Abstract
Study Objectives
To evaluate the efficacy and safety of Dimdazenil, a positive allosteric modulator with selectivity for α1, α5 subunit-containing GABAA receptors, on sleep variables in patients with insomnia disorder.
Methods
In this randomized, double-blind, placebo-controlled trial, adults (18–65 years) with insomnia disorder were randomized (1:1:1:1 to receive daily oral placebo, Dimdazenil (1.5, 2.5, or 5 mg) for 14 days. The primary efficacy outcome was the total sleep time (TST) on day 1/2 and day 13/14, measured by polysomnography. The secondary outcome measures included (1) latency to persistent sleep (LPS), sleep efficiency (SE), wake after sleep onset (WASO) and number of awakenings (NAW) on days 1/2 and day 13/14, and (2) the average subjective sleep latency (sSL), total sleep time (sTST), wake after sleep onset (sWASO) and number of awakenings (sNAW) recorded in sleep diary and sleep questionnaire, and the evaluation of insomnia severity index. Rebound insomnia, withdrawal, and treatment-emergent adverse events were also assessed.
Results
Of 569 patients screened, 288 (76.4% female) were randomized and received one dose. For the primary outcomes, TST was significantly improved in the Dimdazenil 1.5, 2.5, and 5 mg group compared with the placebo group at day 1/2, and significantly improved in the Dimdazenil 2.5 and 5 mg groups compared with the placebo group at day 13/14. The Least Squares Means (standard errors) and 95% Confidence Intervals for the three active doses compared to placebo are 25.5 (8.31), (9.16, 41.89) for the 1.5 mg dose; 17.4 (8.19), (1.29, 33.55) for the 2.5 mg dose; 22.8 (8.15), (6.72, 38.80) for the 5 mg dose on day 1/2. Corresponding data on day 13/14 are 7.6 (8.07), (−8.24, 23.53) and 19.3 (8.06), (3.43, 35.17) and 18.2 (7.95), (2.49, 33.80). LPS was significantly reduced in the Dimdazenil 5 mg group compared with the placebo group on day 1/2. SE was significantly improved in the Dimdazenil 1.5 and 5 mg group compared with the placebo group at day 1/2. In the subjective sleep parameters, sSL on average was significantly lower in the Dimdazenil 1.5, 2.5, and 5 mg groups compared with the placebo group. sTST on average was significantly higher in the Dimdazenil 1.5, 2.5, and 5 mg groups compared with the placebo group. The most common TEAEs were dizziness, vertigo, and weakness with no clinically relevant treatment-related serious adverse events.
Conclusions
Dimdazenil of 1.5, 2.5, and 5 mg improved certain objective and subjective sleep outcomes in people with insomnia disorder, with a favorable safety profile. These findings suggested that Dimdazenil may represent a promising new treatment for insomnia disorder, a prevalent condition with limited effective and safe treatments available.
Clinical Trial Information
A multicenter, randomized, double-blind, multidose, placebo parallel controlled phase II clinical study of EVT201 in the treatment of insomnia disorders (http://www.chinadrugtrials.org), with the number of CTR20150664.
Keywords: GABAA receptors, positive allosteric modulator, Dimdazenil, insomnia disorder, polysomnography
Graphical Abstract
Graphical Abstract.
Statement of Significance.
Insomnia disorder is a highly prevalent ailment affecting 10%–20% of people worldwide. While pharmacological treatments available for insomnia have proven to be safe and effective, they carry a potential risk of compromising postural balance, particularly when individuals rise from bed at night. This increased fall risk, especially among older individuals, has been extensively documented. Dimdazenil is a novel partial positive allosteric modulator of the GABAA receptor with high affinity and moderate efficacy. As a result, Dimdazenil offers an improved safety profile compared to full agonists. This randomized controlled trial provides evidence that Dimdazenil significantly improves objective and subjective measures of sleep onset and sleep maintenance in adults with insomnia disorder compared to placebo. Polysomnography showed Dimdazenil increased total sleep time and reduced sleep latency in a dose-dependent manner. Subjective assessments aligned with these benefits. Dimdazenil exhibited a favorable safety profile and was well-tolerated, without altering sleep architecture or impairing next-day vigilance and cognition. These findings demonstrate Dimdazenil’s promising potential as an insomnia therapy, with rapid sleep promotion, sustained efficacy over time, and an absence of next-day hangover effects. Given the chronic nature of insomnia, results support further large-scale and long-term evaluation of Dimdazenil to reduce the substantial public health impacts of this prevalent disorder.
Introduction
Insomnia disorder is a common clinical problem characterized by difficulty falling or staying asleep, or waking up too early. It affects an estimated 10%–20% of the general population with a higher incidence in women, the elderly, and those with comorbid medical and psychiatric conditions [1]. Insomnia commonly leads to daytime sleepiness, lethargy, and a general feeling of being unwell. One of the most common treatments for insomnia involves the use of GABAA receptor-positive allosteric modulators [2].
