The Efficacy of Tradipitant in Patients With Diabetic and Idiopathic Gastroparesis in a Phase 3 Randomized Placebo-Controlled Clinical Trial.

BACKGROUND: Neurokinin receptor 1 antagonists are effective in reducing nausea and vomiting in chemotherapy-induced emesis. We investigated the safety and efficacy of tradipitant, a neurokinin receptor 1 antagonist, in patients with idiopathic and diabetic gastroparesis. METHODS: A total of 201 adults with gastroparesis were randomly assigned to oral tradipitant 85 mg (n = 102) or placebo (n = 99) twice daily for 12 weeks. Symptoms were assessed by a daily symptom dairy, Gastroparesis Cardinal Symptom Index scores, and other patient-reported questionnaires. Blood levels were monitored for an exposure-response analysis. The primary outcome was change from baseline to week 12 in average nausea severity, measured by daily symptom diary. RESULTS: The intention-to-treat (ITT) population did not meet the prespecified primary endpoint at week 12 (difference in nausea severity change drug vs placebo; P = .741) or prespecified secondary endpoints. Post hoc analyses were performed to control for drug exposure, rescue medications, and baseline severity inflation. Subjects with high blood levels of tradipitant significantly improved average nausea severity beginning at early time points (weeks 2-4). In post hoc sensitivity analyses, tradipitant treatment demonstrated strengthened effects, with statistically significant improvements in nausea at week 12. CONCLUSIONS: Although tradipitant did not reach significance in the ITT population, a pharmacokinetic exposure-response analysis demonstrated significant effects with adequate tradipitant exposure. When accounting for confounding factors such as baseline severity inflation and rescue medication, a statistically significant effect was also observed. These findings suggest that tradipitant has potential as a treatment for the symptom of nausea in gastroparesis. (ClincialTrials.gov, Number: NCT04028492).

Efficacy and Safety of Iloperidone in Bipolar Mania: A Double-Blind, Placebo-Controlled Study.

Objective: To determine if iloperidone, a second-generation antipsychotic, reduces symptoms of bipolar mania.Methods: This phase 3, randomized, double-blind, placebo-controlled study was conducted in adults with bipolar mania at 27 US and international sites between April 2021 and September 2022. Participants were randomized 1:1 to iloperidone (up to 24 mg/d given twice daily) or placebo for 4 weeks. The primary efficacy endpoint was change from baseline to week 4 in Young Mania Rating Scale (YMRS) total score versus placebo. Secondary efficacy endpoints included change from baseline in the Clinical Global Impressions-Severity and Clinical Global Impression of Change scales.Results: Altogether, 414 participants were randomized and administered at least 1 dose of study medication (iloperidone, n = 206; placebo, n = 208). Overall, 139 (67.1%) iloperidone patients and 153 (72.9%) placebo patients completed the study. Iloperidone demonstrated significant improvement versus placebo at week 4 for the primary and secondary endpoints. Differences in the least-squares mean (95% CI; P value) of change from baseline for YMRS total scores were -4.0 (-5.70 to -2.25; adjusted P = .000008). The most encountered adverse events with iloperidone were tachycardia, dizziness, dry mouth, alanine aminotransferase increased, nasal congestion, increased weight, and somnolence. The incidence of akathisia and extrapyramidal symptom-related treatment-emergent adverse events was low.Conclusions: Iloperidone is effective in treating patients with bipolar mania. The tolerability and safety profile of iloperidone in bipolar mania is consistent with previous clinical studies of patients with schizophrenia, and no new safety concerns were identified.Trial Registration: ClinicalTrials.gov identifier: NCT04819776; EudraCT: 2020-000405-83.

Case report: A patient with Delayed Sleep-Wake Phase Disorder and Optic Nerve Hypoplasia treated with tasimelteon: a case study.

We present a case of an adult female diagnosed with Delayed Sleep-Wake Phase Disorder (DSWPD) and Optic Nerve Hypoplasia (ONH), with a confirmed delayed Dim Light Melatonin Onset (DLMO), who reports the inability to fall asleep at their desired bedtime and obtain adequate sleep nightly, despite the ability to have a full night's sleep when not required to be up at a specific time for societal requirements. The participant was enrolled in an 11-month Open-Label Extension (OLE) following the randomized portion of a clinical study and was successfully treated with tasimelteon. DSWPD symptoms were resolved, and their previously delayed sleep-wake cycle was advanced. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT04652882, identifier NCT04652882.

