Bedtime Dose Research Articles

Morning vs Bedtime Dosing and Nocturnal Blood Pressure Reduction in Patients With Hypertension

Nocturnal blood pressure is difficult to manage in clinical practice. Antihypertensive chronotherapy may offer a potential approach for better control. However, the clinical evidence supporting this approach remains controversial. To compare the effects of morning vs bedtime antihypertensive medication administration on nocturnal blood pressure reduction and circadian rhythm among patients with hypertension. This randomized clinical trial was conducted at 15 hospitals in China from June 1, 2022, to April 30, 2024, with a 12-week follow-up. Patients with hypertension without prior antihypertensive treatment or who had discontinued antihypertensive agents for 2 weeks were randomized to the morning (6:00-10:00 am) or bedtime (6:00-10:00 pm) dosing group. Patients received a single pill containing olmesartan, 20 mg, and amlodipine, 5 mg, daily for 12 weeks, with dosage adjustments based on ambulatory and office blood pressure measurements at week 4 and week 8. The primary outcome was the change in nighttime systolic blood pressure from baseline to 12 weeks. Key secondary outcomes included changes in office and other ambulatory blood pressure indicators. The primary and secondary outcomes were analyzed in the intention-to-treat and the per-protocol populations. A total of 720 patients (mean [SD] age, 55.5 [10.6] years; 409 men [56.8%]) were randomized to morning (n = 352) or bedtime (n = 368) dosing groups. The mean (SD) baseline blood pressure values for morning vs bedtime dosing at 24 hours were 148.0 (11.1)/91.4 (9.0) mm Hg vs 147.6 (11.0)/91.6 (9.2) mm Hg, for daytime were 152.3 (11.0)/94.0 (9.2) mm Hg vs 151.5 (11.6)/94.0 (9.8) mm Hg, for nighttime were 138.4 (15.1)/85.4 (10.4) mm Hg vs 138.3 (13.0)/85.8 (9.4) mm Hg, and in the office were 154.4 (12.1)/94.6 (10.3) mm Hg vs 154.3 (12.5)/95.1 (11.1) mm Hg. Compared with patients in the morning dosing group, those in the bedtime dosing group showed significantly greater reductions in nighttime systolic blood pressure (between-group difference, -3.0 mm Hg [95% CI, -5.1 to -1.0 mm Hg]; P = .004), and nighttime diastolic blood pressure (between-group difference, -1.4 mm Hg [95% CI, -2.8 to -0.1 mm Hg]; P = .04), with better nocturnal systolic blood pressure control (79.0% [244 of 309] vs 69.8% [208 of 298]; P = .01) and improved circadian rhythm. The incidence of nocturnal hypotension did not differ. In this randomized clinical trial of antihypertensive chronotherapy, bedtime dosing provided better control of nocturnal blood pressure and improved the circadian rhythm, without reducing the efficacy on mean daytime or 24-hour blood pressure, or increasing the risk of nocturnal hypotension. These findings support the potential advantages of bedtime administration and offer new evidence to guide future research on antihypertensive chronotherapy. Chinese Clinical Trial Registry Identifier: ChiCTR2200059719.

The Effects of Elinzanetant on Simulated Driving Performance in Healthy Women: A Randomized Phase I Study.

Elinzanetant is a dual neurokinin-1 and -3 receptor antagonist in development for treating vasomotor symptoms associated with menopause. Its central nervous system action and bedtime dosing could produce next-morning residual effects that impact safety when driving. We therefore conducted a randomized, double-blind, placebo- and active-controlled, four-period, crossover study to assess the effect of elinzanetant on next-morning simulated driving performance. Sixty-four healthy women aged 40-65 years with regular sleep patterns were randomized to receive elinzanetant 120 mg, elinzanetant 240 mg, zopiclone 7.5 mg, or placebo for 5 days in one of four sequences. The primary endpoint assessed participant's ability to maintain a consistent position within the lane, measured using standard deviation of lateral position (SDLP). Secondary assessments included lane exceedance, cornering speeds, and treatment-emergent adverse events (TEAEs), among others. The least squares mean SDLP for both doses of elinzanetant on Day 2 and Day 6 were significantly below the non-inferiority margin of 4.4 cm (p < 0.0001). Small increases in SDLP with both doses versus placebo were observed on Day 2 but not on Day 6. Secondary assessments were not significantly different to placebo, apart from lane exceedances and cornering speed threshold exceedances. TEAEs were reported in 84% of participants; most were mild, and there was no increase in TEAE frequency with the 240 mg dose. Our study demonstrated no clinically relevant next-morning residual effects following bedtime elinzanetant dosing and confirmed the elinzanetant benefit: risk balance was not adversely impacted by somnolence or fatigue the following morning. Trial Registration: ClinicalTrials.gov identifier: NCT06219902.

Chronotherapy for Hypertension: A Meta-Analysis and Systematic Review of RCTs.

