Aged 18 to 64 years; DSM-IV criteria for chronic primary insomnia; ≥3 months of difficulty initiating or maintaining sleep or experiencing nonrestorative sleep.
Patient's Global Impression (PGI) and Clinical Global Impression-Improvement (CGI-I) were assessed every 4 weeks up to week 24. Patient Morning Questionnaire (PMQ), recorded daily, assessed subjective sleep measures—sleep onset latency (SOL), total sleep time (TST), number of awakenings (NAW), wake time after sleep onset (WASO), and quality of sleep (QOS)—and next-day functioning. At week 12, PGI, Item 1 (aid to sleep), the primary endpoint, was scored as favorable (i.e., “helped me sleep”) by 89.8% of zolpidem patients vs. 51.4% of placebo patients (P < 0.0001, based on rank score) and at week 24 by 92.3% of zolpidem extended-release patients vs. 59.7% of placebo patients. Zolpidem extended-release also was statistically significantly superior to placebo at every time point for PGI (Items 1–4) and CGI-I (P < 0.0001, rank score), TST, WASO, QOS (P < 0.0001), and SOL (P ≤ 0.0014); NAW (Months 2–6; P < 0.0001). Sustained improvement (P < 0.0001, all time points) was observed in morning sleepiness and ability to concentrate (P = 0.0014, month 6) with zolpidem extended-release compared with placebo. Most frequent adverse events for zolpidem extended-release were headache, anxiety and somnolence. No rebound effect was observed during the first 3 nights of discontinuation.
The main secondary efficacy variables were the scores on the following additional assessments performed every fourth week during the treatment period: CGI-I; PGI Items 1, 2, 3, and 4; and the following assessment as summarized for each month of the study treatment period: PMQ parameters TST, WASO, SOL, QOS, and NAW in the ITT population. Tablet-taking behavior was analyzed over each 4-week period of treatment. Measures of daytime ability to function and sleepiness in the morning, provided daily as part of the PMQ, were analyzed on a monthly basis.
A rebound insomnia effect was defined as a worsening of sleep from baseline values. Rebound effect was assessed by patients' TST and WASO scores as recorded in the patient's daily questionnaire during the run-out period.
Multicenter, 25-week, phase IIIb, randomized, double-blind, placebo-controlled, parallel-group.
Patients completed the PMQ each morning upon awakening and recorded their responses via the interactive voice response system (or Internet). The PMQ asks the respondent whether he or she took the study medication the previous evening and assesses the following subjective sleep measures: duration of sleep onset latency (SOL), TST, WASO, NAW, and quality of sleep (QOS). QOS was measured using a 4-point categorical scale scored as excellent (1), good (2), fair (3), and poor (4). In addition, each respondent assessed the level of next-day functioning by rating the level of morning sleepiness using numerical values from 0 (very sleepy) to 10 (not at all sleepy) and by rating ability to concentrate using a 4-point categorical scale scored as excellent (1), good (2), fair (3), and poor (4). The PMQ was completed daily beginning after the screening visit and continuing through to study termination. Data from this questionnaire were used in various assessments: patient eligibility during the run-in period, the effects of treatment on secondary efficacy variables during the 24-week treatment period, the frequency of self-administration of study medication during the 24-week treatment period, and the occurrence of rebound insomnia during the run-out period (for TST and WASO only).
Single-dose zolpidem extended-release 12.5 mg (n = 669) or placebo (n = 349), self-administered from a minimum of 3 nights/week to a maximum of 7 nights/week.
Safety was assessed by physical examination during screening and at the last visit, by measurement of vital signs (heart rate, supine and standing systolic and diastolic blood pressure) during each visit, and by documentation of spontaneously reported or observed adverse events (AEs) throughout the study.
The efficacy and safety of zolpidem extended release 12.5 mg has been evaluated only in a short-term trial. 29 This was a placebo-controlled study involving adult patients with primary insomnia who received nightly administration of zolpidem. Polysomnographic evaluation showed that, in comparison with placebo, treatment with zolpidem extended-release 12.5 mg significantly improved LPS, a measure of sleep onset, and it significantly reduced the duration of wake time after sleep onset (WASO) and the number of awakenings (NAW), both measures of sleep maintenance, on the first 2 nights of treatment and after 2 weeks of treatment.
