sleep initiation, making it a promising therapeutic option for patients with chronic sleep onset insomnia.

Click to read the study in PLOS One

Relevant Reading: 

Management of Chronic Insomnia Disorder in Adults: A Clinical Practice Guideline From the American College of Physicians

In-Depth [Randomized Controlled Trial]: 

Insomnia is the most prevalent clinical sleep complaint, affecting an estimated 10–17% of adults in the United States. Sleep onset insomnia, characterized by difficulty initiating sleep, is often associated with circadian misalignment, where patients attempt sleep at an earlier circadian phase than their intrinsic rhythm supports. Existing pharmacological options such as benzodiazepines and non-benzodiazepine hypnotics promote sedation but do not correct circadian dysregulation and carry risks of tolerance, withdrawal, and next-day residual effects. Melatonin receptor agonists, by contrast, act both to regulate circadian rhythms and to promote sleep. Tasimelteon, a dual MT1/MT2 receptor agonist, is already approved for circadian rhythm disorders such as Non-24-Hour Sleep-Wake Disorder and Smith-Magenis syndrome. This study evaluated its efficacy and safety for primary insomnia characterized by difficulty falling asleep.

This multicenter, randomized, double-blind, placebo-controlled Phase III trial enrolled 322 adults aged 18–64 years with primary insomnia, defined by DSM-IV criteria and confirmed via polysomnography (PSG). Participants reported subjective sleep latency of at least 45 minutes three or more nights per week and had latency to persistent sleep (LPS) of ≥30 minutes on screening PSG. After a placebo lead-in, patients were randomized to 20 mg tasimelteon, 50 mg tasimelteon, or placebo, administered nightly 30 minutes before bedtime over five weeks. PSG was performed on nights 1, 8, 22, and 29, with a placebo washout on night 36. The primary endpoint was change in LPS at the average of nights 1 and 8. Secondary endpoints included wake after sleep onset (WASO), total sleep time (TST), sleep efficiency (SE), and subjective sleep assessments. Cognitive function, mood, and withdrawal effects were also monitored.

Of 322 randomized patients, 294 completed the study. Baseline characteristics were balanced between groups, with a mean age of 42 years and 61% female. The primary endpoint was met: tasimelteon reduced LPS significantly more than placebo. At nights 1 and 8, mean reductions in LPS from baseline were 44.9 minutes (20 mg) and 46.3 minutes (50 mg) compared with 28.2 minutes for placebo (p < 0.001 for both doses). This effect persisted through weeks 3–4, with reductions of 49.4 minutes (20 mg) and 45.1 minutes (50 mg) compared with 33.9 minutes for placebo (p < 0.05). Subjective sleep latency also improved significantly.

Improvements in TST were observed, with tasimelteon increasing sleep duration by 51–60 minutes versus 40–47 minutes for placebo, though statistical significance was limited. Sleep efficiency increased modestly (10–13% with tasimelteon vs. 8–10% with placebo), but these changes did not consistently reach significance. WASO values trended toward improvement but were not statistically significant. Thus, the strongest and most consistent benefit of tasimelteon was in sleep initiation rather than maintenance.

Importantly, tasimelteon was well tolerated. The most common treatment-emergent adverse events were mild, including headache, nasopharyngitis, and increased creatine phosphokinase. Rates of discontinuation were similar across groups. No clinically meaningful changes in laboratory values, vital signs, or ECGs were noted. Cognitive and mood testing revealed no next-day residual effects, and no rebound insomnia or withdrawal symptoms emerged after abrupt discontinuation.

The findings demonstrate that tasimelteon produces rapid and sustained improvement in sleep onset latency in patients with primary insomnia. Unlike traditional hypnotics, tasimelteon exerts circadian regulation as well as soporific effects, which may be especially beneficial in patients with circadian misalignment contributing to insomnia. The drug showed no evidence of tolerance, withdrawal, or next-day impairment, distinguishing it from many existing pharmacologic options.

The study highlights tasimelteon as a safe and effective treatment for chronic sleep onset insomnia. Its efficacy was apparent from the first night, persisted over four weeks, and was achieved without the adverse next-day or dependence risks that limit use of other hypnotics. While improvements in sleep maintenance parameters were less robust, tasimelteon offers a promising targeted therapy for patients whose primary complaint is difficulty initiating sleep.

Image: PD

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