Nightly treatment of primary insomnia with prolonged release melatonin for 6 months: a randomized placebo controlled trial on age and endogenous melatonin as predictors of efficacy and safety

Study design

This was a randomized, double-blind, parallel group clinical trial comprising a 2-week, single-blind, placebo run-in period (Baseline), a 3-week double-blind treatment period (treatment weeks 1-3) followed by a 26- week double-blind extension period (treatment weeks 4 to 29) in which patients were randomized to receive PRM (Circadin^® 2 mg, Neurim Pharmaceuticals Ltd, Tel Aviv, Israel) or placebo, given orally as one tablet per day 2 h before bedtime, and a 2-week single-blind placebo run-out period (withdrawal). The study protocol and relevant documents were approved by Huntingdon Multi-centre Research Ethics Committee, Cambridge, UK. Participants provided written informed consent.

Study subjects

Patients were recruited from Glasgow and the surrounding areas (West of Scotland) and were pre-screened by telephone using the Sleep History Questionnaire (SHQ) within 1 month of the baseline screening visit. The SHQ was adapted from The Management of Insomnia Guidelines for Clinical Practice [26]and resembled that recommended by Clinical Practice Guideline - Adult Insomnia [27, 28]. Suitable patients were invited to Visit 1 during which they were consented and assessed for inclusion.

Men and women aged between 18 and 80 years suffering from primary insomnia according to the Diagnostic and Statistical Manual for Mental Disorders (DSM-IV) criteria with sleep latency longer than 20 min were included in the study.

The major exclusion criteria for the study included the use of benzodiazepine or non-benzodiazepine hypnotics within the previous 2 weeks or any psychoactive treatment within the previous 3 months, sleep disorders associated with a psychiatric disorder (for example, depression, anxiety, dementia), sleep disorders secondary to another medical condition (for example, sleep apnoea, circadian rhythm sleep disorder), use of prohibited concomitant medication [psychotropic treatments - neuroleptics, antiepileptics, barbiturates, antidepressants, anxiolytics and lithium, first generation antihistamines, hypnotics or treatments used as a hypnotic (for example, all benzodiazepines, zopiclone, zolpidem and zaleplon, barbiturates, buspirone and hydroxyzine)] or excessive alcohol consumption, any chronic medical condition that was likely to be the cause of the sleep problem (for example, chronic pain, benign prostatic hypertrophy) or might interfere with the conduct of the study or a lifestyle likely to interfere with sleep patterns (for example, shift work, jet-lag).

A four-step process was used for screening out patients with secondary sleep disorders including depression and other sleep disorders in the study according to DSM-IV criteria.

Step 1: The initial prescreening for primary insomnia as defined in DSM-IV was performed on a telephone interview and was based on the SHQ. The SHQ characterizes the primary sleep complaint according to the differential diagnostic criteria (DSM-IV and International Classification of Diseases-10) and also helps in differentiating primary insomnia from insomnia due to medical and psychiatric disorders (including depression and anxiety) and specific insomnia disorders such as circadian rhythm disorders, movement disorders, parasomnias and breathing related sleep disorders.

Step 2: At the screening visit, a physical examination was performed by a qualified clinician to exclude patients with physical causes of insomnia.

Step 3: At the screening visit the patients went through a detailed psychological assessment that included the Raskin Depression scale, Covi anxiety scale and the Mini Mental State (MMS) in order to exclude psychiatric disorders, including depression anxiety and dementia. In addition, a history of severe psychiatric disorders, especially psychosis, anxiety and depression were major exclusion criteria.

Step 4: Patients who were using psychotropics (neuroleptics, antiepileptics, barbiturates, antidepressants, anxiolytics or lithium) in the 3 months before the study were excluded. A urine drug screen for benzodiazepines and morphine derivatives was undertaken at baseline. Patients with a positive result were excluded. Hypnotic use was monitored throughout the study. Patients were asked at each visit whether they took a hypnotic beside medication and were withdrawn if they did. The common analgesics used in UK for self limiting intermittent problems such as headache frequently contain codeine. Patients for whom pain was a cause of insomnia were excluded from the study. However, due to the long-term nature of the study intermittent use of common analgesics was allowed.