The present study expands upon this finding by examining the long-term efficacy and safety of zolpidem extended-release 12.5 mg, self-administered from a minimum of 3 to a maximum of 7 nights per week for 24 weeks, in adults with chronic primary insomnia who exhibit difficulties with both sleep onset and sleep maintenance.
Outpatient; visits every 4 weeks.
Patient kits contained blister packages of the study medication sufficient for 4 weeks of treatment. At each visit, patients returned the packet from the previous 4 weeks, and the study staff recorded the number of remaining tablets along with the dates on which the patient omitted dosing, as noted on the questionnaire that patients completed each morning. The investigator reviewed the patient questionnaire at each study visit to determine drug compliance and the recording of daily sleep parameters. Patients were considered compliant with treatment if they took between 3 and 7 tablets per week. Patients could withdraw from the study at any time and for any reason. Study staff recorded the reasons for withdrawal or early discontinuation and made every effort to have the patients complete an early termination visit.
To evaluate long-term efficacy and safety of zolpidem extended-release 3 to 7 nights/week for chronic primary insomnia.
The PGI is a 4-item, subjective, patient self-report that assesses treatment aid to sleep (Item 1), treatment benefit to sleep induction (Item 2), treatment benefit to sleep duration (Item 3), and appropriateness of study medication strength (Item 4). Each item, presented to patients as a survey document for them to complete, consists of a 3-point categorical scale, with a recorded score of 1 representing a treatment benefit/advantage on items 1 to 3 (“too strong” on item 4), a rank score of 2 representing no effect/change on items 1 to 3 (“just right” on item 4), and a rank score of 3 representing a worsening/disadvantage on items 1 to 3 (“too weak” on item 4). Each patient completed the PGI at every 4-week study center visit during the 24-week treatment period and at the final visit at week 25 during the run-out period. PGI assessments at each visit were based on the patient's global perception of the effects of treatment on sleep during that treatment period (including nights with and without dosing), as compared to their sleep prior to entering the study.
The primary efficacy variable was the score on the PGI Item 1, treatment aid to sleep, assessed at week 12 of the treatment period in the intent-to-treat (ITT) population. The ITT population consisted of all randomized patients who had received at least one dose of study medication and had undergone at least one post-baseline efficacy assessment. The PGI Item 1 included three ordered categories related to the patient's impression that treatment (1) helped me sleep, (2) did not affect my sleep, or (3) worsened my sleep.
The ESS was used to determine daytime sleepiness and was completed by each patient at each 4-week study center visit during the 24-week treatment period and at the final visit at week 25 of the run-out period. The scale consisted of 8 items assessing the degree of sleepiness during the performance of everyday activities, each item being scored from 0 (would never fall asleep) to 3 (high chance of falling asleep).
A sample size of 1000 patients was required in a ratio of 2:1 (zolpidem extended-release 12.5 mg to placebo) to provide ≥99% power to detect a difference of 0.6 (standard deviation, 0.5) between zolpidem extended-release 12.5 mg and placebo in scores on the primary endpoint, PGI Item 1 (P ≤ 0.05, 2-sided test). This sample size was also powered sufficiently to detect a difference between groups in scores on the secondary endpoints (WASO and TST) at month 3, taking into account a dropout rate of 20% at month 3 (P ≤0.05, 2-sided test).
Patients were excluded if they were shift workers or if they napped more than 3 times per week. Also excluded were patients who consumed more than 5 xanthine-containing beverages per day, as well as patients who had been using over-the-counter sleep remedies or prescription sleep medications within 2 weeks or 5 half-lives (whichever was longer) before screening. Use of any substance associated with effects on sleep/wake function within 1 week or 5 half-lives (whichever was longer) before screening was not permitted. In addition, patients were ineligible if they had primary hypersomnia, narcolepsy, breathing-related sleep disorders, circadian-rhythm sleep disorders, parasomnia, or dyssomnia not otherwise specified (i.e., periodic leg movement disorders). Patients who had a current severe neuropsychiatric disorder (i.e., psychosis, obsessive compulsive disorder, major depression, anxiety disorders, panic disorders, dementia of Alzheimer or vascular type) according to DSM-IV criteria, a history of substance abuse or dependence (including alcohol) within the past year, myasthenia gravis, severe respiratory insufficiency, hepatic insufficiency, any unstable medical condition, or sensitivity to zolpidem or its excipients were not entered into the study. Women who were lactating or pregnant were also excluded, as were any patients who had participated in another clinical trial within the 2 months prior to screening.