The aim of this study was to evaluate the efficacy of chronotherapy for patients with essential hypertension with a range of clinical characteristics. We searched the PubMed, EMBASE, and Cochrane Library databases for randomized controlled trials of antihypertensive therapies in which patients were randomized to morning or evening administration. The primary outcomes of the included studies were ambulatory blood pressure (BP) parameters and patient characteristics, including age, body mass index, percentage of female participants, and drug ingestion, which were described in subgroup analyses. In total, 56 studies were included in the analyses. Meta-analyses and subgroup analyses revealed that specific populations of patients benefited more from bedtime dosing than from morning dosing in both 24-h or 48-h ambulatory systolic BP (SBP) and nighttime SBP, including (1) groups aged < 60 years, (2) those with body mass index ≥ 30 kg/m2, (3) studies with ≥ 50% female participants, and (4) patients receiving antihypertensive calcium channel blockers. However, when controversial data by Hermida et al. were omitted, the effects of BP controls were observed in patients with overweight, particularly obesity. Furthermore, calcium channel blockers contributed to an obvious reduction in nighttime SBP with chronotherapy. Chronotherapy for hypertension may not be completely ineffective, and the clinical program and timing of medication administration can be selected according to the patient's clinical characteristics. Registration PROSPERO identifier number CRD42021292795.

A cross-sectional study on the effects of bedtime administration of selective α1 adrenoceptor antagonists on nocturnal blood pressure in elderly patients with benign prostate hyperplasia.

It remains uncertain whether a bedtime dose of selective α1 adrenoceptor antagonist could result in nocturnal hypotension in elderly patients with benign prostate hyperplasia (BPH). A total of 253 older men with BPH who had taken selective α1 adrenoceptor antagonists before sleep were consecutively recruited from the Geriatric Department of Shanghai Ninth People's Hospital. A total of 221 patients were finally included in the analysis with qualified data including office blood pressure examinations, biochemical tests of blood, and 24-hour ambulatory blood pressure monitoring. Nocturnal hypotension was defined according to the nighttime average systolic blood pressure of ambulatory blood pressure ≤ 100mmHg and/or diastolic blood pressure ≤ 60mmHg. Explore the presence of night hypotension, compare the characteristics of the two groups with or without nocturnal hypotension, and analyze the related risk factors. Among all 221 patients included in the analysis, nocturnal hypotension occurred in 38 patients (17.2%). Compared with those without, patients with nocturnal hypotension were older, had less body mass index, lower office diastolic blood pressure, and lower ambulatory blood pressure in a 24 hour day, and night systolic and diastolic blood pressure, and were less likely to have hypertension. Age (OR 1.064, 95% CI [1.012-1.118], P=0.015) and no hypertension (OR 2.548, 95% CI [1.211-5.359], P=0.014) were independently associated with the presence of nocturnal hypotension. Nocturnal hypotension was common in men 60 years and older with BPH treated with selective α1 adrenoceptor antagonists before sleep. Age and no hypertension were independently associated with nocturnal hypotension positively. Related factors may help clinicians identify hypotension tendencies in the elderly when prescribing such drugs.

Circadian Rhythm and Blood Pressure: research of the latest circadian rhythm in the treatment of hypertension

The goal of this review was to synthesize present knowledge on the effect of circadian rhythms on blood pressure (BP), circadian misalignment mechanisms that contribute to hypertension, circadian rhythm, and hypertension relationship, the latest research of circadian rhythm diet and pharmacological intervention and assess the possibility of chronotherapy in treatment. BP by modulating biological function is determined by the circadian rhythm process mainly under endogenous control, including the central clock in the suprachiasmatic nucleus (SCN) and peripheral clock. Hypertension has been associated with disruption of this rhythm which is a major cardiovascular disease risk factor. A high risk for adverse cardiovascular outcomes is circadian misalignment, which is reflected mostly by nocturnal nondipping. Shift work, hormone release, dietary habits, and others that affect circadian rhythms seem implicated, according to studies. Bedtime dosing of antihypertensive medications and other forms of chronotherapy have the potential to improve BP control. Time-dependent feeding and lifestyle interventions consistent with circadian rhythms offer benefits for hypertension management, as well. Increasingly, it is recognized that circadian rhythm disruption contributes to hypertension. Because interventions that realign circadian rhythms, including chronotherapy or circadian-aligned lifestyle changes, may decrease cardiovascular risk in hypertensives, they are worthy of further study.

Acetylsalicylic acid dosed at bedtime vs. dosed in the morning for circadian rhythm of blood pressure- a systematic review and meta-analysis.