The screening and run-in periods were used to wash-out previously administered medicinal products which were incompatible with the trial, for confirmation of a stable disease and compliance with study medication and procedures and for the qualitative and quantitative baseline assessments of patients. Patients with major short-term fluctuations of their condition and non-compliance with study procedures were excluded. A history of sleep latency of >20 min, required for patients inclusion, was assessed once in the telephone interview (SHQ), confirmed at the screening and then at the baseline visits using the PSQI [28–30]. Eligible patients entered the baseline screening run-in period and received 2 weeks of single-blind treatment with placebo. Patients still eligible after the 2-week placebo run-in and who were compliant with respect to treatment, had a negative drug screen and correctly completed study assessment forms were randomized in a 1:1 ratio to receive either PRM 2 mg or placebo for 3 weeks in a double-blind manner. Randomization was stratified by trial site, 6-SMT levels (low ≤8 μg versus high >8 μg/night) and age group (< 65 versus ≥65 years).

After the 3-week treatment period, completing patients were allowed to proceed into the extension period. All PRM patients stayed on PRM and all placebo patients were randomised in a 1:1 ratio to receive either PRM 2 mg or placebo for 26 weeks, resulting in a 3:1 ratio of PRM to placebo.

At the end of the extension period, all patients received 2 weeks of single-blind placebo in the run-out period to evaluate withdrawal effects. The overall duration of the study was 33 weeks.

Patients were instructed to take one tablet daily of study medication orally, 1-2 h before going to bed (preferably between 2100 h and 2200 h) and after food, and were asked to fill in a diary each morning, reporting on sleep latency, sleep maintenance, total sleep time, time going to bed, sleep offset time, refreshed on waking score, morning alertness score, and sleep quality in the previous night).

The treatment period was double-blind with two parallel treatment groups. Selection for a treatment group was determined by a computer generated randomization list in a 1:1 ratio (PRM mg to placebo). The list was constructed using the method of randomized permuted blocks. Randomization was stratified by trial site, 6-SMT levels (low/high) and age group (< 65/> 65). A centralized randomization system (Interactive Voice Response System [IVRS]) was used. Sites called the IVRS, using a toll-free number. The patient's status: trial site, 6-SMT level (low excretors/high excretors) and age (< 65/>65) were entered into the IVRS. The IVRS randomised the patients and provided a double-blind treatment kit assignment.

By the end of the 3 week treatment period, the PRM patients remained on the active medication and placebo patients were randomized again for the double-blind extension period. Selection for a treatment group was determined by a computer generated randomization list in a 1:1 ratio (PRM 2 mg to placebo). This procedure was performed for all participants using the centralized IVRS randomization system keeping the patient and the study personnel (investigator and nurses) blind to the allocated treatment. The list was constructed using the method of randomized permuted blocks.

Blinding was maintained by use of a matching placebo identical in appearance taste and smell to the active medication and use of an independent IVRS to allocate randomized treatment. During the 33 weeks of the study (run-in, double-blind treatment, double-blind extension and run-out), patients were blinded regarding the type of medication they were receiving (placebo or active). During the double-blind treatment and extension periods, the investigator(s) and their staff were also blinded regarding the treatment administered (double-blind). However, they were aware that the patient was receiving placebo during the run-in and run-out periods.

The blinding was not to be broken (unless in an emergency) until the database was locked to perform planned analyses. The IVRS was used to break a code in case of emergency. This was to be done only when the investigator decided that knowledge of which study treatment the patient had been randomized to, would affect the management of an adverse experience. There were three people for whom the blind was broken all due to a serious adverse event (SAE), two were on PRM and one was on a placebo.

Endpoints

The main objective of this study was to assess the effects of short-term (3-week) therapy with PRM versus placebo on patient reported sleep latency (sleep diary) in their natural setting, in patients with low endogenous melatonin levels (≤8 versus >8 μg urinary 6-SMT/night) and in elderly patients (65-80 years old). Additional sleep and daytime parameters, safety and maintenance of PRM efficacy and safety over a 6-month period were also evaluated.

Efficacy variables were recorded at baseline and each visit. PSQI [29, 30] global score, component scores, and questions 2 and 4 filled in by the investigator with the patient; sleep diary (National Sleep Foundation diary) parameters (daytime and night-time) were filled in by patient each day in the morning in the 7 days preceding each visit; World Health Organization (WHO)-5 Well-being Index (1998 version) [31]and Clinical Global Impression of Improvement (CGI) - Severity of Illness Scale (CGI-S) [32] were filled in by the investigator with the patient at screening and baseline and the improvement (CGI-I) at each subsequent visit.

The PSQI has been recommended as an essential measure for global sleep and insomnia symptoms in recent expert consensus recommendations for a standard set of research assessments in insomnia [28]. It comprises nine questions relating to the patient's usual sleep habits during the previous 2 weeks; the second and third weeks of active treatment. It addresses possible reasons for trouble in sleeping as well as daytime behaviour. An algorithm is used to calculate seven component scores and these are added to give a global PSQI score. The PSQI component scores, Question 2 (Sleep Latency) and Question 4 (Total Sleep Time) after 3 weeks' double-blind treatment, and the change from baseline levels of these parameters. It has been shown that each of the PSQI individual component scores measures a particular aspect of the overall construct. Furthermore, control subjects differ from insomnia patients in all individual components [29]. However, the correlation between individual items and global score ranged from 0.83 (subjective sleep quality) to 0.07 (cough or snore during sleep) [29]. In the evaluation of the drug effects it was therefore interesting to look at each component.

