Ge-Bu Indication
What is Ge-Bu’s opinion?
- Randomised research has found that daridorexant 50 mg is statistically significantly more effective than placebo on the primary endpoints of ‘wake after sleep onset’ (WASO) and ‘latency to persistent sleep’ (LPS).
- Limited research has found a minor, not clinically relevant reduction of daytime sleepiness compared to placebo.
- Adverse effects appear mild and largely comparable to placebo, and research found no withdrawal symptoms. Driving performance is negatively affected after single-dose administration, but this effect disappears after multiple consecutive doses.
- It is not possible to indicate the value of this drug relative to cognitive behavioural therapy or treatment with benzodiazepine agonists, as there have been no directly comparative studies.
- Based on the available information, the added value of daridorexant is unclear, and there are insufficient reasons to prescribe it to patients with sleeping problems.
Is there a need for new sleep medications?
Existing sleep medications for primary insomnia disorders include (short-acting) benzodiazepine agonists like temazepam and zolpidem. These benzodiazepine agonists affect daytime functioning by causing sleepiness during the day. In addition, long-term treatment results in tolerance for the effect and dependence.1 A sufficiently effective sleeping pill without the disadvantages of benzodiazepines could be a welcome addition to the pharmacotherapeutic arsenal. There is insufficient evidence for the effectiveness of melatonin (the drug of first choice for people over 55 years of age) to treat primary insomnia disorders2 and the same goes for antidepressants used as sleep medication3.
Dual orexin receptor antagonists (DORA)
The EMA has recently authorised daridorexant, the first dual orexin receptor antagonist (DORA) in Europe. In the United States, the dual orexin antagonists suvorexant and lemborexant have been on the market for some years4, and daridorexant has also been authorised in the US since the beginning of 2022 5.
Daridorexant is an antagonist for the orexin receptors OX1 and OX2. These receptors bind the neuropeptides orexin A and orexin B, which are produced by the hypothalamus. This binding results in increased wakefulness and reduced somnolence, making it harder to fall asleep. Daridorexant antagonises the action of orexin A and B, thus reducing wakefulness and increasing somnolence.4
The effectiveness of daridorexant
Two randomised studies found that the quality of sleep was significantly better when using daridorexant, compared with placebo. The patient-reported total sleep time was significantly longer and daytime sleepiness was reduced. However, the increase in total sleep time compared to placebo appears rather modest, at 20 minutes. A striking aspect was that placebo also induced a substantial improvement of sleep time compared to baseline.6 An indirect comparison in a network meta-analysis found no major differences with the benzodiazepines.7
One problem is that the way clinical sleep medication studies are conducted is not standardised, so research is highly heterogeneous.8 Furthermore, no studies have been published which compared daridorexant with cognitive behavioural therapy, which is the treatment of first choice according to Dutch and European guidelines.9,10
Adverse effects of daridorexant are mild, but there have been reports of driving performance being affected. One study showed that driving performance is affected after the first dose, but that this influence disappears after repeated administrations, possible by habituation. No official driving performance advice has been established for daridorexant. With temazepam, the sleep medication of first choice, the influence on driving performance after a single dose of at most 20 mg has disappeared 8 hours after ingestion, and after these 8 hours there are no longer any limitations to participation in traffic.11
Efficacy of daridorexant in the registration studies
Study design
The efficacy was examined in two large randomised double-blind trials, comparing daridorexant with placebo. These trials were published in one article.6 Both trials included adults with moderate to severe insomnia disorder, as determined using the Insomnia Severity Index (ISI, score ≥15). The trials began with a 13–24 day single-blind run-in period in which all participants received a placebo. This period was also used to establish whether the participants met the criteria for insomnia, using polysomnography. The double-blind study period lasted 3 months, and was followed by a single-blind run-out period of 7 days, in which all participants once again received a placebo.