Validation of the motion sickness severity scale: Secondary analysis of a randomized, double-blind, placebo-controlled study of a treatment for motion sickness.

BACKGROUND: Motion sickness is characterized by nausea and vomiting among a constellation of symptoms. Symptom severity is dynamic and distressing. Most validated motion sickness scales are time-intensive and effortful, with alternative scales having uncertain performance or non-specific measures. A validated instrument allowing for facile, rapid assessment of core motion sickness symptom severity would therefore be valuable. We assessed the performance of the Motion Sickness Severity Scale (MSSS), a six-item questionnaire designed to measure real-time motion sickness symptoms. METHODS: MSSS construct validity was assessed as a secondary analysis of data from 63 healthy participants without antiemetic treatment in a clinical trial (Unique Identifier = NCT03772340) conducted to evaluate the safety and efficacy of Tradipitant-a novel neurokinin-1 receptor antagonist-in the treatment of motion sickness. Clinical outcome assessments included the MSSS, the Patient Global Impression of Severity (PGI-S), and the Motion Sickness Assessment Questionnaire (MSAQ). The performance of the MSSS through Pearson correlation coefficients, within-group analysis of variance, empirical cumulative distribution functions, and Kolmogorov-Smirnov tests. RESULTS: The MSSS correlated very highly with the PGI-S (r = 0.93, p-value<0.0001) and highly with the MSAQ (r = 0.83, p-value<0.0001). Mean MSSS scores between increasing PGI-S severity levels increased significantly in all four increments (None-to-Mild: p-value = 0.006, Mild-to-Moderate: p-value<0.0001, Moderate-to-Severe: p-value = 0.006, Severe-to-Very-Severe: p-value = 0.002). There were statistically significant differences in MSSS score distributions stratified by PGI-S severity level, with higher MSSS scores associated with higher PGI-S severity levels and lower MSSS scores associated with lower PGI-S severity levels. DISCUSSION: The MSSS is a valid instrument for the assessment of the core motion sickness symptoms and is reflective of global disease severity. Implementation of the MSSS and comparable simplified, short questionnaires in motion sickness research will provide rapid and accurate measures of disease severity. These measures will enable further elucidation of motion sickness as an illness and inform the development and evaluation of motion sickness therapies.

Enrichment of Patients With Ehlers Danlos Syndrome in Idiopathic Gastroparesis-A Gene Set Enrichment Analysis.

INTRODUCTION: Ehlers Danlos syndrome (EDS) is a heritable disorder of the connective tissue usually inherited as an autosomal dominant trait. We observe an enrichment of EDS cases in a gastroparesis clinical study. METHODS: We explored the frequency of EDS cases in 2 consecutive gastroparesis clinical studies. To explore the genetic surrogates of EDS, we have performed whole-genome sequencing analysis and we focused the analyses on the frequencies of consequential variants in core EDS genes. RESULTS: We report a significant enrichment of EDS cases in a set of patients with gastroparesis (14/686 vs 1/5,000 OR 104 (confidence interval 13.7-793.3) P value <0.0001). We report a significant enrichment of variants in EDS genes in patients with idiopathic gastroparesis. DISCUSSION: The enrichment may be suggestive of converging pathways at the heart of etiology or predisposing patients to EDS with gastroparesis.

Corrigendum: Case report: A patient with Delayed Sleep-Wake Phase Disorder and Optic Nerve Hypoplasia treated with tasimelteon: a case study.

[This corrects the article DOI: 10.3389/fnins.2023.1287514.].

Once-daily tasimelteon (VEC-162) for jet lag following transmeridian travel: A multicenter, randomized, double-blind, placebo-controlled trial.