Cardiovascular disease (CVD) is a leading global cause of morbidity and mortality, with high systolic blood pressure (SBP) identified as a major risk factor. Aspirin (Acetylsalicylic acid-ASA) has been considered for CVD prevention, prompting questions about its optimal use in primary and secondary prevention and the ideal dosing time to maximize its impact on circadian blood pressure rhythms. Previous research suggests a potential benefit of bedtime aspirin dosing in reducing blood pressure, attributed to its effects on the renin-angiotensin-aldosterone system and nitric oxide production. This systematic review and meta-analysis aim to further explore the circadian effects of aspirin on blood pressure, focusing on the timing of administration. Adhering to PRISMA guidelines, a comprehensive search of PubMed, Cochrane Library, and clinicaltrials.gov was conducted. Randomized controlled trials (RCTs) involving patients aged >18 with cardiovascular history and hypertension were included. The primary objective was to assess the impact of bedtime-dosed and morning-dosed aspirin on systolic and diastolic blood pressure. Low-dose aspirin was administered for primary or secondary prevention. The Cochrane Risk of Bias tool evaluated study quality. Meta-analyses were conducted using RevMan 5.3, with mean deviations and 95% confidence intervals employed for outcomes. Initial searches yielded 1,181 articles, with six studies meeting the inclusion criteria. These RCTs involved 1,470 patients, with 1,086 completing follow-up. Bedtime aspirin dosing demonstrated a significant reduction in both systolic and diastolic blood pressure compared to morning dosing (p < 0.05). Meta-analysis results for systolic blood pressure revealed a weighted mean difference of approximately 3.65 mmHg in favour of bedtime dosing, with low heterogeneity (I 2 = 0%). For diastolic blood pressure, the weighted mean difference was 1.92, again favouring bedtime dosing, with 3% heterogeneity. This meta-analysis, involving over 1,300 cardiovascular/hypertensive patients, supports the effectiveness of bedtime aspirin in reducing systolic and diastolic blood pressure compared to morning dosing. The results align with previous findings but distinguish themselves by incorporating a more diverse patient population and addressing moderate heterogeneity. While the study's outcomes are promising, further research, including larger sample sizes and longer durations, is warranted for comprehensive clinical implementation. As the study exclusively focused on aspirin timing, future investigations should explore sustained blood pressure effects in patients with clinical indications for aspirin alongside other hypertensive medications.

Should antihypertensives be administrated at bedtime?

Ongoing monitoring and targeted treatment are important to ensure the best blood-pressure control and thus prevent cardiovascular risks. In this review, we evaluate the findings of four clinical studies investigating the effects of morning versus bedtime dosing of antihypertensives. In three out of four studies, overwhelming results were found favouring bedtime dosing. The same studies have been criticized for mechanistic implausible results and multiple study biases. No harmful effects were reported in relation to bedtime dosing. Thus, antihypertensives can be taken as it is most convenient for the patient.

THE EFFECTS OF OLMESARTAN/AMLODIPINE ADMINISTERED IN THE MORNING OR AT NIGHT ON NOCTURNAL BLOOD PRESSURE IN CHINESE PATIENTS WITH MILD-MODERATE ESSENTIAL HYPERTENSION (OMAN TRIAL)

Objective: The clinical evidence of antihypertensive chronotherapy remains controversial. This study aimed to compare the effects of morning and bedtime antihypertensive administration on the nocturnal blood pressure (BP) reduction and the circadian rhythm of hypertensives. Design and method: A randomized, multicenter, open-label clinical trial was conducted in China from March, 2022. Patients aged 18-75, not taking or stopped using antihypertensive drugs for 2 weeks, were recruited. At baseline, all patients received 24-h ambulatory BP measurement (ABPM) and office BP measurement (OBPM), and were randomized to the morning (06:00-10:00 AM, group 1) or the bedtime dosing group (6:00-10:00 PM, group 2). Each patient received one tablet of olmesartan/amlodipine (OA) (20/5 mg) daily for 4 weeks, and then followed up every 4 weeks for 12 weeks. The OA dosage was adjusted based on the ABPM and OBPM. Patients with uncontrolled BP at the first follow-up received an increased dosage to 1.5 tablets, and increased to 2 tablets if BP was uncontrolled after 4 weeks of dosage increase. Results: 700 patients were recruited (mean age 56.54±10.52 years; 45.5% female), with 382 finished the 12-week follow-up and were included in the analysis (follow-ups are continuing). At week 4, the mean BP differences of ABPM and OBPM did not differ significantly between groups. At week 12, compared with group 1, patients in group 2 showed significantly greater reductions from baseline in nighttime systolic BP (SBP) (between-group difference -5.04mmHg, 95% confidence interval (CI): -8.38 to -1.70), and diastolic BP (DBP) (-3.03mmHg, 95% CI -5.08 to -0.97); with better nocturnal SBP control (67.4% vs. 76.7%, P=0.04), and decrease in nocturnal BP load. The proportion of non-dipper or reverse dipper increased from 52.3% to 54.4% in group 1 (P=0.64), and dropped from 57.9% to 45.5% in group 2 (P&lt;0.01). The incidence of nocturnal hypotension (SBP/DBP&lt;100/90mmHg) did not differ. Conclusions: Compared with morning dosing, bedtime dosing can better control nocturnal BP, and improve the circadian rhythm without increasing the risk of nocturnal hypotension. It represents a reasonable strategy to optimize BP control, especially nocturnal BP control.