Both trials randomised the participants into three equal-sized groups. In the first trial, participants received daridorexant 50 mg, 25 mg or placebo, in the second trial they received daridorexant 25 mg, 10 mg or placebo. Primary outcome measures were the change in the WASO (wake after sleep onset) and LPS (latency to persistent sleep), compared to the baseline values, measured in the first and third months using polysomnography in a sleep laboratory. Secondary outcome measures included change in self-reported total sleep time and change in daytime sleepiness (score on the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ), sleepiness domain), based on data recorded by the patients in a diary.
The results for the sleep parameters measured were determined for each group, compared to the baseline values, after which the difference between daridorexant and placebo was calculated. Withdrawal symptoms were examined during the placebo run-out period, using the ‘Benzodiazepine Withdrawal Symptom Questionnaire’ (BWSQ).6
Results
The first trial included 930 participants. They were randomised into three groups of 310 participants each, who received 25 mg daridorexant, 50 mg daridorexant or placebo, respectively. The second trial included 924 participants, who were also randomised into three groups. The first group, with 307 participants, received 10 mg daridorexant, the second group, with 309 participants, received 25 mg daridorexant and the third group, with 308 participants, received a placebo.
In the first trial, WASO and LPS had decreased significantly in both the 50 mg and 25 mg daridorexant groups, compared to the placebo group (table 1). Self-reported total sleep time was significantly increased compared to placebo in the 50 mg and 25 mg daridorexant groups. Change in the IDSIQ score (daytime sleepiness) was significantly smaller relative to placebo in the 50 mg, but not the 25 mg daridorexant group.
Table 1. Difference between daridorexant and placebo regarding WASO, LPS, total sleep time and IDSIQ score (sleepiness domain) in trial 1 6
|
| Daridorexant 50 mg compared to placebo (after 1 month) | Daridorexant 50 mg compared to placebo (after 3 months)
| Daridorexant 25 mg compared to placebo (after 1 month) | Daridorexant 25 mg compared to placebo (after 3 months) |
|---|---|---|---|---|
| WASO (min) (95% CI) | -22.8 (-28.0 to -17.6) | -18.3 (-23.9 to -12.7) | -12.2 (-17.4 to -7.0) | -11.9 (-17.5 to -6.2) |
| LPS (min) (95% CI) | -11.4 (-16.0 to -6.7) | -11.7 (-16.3 to -7.0) | -8.3 (-13.0 to -3.6) | -7.6 (-12.3 to -2.9) |
| Total sleep time (min) (95% CI) | 22.1 (14.4 to 29.7) | 19.8 (10.6 to 28.9) | 12.6 (5.0 to 20.3) | 9.9 (0.8 to 19.1) |
| IDSIQ score sleepiness domain (95% BI) | -1.8 (-2.5 to -1.0) | -1.9 (-2.9 to -0.9) | -0.8 (-1.5 to 0.01) NS | -1.0 (-2.0 to 0.01) NS |
CI = confidence interval, LPS = latency to persistent sleep, NS = non-significant, WASO = wake after sleep onset
In the second trial, WASO had decreased significantly, while self-reported total sleep time had significantly increased in the 25 mg daridorexant group compared to the placebo group. There were no significant differences in the reduction of LPS, unlike the findings in the first trial, where the difference at 25 mg compared to placebo was statistically significant. Nor was there a difference in the change of the IDSIQ sleepiness score (daytime sleepiness). In the 10 mg daridorexant group, no significant differences with placebo were found for any of the sleep parameters (WASO, LPS, self-reported total sleep time and IDSIQ score) (table 2). The time distribution of the various stages of sleep was comparable between all three treatment groups. The various sleep parameters did not differ between the measurements after 1 and 3 months.