γ-Aminobutyric acid (GABA), which is the main inhibitory neurotransmitter, exerts its effects via ionotropic (GABAA) and metabotropic (GABAB) receptors. It is well established that activation of GABAA receptors promotes sleep [3]. GABAA receptors are heteropentameric membrane proteins that form a GABA-gated chloride channel, which contains the α subunit α1, α2, α3 or α5, a β subunit (mainly β2 or β3) and, in nearly all cases, the γ2 subunit in a 2:2:1 stoichiometry [4, 5]. In addition, GABAA receptor agonists (benzodiazepines, non-benzodiazepines, etc.) that act on the α1, α2, α3, or α5 subunits of GABAA receptors are commonly used clinically to treat insomnia [6]. Specifically, the sedative, memory, and cognition effects of GABAA receptor agonists have been attributed to their action at α1 and α5 subunits, while the anxiolytic and muscle relaxant effects are attributed to the α2 and α3 subunits, and the anticonvulsant activity is attributed to the α1 subunit [7, 8].
Dimdazenil is a positive allosteric modulator with selectivity for α1, α5 subunit-containing GABAA receptors being developed by Zhejiang Jingxin Pharmaceutical Co. Ltd in China, under the license of Evotec, for the treatment of insomnia. According to the preclinical study of the compound, Dimdazenil selectively acts on the α1-containing GABAA receptors with high affinity and moderate levels of maximum receptor activation. Thus, Dimdazenil has the potential to reduce the side effects associated with the full agonists in current use. In addition, the compound also demonstrates a medium elimination half-life of 3–4 hours in humans, which is predictive of a reduced risk of tolerance development and residual side effects. This study was conducted to investigate three doses of Dimdazenil, compared with placebo on sleep efficiency (SE) and safety in individuals with insomnia disorder. Sleep was assessed using both polysomnography (PSG) and subjective sleep measures.
Methods
Study design
This randomized, multicenter, double-blind, placebo-controlled, parallel-group, phase II study was conducted in hospitals at 29 sites in China. The study was approved by the appropriate Health Authority, ethics committee, or institutional review board for each participating site. This study was registered on the official Drug Clinical Trial Information Management Platform in China (http://www.chinadrugtrials.org), with the number CTR20150664. The study protocol remained unchanged following the initiation of the study.
Patients
All patients signed informed consent prior to any study-mandated procedures, which were conducted in accordance with the Declaration of Helsinki. Demographic characteristics including age and sex were collected.
Eligible patients were men and women aged 18 to 65 years who met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria (DSM-5) for insomnia disorder [9]. Patients were required to meet the following inclusion criteria simultaneously: (1) over the last 3 months, they must have a normal bedtime between 9 pm and 1 am and spend at least 7 hours in bed, (2) they must have had a history of ≥ 30 minutes latency to sleep onset and a total sleep time (TST) ≤ 6 hours on at least 3 of the 7 consecutive nights in the last month, and (3) at least 1 of the 2 nights of polysomnography (PSG) evaluation conducted during the screening period met the following requirements: (1) the sleep latency was greater than 20 minutes, (2) wake after sleep onset (WASO) was > 40 minutes, (3) or TST was less than 420 minutes.
A screening period of 14 days was followed by a 7-day single-blind run-in phase, a 14-day double-blind treatment period, a single-blind placebo run-out for 3 days, and a 7-day safety follow-up period (Figure 1). During the screening phase, patients who passed the screening period took a placebo for 7 days. From days 7 to 3, the patients took a placebo at home and completed their sleep diary. On days 2 and 1, the patients entered the sleep center to receive PSG for 2 consecutive nights. They took a placebo and filled in the sleep questionnaire at the sleep center. Patients meeting the PSG screening requirements were randomly assigned to each dose group or placebo group.
Figure 1.
Study design. The study comprised a screening period followed by a single-blind placebo run-in phase, a double-blind treatment phase, a single-blind placebo run-out period, and a safety follow-up period.
Patients were excluded if they met any of the following criteria: allergy to benzodiazepine receptor agonists; central nervous system drugs were taken in the past 7 days; drugs or health products that regulate sleep function were taken in the past 2 weeks; work or live across 3 or more time zones in the past 2 weeks; participated in other clinical studies in the past 30 days; sleep was affected due to weight loss plan or change of exercise habits in the past 30 days; change of work and rest time in the past 3 months due to work; a history of tumor, myocardial infarction, heart failure, mental disorder, drug abuse, and drug addiction in the past year; a regular drinking history that women drank more than seven cups per week or men drank more than 14 cups per week [1 cup = 5 ounces (150 mL) of wine = 12 ounces (360 mL) of beer = 1.5 ounces (45 mL) of spirits]; a history of epilepsy, sleep apnea, chronic obstructive pulmonary disease, schizophrenia, bipolar disorder, neurodevelopmental retardation, cognitive impairment, restless leg syndrome; with heart, liver, kidney and respiratory insufficiency, or other serious diseases, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) exceeds 1.5 times the upper limit of normal value, and serum creatinine exceeds the upper limit of normal value; intraocular pressure exceeds the upper limit of normal value or a history of glaucoma; the score of Hamilton Anxiety Scale (HAMA) is greater than 14 points, and the score of Hamilton Anxiety Scale (HAMD) is ≥ 18 points in the screening period; smoking more than 10 cigarettes/day or unable to control smoking in the sleep center; pregnant women and lactating women, or women of childbearing age cannot ensure the use of effective and reliable contraceptives; patients who take drugs that influence wake-up function or evaluation of investigational drugs after enrollment. All participants provided written informed consent.
Randomization and masking
Eligible patients were centrally randomized using an Interactive Web Response System in a 1:1:1:1 ratio to one of the four treatment arms: 1.5, 2.5, or 5 mg Dimdazenil, or placebo (0 mg). The randomization list was generated independently and kept strictly confidential. Only patients were masked to treatment during placebo run-in and run-out periods. Investigational treatment and matching placebo were indistinguishable, and all outer packaging of treatment were packaged in the same way. Study treatment comprised two capsules for each intake: Dimdazenil and placebo capsules. In the event of a medical emergency, investigators were permitted to initiate the unmasking process; no unmasking events occurred in this study (Figure 2).