Jet Lag Disorder is a Circadian Rhythm Sleep-Wake Disorder resulting from a misalignment of the endogenous circadian clock and the sleep and wake pattern required by a change in time zone. Jet lag is most severe following eastward travel. This multicenter, randomized, placebo-controlled clinical trial (JET) assessed the physiological mechanism of jet lag induced by a real-life transmeridian flight and evaluated the efficacy of tasimelteon-a circadian regulator acting as a dual melatonin receptor agonist, in the treatment of Jet Lag Disorder (JLD). Tasimelteon-treated participants slept 76 min longer on Night 3 during their second trip (evaluation phase) as compared to their first (observational phase). Over the three travel nights evaluated, transmeridian jet travelers in the tasimelteon group slept 131 min more (TST2/3) than those in the placebo group. The JET study demonstrated clinically meaningful improvements in nighttime sleep and daytime alertness in both objective and subjective measures as well as global functioning after a real-world flight. These results suggest that tasimelteon can be an effective therapeutic tool to treat JLD in the context of transmeridian travel.

Enrichment of Motilin Receptor Loss-of-Function Variants in Gastroparesis.

INTRODUCTION: Gastroparesis is a serious medical condition characterized by delayed gastric emptying and symptoms of nausea, vomiting, bloating, fullness after meals, and abdominal pain. METHODS: To ascertain the genetic risk factors for gastroparesis, we conducted the largest thus far whole-genome sequencing study of gastroparesis. We investigated the frequency and effect of rare loss-of-function variants in patients with both idiopathic and diabetic gastroparesis enrolled in a clinical study of gastroparesis. RESULTS: Among rare loss-of-function variants, we reported an increased frequency of a frameshift mutation p.Leu202ArgfsTer105, within the motilin receptor gene, variant rs562138828 (odds ratio 4.9). We currently replicated this finding in an independent large cohort of gastroparesis samples obtained from patients participating in the ongoing phase III gastroparesis clinical study. DISCUSSION: Motilin receptor is an important therapeutic target for the treatment of hypomotility disorders. The identified genetic variants may be important risk factors for disease as well as may inform treatments, especially those targeting motilin receptor.

Simulated driving performance in healthy adults after night-time administration of 20 mg tasimelteon.

An impairment in next day driving performance has been reported for almost every drug currently United States Food and Drug Administration (FDA) approved for improvement of sleep in chronic and transient insomnia. Tasimelteon, a melatonin receptor agonist, demonstrated significant improvements in night-time sleep, daytime naps, and sleep timing in non-24-hr sleep-wake disorder (Non-24) by entraining these patients to a 24-hr day as measured by melatonin and cortisol rhythms. Given this new mechanism of action of entraining the biological clock, we conducted a study to evaluate the potential effect tasimelteon may have on the ability to operate a motor vehicle. The study was conducted in 48 healthy adult subjects using a randomised, double-blind, placebo and active (zopiclone 7.5 mg) controlled study with a 3-period cross-over design. Driving performance was assessed by measuring standard deviation of lateral position (SDLP) using the validated Cognitive Research Corporation Driving Simulator-MiniSim. The difference in least square mean SDLP for tasimelteon was 1.22 cm reflecting a non-significant increase in SDLP change from placebo (p = .1119). In contrast, treatment with the active control, zopiclone 7.5 mg, was associated with a meaningful and significant increase in SDLP, change from placebo for zopiclone was 4.14 cm (p < .0001). The lack of clinically meaningful and statistically significant finding with tasimelteon was further supported by the symmetry analysis, which showed the distribution of within-subject differences between tasimelteon and placebo was symmetric about zero. At the FDA-approved 20 mg dose to treat Non-24, tasimelteon did not impair next-day driving performance compared to placebo in adult healthy volunteers.

An observational study investigating the CRY1Δ11 variant associated with delayed sleep-wake patterns and circadian metabolic output.

We conducted an observational research study to collect information on sleep-wake patterns from participants with a confirmed status of the cryptochrome circadian clock 1 (CRY1) splicing variant, CRY1Δ11 c.1657 + 3A > C, and their controls, defined as wild-type (WT) family members. Altogether, 67 participants were enrolled and completed this study in Turkey, recruited from a list of families with at least one CRY1-confirmed member. We measured sleep-wake patterns and metabolic output, specifically time and frequency of bowel movements, for all participants by daily post-sleep diaries over 28 days. The sleep diary measured self-reported bed time, wake time, midpoint of sleep, and latency to persistent sleep (LPS), and accounted for naps and awakenings for religious purposes. Wake time and midpoint of sleep were significantly later in the CRY1Δ11 variant group versus WT, and LPS was significantly greater in participants in the CRY1Δ11 variant group. The mean bed time on all nights of sleep was later in participants with a CRY1Δ11 variant versus WT. Additionally, participants with a CRY1Δ11 variant had significantly affected metabolic outputs, measured by later bowel movements than WT participants. These results demonstrate that, on average, individuals with the studied splicing variant experience pronounced delays in sleep period and circadian-related metabolic processes.

