Statistical analyses were performed based on per protocol analysis and LOCF method, and the data included all patients for whom at least a baseline measurement was available. The LOCF method was applied for endpoint analysis. All subjects who received at least one dose of the study medication were included in the safety analysis. In addition, second analysis was conducted using complete analysis. Categorical variables are presented as absolute numbers and relative frequencies (%) and nominal variables as means and standard deviations. Scores on each psychometric scale were analyzed by the Mann-Whitney U test, paired t-test, and repeated measures analysis of variance (RM-ANOVA). The Greenhouse–Geisser correction was used to test for non-sphericity in RM-ANOVA. The chi-square test or Fisher’s exact test was used to analyze categorical variables. All statistical tests were two-tailed with a significance level of 0.05. All statistical analyses were conducted using SPSS software (version 25, IBM Corp., Armonk, NY, USA).

The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practices. Written informed consent was obtained from all subjects after they had been given an extensive explanation of the nature and procedures of the study. The study protocol was approved by the institutional review or ethics committees at each study site (ISPAIK 2015-10-001).

The results of the per protocol analysis indicated significant improvements in all five measured variables after 8 weeks of the prolonged-release melatonin treatment compared to baseline (Figure 1). Specifically, sleep latency and total PSQI showed a significant decrease over the 8-week treatment period, indicating that it took less time for patients to fall asleep, and their overall sleep quality improved (p<0.001) (Table 1 and Figure 1A, D). Additionally, total sleep time, sleep efficiency, and WHO-5 Well-being Index demonstrated a significant increase, suggesting that patients experienced longer and more efficient sleep and reported better overall well-being (p<0.001) (Table 1 and Figure 1B, C, E). When comparing the data at 4 weeks and 8 weeks of treatment with baseline, significant differences were observed in four of the five variables, except for PSQI (post-hoc test) (Table 1). These findings suggest that most of the improvements occurred by the 4-week and were sustained through the 8-week treatment period. Notably, the PSQI showed a significant difference only at 8 weeks, indicating that it might take more time for Circadin to have a noticeable impact on certain aspects of sleep quality.

The LOCF analysis provided results nearly consistent with the per protocol analysis. After 8 weeks of Circadin treatment, all five variables showed statistically significant differences compared to baseline (Figure 2). Similar to the per protocol analysis, sleep latency and total PSQI demonstrated a significant decrease over the 8-week period, indicating improved sleep initiation and overall sleep quality (p<0.001) (Table 2 and Figure 2A, D). In contrast, total sleep time, sleep efficiency, and WHO-5 Well-being Index significantly increased, indicating longer and more efficient sleep and improved well-being (p<0.001) (Table 2 and Figure 2B, C, E). Like the per protocol analysis, significant differences were observed at 4 weeks and 8 weeks when compared to baseline, except for the PSQI variable, which showed a significant difference only after 8 weeks of treatment (Table 2).

During the study period, a careful assessment of adverse events associated with the prolonged-release melatonin treatment was conducted. Table 3 provides a summary of the observed adverse events. Among the reported adverse events, dizziness and heartburn were the most frequently encountered, with each occurring in three cases. Additionally, one instance of insomnia aggravation, headache, and dyspepsia was documented.

A notable aspect of the study was the dropout rate, which occurred in 48 out of 115 participants, representing a dropout rate of 41.7%. The reasons for dropout varied and included follow-up loss, discontinuation due to lack of efficacy, and discontinuation due to adverse events. Among the participants who dropped out, 21 individuals were lost to follow-up, which accounted for a significant portion of the total dropouts. Additionally, 19 participants discontinued the study due to perceived lack of efficacy, indicating the challenges some participants faced in experiencing the desired outcomes from the treatment. Furthermore, 8 participants chose to discontinue the study due to adverse events. These adverse events may have contributed to their decision to withdraw from the study prematurely.

The findings from both per protocol and LOCF analyses demonstrated consistent improvements in various sleep parameters and well-being following the prolonged-release melatonin treatment. Notably, sleep latency significantly decreased, indicating that patients experienced faster sleep initiation after 4 and 8 weeks of treatment. This improvement is in line with the results of a study which similarly reported a reduction in sleep latency among elderly individuals treated with the prolonged-release melatonin [8]. Total sleep time and sleep efficiency also improved significantly, suggesting that patients experienced longer and more restful sleep. These findings are consistent with a randomized controlled trial, where the prolonged-release melatonin was associated with improved total sleep time and sleep efficiency in elderly patients with insomnia [13]. The observed increase in the WHO-5 well-being index underscores the positive impact of the prolonged-release melatonin treatment on patients’ overall sense of well-being, which demonstrated improvements in well-being following melatonin treatment [8]. The safety profile of the prolonged-release melatonin appears promising, with the most commonly reported adverse events being dizziness and heartburn. These adverse events were generally mild and manageable, consistent with the findings of a study which reported similar adverse events in elderly patients treated with the prolonged-release melatonin [7]. Importantly, no significant concerns regarding dependence, withdrawal, or behavioral abnormalities were observed, further highlighting the potential advantages of the prolonged-release melatonin over traditional sleep medications such as benzodiazepine hypnotics and certain Z-drugs. These safety considerations are particularly relevant in the elderly population, where drug interactions and side effects can pose significant challenges, as noted in studies [14]. The study’s dropout rate of 41.7% is noteworthy and highlights some of the challenges faced by elderly patients in adhering to insomnia treatment regimens. This high dropout rate aligns with previous studies where dropout rates in insomnia trials involving elderly individuals have been commonly reported [15]. Factors contributing to dropout included followup loss, perceived lack of efficacy, and adverse events [16]. However, it is highly likely that the dropout rate was high in this study due to a lack of efficacy. This is because the frequency of adverse effects in per protocol analysis was very low, and 61% of the subjects complained of insomnia even though they were already taking sleeping pills, so they can be seen as treatment-resistant patients.

The distinct advantage of the prolonged-release melatonin lies in its sustained-release formulation, which provides a more physiological mimicry of the natural circadian rhythm of melatonin secretion [7]. While the efficacy of the prolonged-release melatonin may be slightly lower than that of traditional sleeping pills, its favorable safety profile and potential for sustained benefits make it a promising option, especially for elderly patients who may be more susceptible to adverse effects and drug interactions, as emphasized in the studies [17,18].

Several limitations of the study should be acknowledged. The high dropout rate raises questions about the generalizability of the findings to the broader population of elderly patients with insomnia. Additionally, the study’s duration of 8 weeks may not capture long-term effects or potential changes in efficacy over extended periods of use. Further research is warranted to explore the longer-term effects of the prolonged-release melatonin and its potential for preventing relapse after treatment discontinuation [17].

The present study provides valuable evidence supporting the efficacy, tolerability, and safety of the prolonged-release melatonin, a sustained-release melatonin drug, in improving sleep quality and overall well-being among elderly patients with insomnia. The observed improvements in sleep latency, total sleep time, sleep efficiency, and well-being align with findings from previous studies, highlighting the potential benefits of this novel treatment approach. While challenges such as a high dropout rate and individual variability in treatment response exist, the prolonged-release melatonin holds promise as a valuable therapeutic option for addressing the sleep disturbances experienced by the elderly population. Further research, building upon the contributions of prior studies, is needed to refine treatment strategies, enhance adherence, and establish the long-term benefits of the prolongedrelease melatonin in this clinical context.