Figure 2.
Trail flow diagram.
Procedures
During the placebo run-in period, polysomnography assessments were conducted on 2 consecutive nights for eligible patients who completed sleep diary and questionnaire to define baseline values. During the double-blind treatment period, patients were administered orally with Dimdazenil of 1.5 mg, 2.5 mg, 5 mg, or placebo 15–20 minutes before going to bed every evening for 14 days. During the double-blind treatment period, patients attended 2 consecutive nights of PSG recording and filled in a sleep diary and questionnaire on day 1/2 and day 13/14. TST (defined as time [min] of total sleep duration), WASO (defined as the time [min] spent awake between the onset of persistent sleep and lights on), and latency to persistent sleep (LPS) (defined as time [min] from lights off to persistent sleep) [10] from each overnight PSG recording were scored centrally. All PSG parameters were averaged over 2 consecutive recording nights. A 3-day placebo run-out period followed the double-blind treatment period (Figure 1). Patients were required to complete a sleep daily throughout the trials, from screening to the end of the placebo run-out period. The insomnia severity index (ISI) was completed at baseline and at the end of the double-blind treatment [11].
Outcomes
The primary efficacy outcome measure was PSG-derived TST averaged over days 1/2 and 13/14. Secondary efficacy outcome measures were (1) LPS, WASO, SE, and number of awakenings (NAW) averaged over day 1/2 and 13/14; (2) subjective sleep latency (sSL), sTST, sWASO, sNAW, and ISI score averaged over sleep diary and wake-up questionnaire records during the double-blind treatment period.
Safety and tolerability were assessed by adverse event reports, physical examination, changes in vital signs, electrocardiograms (ECGs), clinical laboratory reports, and ophthalmic examination. Withdrawal symptoms and rebound effects were collected during the 72 hours following study treatment discontinuation using the Benzodiazepine Withdrawal Symptom Questionnaire scores [12]. Drug residues were assessed using the Sleep Questionnaire for attention, sleep questionnaire, energy recovery, and vigilance level at days 1, 2, 3, and 14. No changes to trial outcomes were made after the trial commenced.
Statistical analysis
The comparison between each dose group is conducted using the superiority test, and significance level for rejection of the null hypothesis was set at α = 0.05. Descriptive statistics were provided for continuous variables expressed as mean (SD) and compared using the ANOVA test. Discrete data are presented as frequencies and compared with chi-square or Fisher’s exact tests, where appropriate.
The primary and secondary endpoints were analyzed in the intention-to-treat population, defined as all participants who were randomly assigned. The efficacy analysis for primary and secondary endpoints was conducted using the full analysis set. The missing data in this study refers to the objective sleep indicators recorded by PSG on day 13/14. According to the provisions of this study protocol, the missing data were replaced by the corresponding data recorded by PSG on day 1/2, which is a technique called last observation carried forward (LOCF) [13]. Occurrences of AEs and serious adverse events (SAEs) and changes in laboratory markers, questionnaires, vital signs, ECGs, and vital signs were summarized using descriptive statistics. The Kruskal–Wallis rank sum test was used for the comparison between groups of drug withdrawal rebound evaluation and drug residues.
No interim analysis or stopping guidelines were applied in this trial. All tests were carried out by SAS version 9.2 (SAS Institute) and two-sided p-values lower than 0.05 were considered statistically significant.
Results
The trial was halted when we reached our predetermined sample size. The first posted date was October 19, 2015, on Center for Drug Evaluation, National Medical Products Administration. Between December 2015 and December 2018, a total of 569 patients were screened, of whom 288 were randomized patients and received one dose of double-blind study treatment. Most participants were females (220, 76.4% of 288 participants). Demographic and basic characteristics were comparable across treatment groups (Table 1). There were no significant differences in the demographic and baseline characteristics.
Table 1.