Loss-of-function mutations in IFNAR2 in COVID-19 severe infection susceptibility.

Recent COVID-19 (coronavirus disease 2019) host genetics studies suggest enrichment of mutations in genes involved in the regulation of type I and type III interferon (IFN) immunity in patients with severe COVID-19 infection. We performed whole-genome sequencing analysis of samples obtained from patients participating in the ongoing ODYSSEY phase 3 study of hospitalised patients with severe COVID-19 infection receiving supplemental oxygen support. We focused on burden testing of categories of rare and common loss-of-function (LOF) variants in all of the IFN pathway genes, specifically with MAF < 0.1% and MAF < 1%. In a model including LOF and missense variants (MAF < 1%), we report a significant signal in both INFAR1 and IFNAR2. We report carriers of rare variants in our COVID-19 cohort, including a stop-gain IFNAR2 (NM_000874:exon9:c.C966A:p.Y322X) amongst carriers of several other IFNAR rare nonsynonymous variants. Furthermore, we report an increased allelic frequency of common IFNAR2 variants in our data, reported also by the COVID-19 Host Genetics Initiative.

Tasimelteon safely and effectively improves sleep in Smith-Magenis syndrome: a double-blind randomized trial followed by an open-label extension.

PURPOSE: To assess the efficacy of tasimelteon to improve sleep in Smith-Magenis syndrome (SMS). METHODS: A 9-week, double-blind, randomized, two-period crossover study was conducted at four US clinical centers. Genetically confirmed patients with SMS, aged 3 to 39, with sleep complaints participated in the study. Patients were assigned to treatment with tasimelteon or placebo in a 4-week crossover study with a 1-week washout between treatments. Eligible patients participated in an open-label study and were followed for >3 months. RESULTS: Improvement of sleep quality (DDSQ50) and total sleep time (DDTST50) on the worst 50% of nights were primary endpoints. Secondary measures included actigraphy and behavioral parameters. Over three years, 52 patients were screened, and 25 patients completed the randomized portion of the study. DDSQ50 significantly improved over placebo (0.4, p = 0.0139), and DDTST50 also improved (18.5 minutes, p = 0.0556). Average sleep quality (0.3, p = 0.0155) and actigraphy-based total sleep time (21.1 minutes, p = 0.0134) improved significantly, consistent with the primary outcomes. Patients treated for ≥90 days in the open-label study showed persistent efficacy. Adverse events were similar between placebo and tasimelteon. CONCLUSION: Tasimelteon safely and effectively improved sleep in SMS.

Efficacy and Safety of Tradipitant in Patients With Diabetic and Idiopathic Gastroparesis in a Randomized, Placebo-Controlled Trial.