After successful completion of the screening visit and run-in period, eligible patients were randomly assigned to receive either zolpidem extended-release 12.5 mg or placebo in a 2:1 ratio, according to a randomization schedule supplied by Sanofi-Aventis. Placebo tablets were the same size, shape, color, and taste as zolpidem extended-release tablets and were therefore indistinguishable from active treatment. Patients were instructed to take no more than 1 tablet per night of study medication immediay before bedtime with a glass of water, for a minimum of 3 tablets and a maximum of 7 tablets per week. The 3-tablet minimum was judged to be necessary to produce a minimum drug-treatment effect in this chronically ill population. During week 25, the run-out period, patients took no medication.
CHRONIC INSOMNIA, DEFINED AS A COMPLAINT OF PERSISTENT DIFFICULTY FALLING ASLEEP, MAINTAINING SLEEP, AND/OR EXPERIENCING nonrestorative sleep accompanied by significant dysfunction in next-day cognitive, physical, or social functioning, affects approximay 10% of the population. 1 – 3 This condition continues to represent an under-recognized public health burden and clinical challenge. 3 One particularly challenging aspect of clinical management is the implementation of effective treatment that takes into account the chronic nature of this disorder. Patients often continue to report symptoms for many years after the disorder's onset, with approximay 45% of patients remaining symptomatic after 10 years. 2, 4 Correspondingly, many chronic insomnia patients take sedative-hypnotics for longer durations (∼5 years) than clinically evaluated and traditionally recommended. 5 – 7 So far, only one placebo-controlled trial of 6 months' duration has been carried out with a medication of this type, 8 although two open-label studies of 12 months' treatment have been completed. 9, 10 The fact that long-term use of insomnia medications is widespread and that little of the treatment research has been conducted over extended periods underscores the need for more studies of long-term pharmacotherapy of insomnia.
This was a national (United States), multicenter, phase IIIb, randomized, double-blind, placebo-controlled, two-parallel-group study in adult patients with chronic primary insomnia. The 26-week study was divided into the following three phases: (1) a run-in period of 7 days (±3 days), comprising screening and baseline determination; (2) a post-randomization treatment period of 24 weeks (±3 days), in which patients received study medication; and (3) a run-out period, with no medication for 7 days (±3 days), to assess rebound effects after abrupt discontinuation of study medication. During the treatment period, patients received either zolpidem extended-release 12.5 mg tablets or identical placebo tablets. Patients were instructed to take the medication on those nights when they judged it to be necessary, with the caveat that they were required to self-administer study medication at least 3 nights per week. Patients were given sleep hygiene instructions, which included a directive to refrain from alcohol. Patients were scheduled to report to their study center every 4 weeks for clinical evaluation; those who completed the trial were evaluated at a total of 9 study center visits ( Figure 1 ). Each patient signed an informed consent form before the conduct of any study-related procedure. The appropriate Institutional Review Board at each investigative site approved the protocol.
An important methodological point is that, in the few long-term pharmacotherapy studies that have been done, patients with insomnia received nightly medication dosing throughout the treatment period. As the duration of treatment increases, the costs and risks of adverse effects associated with taking a medication nightly become increasingly important considerations. There is good reason to believe that, for many insomnia patients, it may be possible to achieve effective treatment while decreasing risks and costs by employing non-nightly medication dosing. Studies of patient dosing behaviors have, in fact, indicated that approximay 41% of chronic insomnia patients take hypnotic medications intermittently on an “as needed” basis, as opposed to consistent, nightly administration. 11 A potential explanation for this dosing behavior is the waxing and waning severity of insomnia 12 – 15 and the unpredictable variability in the presentation of specific symptoms over time (e.g., difficulties with sleep onset, sleep maintenance, or both). 16 Thus, utilizing a dosing strategy that allows for some degree of patient choice may better match the pattern of sleep difficulties in many insomnia patients and reduce the incidence of their taking medications when not needed. 17.