Baseline Demographics and Baseline Characteristics
| Dimdazenil | Placebo (n = 73) | |||
|---|---|---|---|---|
| 1.5 mg (n = 70) | 2.5 mg (n = 72) | 5 mg (n = 73) | ||
| Age, years | 46.2 (12.4) | 46.0 (12.3) | 43.5 (12.6) | 42.9(12.5) |
| Male, n (%) | 19 (27.1) | 22 (30.6) | 16 (21.9) | 11 (15.1) |
| Female, n (%) | 51 (72.9) | 50 (69.4) | 57 (78.1) | 62 (84.9) |
| Systolic pressure, mmHg | 116.3 (13.9) | 116.5 (12.7) | 116.1 (15.7) | 116.0 (12.8) |
| Diastolic pressure, mmHg | 74.2 (9.6) | 74.2 (8.3) | 72.9 (9.4) | 72.5 (8.8) |
| Heart rate, beats/min | 71.8 (11.5) | 71.3 (7.3) | 71.8 (8.7) | 70.4 (7.2) |
| Respiratory rate, beats/min | 17.5 (1.6) | 17.4 (1.5) | 17.5 (1.6) | 17.5 (1.4) |
| Temperature, °C | 36.3 (0.4) | 36.4 (0.3) | 36.4 (0.4) | 36.4 (0.3) |
| TST, min | 391.2 (73.6) | 392.1 (77.7) | 393.4 (76.4) | 404.8 (69.1) |
| LPS, min | 30.5 (23.2) | 36.1 (37.8) | 33.1 (34.6) | 26.8 (31.4) |
| SE, % | 78.0 (10.3) | 78.2 (13.3) | 77.8 (13.9) | 80.3 (12.2) |
| WASO, min | 79.9 (44.5) | 81.5 (53.8) | 76.5 (61.1) | 76.1 (52.7) |
| NAW, times | 19.1 (26.1) | 18.1 (19.2) | 20.6 (29.6) | 20.4 (28.5) |
| sSL, min | 83.07 (56.6) | 75.16 (39.6) | 86.94 (50.4) | 89.20 (59.2) |
| sTST, min | 262.3 (90.0) | 258.3 (107.4) | 266.5 (88.0) | 274.3 (100.4) |
| sWASO, min | 74.5 (64.6) | 77.0 (60.5) | 79.4 (56.8) | 69.6 (60.6) |
| sNAW, times | 2.08 (1.4) | 1.93 (1.1) | 2.02 (1.2) | 2.05 (1.2) |
| ISI, score | 16.7 (5.9) | 17.4 (5.5) | 16.6 (5.2) | 17.3 (6.4) |
TST, total sleep time; LPS, latency to persistent sleep; SE, sleep efficiency; WASO, wake after sleep onset; NAW, number of awakenings; sSL, subjective sleep latency; ISI, insomnia severity index.
Dimdazenil improves TST assessed by PSG and subjective sleep measures
The clinical outcomes of the study are presented in Table 2. For the primary outcomes, TST was significantly improved in the Dimdazenil 1.5, 2.5, and 5 mg groups compared with the placebo group on day 1/2, and significantly improved in the Dimdazenil 2.5 and 5 mg groups compared to the placebo group on day 13/14 (Figure 3). The least squares means (standard errors) and 95% confidence intervals for the three active doses compared to placebo are 25.5 (8.31), (9.16, 41.89) for the 1.5 mg dose; 17.4 (8.19), (1.29, 33.55) for the 2.5 mg dose; 22.8 (8.15), (6.72, 38.80) for the 5 mg dose on day 1/2. Corresponding data on day 13/14 are 7.6 (8.07), (−8.24, 23.53) and 19.3 (8.06), (3.43, 35.17) and 18.2 (7.95), (2.49, 33.80). For the primary outcomes, LPS was significantly reduced in the Dimdazenil 5 mg group compared with the placebo group on day 1/2. The least squares means (standard errors) and 95% confidence intervals for the three active doses compared to placebo are −6.3 (3.82), (−13.79, 1.24) for the 1.5 mg dose; −3.6 (3.79), (−11.09, 3.83) for the 2.5 mg dose; −10.6 (3.79), (−18.04, −3.10) for the 5 mg dose on day 1/2. SE was significantly improved in the Dimdazenil 1.5 and 5 mg groups compared with the placebo group on day 1/2 (Figure 3). The least squares means (standard errors) and 95% confidence intervals for the three active doses compared to placebo are 3.6 (1.54), (0.54, 6.60) for the 1.5 mg dose; 2.5 (1.53), (−0.55, 5.47) for the 2.5 mg dose; 4.0 (1.53), (0.99, 7.00) for the 5 mg dose on day 1/2. There was no statistically significant difference for WASO and NAW between Dimdazenil group and placebo group.
Table 2.
Primary and Secondary Outcomes
| Dimdazenil | Placebo (n = 73) | |||
|---|---|---|---|---|
| 1.5 mg (n = 70) |
2.5 mg (n = 72) |
5 mg (n = 73) |
||
| Day 1/2 | ||||
| TST, min | 444.7 (53.4)△ | 437.9 (64.3)△ | 444.0 (74.1)△ | 424.3 (54.3) |
| LPS, min | 19.4 (14.3) | 24.2 (31.4) | 16.2 (17.89)△ | 24.5 (31.94) |
| SE, % | 87.2 (7.4)△ | 86.2 (11.4) | 87.5 (12.5)△ | 84.6 (9.4) |
| WASO, min | 50.4 (38.9) | 52.6 (55.3) | 47.4 (66.0) | 57.0 (39.0) |
| NAW, times | 15.9 (22.4) | 18.7 (36.1) | 17.7 (22.9) | 20.1 (31.1) |
| Day 13/14 | ||||
| TST, min | 428.2 (54.8) | 441.6 (49.2)△ | 441.3 (59.4)△ | 424.4 (56.4) |
| LPS, min | 21.5 (23.6) | 17.6 (17.3) | 22.8 (25.8) | 27.1 (35.2) |
| SE, % | 84.8 (9.2) | 87.7 (8.4) | 85.7 (10.9) | 85.1 (8.7) |
| WASO, min | 57.5 (43.2) | 46.6 (41.2) | 53.6 (56.2) | 53.4 (43.9) |
| NAW, times | 15.4 (20.4) | 16.9 (20.7) | 15.1 (19.7) | 17.1 (18.5) |
| Subjective sleep parameters | ||||
| sSL, min | 50.2 (37.6)△ | 47.0 (27.1)△ | 45.1 (30.8)△ | 73.3 (52.9) |
| sTST, min | 354.21 (73.1)△ | 352.28 (81.5)△** | 383.14 (67.4)△*** | 332.28 (101.7) |
| sWASO, min | 48.8 (53.3) | 45.6 (42.7) | 38.5 (33.5) | 46.8 (41.4) |
| sNAW, times | 1.5 (1.1) | 1.4 (0.9) | 1.3 (1.0) | 1.6 (1.0) |
| ISI, score | 12.7 (6.3) | 13.4 (6.0) | 11.7 (6.2) | 12.9 (6.5) |
TST, total sleep time; LPS, latency to persistent sleep; SE, sleep efficiency; WASO, wake after sleep onset; NAW, number of awakenings; sSL, subjective sleep latency; ISI, insomnia severity index.
