Circadin® is approved for marketing as a patent-protected 2mg prolonged-release melatonin formulation. It mimics the physiological secretion profile of melatonin.
Neurim’s database has shown that elderly patients suffering from primary insomnia secrete significantly lower levels of melatonin than those with good sleep quality. The rationale for the use of Circadin® is to reconstitute the decreased melatonin levels in this patient population. Consequently, patients are able to improve the quality of their sleep and subsequently improve day-time functioning and quality of sleep. This treatment approach thus fundamentally differs from currently available CNS-depressant hypnotics that act through the GABA-A receptor.
The clinical development of Circadin® is based on the observation that it improves sleep quality in elderly insomnia patients as shown in controlled clinical studies by Haimov et al 1995, Garfinkel et al 1995 and by Leger et al 2004. To date it has undergone a full preclinical and clinical development program including multicenter trials conducted by reputable CROs (Wade et al 2007, Lemoine et al 2007, Luthringer et al 2009, Wade et al 2010 and Wade et al 2011). Circadin® is extremely well tolerated and safe as reflected by the low rate of adverse events and dropouts in clinical trials and low level of reported Adverse Reactions in post marketing safety database. Circadin® was found effective in improving quality of sleep and sleep latency while also improving day time functioning and quality of life:
The effects of Circadin® versus placebo treatment were assessed in a multi-center randomized placebo-controlled study. Circadin® is the first drug shown to significantly improve quality of sleep and morning alertness in primary insomnia patients aged 55 years and older-suggesting more restorative sleep, and without withdrawal symptoms upon discontinuation Lemoine et al 2007.
Prolonged-release melatonin treatment results in significant and clinically meaningful improvements in sleep quality, morning alertness, sleep onset latency and quality of life in primary insomnia patients aged 55 years and over as shown in double-blind study by Wade et al 2007.
In a long term study (26 weeks double blind) Circadin® improved sleep latency, quality of sleep and morning alertness, with no withdrawal symptoms and rebound insomnia. The study showed that the benefit observed after 3 weeks were increased up to 3 months and maintained up to 6 months. At 3 months, about an extra 10% of responders were seen in the Circadin® treated group Wade et al 2010 and Wade et al 2011.
Circadin® was not associated with impairment of memory, vigilance, and driving performance as compared with placebo and other hypnotics as shown in studies by Paul et al 2003 and Otmani et al 2008 and had no discernible withdrawal symptoms.
In exploratory studies, Circadin® also improves sleep quality in patients with chronic schizophrenia as shown in a randomised double-blind clinical trial by Shamir et al 2000 as well as in patients with major depressive disorder as shown in a double-blind study by Dolberg et al 1998, an open-label study by Dalton et al 2000 and treating sleep-wake cycle disorders in children with underlying neuro-developmental difficulties as shown in a studies by Jan et al 2000 and De Leersnyder et al 2003. In addition, Circadin® as add-on to antihypertensive therapy improved blood pressue control in patients with nocturnal hypertension as shown in a randomised double-blind placebo controlled study by Grossman et al 2006.