Table 2. Difference between daridorexant and placebo regarding WASO, LPS, total sleep time and IDSIQ score (sleepiness domain) in trial 2 6
|
| Daridorexant 25 mg compared to placebo (after 1 month) | Daridorexant 25 mg compared to placebo (after 3 months)
| Daridorexant 10 mg compared to placebo (after 1 month) | Daridorexant 10 mg compared to placebo (after 3 months) |
|---|---|---|---|---|
| WASO (min) (95% CI) | -11.6 (-17.6 to -5.6) | -10.3 (-17.0 to -3.5) | -2.7 (-8.7 to 3.2) NS | -2.0 (-8.7 to 4.8) NS |
| LPS (min) (95% CI) | -6.5 (-12.3 to -0.6) NS | -9.0 (-15.3 to -2.7) NS* | -2.6 (-8.4 to 3.2) NS | -3.2 (-9.5 to 3.1) NS |
| Total sleep time (min) (95% CI) | 16.1 (8.2 to 24.0) | 19.1 (10.1 to 28.0) | 13.4 (5.5 to 21.2) NS* | 13.6 (4.7 to 22.5) NS* |
| IDSIQ score sleepiness domain (95% CI) | -0.8 (-1.6 to 0.1) NS | -1.3 (-2.2 to -0.3) NS* | -0.4 (-1.3 to 0.4) NS | -0.7 (-1.7 to 0.2) NS |
* non-significant after adjustment for repeated statistical tests
CI = confidence interval, LPS = latency to persistent sleep, NS = non-significant, WASO = wake after sleep onset
Less daytime sleepiness?
The new ‘Insomnia Daytime Symptoms and Impact Questionnaire’ (IDSIQ) is a validated questionnaire which can be used to evaluate daytime symptoms of people with insomnia. The IDSIQ-14 comprises 14 items, grouped into three domains, the sleepiness domain, the mood domain and the alert/cognition domain.12 Scores on the sleepiness domain go from 0 to 40 (0 representing no sleepiness, 40 representing maximum sleepiness). The authors indicate that they regard a reduction by >4 points from baseline as a clinically relevant improvement.6 The sleepiness score for daridorexant 50 mg was significantly reduced by about 4 points compared to baseline after 1 and 3 months. Since placebo also yielded a considerable reduction, the eventual difference between daridorexant and placebo is -1.8 after 1 month and -1.9 after 3 months), which is fairly small and possibly not clinically relevant. The results on the IDSIQ sleepiness score are difficult to interpret, as this questionnaire is an entirely new instrument, so no benchmarking is possible.12
Daridorexant versus other sleep medications
Adverse effects
The adverse effects were comparable between the two registration studies. There was no significant difference in the prevalence of adverse effects between the daridorexant group and the placebo group. The percentage of patients who experienced at least one adverse event was 38% (50 mg), 38% (25 mg) and 34% (placebo) in the first trial and 39% (25 mg), 38% (10 mg) and 33% (placebo) in the second. The distribution between adults younger and older than 65 years was also comparable. The percentages of participants who had to drop out of the trial due to an adverse event were 1%, 2% and 3%, respectively, for the first trial, and 1%, 2% and 2%, respectively, for the second. So-called ‘serious adverse events’ occurred in 1%, 1% and 2%, respectively, of the patients in the first trial and in 1% in all groups of the patients in the second trial. According to the researchers, these adverse events were probably not treatment-related. No indications were found for withdrawal symptoms after discontinuation of the treatment. The most common adverse events were nasopharyngitis (3–10% in all groups) and headache (4–6% in all groups).6 Besides headache, the product information mentions daytime sleepiness as the most common adverse effect. It occurred in 2% of the patients using daridorexant 50 mg, 3% of those using 25 mg and 2% of those using placebo.15
Influence on driving performance
The use of sleep medication can be associated with a residual effect the next morning, which can result in reduced driving performance. This is the case with most of the sleep medications of the benzodiazepine group.16 The American Food and Drug Administration (FDA) has published guidelines on ways to investigate the effects of new psychoactive drugs on driving performance.17 A consensus protocol was developed, establishing both an over-the-road driving test and a simulator test as valid methods.18
This protocol was followed in a study of the influence of daridorexant on driving performance.19 The primary outcome measure was the effect of daridorexant on driving performance, measured in a simulator as the ‘standard deviation of the lateral position’ (SDLP – the degree of deviation from driving in a straight line). The study population included 60 healthy experienced drivers without sleeping problems, all middle-aged or older. In a double-blind cross-over study, all participants were given daridorexant 50 mg, daridorexant 100 mg, placebo or zopiclone 7.5 mg (as control) respectively, on 4 days, at intervals of at least a week. Their driving performance was tested for one hour on the second day (after the initial dose), and on the fifth day, after four days with one dose a day. The test took place 9 hours after ingestion of the drug or placebo. On the second day, a statistically significant difference in SDLP was found for 50 and 100 mg daridorexant compared to placebo. On the fifth day, no significant difference was found. It was concluded that a single dose of daridorexant reduces driving performance, while repeated dosing does not.19 The findings with the control drug zopiclone showed a statistically significant difference in SDLP on both the second and fifth days. To explain the difference in effect between a single dose and repeated dosing of daridorexant, the authors suggest that habituation sets in after repeated use.