**significant difference between 2.5 mg group and 5 mg group.
***significant difference between 1.5 mg group and 5 mg group.
△significantly different from placebo group.
Figure 3.
Objective sleep parameters. TST, total sleep time; LPS; latency to persistent sleep; SE, sleep efficiency; WASO, wake after sleep onset; NAW, number of awakenings.
In the subjective sleep parameters, sSL on average was significantly lower in the Dimdazenil 1.5, 2.5, and 5 mg groups compared with the placebo group. The least squares means (standard errors) and 95% confidence intervals for the three active doses compared to placebo are −20.7 (5.52), (−31.56, −9.84) for the 1.5 mg dose; −20.9 (5.52), (−31.74, −10.02) for the 2.5 mg dose; −27.3 (5.47), (−38.06, −16.52) for the 5 mg dose. sTST on average was significantly higher in the Dimdazenil 1.5, 2.5, and 5 mg groups compared with the placebo group (Figure 4). The least squares means (standard errors) and 95% confidence intervals for the three active doses compared to placebo are 29.1 (9.72), (10.00, 48.26) for the 1.5 mg dose; 29.6 (9.66), (10.61, 48.62) for the 2.5 mg dose; 55.6 (9.64), (36.60, 74.57) for the 5 mg dose. There was no statistically significant difference for sWASO, sNAW, and ISI between Dimdazenil group and placebo group.
Figure 4.
Subjective sleep parameters. sSL, subjective sleep latency; sTST, subjective total sleep time; sWASO; subjective wake after sleep onset; sNAW, subjective number of awakenings; ISI, insomnia severity index.
Safety
The incidence of treatment-emergent adverse events (TEAE) was 61.4%, 69.4%, and 72.6% in patients treated with 1.5, 2.5, and 5 mg Dimdazenil, respectively, compared with 64.4% in patients on placebo (Table 3). No relationship to the Dimdazenil dose was seen in the overall incidence of TEAEs. The most frequent TEAEs in patients treated with Dimdazenil were dizziness (31.5%), vertigo (12.3%), and weakness (14.3%). There were no SAEs in all treatment groups. TEAEs leading to premature discontinuation of double-blind treatment were reported for three patients who all complained of dizziness (one participant on 2.5 mg Dimdazenil, one participant on 5 mg Dimdazenil, and one participant on placebo). The composition of severity for TEAEs in each group was presented in Figure 5 and no significant differences were observed.
Table 3.
Treatment-Emergent Adverse Events by Treatment Group
| n (%) | Dimdazenil | Placebo (n = 73) | ||
|---|---|---|---|---|
| 1.5 mg (n = 70) | 2.5 mg (n = 72) | 5 mg (n = 73) | ||
| TEAE | 43 (61.4) | 50 (69.4) | 53 (72.6) | 47 (64.4) |
| Serious TEAE | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| TEAE leading to treatment discontinuation |
0 (0) | 1 (1.4) | 1 (1.4) | 1 (1.4) |
| TEAE rate more than 5% in any group | ||||
| Auditory hyperesthesia | 7 (10.0)△ | 4 (5.6) | 3 (4.1) | 1 (1.4) |
| Hyperesthesia | 5 (7.1)△ | 1 (1.4) | 1 (1.4) | 0 (0.0) |
| Vertigo | 8 (11.4) | 6 (8.3) | 9 (12.3) | 2 (2.7) |
| Urinary tract infection | 3 (4.3) | 5 (6.9) | 3 (4.1) | 5 (6.8) |
| Oxygen desaturation | 5 (7.1) | 5 (6.9) | 7 (9.6) | 5 (6.8) |
| RSL | 5 (7.1) | 5 (6.9) | 5 (6.8) | 2 (2.7) |
| Headache | 5 (7.1) | 6 (8.3) | 3 (4.1) | 6 (8.2) |
| Dizzy | 8 (11.4) | 18 (25.0)△ | 23 (31.5)△*** | 7 (9.6) |
| Dysosmia | 5 (7.1)△ | 2 (2.8) | 1 (1.4) | 0 (0.0) |
| Myalgia | 4 (5.7) | 5 (6.9)** | 0 (0.0) | 1 (1.4) |
| SAS | 5 (7.1) | 5 (6.9) | 9 (12.3) | 12 (16.4) |
| Depression | 4 (5.7) | 1 (1.4) | 1 (1.4) | 0 (0.0) |
| Weakness | 10 (14.3)△ | 7 (9.7) | 5 (6.8) | 2 (2.7) |
| Nausea | 2 (2.9) | 3 (4.2) | 2 (2.7) | 4 (5.5) |
| Halitosis | 4 (5.7) | 5 (6.9) | 1 (1.4) | 1 (1.4) |
| Photophoby | 4 (5.7) | 4 (5.6) | 0 (0) | 1 (1.4) |
| Ophthalmalgia | 7 (10.0) | 5 (6.9) | 3 (4.1) | 5 (6.8) |
TEAE, treatment-emergent adverse events; RSL, restless leg syndrome; SAS, sleep apnea syndrome.