Once-nightly sodium oxybate (FT218) improved symptoms of disrupted nighttime sleep in people with narcolepsy: a plain language summary.

This is a plain language summary of a published article in the journal CNS Drugs. Narcolepsy is a rare sleep condition. Most people with narcolepsy experience disrupted nighttime sleep and have poor quality of sleep. Sometimes these symptoms are not easily diagnosed as a symptom of narcolepsy. Sodium oxybate is an approved treatment for narcolepsy. The only version of sodium oxybate that was available until 2023 required people to take their sodium oxybate at bedtime and then again in the middle of the night. The US Food and Drug Administration (FDA for short) has approved a once-nightly bedtime dose of sodium oxybate (ON-SXB for short, also known as FT218 or LUMRYZ™) to treat symptoms of narcolepsy in adults. These symptoms are daytime sleepiness and cataplexy, which is an episode of sudden muscle weakness. The once-nightly bedtime dose of ON-SXB removes the need for a middle-of-the-night dose of sodium oxybate. The REST-ON clinical study compared ON-SXB to a placebo (a substance that contains no medicine) to determine if it was better at treating symptoms of disrupted nighttime sleep associated with narcolepsy. This summary looks at whether; ON-SXB was better than placebo at treating symptoms of disrupted nighttime sleep. Compared to people who took placebo, people who took ON-SXB had fewer number of changes from deeper to lighter sleep stages and woke up less during the night. They also reported that they slept better at night and felt more refreshed when waking up in the morning. People with narcolepsy sometimes take alerting agents to help with sleepiness during the day, but alerting agents can cause difficulty sleeping at night. This study showed that people who took ON-SXB had better nighttime sleep even if they were taking alerting agents during the day. The most common side effects of ON-SXB included dizziness, nausea (feeling sick to your stomach), vomiting, headache, and bedwetting. A once-nightly bedtime dose of ON-SXB is a narcolepsy treatment option for people without the need for a middle-of-the-night dose of sodium oxybate.

Evening anti-hypertensive dosing, blood pressure and cardiovascular events in hypertensive: Updated meta-analysis of 41 trials in 65,271 patients

Abstract Introduction In 2022, the International Society of Hypertension and World Hypertension League released a position paper noting that there is limited evidence on the impact of bedtime versus other time dosing of antihypertensives on 24-h BP profile and on cardiovascular morbidity and mortality. Since then, the Treatment In Morning versus Evening (TIME) trial results which enrolled over 20 thousand participants was published. This study aims to update our prior meta-analysis in 2020 (Sunjaya et al. EHJ. Vol. 41:S2) in light of this new results. Purpose In patients with hypertension does evening dosing of anti-hypertensive compared to morning dosing led to better reduction in pressure, blood pressure control and reduced cardiovascular morbidity. Methods A meta-analysis was performed based on randomized controlled trials obtained from Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, Medline and Medline ahead of print published between 2000 and February 2023. Main outcome measures include mean 24 hour systolic and diastolic blood pressure, cardiovascular events as well as prevalence of blood pressure in control. Data synthesis and analysis was done using RevMan 5.3 using a random effects model. Results A total of 41 randomized controlled trials, representing 65,271 patients were included in this meta-analysis. Most studies evaluate the administration of mixed anti-hypertensive with ≥1 medication ingested at bedtime, calcium channel blockers (CCBs) or angiotensin receptor blockers (ARBs) with sample sizes ranging from 30 to 21,104 patients. Evening administration of anti-hypertensive was found to significantly lower 24-hour systolic blood pressure (Mean difference = -1.09, 95% CI -1.97 to -0.20, p = 0.02) and 24-hour diastolic blood pressure (Mean difference = -1.05, 95% CI -1.60 to -0.51, p = 0.0002). Significant reduction in cardiovascular events were found in the evening dosing group (RR = 0.53, 95% CI 0.38 to 0.73, p = 0.0001). Discussion: While evening administration was found to result in significantly lower systolic and diastolic blood pressure, both reductions were found to not be clinically meaningful (At least 5 mmHg for systolic and at least 3 mmHg as per 2022 Hypertension Academic Research Consortium consensus). Few studies have reported the impact on cardiovascular events (7 studies), mostly contributed by one research group (Hermida et al. 4 studies). Sensitivity analyses conducted removing studies conducted by this research group resulted in a non-significant pooled risk being found, though with result from only 3 studies. Conclusion For patients with hypertension, current evidence suggests no significant impact on blood pressure levels. While a reduction in the risk for cardiovascular events was found, this result was strongly contributed by that from one setting. Further studies remain required to answer this important question due to its possible widespread impact on clinical practice.Figure 1MACEFigure 2Systolic Blood Pressure