Background information
Treatment of primary insomnia
After a diagnosis of primary insomnia has been established, the treatment of first choice is behavioural therapy.9 Behavioural therapy involves advice on stimulus control, sleep restriction, relaxation exercises, cognitive therapy and systematic exercise. Studies among patients with persistent insomnia have found that this combined approach is more effective in the longer term than the use of sleep medication. Sleep medication should only be given in exceptional cases, and only for a short time in case of acute, transitory problems or if no improvement can be achieved and the insomnia leads to serious daytime dysfunctioning. The preferred medication in such cases is short-acting hypnotics like temazepam or zolpidem, at the lowest possible dosage, with a maximum of 5 to 10 tablets being prescribed.9,10
Daridorexant
Daridorexant is marketed by Idorsia Pharmaceuticals under the brand name Quviviq®, as 25 and 50 mg tablets. The authorised indication is the treatment of adult patients with insomnia characterised by symptoms having persisted for at least 3 months and causing a considerable impairment of daytime functioning. The dosage is 50 mg, to be taken half an hour before going to bed. The treatment should be as short as possible, and its effectiveness should be established within 3 months.15 Maximum plasma levels of daridorexant are reached within 1 to 2 hours after ingestion. The half-life is about 8 hours. The hepatic enzyme CYP3A4 metabolises 89% of daridorexant. Using daridorexant in combination with strong inhibitors of this enzyme, like itraconazole, clarithromycin and grapefruit juice, is contra-indicated. When using moderate CYP3A4 inhibitors like ciprofloxacin and diltiazem, the maximum dosage is 25 mg. Using CYP3A4 inductors like rifampicin or carbamazepine can reduce the therapeutic effect of daridorexant.15 Daridorexant has not been marketed in the Netherlands as yet, so its price and reimbursement status are not yet know.
Polysomnography
Polysomnography (PSG) is a form of sleep examination, in which various physiological parameters are recorded during the patient’s sleep. This test is carried out during the night at a hospital, sleep centre or sometimes at the patient’s home. It is the standard test for an objective diagnosis of sleep disorders. Assessment of the various stages of sleep is mainly based on the findings of electro-encephalography (EEG), electro-oculography (EOG) and electromyography (EMG).20
Details of the studies discussed
Registration studies6
Inclusion criteria: adults (>18 years) with moderate to severe insomnia disorder according to the DSM-5 definition and an insomnia severity index score ≥15, self-reported history of disturbed sleep for at least three nights a week during the 3 months before screening (disturbed sleep being defined as needing >30 minutes to fall asleep, lying awake for >30 minutes during the sleep time and a sleep time <6.5 hours). These self-reported parameters also had to be present at least three nights a week during a placebo run-in period. In addition, the patients had to meet polysomnography criteria during the placebo run-in period, including LPS > 20 minutes, WASO > 30 minutes and a mean total sleep time <7 hours
Main exclusion criteria: daytime napping (>1 hour a day >3 days a week), psychiatric conditions, apnoea or hyperpnoea, restless legs syndrome, circadian rhythm disorder or REM rhythm disorder or narcolepsy
Intervention: oral administration of 50 mg, 25 mg daridorexant or placebo (trial 1); or 25 mg, 10 mg daridorexant or placebo (trial 2) ingested before going to bed at night, for 3 months. During the polysomnography examinations, the tablet had to be ingested at least 2 hours after the meal, and about 30 minutes before going to bed. The trial included a single-blind placebo run-in period (13–24 days), a double-blind treatment period of 3 months and a single-blind placebo run-out period (7 days), followed by a 23-day follow-up during which adverse events were monitored
Primary endpoint(s) and study duration: changes in WASO and LPS compared to baseline, measured using polysomnography in a sleep laboratory in months 1 and 3
Intended number of patients and power: calculations based on the results of the phase 2 trials showed that 900 participants per trial would yield 90% power for an effect size of 0.37 (standardised difference in WASO, LPS and total sleep time) for testing 9 independent null hypotheses per trial
Randomisation: using an ‘interactive response technology system’ (1:1:1 daridorexant 50 mg, 25 mg or 10 mg, and a placebo group), stratified by age >65 years and <65 years
Blinding: participants, investigators and personnel were blinded for treatment allocation; during the placebo run-in and run-out periods, only the participants were blinded.