**significant difference between 2.5 mg group and 5 mg group.
***significant difference between 1.5 mg group and 5 mg group.
△significantly different from placebo group.
Figure 5.
Composition of severity for TEAEs in each group. TEAE, treatment-emergent adverse event.
Sleep architecture
The evaluation of sleep architecture is presented in Supplementary Table S1. The patient’s basic sleep architecture had not been seriously disturbed. The difference in sleep time, rapid eye movement (REM) sleep latency, percentage of sleep, and percentage of REM sleep time between the treatment groups on day 1/2 was statistically significant in stage 2. The sleep time and percentage of sleep in stage 2, and sleep time, REM sleep latency, and percentage of sleep in stage 3 were statistically significant on Day 13/14. It seems that Dimdazenil increases sleep time, percentage of sleep in stage 2 and REM sleep latency, and decreases percentage of REM sleep time, sleep time in stage 3, in a dose-dependent manner.
Withdrawal symptoms, rebound effects, and drug residues
The withdrawal symptoms and rebound effects are presented in Supplementary Table S2. Most of the evaluation indicators had no significant statistical difference. There were just statistically significant differences among muscle pain, muscle tremor, and vertigo groups. For the drug residues, there were significant differences in sleep quality, energy recovery, vigilance level, and attention between the groups on days 2 and 3. The difference in sleep quality between the treatment groups on day 14 was statistically significant (Supplementary Table S3). Like the withdrawal symptoms and rebound effects, most of the evaluation indicators had no significant statistical difference in the drug residues.
Discussion
The phase II study of Dimdazenil, a new positive allosteric modulator with selectivity for α1, α5 subunit-containing GABAA receptors [14], demonstrated an objectively assessed, significant improvement compared with placebo in sleep induction and TST with insomnia disorder. In the study, not only were polysomnography-based objective variables measured, but also participant-reported subjective assessments of night and day symptoms were incorporated, with robust control for study-wise type I error for all primary and secondary endpoints [15].
For the primary outcomes, TST was significantly improved in the Dimdazenil 1.5, 2.5, and 5 mg groups compared with the placebo group on day 1/2, and significantly improved in the Dimdazenil 2.5 and 5 mg groups compared to the placebo group on day 13/14. The improvement in TST, which was objectively measured by polysomnography, was consistent with sTST perceived by participants. This concordance was in contrast to the frequent discordance between subjective and objective measures of sleep in people with insomnia [16]. This appropriate estimation of total sleep by the participants might reflect preservation of memory [17] and, perhaps the fact that with Dimdazenil, the proportion of time spent in different sleep stages is preserved, in contrast to findings reported with benzodiazepine receptor agonists [18]. For the primary outcomes, the improvements in sleep variables seen with Dimdazenil included both a reduction in LPS and sSL. The highest dose Dimdazenil (5 mg) was the most efficacious on sSL, followed by 2.5 and 1.5 mg, which indicates a dose–response trend in sleep induction parameters for LPS and sSL.
One of the main concerns with current insomnia products is the potential for residual next-morning effects. The assessment of morning sleepiness shows that most of the evaluation indicators have no significant statistical difference regarding the drug residues. This is assumed to be related to the short half-life of Dimdazenil, which is about 4 hours according to our pharmacokinetics research results. The relatively shorter half-life of Dimdazenil may also result in fewer residual effects that would be expected and would support the data generated showing objective improvement [10]. Other concerns are the presence of withdrawal symptoms following cessation of treatment and the development of tolerance [19]. Our study includes a run-out period to assess potential for rebound or occurrence of drug withdrawal effects, and most of the evaluation indicators have no significant statistical difference with Dimdazenil on subjective or objective parameters during the withdrawal period. Dimdazenil is well tolerated and safe in the study. There are no SAEs in all treatment groups. Although tolerance and safety are important considerations concerning sleep medications [19], the current data from this phase II study are limited to definitively conclude potential tolerance. Phase III clinical trials (CTR20201068) will further explore any potential tolerance and safety of Dimdazenil.
Benzodiazepines (BZDs) and non-BZD hypnotics, zolpidem, zopiclone eszopiclone, and zaleplon (termed “Z drugs”), are the mainstay of pharmacological treatment of insomnia [20]. However, when used as hypnotics, sedation, and motor impairment are frequently observed the morning after administration. Currently used benzodiazepines also with other limitations, including the development of tolerance, unwanted withdrawal signs and symptoms, and a significant pharmacodynamic interaction with ethanol [21]. Consequently, there is considerable scope for the development of novel compounds lacking these adverse properties. The mechanism of action of Dimdazenil, as for other Benzodiazepines, is a positive allosteric modulator of the GABAA receptor, which selectively acts on the α1-containing GABAA receptors with high affinity and moderate levels of maximum receptor activation based on the results of phase I clinical study performed by Evotec (A phase I single and repeated dose pharmacokinetic, safety and pharmacodynamics study of EVT 201 in young and elderly volunteers. Clinical Study Report Unpublished Data). Dimdazenil is considered to be a “partial positive allosteric modulator” due to its intermediate intrinsic activity (relative to other molecules acting at the same receptor). This may imply a lower maximal effect for Dimdazenil compared with other compounds in relation to some of the unwanted effects [22, 23].