Safety variables and vital signs (pulse, blood pressure) were assessed at each visit including spontaneously reported adverse events (AEs); unusual events and AEs observed by the investigator. Physical examination was performed at screening, end of run-in, after three and 29 treatment weeks and at discontinuation. An electrocardiograph was recorded at end of run-in, after three, seven and 29 treatment weeks and at discontinuation. Vital signs (pulse, blood pressure) were recorded at all visits. Laboratory tests (haematology, biochemistry and urinalysis) were assessed at screening, after three, seven and 29 treatment weeks and at discontinuation. Endocrine evaluations were performed at screening and after 29 treatment weeks in 80 patients who were not using any hormonal contraceptives or hormonal replacement therapies and who were not suffering from any significant endocrine disease. Cortisol was assessed at screening and after 29 treatment weeks in 56 patients before and after synacthen test. The Tyrer scale [33]was completed by the investigator after 29 treatment weeks and at withdrawal.

Statistical issues

The predefined primary efficacy variable was the comparison of sleep latency as measured by the sleep diary at 3 weeks treatment weeks with PRM (2 mg) or placebo in the pre-defined subgroups of patients who were low excretors of melatonin regardless of age (primary endpoint) and the patients aged 65-80 years, regardless of melatonin levels. The comparison was done using a linear regression model with terms for treatment (PRM versus placebo), baseline sleep latency and age group (≥65 or <65 - only for the primary endpoint). In compliance with US Food Drug Administration regulatory procedures, no correction for multiple comparisons were performed for the primary outcome measure.

All other efficacy endpoints were pre-defined as exploratory and aimed at confirming the results of the primary analysis using additional instruments (for example, PSQI) or adding information on other aspects of the sleep and daytime consequences of the treatment including: (1) time going to bed and sleep offset times, sleep maintenance, total sleep time, sleep quality and morning alertness from the sleep diaries; (2) the PSQI global score; (3) PSQI questions 2 (sleep latency in minutes) and 4 (total sleep time in minutes) and the individual PSQI components; (4) the CGI-I score assessed by the clinician at three to 29 treatment weeks) quality of life derived from the WHO-5 Well-being index covering positive mood, vitality and general interests.

Our main conclusion was based on sleep latency, the predefined primary variable. No correction was made for multiple statistical testing for the exploratory variables. Accordingly, the overall conclusions from the results are based on the accumulation of evidence for between-treatment differences which were, in many cases, correlated or complementary, rather than on isolated P-values.

Patient disposition and demographics

A total of 930 patients were enrolled into the study between October 2006 and December 2008 and entered the run-in period; 139 of these patients discontinued during the run-in period. The overall disposition of the patients in this study is summarized in Figure 1.

The number of patients in the low excretors (86 per treatment group) and 65-80 year-old subgroups (PRM 137; placebo 144) of the FAS was lower than planned. The study failed to meet the design requirements for a 95% statistical power on the primary endpoint (120 low excretors per treatment group) and 90% power on the first secondary endpoint (179 patients ≥65 years per treatment group) involving sleep latency. The power reached with these sample sizes was 86% for the patients with low endogenous melatonin and 82% for the patients aged 65 and older. The 722 patients (225, 31% men; 497 women, 69%) in the FAS had a mean age of 62 years (range 20 to 80 years).

The treatment groups in the FAS were very similar regarding gender, age, race, BMI, pulse, blood pressure, ECG, medication use, medical history, and physical examination abnormalities (Tables 1 and 2). Caffeine, alcohol intake and smoking status were also generally similar between the treatment groups. The treatment groups were generally well balanced regarding demographic characteristics, pulse, ECG, blood pressure, compliance, medication use, medical history and physical examination characteristics. In this study 15.3% of the age 65-80 population and 8.7% of the low excretor population were confirmed to be taking common analgesia medications that included codeine at anytime during the study. As can be seen in the demography (Tables 1 and 2), the patients reporting usage of codeine containing medications were evenly randomized to PRM and Placebo in both randomization periods.