BACKGROUND & AIMS: Treatments are needed for gastroparesis; antagonists of tachykinin receptor 1 (TACR1, also called NK1R) can reduce symptoms of nausea and vomiting. We investigated the safety and efficacy of tradipitant, an antagonist of NK1R, in patients with idiopathic or diabetic gastroparesis. METHODS: We performed a double-blind trial of 152 adults with gastroparesis at 47 sites in the United States from November 2016 through December 2018. Participants were randomly assigned to groups given oral tradipitant 85 mg (n = 77) or placebo (n = 75) twice daily for 4 weeks. Symptoms were assessed by a daily symptom dairy, Gastroparesis Cardinal Symptom Index scores, and other patient-reported questionnaires. The primary outcome from the intent-to-treat analysis was change from baseline to week 4 in average nausea severity, measured by the Gastroparesis Core Symptom Daily Diary. RESULTS: Patients receiving tradipitant had a significant decrease in nausea score (reduction of 1.2) at week 4 compared with placebo (reduction of 0.7) (P = .0099) and a significant increase in of nausea-free days at week 4 (28.8% increase on tradipitant vs 15.0% on placebo; P = .0160). Patients with nausea and vomiting at baseline (n = 101) had an even greater decrease in nausea in when given tradipitant (reduction of 1.4) compared with those given placebo (reduction of 0.4) (P < .0001), as well as an increase in nausea-free days at week 4 (32.3% improvement on tradipitant vs 7.6% on placebo; P = .0003). The average nausea score was 1 or less at week 4 in 32.9% of patients given tradipitant compared with 11.8% of patients given placebo (P = .0013). A greater than 1-point improvement in Gastroparesis Cardinal Symptom Index score was observed in 46.6% of patients given tradipitant compared with 23.5% of patients given placebo (P = .0053). CONCLUSIONS: Tradipitant resulted in statistically and clinically meaningful improvements in nausea and reduced vomiting, compared with placebo, in patients with idiopathic or diabetic gastroparesis. ClinicalTrials.gov, Number: NCT02970968.

Tradipitant in the Treatment of Motion Sickness: A Randomized, Double-Blind, Placebo-Controlled Study.

Introduction: Novel therapies are needed for the treatment of motion sickness given the inadequate relief and bothersome and dangerous adverse effects of currently approved therapies. Neurokinin-1 (NK1) receptor antagonists have the potential to be effective in improving the symptoms of motion sickness, given the involvement of Substance P in nauseogenic and emetic pathways and the expression of NK1 receptors in the gastrointestinal system. Here we evaluated the efficacy of tradipitant, a novel NK1 receptor antagonist, in preventing motion sickness in variable sea conditions. Methods: A total of 126 adults participated in the Motion Sifnos study. Groups of participants were assigned to one of seven boat trips lasting ~4 h on the Pacific Ocean. Participants were randomized 1:1 to tradipitant 170 mg or placebo and completed the Motion Sickness Severity Scale (MSSS) every 30 min, in addition to other assessments. Severity of motion sickness was assessed with the incidence of vomiting and the MSSS. Results: Participants on tradipitant had a significantly lower incidence of vomiting as compared to those on placebo across all boat trips (tradipitant = 17.5%, placebo = 39.7%, p = 0.0039). For trips exposed to rough sea conditions, the difference in the incidence of vomiting between the groups was more dramatic (tradipitant = 15.79%, placebo = 72.22%, p = 0.0009). Across these trips, motion sickness symptoms were significantly lower in the tradipitant group compared to the placebo group (tradipitant = 3.19, placebo = 4.57, p = 0.0235). Discussion: Tradipitant has the potential to be an effective therapy for the prevention of vomiting and treatment of nausea in people with motion sickness.

Efficacy of Tasimelteon (HETLIOZ®) in the Treatment of Jet Lag Disorder Evaluated in an 8-h Phase Advance Model; a Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

Background: Most travelers experience Jet Lag Disorder (JLD) symptoms due to misalignment of their circadian rhythms with respect to the new time zone. We assessed the efficacy and safety of tasimelteon (HETLIOZ®) in healthy participants using a laboratory model of JLD induced by an 8-h phase advance of the sleep-wake cycle (JET8 Study). We hypothesized that tasimelteon treatment in participants experiencing JLD would cause increased sleep time, increased next-day alertness, and reduced next-day sleepiness. Methods: We undertook a randomized, double-blind, placebo-controlled trial in 12 US clinical research sleep centers. We screened healthy adults ages 18-73 years, who were eligible for the randomization phase of JET8 if they typically went to bed between 21:00 and 01:00, slept between 7 and 9 h each night, and slept at a consistent bedtime. We used block randomization stratified by site to assign participants (1:1) to receive a single oral dose of tasimelteon (20 mg) or placebo 30 min before their 8-h phase-advanced bedtime. The primary endpoint was Total Sleep Time in the first 2/3 of the night (TST2/3), which was measured by polysomnography during the 8-h sleep episode, and assessed in the intent-to-treat population. The trial is completed and registered with ClinicalTrials.gov, NCT03373201. Results: Between October 16, 2017 and January 17, 2018, we screened 607 healthy participants for JET8, of whom 320 (53%) were assigned to receive tasimelteon (n = 160) or placebo (n = 160). Tasimelteon treatment increased TST2/3 (primary endpoint) by 60.3 min (95%CI 44.0 to 76.7, P < 0.0001) and whole night TST by 85.5 min (95% CI 64.3 to 106.6, P < 0.0001), improved next day alertness, next day sleepiness, and shortened latency to persistent sleep by -15.1 min (95% CI -26.2 to -4.0, P = 0.0081). Conclusion: A single dose of tasimelteon improves the primary symptoms of JLD, including nighttime insomnia and next day functioning among participants in a laboratory model of JLD simulating eastward trans-meridian travel by inducing an 8-h phase advance of the sleep-wake cycle.