Population analysed: intention-to-treat
Number of patients included and patient characteristics: 930 participants in trial 1. Average ages in the three groups were 55.5, 55.8 and 55.1 years, respectively. 39% were >65 years and 64, 69 and 68%, respectively, were women. 924 participants in trial 2. Average ages were 56.3, 57.1 and 56.7 years, respectively. 39% were >65 years and 71, 70 and 67%, respectively, were women
Trial registration: NCT03545191 (trial 1) and NCT03575104 (trial 2)
Funding: Idorsia Pharmaceuticals Ltd
Conflicts of interest: 9 of the 9 authors
Literature references
- Helmerhorst FM, Nieuwhof MA. Benzodiazepinegebruik in Nederland. Gebu. 2020;54(9):102-106.
- Stolk LM. Geen melatonine bij primaire slaapstoornissen. Gebu. 2020;54(4):41-44.
- Nieuwhof MA, Janssens HJ. Antidepressiva als slaapmedicatie? Gebu. 2019;53(11-12):102-105.
- Kishi T, Nishida M, Koebis M, Taninaga T, Muramoto K, Kubota N, Moline M, Sakuma K, Okuya M, Nomura I, Iwata N. Evidence-based insomnia treatment strategy using novel orexin antagonists: A review. Neuropsychopharmacol Rep. 2021 Dec;41(4):450-458. doi: 10.1002/npr2.12205. Epub 2021 Sep 23. PMID: 34553844; PMCID: PMC8698673.
- Markham A. Daridorexant: First Approval. Drugs. 2022 Apr;82(5):601-607. doi: 10.1007/s40265-022-01699-y. Erratum in: Drugs. 2022 May;82(7):841. PMID: 35298826; PMCID: PMC9042981.
- Mignot E, Mayleben D, Fietze I, Leger D, Zammit G, Bassetti CLA, Pain S, Kinter DS, Roth T; 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 Feb;21(2):125-139. doi: 10.1016/S1474-4422(21)00436-1. Erratum in: Lancet Neurol. 2022 Jan 20;: Erratum in: Lancet Neurol. 2022 Jun;21(6):e6. PMID: 35065036.
- De Crescenzo F, D'Alò GL, Ostinelli EG, Ciabattini M, Di Franco V, Watanabe N, Kurtulmus A, Tomlinson A, Mitrova Z, Foti F, Del Giovane C, Quested DJ, Cowen PJ, Barbui C, Amato L, Efthimiou O, Cipriani A. Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis. Lancet. 2022 Jul 16;400(10347):170-184. doi: 10.1016/S0140-6736(22)00878-9. PMID: 35843245.
- Buysse DJ, Ancoli-Israel S, Edinger JD, Lichstein KL, Morin CM. Recommendations for a standard research assessment of insomnia. Sleep. 2006 Sep;29(9):1155-73. doi: 10.1093/sleep/29.9.1155. Erratum in: Sleep. 2006 Nov 1;29(11):1380. PMID: 17040003.
