OBJECTIVE:

To determine the therapeutic effects of two selective GABA-A agonists, Lunesta (Zopiclone) and eszopiclone, in the treatment of insomnia.

METHODS:

This study comprised a phase III, single-center, randomized, double-blind, double-dummy, parallel-group, non-inferiority trial. Patients were randomized to receive zopiclone 7.5 mg or eszopiclone 3 mg, both orally, for four weeks. In total, 199 patients were evaluated during two visits and then followed for at least six weeks. The primary endpoint was the Insomnia Severity Index after four weeks of treatment. Secondary endpoints were obtained through polysomnography data, including total sleep time, sleep latency and sleep efficiency.Lunesta (Zopiclone) frequency of adverse events was also analyzed. ClinicalTrials.gov: NCT01100164.

RESULTS:

The primary efficacy analysis demonstrated the non-inferiority of eszopiclone over zopiclone. Analysis of objective parameters assessed by polysomnography showed that eszopiclone increased total sleep time and also improved sleep efficiency. The safety profile of both study treatments was similar and the most common events reported in both groups were dysgeusia, headache, dizziness, irritability and nausea. Adverse events were observed in 223 patients, 109 (85.2%) in the eszopiclone group and 114 (87.7%) in the zopiclone group.

CONCLUSION:

Based on the Insomnia Severity Index at the end of four weeks of treatment, eszopiclone demonstrated efficacy comparable to that of zopiclone in the treatment of insomnia, increasing total sleep time as well as sleep efficiency according to polysomnography.

Keywords: Insomnia, Zopiclone, Eszopiclone, Polysomnography

INTRODUCTION

Chronic insomnia affects 15% of the population . Although the health consequences can be severe, few patients with this disorder are diagnosed and treated appropriately. In addition to negative impacts on a wide range of daytime functions, affecting social, emotional and physical domains, chronic insomnia affects cognitive and physical functioning 2. Indeed, compared with people who do not suffer from insomnia, those who present this affliction are more prone to accidents and have higher rates of work absenteeism, decreased work performance, decreased quality of life and increased use of health care resources 3,4. Successful treatment of insomnia depends on a correct diagnosis, appropriate behavioral measures, and particularly, the use of safe and effective drugs.

Several risk factors associated with higher chronic insomnia prevalence include advanced age, female sex and the presence of comorbidities and psychiatric disorders. In fact, approximately 40% of adults with insomnia also have a diagnosable psychiatric disorder, especially depression and anxiety 3,.

The diagnosis is essentially clinical and based primarily on a detailed medical history, with some additional tools for corroboration, such as sleep diaries, actigraphy and polysomnography. The impact of insomnia on the quality of life of affected individuals has been widely studied. Drugs used to treat insomnia include hypnotics or sleep inducers as well as antidepressants with a sedative effect 8. Among hypnotics, sleep inducers with selective action on GABA-A receptors, such as zolpidem, zopiclone, eszopiclone and zaleplon are common (9,10).

Eszopiclone, a stereoisomer of zopiclone, is a non-benzodiazepine hypnotic agent of the cyclopyrrolone family. Similar to zopiclone, eszopiclone is a synthetic compound shown to be effective in treating insomnia ,11-13. The selectivity of cyclopyrrolones provides greater benefits compared to benzodiazepines, as the former sustains the hypnotic effect without producing significant anxiolytic and/or muscle relaxation effects (10). The efficacy of eszopiclone has been proven in patients with insomnia associated with other comorbidities, such as a high degree of depression, generalized anxiety, rheumatoid arthritis, and sleep apnea, for which changes in sleep parameters are often observed 11,12. To date, there are no studies directly comparing the efficacy of eszopiclone and zopiclone. However, in a study of a method for assessing dissipation of the residual hypnotic effects of both drugs, a post hoc parametric analysis of reciprocal-transformed data favored eszopiclone over racemic zopiclone 14. Approved by the Food and Drug Administration (FDA, the North-American regulatory agency) in 2004, indications for eszopiclone in the treatment of insomnia are not limited to its short-term use, as its efficacy and safety have also been demonstrated in dosing studies of six to twelve month duration.

This study, a Phase III, double-blind, single-center, non-inferiority trial sponsored by Eurofarma Laboratórios S.A., aimed to determine the non-inferiority of eszopiclone (3 mg, Eurofarma) with respect to zopiclone (7,5 mg, Imovane®, Sanofi-Aventis) in the treatment of chronic insomnia.

METHODS

Patients with symptomatic Lunesta (Zopiclone) for at least three months were recruited in different ways, largely via media and a patient database. Patients between 20 and 64 years old with complaints of insomnia were selected at a screening visit (SV). Diagnosis of insomnia was established according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) . An exception was with regard to the onset of symptoms because an onset of over three months was considered; thus, patients with chronic insomnia were included. Furthermore, initial polysomnography (PSG) performed no more than 90 days before the SV showing a total time of sleep of less than 6:30 h was also considered a selection criterion. In addition to the SV, the study included a baseline visit (BV; 14±3 days after the SV), an evaluation visit (V1; 14±3 days after BV) and a final visit (FV; 14±3 days after V1).