Estimating Burden of Disease Among Blind Individuals With Non-24-Hour Sleep-Wake Disorder.

Purpose: To quantify the burden of disease in blind patients with Non-24-H Sleep- Wake Disorder (N24HSWD), utilizing longitudinal sleep diary data. N24HSWD is a circadian disorder characterized by a cyclical pattern of aberrant circadian and sleep-wake cycles that are associated with increased frequency of sleep episodes during the school/work day hours. Daytime sleep episodes would be predicted to decrease the opportunity for school/work participation, significantly impacting the quality of life of the patient. Methods: We used the sleep diary data of daytime sleep from a period of ~90 days in blind individuals that presented with a sleep complaint. These subjects were identified from a group of blind individuals with N24HSWD (n = 121) and a control group of blind individuals without N24HSWD (n = 57). Results: N24HSWD patients had more frequent and longer episodes of daytime sleep as compared to a control group. Using duration of daytime sleep as a surrogate for defining a healthy or unhealthy day, N24HSWD patients also had significantly fewer healthy days, defined by daytime sleep free days (DSFD), days without a sleep episode between 9:00 a.m. and 5:00 p.m, as compared to the control group. Conclusion: Daytime sleep free day (DSFD) is a useful and specific measure of disease burden in patients with N24HSWD and it is predicted to be correlated with the standardized HRQOL-4, Healthy Days measurement.

Self-Management of Arthritis Symptoms by Complementary and Alternative Medicine Movement Therapies.

OBJECTIVES: This study describes the association between current use of different complementary and alternative medicine (CAM) movement therapies (MTs) and arthritis symptoms (pain, fatigue, difficulty with physical function, and feelings of helplessness). METHODS: By using a cross-sectional design, 2140 participants with arthritis or chronic joint symptoms completed a survey about CAM use. Adjusted means for arthritis symptoms were reported by current use of CAM MTs and current use of yoga. RESULTS: Approximately 19% (n = 398) of the total respondents were "currently using" some form of MT. Of those reporting current use, 89.2% of the participants reported current use of yoga. After adjustment for a variety of characteristics, relative to participants who reported no current CAM MT use, participants with current use of CAM MT had significantly increased pain symptoms and a higher level of perceived helplessness. CONCLUSIONS: This descriptive study indicates that patients with arthritis or chronic joint symptoms selecting CAM MT for self-management may be doing so because of more symptom involvement, specifically more pain and feelings of helplessness. Because of its increasing use, yoga warrants special attention by practitioners as a nonpharmacologic self-management therapy for arthritis symptoms.

Tasimelteon for non-24-hour sleep-wake disorder in totally blind people (SET and RESET): two multicentre, randomised, double-masked, placebo-controlled phase 3 trials.