Limitations
First, no significant effects were observed on WASO, NAW, and ISI. Such a limitation on interpretation of subjective parameters is inherent in a relatively small phase II study, with the study neither designed nor powered to address questions of clinically significant improvement but to determine the dose–response and identify which dose(s) should be pursued in further development. Second, the 2-week duration does not allow for assessment of efficacy and safety of long-term use. Third, this study did not include elderly patients (aged over 65 years) or patients with comorbid insomnia disorders. The effects of Dimdazenil in elderly patients will be investigated in a phase IV post-marketing study. Finally, due to the constraints of the prespecified analysis protocol, the method of LOCF was used to impute missing data in this study. LOCF may introduce bias and does not appropriately account for the uncertainty of imputed values. The use of LOCF may have affected the results in unknown ways. More principled methods such as multiple imputation should be considered in future studies to better handle missing data.
Conclusion
Dimdazenil of 1.5, 2.5, and 5 mg improved certain objective or subjective sleep outcomes in patients with insomnia disorder, with a favorable safety profile.
Supplementary Material
Acknowledgments
The authors would like to thank all patients, study investigators, study staff, and nursing teams for their participation in this research. The authors would also like to acknowledge Gang Lv, chairman of the board of ZHEJIANG JINGXIN PHARMACEUTICAL CO., LTD, for providing editorial and logistical support in the final preparation of the manuscript, which was sponsored and funded by ZHEJIANG JINGXIN PHARMACEUTICAL CO., LTD. The sponsor participated in the design and conduct of the study; collection, management, analysis, and interpretation of the data. All authors had access to the full dataset and analysis. All authors reviewed the data and analysis, formulated their own interpretation of the data, and wrote the conclusions. All conclusions within the manuscript were agreed upon unanimously by all authors.
Contributor Information
Yanpeng Li, Neurology Department, Shanghai Changzheng Hospital, Shanghai, China.
Ruoxi Zhang, Shanghai Research Institute, Zhejiang Jingxin Pharmaceutical Co., Ltd, Shanghai, China.
Yanling Zhou, Shanghai Research Institute, Zhejiang Jingxin Pharmaceutical Co., Ltd, Shanghai, China.
Cungang Bao, Shanghai Research Institute, Zhejiang Jingxin Pharmaceutical Co., Ltd, Shanghai, China.
Zhaocun Lin, Shanghai Research Institute, Zhejiang Jingxin Pharmaceutical Co., Ltd, Shanghai, China.
Chunyan Chen, Shanghai Research Institute, Zhejiang Jingxin Pharmaceutical Co., Ltd, Shanghai, China.
Jingjing He, Shanghai Research Institute, Zhejiang Jingxin Pharmaceutical Co., Ltd, Shanghai, China.
Zhiping Jin, The president's office, Zhejiang Jingxin Pharmaceutical Co., Ltd, Zhejiang, China.
Lihua Song, Shanghai Research Institute, Zhejiang Jingxin Pharmaceutical Co., Ltd, Shanghai, China.
Min Zhang, Shanghai Research Institute, Zhejiang Jingxin Pharmaceutical Co., Ltd, Shanghai, China.
Sigen Guo, Shanghai Research Institute, Zhejiang Jingxin Pharmaceutical Co., Ltd, Shanghai, China.
Yu Jiang, Shanghai Research Institute, Zhejiang Jingxin Pharmaceutical Co., Ltd, Shanghai, China.
Zhongxin Zhao, Neurology Department, Shanghai Changzheng Hospital, Shanghai, China.
Author Contributions
Zhongxin Zhao, Yanling Zhou, Zhiping Jin, and Yu Jiang were responsible for the conception and design of the study. Cungang Bao and Zhaocun Lin contributed substantially to data acquisition. Ruoxi Zhang, Chunyan Chen, and Yanling Zhou contributed to data interpretation. Jingjing He and Zhaocun Lin were responsible for statistical analysis. Yanpeng Li, Ruoxi Zhang, and Yanling Zhou drafted and revised the manuscript. Lihua Song, Min Zhang, and Sigen Guo were responsible for the manufacture of the Dimdazenil. Yu Jiang and Zhongxin Zhao supervised the manuscript. All authors contributed to the article and approved the submitted version.
Disclosure Statement
Financial disclosure: The authors declare no competing financial interests. Nonfinancial disclosure: Ruoxi zhang, Yanling Zhou, Cungang Bao, Zhaocun Lin, Chunyan Chen, Jingjing He, Zhiping Jin, Lihua Song, Min Zhang, Sigen Guo, and Yu Jiang are full-time employees of ZHEJIANG JINGXIN PHARMACEUTICAL CO., LTD. The authors declare that they have no conflicts of interest.
Data Availability
People can get a copy of trial protocol by emailing the corresponding author.