Abstract 16765: Association of Evening or Bedtime Dosing of Antihypertensive Medications With Nighttime Blood Pressure and Cardiovascular Prognoses

Introduction: Previous studies suggested that bedtime use of antihypertensive medications does not improve cardiovascular outcomes. However, there is a few studies reporting the association of bedtime dosing of antihypertensives with nighttime blood pressure (BP) and cardiovascular prognoses. Hypothesis: Evening/bedtime dosing of antihypertensives may improve cardiovascular outcomes through reductions in nocturnal BP. Methods: We used the dataset of nationwide prospective, the Japan Ambulatory Blood Pressure Monitoring Prospective (JAMP) study to assess the association of evening/bedtime dosing with nighttime BP and cardiovascular prognoses. Among whole 6,359 participants underwent 24h ambulatory BP monitoring, participants with pre-history of cardiovascular disease and not use antihypertensives were excluded in this analysis. Evening or bedtime and two occasions (morning and evening/bedtime) use of antihypertensives were defined as the group of evening/bedtime dosing. Results: Among 4,085 participants (69.1 years and 45% of male), there was no difference between the group of evening/bedtime and morning/others dosing in 24h systolic BP (SBP) (132.9±14.2 vs. 132.0±14.0, p=0.086). Nighttime SBP was higher in evening/bedtime dosing (123.1±17.5 vs. 121.4±16.8, p=0.004). During the median 4.9-years followed-up, 150 cardiovascular events (coronary artery disease, stroke, heart failure) occurred. The evening/bedtime dosing was not associated with cardiovascular events risk adjusted by 24h ambulatory BP (adjusted HR [95%CI], 1.11 [0.78-1.57]) or nighttime BP (Figure). In stratified analysis of participants with or without nocturnal hypertension (nighttime SBP≥120 mmHg or diastolic BP≥70 mmHg), evening/bedtime dosing was also not associated with cardiovascular outcomes. Conclusions: Our study suggested that evening/bedtime dosing of antihypertensives did not give benefit for nighttime BP control and cardiovascular prognoses.

IPX203 vs Immediate-Release Carbidopa-Levodopa for the Treatment of Motor Fluctuations in Parkinson Disease

Levodopa has a short half-life and a limited window of opportunity for absorption in the proximal small intestine. IPX203 is an oral, extended-release formulation of carbidopa-levodopa developed to address these limitations. To assess the efficacy and safety of IPX203 vs immediate-release carbidopa-levodopa in patients with Parkinson disease who are experiencing motor fluctuations. RISE-PD was a 20-week, randomized, double-blind, double-dummy, active-controlled, phase 3 clinical trial. The study was conducted between November 6, 2018, and June 15, 2021, at 105 academic and clinical centers in the US and Europe. Patients with Parkinson disease taking a total daily dose of 400 mg or more of levodopa and experiencing an average of 2.5 hours or more daily off-time were included in the study. A total of 770 patients were screened, 140 were excluded (those taking controlled-release carbidopa-levodopa apart from a single daily bedtime dose, Rytary (Amneal Pharmaceuticals), additional carbidopa or benserazide, or catechol O-methyl transferase inhibitors or who had a history of psychosis within the past 10 years), and 630 were enrolled in the trial. Following open-label immediate-release carbidopa-levodopa dose adjustment (3 weeks) and conversion to IPX203 (4 weeks), patients were randomized in a 1:1 ratio to double-blind, double-dummy treatment with immediate-release carbidopa-levodopa or IPX203 for 13 weeks. The primary end point was mean change in daily good on-time (ie, on-time without troublesome dyskinesia) from baseline to the end of the double-blind treatment period. A total of 630 patients (mean [SD] age, 66.5 [8.95] years; 396 [62.9%] men) were enrolled, and 506 patients were randomly assigned to receive IPX203 (n = 256) or immediate-release carbidopa-levodopa (n = 250). The study met its primary end point, demonstrating statistically significant improvement in daily good on-time for IPX203 compared to immediate-release carbidopa-levodopa (least squares mean, 0.53 hours; 95% CI, 0.09-0.97; P = .02), with IPX203 dosed a mean 3 times per day vs 5 times per day for immediate-release carbidopa-levodopa. Good on-time per dose increased by 1.55 hours with IPX203 compared to immediate-release carbidopa-levodopa (95% CI, 1.37-1.73; P < .001). IPX203 was well tolerated. The most common adverse events in the double-blind phase (IPX203 vs immediate-release carbidopa-levodopa) were nausea (4.3% vs 0.8%) and anxiety (2.7% vs 0.0%). In this study, IPX203 provided more hours of good on-time per day than immediate-release carbidopa-levodopa, even as IPX203 was dosed less frequently. ClinicalTrials.gov Identifier: NCT03670953.

The effect of bedtime versus morning dosing of antihypertensive drugs on the cardiovascular outcomes: a systematic review and meta-analysis of randomized controlled trials.