BACKGROUND: Most totally blind people have non-24-hour sleep-wake disorder (non-24), a rare circadian rhythm disorder caused by an inability of light to reset their circadian pacemaker. In two consecutive placebo-controlled trials (SET and RESET), we assessed safety and efficacy (in terms of circadian entrainment and maintenance) of once-daily tasimelteon, a novel dual-melatonin receptor agonist. METHODS: We undertook the placebo-controlled, randomised, double-masked trials in 27 US and six German clinical research centres and sleep centres. We screened totally blind adults (18-75 years of age), who were eligible for the randomisation phase of SET if they had a non-24-hour circadian period (τ) of 24·25 h or longer (95% CI greater than 24·0 and up to 24·9 h), as calculated from measurements of urinary 6-sulphatoxymelatonin rhythms. For SET, we used block randomisation to assign patients (1:1) to receive tasimelteon (20 mg) or placebo every 24 h at a fixed clock time 1 h before target bedtime for 26 weeks. Patients who entered the open-label group receiving tasimelteon in SET or who did not meet the SET inclusion criteria but did meet the RESET inclusion criteria were screened for RESET. A subset of the patients who entered the open-label group before the RESET study and who had eligible τ values were screened for RESET after completing the open-label treatment. In RESET, we withdrew tasimelteon in a randomised manner (1:1) in patients who responded (ie, entrained) after a tasimelteon run-in period. Entrainment was defined as having τ of 24·1 h or less and a 95% CI that included 24·0 h. In SET, the primary endpoint was the proportion of entrained patients, assessed in the intention-to-treat population. The planned step-down primary endpoint assessed the proportion of patients who had a clinical response (entrainment at month 1 or month 7 plus clinical improvement, measured by the Non-24 Clinical Response Scale). In RESET, the primary endpoint was the proportion of non-entrained patients, assessed in the intention-to-treat population. Safety assessments included adverse events and clinical laboratory measures, assessed in all treated patients. These trials are registered with ClinicalTrials.gov, numbers NCT01163032 and NCT01430754. FINDINGS: Between Aug 25, 2010, and July 5, 2012, we screened 391 totally blind patients for SET, of whom 84 (22%) were assigned to receive tasimelteon (n=42) or placebo (n=42). Two patients in the tasimelteon group and four in the placebo group discontinued the study before τ was measured, due to adverse events, withdrawal of consent, and a protocol deviation. Circadian entrainment occurred in eight (20%) of 40 patients in the tasimelteon group compared with one (3%) of 38 patients in the placebo group at month 1 (difference 17%, 95% CI 3·2-31·6; p=0·0171). Nine (24%) of 38 patients showed a clinical response, compared with none of 34 in the placebo group (difference 24%, 95% CI 8·4-39·0; p=0·0028). Between Sept 15, 2011, and Oct 4, 2012, we screened 58 patients for eligibility in RESET, 48 (83%) of whom had τ assessed and entered the open-label tasimelteon run-in phase. 24 (50%) patients entrained, and 20 (34%) were enrolled in the randomisation phase. Two (20%) of ten patients who were withdrawn to placebo remained entrained compared with nine (90%) of ten who continued to receive tasimelteon (difference 70%, 95% CI 26·4-100·0; p=0·0026). No deaths were reported in either study, and discontinuation rates due to adverse events were comparable between the tasimelteon (3 [6%] of 52 patients) and placebo (2 [4%] of 52 patients) treatment courses. The most common side-effects associated with tasimelteon in SET were headache (7 [17%] of 42 patients given tasimelteon vs 3 [7%] of 42 patients given placebo), elevated liver enzymes (4 [10%] vs 2 [5%]), nightmares or abnormal dreams (4 [10%] vs none), upper respiratory tract infection (3 [7%] vs none], and urinary tract infections (3 [7%] vs 1 [2%]). INTERPRETATION: Once-daily tasimelteon can entrain totally blind people with non-24; however, continued tasimelteon treatment is necessary to maintain these improvements. FUNDING: Vanda Pharmaceuticals.

Dose finding when the target dose is on a plateau of a dose-response curve: comparison of fully sequential designs.

Consider the problem of estimating a dose with a certain response rate. Many multistage dose-finding designs for this problem were originally developed for oncology studies where the mean dose-response is strictly increasing in dose. In non-oncology phase II dose-finding studies, the dose-response curve often plateaus in the range of interest, and there are several doses with the mean response equal to the target. In this case, it is usually of interest to find the lowest of these doses because higher doses might have higher adverse event rates. It is often desirable to compare the response rate at the estimated target dose with a placebo and/or active control. We investigate which of the several known dose-finding methods developed for oncology phase I trials is the most suitable when the dose-response curve plateaus. Some of the designs tend to spread the allocation among the doses on the plateau. Others, such as the continual reassessment method and the t-statistic design, concentrate allocation at one of the doses with the t-statistic design selecting the lowest dose on the plateau more frequently.