The CGI is a clinician-rated scale composed of two subscales that measure disease severity and degree of improvement, respectively. CGI-Severity (CGI-S) is a single-item, global scale of disease severity that requires the investigator to compare the patient's symptoms with those of all other patients who have the disorder. It is scored from 1 (normal) to 7 (among the most extremely ill). CGI-S was assessed at the baseline visit. CGI-Improvement (CGI-I) is a single-item scale of symptomatic improvement or worsening that requires the investigator to compare the patient's status at the time of assessment with baseline severity (baseline CGI-S). CGI-I is scored from 1 (very much improved) to 7 (very much worsened). CGI-I was assessed at each 4-week study center visit during the 24-week treatment period and at the final visit at week 25 during the run-out period.
These findings establish the efficacy of 3 to 7 nights per week dosing of zolpidem extended-release 12.5 mg for up to 6 months. Treatment provided sustained and significant improvements in sleep onset and maintenance and also improved next-day concentration and morning sleepiness.
The primary objective of the study was to evaluate the efficacy of 6 months of treatment with zolpidem extended-release 12.5 mg, as compared with placebo, when taken 3 to 7 nights per week by patients with chronic primary insomnia. Additional objectives included evaluation of the safety and tolerability of zolpidem extended-release 12.5 mg, compared with placebo, when taken for a long-term period of time, and evaluation of the potential for rebound effects after abrupt discontinuation. Next-day functioning, including the ability to concentrate and level of sleepiness in the morning, was also subjectively assessed throughout the treatment period.
The efficacy and safety of optional dosing of a hypnotic within a prespecified range has thus far only been demonstrated for zolpidem tartrate, a short-acting nonbenzodiazepine agent indicated for the short-term treatment of insomnia, 18 in clinical trials of 8 and 12 weeks' duration. 19, 20 Similar to other short-acting nonbenzodiazepine hypnotics (e.g., zaleplon, eszopiclone), zolpidem selectively binds to the alpha-1 subunit subtype of the gamma-aminobutyric acid receptor. 21 Characterized by a relatively short half-life (2.5 h), zolpidem is effective at reducing the latency time to persistent sleep (LPS) and at increasing total sleep time (TST), but it is not consistently efficacious for the treatment of sleep maintenance symptoms, 22 – 24 which occur in 60% to 73% of insomnia patients. 22, 25, 26.
Krystal AD; Erman M; Zammit GK; Soubrane C; Roth T. Long-Term Efficacy and Safety of Zolpidem Extended-Release 12.5 mg, Administered 3 to 7 Nights Per Week for 24 Weeks, in Patients With Chronic Primary Insomnia: A 6-Month, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study. SLEEP 2008;31(1):79-90.
Eligible study participants included male and female patients, 18 to 64 years of age, who met criteria for chronic primary insomnia from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). 1 These criteria included a history of at least 3 months (before screening) of difficulty falling asleep, difficulty maintaining sleep, or experiencing nonrestorative sleep, with reports of clinically significant impairment in social, occupational, or other important areas of functioning. Women of childbearing potential were required to have a negative serum pregnancy test at the screening visit and to agree to use an acceptable form of contraception throughout the study. In addition, patients were required to have experienced ≥1 h of wakefulness for at least 4 nights per week over the past month and to have spent >6.5 h but <8.5 h per night in bed trying to sleep over the past 2 weeks. During the run-in period, when patients completed a daily questionnaire, the data were required to confirm a mean TST of >3 h but <6.5 h per night and a mean WASO of ≥40 min.
Zolpidem tartrate extended-release 12.5 mg, developed to extend the duration of action of the original zolpidem formulation, is a dual-layered tablet that provides a biphasic release of zolpidem: an initial release of drug to facilitate sleep onset, and a delayed release to benefit the maintenance of sleep throughout the middle of the night. 27, 28 While zolpidem extended-release 12.5 mg and the original zolpidem 10 mg formulation share similar rapid onsets of peak plasma concentrations (T max : 1.5 h vs. 0.88 h, respectively) and elimination half-lives (T 1/2 : 2.8 ho vs. 2.6 h, respectively), zolpidem extended-release exhibits higher, prolonged plasma concentrations than original zolpidem, beyond 3 h postdose. 28.