Antihypertensive drugs are one of the most effective strategies to prevent disability and mortality; however, there have been contradictory findings about the best dosing time for antihypertensive drugs. Therefore, we aim to evaluate the effect of bedtime versus morning dosing of antihypertensive drugs on cardiovascular outcomes. We synthesized randomized controlled studies (RCTs) from the Web of Science, SCOPUS, EMBASE, PubMed, and CENTRAL until 13 October 2022. The risk ratio (RR) for dichotomous outcomes with the corresponding 95% confidence interval (CI) was used. The study protocol was registered in PROSPERO with ID: CRD42022368612. Five RCTs with 59 200 participants were included. Bedtime dosing was significantly associated with less incidence of myocardial infarction (MI) [RR: 0.80 with 95% CI (0.70-0.91), P = 0.0007] compared with morning dosing; however, there was no statistically significant difference between bedtime and morning dosing, regarding all-cause mortality [RR: 0.77 with 95% CI (0.51-1.16), P = 0.21], cardiovascular mortality [RR: 0.65 with 95% CI (0.35-1.21), P = 0.17], major adverse cardiac events (MACE) [RR: 0.79 with 95% CI (0.56-1.10), P = 0.16], heart failure [RR: 0.68 with 95% CI (0.42-1.09), P = 0.11], cerebrovascular accidents [RR: 0.80 with 95% CI (0.53-1.22), P = 0.30], coronary revascularization [RR: 0.79 with 95% CI (0.50-1.24), P = 0.30}, and angina [RR: 0.91 with 95% CI (0.55-1.50), P = 0.70]. Evidence about the comparative efficacy of bedtime versus morning dosing of antihypertensives is still uncertain. However, bedtime dosing significantly reduced MI, which warrants more robust RCTs to validate.

0581 Patient Preferences and Nocturnal Experiences With Oxybate Therapy for Narcolepsy: RESTORE Study Interim Analysis

Abstract Introduction Sodium oxybate (SXB) is a standard-of-care treatment for adults with narcolepsy. Existing oxybate formulations are immediate release (IR), requiring patients to awaken for a second dose 2.5–4 hours after the first bedtime dose. Once-nightly SXB (ON-SXB; FT218), an investigational extended-release formulation, replaces this middle-of-the-night dosing with a once-at-bedtime regimen. RESTORE (NCT04451668) is an open-label/switch study evaluating the safety/tolerability of ON-SXB and patient preferences for ON-SXB or IR oxybate. Methods RESTORE includes participants aged ≥16 years with narcolepsy type 1 or 2 who completed the phase 3 REST-ON trial, were on stable-dose (≥1 month) IR oxybate, or were oxybate-naive. Initial doses for participants switching from IR oxybate are equivalent/closest to the previous total dose/night; incremental adjustments (1.5 g/week; maximum, 9 g/night) are allowed. A nocturnal adverse event (AE) questionnaire about switch participants’ IR oxybate experience in the previous 3 months was completed at baseline. Switch participants completed the preference questionnaire after 3 months of ON-SXB treatment. Results Data available from preference questionnaires (n=78) and nocturnal AE questionnaires (n=130) were analyzed at the interim data cutoff (01 July 2022). Most common AEs thus far were nausea, headache, and somnolence. The once-nightly dosing regimen was preferred by 93.6% (73/78) of participants. The second nightly IR oxybate dose was unintentionally missed in the previous 3 months by 65.4% (85/130) of switch participants; 80.2% (73/91) who intentionally and/or unintentionally missed the second dose felt worse the next day. Participants who took their second nightly IR oxybate dose &amp;gt;4 h after the first dose (51/130 [39.2%]) reported being somewhat, quite a bit, or extremely groggy/unsteady the next morning (26/51 [51.0%]). Inconvenience of the second dose was reported by 70.8%. Other issues related to the second dose were anxiety (29.2%) and the need to be woken by someone else (23.1%). In the past 3 months, 118 participants (90.8%) arose from bed after waking to take the second dose; 9 of these participants reported having fallen, with 5 reporting injuries. Conclusion These interim RESTORE data demonstrate patient preference for once-at-bedtime dosing of ON-SXB and indicate treatment burden associated with twice-nightly IR oxybate. Support (if any) Avadel Pharmaceuticals

Efficacy of Once-Nightly Sodium Oxybate (FT218) in Narcolepsy Type 1 and Type 2: Post Hoc Analysis From the Phase 3 REST-ON Trial.