- Nederlands Huisartsengenootschap. Gorgels W, Knuistingh Neven A, Lucassen PLBJ, Smelt A, Damen-van Beek Z, Bouma M, Verduijn MM, Van Venrooij M. NHG-Standaard Slaapproblemen en slaapmiddelen (M23). July 2014. Latest adjustment July 2014. Available from: https://richtlijnen.nhg.org/standaarden/slaapproblemen-en-slaapmiddelen. Accessed 8 July 2022.
- Riemann D, Baglioni C, Bassetti C, Bjorvatn B, Dolenc Groselj L, Ellis JG, Espie CA, Garcia-Borreguero D, Gjerstad M, Gonçalves M, Hertenstein E, Jansson-Fröjmark M, Jennum PJ, Leger D, Nissen C, Parrino L, Paunio T, Pevernagie D, Verbraecken J, Weeß HG, Wichniak A, Zavalko I, Arnardottir ES, Deleanu OC, Strazisar B, Zoetmulder M, Spiegelhalder K. European guideline for the diagnosis and treatment of insomnia. J Sleep Res. 2017 Dec;26(6):675-700. doi: 10.1111/jsr.12594. Epub 2017 Sep 5. PMID: 28875581.
- Informatorium Medicamentorum. Available from: KNMP Kennisbank. Accessed 4 August 2022.
- Hudgens S, Phillips-Beyer A, Newton L, Seboek Kinter D, Benes H. Development and Validation of the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). Patient. 2021 Mar;14(2):249-268. doi: 10.1007/s40271-020-00474-z. Epub 2020 Nov 1. PMID: 33131027; PMCID: PMC7884372.
- Dauvilliers Y, Zammit G, Fietze I, Mayleben D, Seboek Kinter D, Pain S, Hedner J. Daridorexant, a New Dual Orexin Receptor Antagonist to Treat Insomnia Disorder. Ann Neurol. 2020 Mar;87(3):347-356. doi: 10.1002/ana.25680. Epub 2020 Feb 5. Erratum in: Ann Neurol. 2020 Sep;88(3):647-651. PMID: 31953863.
- Samara MT. What is the right drug for insomnia disorder? Lancet. 2022 Jul 16;400(10347):139-141. doi: 10.1016/S0140-6736(22)01322-8. PMID: 35843230.
- EMA. Product information. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/quviviq. Accessed 19 September 2022
- van der Sluiszen NNJJM, Vermeeren A, Verster JC, van de Loo AJAE, van Dijken JH, Veldstra JL, Brookhuis KA, de Waard D, Ramaekers JG. Driving performance and neurocognitive skills of long-term users of benzodiazepine anxiolytics and hypnotics. Hum Psychopharmacol. 2019 Nov;34(6):e2715. doi: 10.1002/hup.2715. PMID: 31837049; PMCID: PMC7003498.
- U.S. Food and Drug Administration. Guidance for industry: evaluating drug effects on the ability to operate a motor vehicle. November 2017. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/evaluating-drug-effects-ability-operate-motor-vehicle. Accessed 2 August 2022.
- Kay GG, Loagan BK. Drugged driving expert panel report: a consensus protocol for assessing the potential of drugs to impair driving. U.S. Department of Justice. Office of Justice Programs. NCJ Number 239458. March 2011. Available from: https://www.ojp.gov/ncjrs/virtual-library/abstracts/drugged-driving-expert-panel-report-consensus-protocol-assessing. Accessed 2 August 2022
- Muehlan C, Brooks S, Vaillant C, Meinel M, Jacobs GE, Zuiker RG, Dingemanse J. Driving Performance after Bedtime Administration of Daridorexant, Assessed in a Sensitive Simulator. Clin Pharmacol Ther. 2022 Jun;111(6):1334-1342. doi: 10.1002/cpt.2592. Epub 2022 Apr 20. PMID: 35426136; PMCID: PMC9320895.
- Patil SP. What every clinician should know about polysomnography. Respir Care. 2010 Sep;55(9):1179-95. PMID: 20800000.