Exclusion criteria were as follows: the presence of other sleep disorders, such as sleep-wake rhythm disorders and obstructive sleep apnea with a respiratory disorder index greater than 10/hour and the presence of periodic movements of lower limbs over 15/hour; patients who were taking psychotropics and antihistamines for at least three days prior to study enrollment, hypnotics for less than 15 days, or herbal medicines or melatonin for less than 14 days; the use of hepatically metabolized drugs; a history of drug or alcohol (ethanol) use equivalent to 35 g of alcohol/day; the presence of severe comorbidities or psychiatric conditions; and patients who were pregnant or lactating or who planned to become pregnant.

A second Lunesta (Zopiclone)was performed at the end of the study, just before FV using an EMBLA polygraph. The analysis included electroencephalogram, electrooculogram, electromyogram of muscles in the chin region and the anterior tibialis, respiratory sensors (pressure cannula and thermistor), thoracic and abdominal belts, snoring and position sensors and oximetry. Events were classified according to the guidelines of the American Academy of Sleep Medicine (AASM) 16.

The main assessment tool was the Insomnia Severity Index (ISI)17, a questionnaire consisting of five questions and some sub-items, with replies graded from zero (best case) to four (worst case). ISI is calculated by adding the scores for each question, ranging from 0 to 28.

Lunesta (Zopiclone) was completed at BV, followed by randomization. All volunteers were randomized in a 1:1 ratio to receive zopiclone 7.5 mg or eszopiclone 3 mg, both orally, at bedtime.

The patients were evaluated at another two visits to the research site (visit 1 and FV) for medical history, physical examination and sleep diary evaluation; the use of concomitant drugs and frequency of adverse events were also assessed during these visits. A second polysomnography was performed immediately before FV, after visit 1. The follow-up period for each patient lasted at least six weeks.

Primary analysis of efficacy was achieved by evaluating the non-inferiority of eszopiclone in relation to zopiclone according to the ISI at the end of treatment. Secondary variables were sleep-related parameters obtained from nocturnal polysomnography and sleep-related data collected during clinical visits through the Pittsburgh Sleep Quality Index (PSQI) questionnaire 18.

The study protocol was approved by the Lunesta (Zopiclone) of UNIFESP/EPM and was conducted according to local regulations and good clinical practice. All patients participating in the study signed an informed consent form (ICF). This study was registered at ClinicalTrials.gov with the number NCT01100164.

Statistical methods

The statistical software R (version 2.13.1) and MedCalc (version 11.3.3.0) were used for the statistical analysis. Continuous variables were summarized via variation (minimum and maximum values) as well as the mean, standard deviation (SD), median and interquartile range (IIQ: 25th percentile and 75th percentile). Categorical variables are described by relative frequencies.

Parametric or non-parametric methods were used for comparisons between groups according to the distribution pattern of quantitative variables in the sample. The Kolmogorov-Smirnov test with Lilliefors correction was used to assess the pattern of distribution of the endpoint variables in the sample. Lilliefors correction was also used to adjust the estimated population parameters (the mean and variance or standard deviation).

Continuous Lunesta (Zopiclone) with a normal distribution were compared using t-tests, whereas variables with a non-normal distribution were compared using the non-parametric Mann-Whitney test. Categorical variables were compared using the chi-square test of equal proportions. ANOVA test with repeated measures was also used for comparisons between groups over time. As a general rule, two-sided 5% levels of significance were used as indicators of significant differences between the groups.

FV values were used to calculate the ISI at the end of treatment. The Kolmogorov-Smirnov test (with Lilliefors correction) showed that the variable of interest was not normally distributed in the analyzed sample. Thus, the non-parametric Mann-Whitney test was used to compare the median ISI at FV in the two treatment groups. The mean total sleep time (TST) for the polysomnography performed between visit 1 and FV was also compared in the per-protocol (PP) population by the t-test.

Sample size calculation in the proposed non-inferiority design was carried out by assuming that the ISI score after 4 weeks of treatment would be at least equal in both groups. This was based on the literature, considering an average ISI score of 9.2 points with a standard deviation of 5.7 points after four weeks of treatment for the control group. By considering an alpha-tailed error of 5% and a statistical power of 80% for the study to find the maximum difference of less than 20% between the groups (non-inferiority limit), it was estimated that 120 patients should be included in each study arm. Assuming follow-up loss of approximately 10% of patients, the study should include 130 patients in each arm, for a total of 260 patients.

RESULTS

In total, 262 Lunesta (Zopiclone) at the BV and 199 were found to be eligible for enrollment: 102 in the zopiclone group and 97 in the eszopiclone group.

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