Post hoc analyses from the phase 3 REST-ON trial evaluated efficacy of extended-release once-nightly sodium oxybate (ON-SXB; FT218) vs placebo for daytime sleepiness and disrupted nighttime sleep in narcolepsy type 1 (NT1) and 2 (NT2). Participants were stratified by narcolepsy type and randomized 1:1 to ON-SXB (4.5g, week 1; 6g, weeks 2-3; 7.5g, weeks 4-8; and 9g, weeks 9-13) or placebo. Assessments included mean sleep latency on Maintenance of Wakefulness Test (MWT) and Clinical Global Impression-Improvement (CGI-I) rating (coprimary endpoints) and sleep stage shifts, nocturnal arousals, and patient-reported sleep quality, refreshing nature of sleep, and Epworth Sleepiness Scale (ESS) score (secondary endpoints) separately in NT1 and NT2 subgroups. The modified intent-to-treat population comprised 190 participants (NT1, n=145; NT2, n=45). Significant improvements were demonstrated with ON-SXB vs placebo in sleep latency for NT1 (all doses, P<0.001) and NT2 (6 and 9g, P<0.05) subgroups. Greater proportions of participants in both subgroups had CGI-I ratings of much/very much improved with ON-SXB vs placebo. Sleep stage shifts and sleep quality significantly improved in both subgroups (all doses vs placebo, P<0.001). Significant improvements with all ON-SXB doses vs placebo in refreshing nature of sleep (P<0.001), nocturnal arousals (P<0.05), and ESS scores (P≤0.001) were reported for NT1 with directional improvements for NT2. Clinically meaningful improvements of a single ON-SXB bedtime dose were shown for daytime sleepiness and DNS in NT1 and NT2, with less power for the limited NT2 subgroup.

0584 Sodium Oxybate Treatment Patterns in Narcolepsy Patients: A Propensity Score–Matched Cohort Study Subanalysis

Abstract Introduction Sodium oxybate (SXB) is strongly recommended for treatment of narcolepsy. Patients treated with available immediate-release oxybates are required to awaken for a second dose 2.5–4 hours after the bedtime dose to cover a full night of sleep. This study characterized SXB treatment patterns and discontinuation in narcolepsy patients. Methods Mayo Clinic patients from 1975–2020 were identified using an electronic health record–based search. Patients with ≥1 narcolepsy-specific ICD-9/-10 code and ≥1 diagnostic mention of narcolepsy in clinical notes (identified using a natural-language-processing [NLP] algorithm) were included. NLP was used to identify SXB non-use events with manual chart reviews performed to characterize reasons for discontinuation, switching, or missing the second dose and effects of missing the second dose. Results Of the patients with narcolepsy prescribed SXB (n=351; mean age at first diagnosis code observed at Mayo Clinic, 32 y [IQR: 23.2–46.1]; 65.5% female; 92.3% white), 113 (32.2%) had clinical notes indicating discontinuation of SXB, with 71 (20.2%) including reasons for discontinuation. The most common reasons for discontinuation (n≥5) included lack of efficacy (n=11), side effects (n=10), gastrointestinal side effects (n=10), neurological side effects (n=9), psychiatric side effects (n=8), lack of access (insurance/cost, n=10), and resolution/absence of cataplexy (n=5). Mentions of switching from SXB to other drugs (n=12 patients) included switching to stimulants (mixed amphetamine salts, n=3; dextroamphetamine, n=2; methylphenidate, n=1), sedative hypnotics (zolpidem, n=2), antidepressants (mirtazapine, n=1), and wake-promoting agents (solriamfetol, n=1). Of the 38 patients (10.8%) with mentions of missing the second nightly SXB dose, reasons were recorded for 24 (63.2%), including inability to wake up (n=14), forgetting the second dose (n=3), and having to wake up early the following day (n=3). Consequences of missing the second dose were recorded for a small subset (increased cataplexy, n=4; lower daytime alertness, n=3; awakens earlier, n=1; tiredness, n=1). Conclusion Limited data are available regarding real-world use of SXB. This novel study used a combination of NLP algorithm and manual chart review to identify difficulties patients have with the second, middle-of-the night immediate-release oxybate dose and patient-experienced consequences of not adhering to the prescribed dosing regimen. Support (if any) Avadel Pharmaceuticals

0407 Impact of Lemborexant on Daytime Ratings of Sleepiness/Alertness in Subjects with Insomnia Disorder and Baseline Sleepiness