Efficacy

Primary efficacy variable

The effects of 3 weeks treatment with PRM or placebo on patient reported sleep latency (sleep diary) for low excretors and elderly patients are shown in Table 3. Sleep latency after 3 weeks of treatment was not significant in low excretors aged 18-80 between the PRM and placebo groups, as measured by the sleep diary, whereas a significant difference in favour of PRM was found for patients aged 65-80 years (-15.6 min; 95% CI -25.3 to -6.0, P = 0.002; Table 3; Figure 2).

	Treatment		Treatment effect difference PRM - placebo; (95% confidence interval)	Pvalue* effect PRM versus placebo
	PRM	Placebo
Low excretor population
N	86	86
Baseline: mean (SD)	74.1 (54.9)	75.5 (58.5)
Treatment: mean (SD)	65.1 (59.9)	66.5 (51.6)
Change from baseline: mean (SD)	-9.0 (50.5)	-9.0 (48.7)	-0.6 (-14.0, 12.7)	0.924
65-80 year population
N	137	144
Baseline: mean (SD)	76.7 (63.7)	72.5 (51.4)
Treatment: mean (SD)	57.6 (51.8)	70.9 (54.0)
Change from baseline: mean (SD)	-19.1 (47.3)	-1.7 (47.8)	-15.6 (-25.3, -6.0),	0.002

*Linear regression model with terms for treatment (PRM versus placebo), baseline sleep latency and age group (≥65 or <65 - only for the low excretors).

PRM, prolonged release melatonin; SD, standard deviation.

Other variables in the short-term period

Long-term period

The results of the long-term analyses using MMRM for low excretors aged 18-80 are presented in Tables 4 and 5.

In the low excretors (regardless of age) a longer total sleep time was seen with PRM compared to placebo treated patients (estimated difference 13.1 min, 95% CI 1.0 to 25.2, P = 0.035; Table 4). PSQI global scores were lower (improved) in the PRM group across study visits with significant global treatment effects [-0.66 (-1.30, -0.01), P = 0.046; Table 5]. WHO-5 Index scores were significantly improved in PRM patients for the low excretors [0.91 (0.16, 1.66), P = 0.017; Table 5]. CGI-I scores were significantly lower (improved) across study visits in the PRM group compared with placebo for these patients [-0.25 (-0.49, -0.01), p = 0.042; Table 5]. Concerning sleep latency, there was a significant improvement with PRM over placebo in the low excretors when measured with the PSQI question 2 [-11.6 (-22.0, -1.1) min, P = 0.030] that was less consistently observed with the diary [-6.7 (-16.4, 3.0) min, P = 0.174; Tables 4 and 5].

The results of the long-term analyses using MMRM for low excretors aged 18-80 and for patients aged 65-80 years are presented in Tables 6 and 7. In patients aged 65-80 (regardless of melatonin excretion), sleep latency throughout the long term period was significantly shorter in the PRM group as assessed by the sleep diary with a mean difference from placebo of -14.5 min (-21.4, -7.7; P < 0.001; Table 6). Similar results were observed with sleep latency recorded by PSQI component 2 and PSQI question 2 (Table 7) The estimated treatment effect differences for sleep latency during the extension period for these patients show incremental difference between PRM and placebo with time of treatment up to 3 months reaching plateau levels that are maintained to the rest of the 6 months period (Figure 3). A similar pattern was seen for time going to bed, with PRM patients going to bed significantly earlier than placebo patients (treatment difference -0.21 h over placebo; 95% CI -0.33 to -0.08, P = 0.002; Table 6 and Figure 4). There was some indication that PRM patients also woke up somewhat earlier (treatment difference -0.12 h; 95% CI -0.24 to 0.00, P = 0.051).

PSQI global scores were lower (improved) in the PRM group across study visits with significant global treatment effects [-0.70 (-1.17, -0.23) P = 0.003; Table 7].

Consistent with the improvements in quality of sleep (PSQI global score) and sleep latency (diary), components 1 (sleep quality) and 2 (sleep latency) of the PSQI were significantly lower (improved) in the PRM group across study visits in patients aged 65-80 years [-0.15 (-0.25, -0.04), P = 0.006, -0.24 (-0.38, -0.10), P = 0.001]. PSQI question 2 (sleep latency) was significantly lower across study visits in the PRM group in the age 65-80 population [-12.1 min (-19.1, -5.1), P = 0.001].

PRM patients aged 65-80 years were significantly more alert in the morning than placebo patients [-0.10 (-0.19, -0.01), P = 0.032; Table 6]. The effects of treatment on morning alertness were enhanced during the long term period as evidenced by a linear trend in treatment by visit effects (P = 0.012), with greater benefits for PRM patients at later visits. CGI-I scores were significantly lower (improved) across study visits in the PRM group compared with placebo for these patients [-0.20 (-0.38, -0.02), P = 0.027; Table 7].

Safety