References
- 1. Ohayon MM. Epidemiology of insomnia: what we know and what we still need to learn. Sleep Med Rev. 2002;6:97–111. doi: 10.1053/smrv.2002.0186 [DOI] [PubMed] [Google Scholar]
- 2. Djokic G, Vojvodić P, Korcok D, et al. The effects of magnesium - melatonin - Vit B complex supplementation in treatment of insomnia. Open Access Maced J Med Sci. 2019;7:3101–3105. doi: 10.3889/oamjms.2019.771 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Jembrek MJ, Vlainic J.. GABA receptors: pharmacological potential and pitfalls. Curr Pharm Des. 2015;21:4943–4959. doi: 10.2174/1381612821666150914121624 [DOI] [PubMed] [Google Scholar]
- 4. Rudolph U, Möhler H.. GABA-based therapeutic approaches: GABAA receptor subtype functions. Curr Opin Pharmacol. 2006;6:18–23. doi: 10.1016/j.coph.2005.10.003 [DOI] [PubMed] [Google Scholar]
- 5. Castellano D, Shepard RD, Lu W.. Looking for novelty in an “old” receptor: recent advances toward our understanding of GABA(A)Rs and their implications in receptor pharmacology. Front Neurosci. 2020;14:616298. doi: 10.3389/fnins.2020.616298 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Gottesmann C. GABA mechanisms and sleep. Neuroscience. 2002;111:231–239. doi: 10.1016/s0306-4522(02)00034-9 [DOI] [PubMed] [Google Scholar]
- 7. Oh DR, Kim Y, Jo A, et al. Sedative and hypnotic effects of Vaccinium bracteatum Thunb through the regulation of serotonegic and GABA(A)-ergic systems: Involvement of 5-HT(1A) receptor agonistic activity. Biomed Pharmacother. 2019;109:2218–2227. doi: 10.1016/j.biopha.2018.10.003 [DOI] [PubMed] [Google Scholar]
- 8. Xiang T, Liao J, Cai Y, et al. Impairment of GABA inhibition in insomnia disorders: evidence from the peripheral blood system. Front Psychiatry. 2023;14:1134434. doi: 10.3389/fpsyt.2023.1134434 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. APA. Diagnostic and statistical manual of mental disorders (5th edition). 5 ed. Arlington, VA: American Psychiatric Association. 2013. [Google Scholar]
- 10. Dauvilliers Y, Zammit G, Fietze I, et al. Daridorexant, a new dual orexin receptor antagonist to treat insomnia disorder. Ann Neurol. 2020;87:347–356. doi: 10.1002/ana.25680 [DOI] [PubMed] [Google Scholar]
- 11. Bastien CH, Vallières A, Morin CM.. Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med. 2001;2:297–307. doi: 10.1016/s1389-9457(00)00065-4 [DOI] [PubMed] [Google Scholar]
- 12. Tyrer P, Murphy S, Riley P.. The benzodiazepine withdrawal symptom questionnaire. J Affect Disord. 1990;19:53–61. doi: 10.1016/0165-0327(90)90009-w [DOI] [PubMed] [Google Scholar]
- 13. Lachin JM. Fallacies of last observation carried forward analyses. Clin Trials. 2016;13:161–168. doi: 10.1177/1740774515602688 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Mele M, Costa RO, Duarte CB.. Alterations in GABA(A)-receptor trafficking and synaptic dysfunction in brain disorders. Front Cell Neurosci. 2019;13:77. doi: 10.3389/fncel.2019.00077 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Mignot E, Mayleben D, Fietze I, et al.; investigators. Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials. Lancet Neurol. 2022;21:125–139. doi: 10.1016/S1474-4422(21)00436-1 [DOI] [PubMed] [Google Scholar]
- 16. Bianchi MT, Williams KL, McKinney S, Ellenbogen JM.. The subjective-objective mismatch in sleep perception among those with insomnia and sleep apnea. J Sleep Res. 2013;22:557–568. doi: 10.1111/jsr.12046 [DOI] [PubMed] [Google Scholar]
- 17. Gotter AL, Garson SL, Stevens J, et al. Differential sleep-promoting effects of dual orexin receptor antagonists and GABAA receptor modulators. BMC Neurosci. 2014;15:109. doi: 10.1186/1471-2202-15-109 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Neylan TC, Richards A, Metzler TJ, et al. Acute cognitive effects of the hypocretin receptor antagonist almorexant relative to zolpidem and placebo: a randomized clinical trial. Sleep. 2020;43(10). doi: 10.1093/sleep/zsaa080 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Yardley J, Kärppä M, Inoue Y, et al. Long-term effectiveness and safety of lemborexant in adults with insomnia disorder: results from a phase 3 randomized clinical trial. Sleep Med. 2021;80:333–342. doi: 10.1016/j.sleep.2021.01.048 [DOI] [PubMed] [Google Scholar]
- 20. de Mendonça FMR, de Mendonça G, Souza LC, et al. Benzodiazepines and sleep architecture: a systematic review. CNS Neurol Disord Drug Targets. 2023;22:172–179. doi: 10.2174/1871527320666210618103344 [DOI] [PubMed] [Google Scholar]
- 21. Zhu S, Noviello CM, Teng J, WalshRM, Jr, Kim JJ, Hibbs RE.. Structure of a human synaptic GABA(A) receptor. Nature. 2018;559:67–72. doi: 10.1038/s41586-018-0255-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Latimer DR, Edinoff AN, Ruff RD, et al. Cenobamate, a sodium Channel inhibitor and positive allosteric modulator of GABA(A) ion channels, for partial onset seizures in adults: a comprehensive review and clinical implications. Neurol Int. 2021;13:252–265. doi: 10.3390/neurolint13020026 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Roberti R, De Caro C, Iannone LF, Zaccara G, Lattanzi S, Russo E.. Pharmacology of cenobamate: mechanism of action, pharmacokinetics, drug-drug interactions and tolerability. CNS Drugs. 2021;35:609–618. doi: 10.1007/s40263-021-00819-8 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
People can get a copy of trial protocol by emailing the corresponding author.