Abstract Introduction Since the use of sleep-promoting drugs can also lead to residual morning sleepiness, it is important to determine if a new hypnotic is associated with such a carryover effect of treatment. To this end, an assessment of sleepiness/alertness was included in lemborexant (LEM) phase 3 studies. LEM is a competitive dual orexin receptor antagonist approved in several countries for the treatment of adults with insomnia. This post-hoc analysis of Study 304 (E2006-G000-304; NCT02783729) assessed the impact of LEM on morning sleepiness/alertness in subjects who reported at least mild/moderate morning sleepiness at baseline. Methods Study 304 was a randomized controlled study in adults ≥55y with insomnia disorder (N=1006). Subjects received bedtime doses of placebo (PBO), LEM 5mg (LEM5), LEM 10mg (LEM10), or zolpidem tartrate extended release 6.25 mg (not reported here) for 1 month. A daily Sleep Diary assessed morning sleepiness, within 90 min of waketime, with the question “How alert/sleepy do you feel this morning?” rated from 1 (extremely sleepy) to 9 (extremely alert). Scores were averaged over 7-day periods for baseline (single-blind run-in) and first and last 7 days of treatment. Chi-square tests were used to compare the shift from sleepy (≤3) to more alert (&amp;gt;3) between PBO and treatment groups. Results At baseline, 59/203 (29.1%), 66/261 (25.3%), and 79/265 (29.8%) of the PBO, LEM5, and LEM10 subjects reported a score ≤3, indicating at least mild/moderate morning sleepiness. At the end of 1 month of treatment, 37/57 (64.9%) of the PBO subjects rated themselves as less sleepy and more alert (&amp;gt;3), compared with 50/64 (78.1%; P=0.11) LEM5- and 58/76 (76.3%; P=0.15) LEM10-treated subjects. Conclusion In this study, ~28% of subjects reported morning sleepiness at baseline. More subjects who reported sleepiness at baseline and received LEM reported improved morning alertness during the last week of treatment compared with PBO subjects. These data are concordant with previous findings of a lack of effect of LEM on tasks requiring alertness in the morning. Support (if any) Eisai Inc.

Patient Preference and Nocturnal Experience With Oxybate Treatment for Narcolepsy: Interim Analysis of Data From RESTORE (P5-13.004)

<h3>Objective:</h3> This study aims to assess patient preference for once- vs twice-nightly oxybate dosing regimens and experiences with the second dose of twice-nightly, immediate-release (IR) oxybate. <h3>Background:</h3> IR oxybates require patients with narcolepsy to awaken for a second dose 2.5–4 hours after the bedtime dose. RESTORE, an ongoing open-label/switch study (NCT04451668), evaluates long-term safety/tolerability of investigational, extended-release once-nightly sodium oxybate (FT218; ON-SXB). <h3>Design/Methods:</h3> Participants aged ≥16 years with narcolepsy type 1 or 2 who completed the phase 3 REST-ON trial, were on stable-dose (≥1 month) IR oxybate, or were oxybate-naive were eligible. For those switching to ON-SXB, initial doses were equivalent/closest to the previous total IR oxybate dose/night; adjustments were allowed in 1.5-g increments/week. Switch participants completed the nocturnal adverse event (AE) questionnaire about their IR oxybate experience at baseline and preference questionnaire 3 months after switching to ON-SXB. Safety and dose titration data are presented separately. <h3>Results:</h3> RESTORE enrollment completed 30June2022. At the interim data cutoff (01July2022), 78 switch participants completed preference questionnaires; 130 completed nocturnal AE questionnaires. Preference for the ON-SXB dosing regimen was stated by 93.6% (73/78) of participants. On the nocturnal AE questionnaire, 65.4% (85/130) unintentionally missed their second IR oxybate dose in previous 3 months; of participants who intentionally and/or unintentionally missed the second dose, 80.2% (73/91) felt worse the next day. Second nightly IR oxybate doses were taken &gt;4 h after the first by 39.2% (51/130); 51.0% (26/51) were somewhat to extremely groggy/unsteady the next morning. The second dose was rated somewhat to extremely inconvenient for 70.8%. Second-dose-related anxiety (29.2%) and need for someone to wake them (23.1%) were also reported. Most (90.8% [118/130]) arose from bed when waking for the second dose; 9 had falls and 5 reported injuries. <h3>Conclusions:</h3> These data indicate patient preference for once-at-bedtime dosing and reveal the treatment burden of twice-nightly IR oxybate. <b>Disclosure:</b> Dr. Roy has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Jazz Pharma. Dr. Roy has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Harmony biosciences. Dr. Roy has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Eisai . Dr. Roy has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Inspire. The institution of Dr. Roy has received research support from Jazz . The institution of Dr. Roy has received research support from Inspire. The institution of Dr. Roy has received research support from Avadel. Dr. Harsh has nothing to disclose. Akinyemi Ajayi has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Jazz Pharmaceutical. Akinyemi Ajayi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Jazz Pharmaceutical. Dr. Stern has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Avadel Pharmaceutical. Dr. Stern has received intellectual property interests from a discovery or technology relating to health care. Dr. Seiden has received personal compensation for serving as an employee of Avadel Pharmaceuticals. Dr. Seiden has received stock or an ownership interest from Avadel Pharmaceuticals. Dr. Dubow has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Paragon Biosciences. Dr. Dubow has stock in Avadel Pharmaceuticals. Miss Gudeman has received personal compensation for serving as an employee of Avadel Pharmaceuticals. Miss Gudeman has stock in Avadel Pharmaceuticals.

Prevention of mania in a primigravida at ultra-high risk of postpartum recurrence.

Prevention of mania in a primigravida at ultra-high risk of postpartum recurrence.

The cenobamate-clobazam interaction- evidence of synergy in addition to pharmacokinetic interaction

The cenobamate-clobazam interaction- evidence of synergy in addition to pharmacokinetic interaction