scholarly journals 0478 A Multicenter Pilot Study to Evaluate Next-Dose Transition from Zolpidem to Lemborexant for the Treatment of Insomnia

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A183-A183
Author(s):  
R Rosenberg ◽  
J Amchin ◽  
D Kumar ◽  
C Perdomo ◽  
M Moline ◽  
...  
Keyword(s):  
Pilot Study ◽  
Receptor Antagonist ◽  
Treatment Phase ◽  
Phase 3 ◽  
Two Phase ◽  
Dsm 5 ◽  
Phase Maintenance ◽  
Titration Period ◽  
Insomnia Treatment ◽  
Cutoff Date

Abstract Introduction Switching of medications for insomnia occurs often in clinical practice based on a variety of reasons. However, few clinical studies have examined methods for transitioning patients between different insomnia medications. This is especially important to consider when the classes of drugs are different (e.g., GABA-ergic agonism vs orexin receptor antagonism); thus, clinical guidance would be valuable. The safety and efficacy of the dual orexin receptor antagonist lemborexant (LEM) for the treatment of insomnia was confirmed in two Phase 3 studies, SUNRISE-1 (NCT02783729, E2006-G000-304) and SUNRISE-2 (NCT02952820, E2006-G000-303). This pilot study (NCT04009577, E2006-A001-312) was designed to assess pre-specified dosing approaches for directly transitioning from the sedative-hypnotic zolpidem (ZOL), a commonly prescribed sleep aid, to LEM. Methods This multicenter pilot study has enrolled subjects age ≥18 years with an insomnia diagnosis (DSM-5 criteria), who used ZOL (intermittently or frequently) as their only insomnia treatment. Following a 3-week Screening period, eligible subjects enter the Treatment Phase (2-week titration period: assigned to 1 of 3 treatment arms based on ZOL use during Screening), and then the Extension Phase (maintenance period up to 12 weeks). During both the Treatment and Extension Phases, the dose of LEM is flexible between 5 and 10 mg, depending on efficacy and tolerability. The primary endpoint is to evaluate the proportion of subjects taking ZOL who successfully transition to LEM (lemborexant 5 mg [LEM5] or lemborexant 10 mg [LEM10]) after 2 weeks of LEM treatment. Results Enrollment began July 15, 2019. It was initially projected that approximately 110 subjects would be screened to provide about 60 subjects for randomization across 3 treatment arms. Interim data will be presented (planned cutoff date Jan 08, 2020). Conclusion This pilot study will help inform on dosing guidance when transitioning a patient from a GABA-ergic drug to an orexin receptor antagonist. Support Eisai Inc.

scholarly journals 0477 Characteristics of Insomnia Subjects Screened for Transitioning from Zolpidem Tartrate to Lemborexant in a Multicenter Pilot Study

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A183-A183
Author(s):  
M Ahmad ◽  
M Malhotra ◽  
J Amchin ◽  
D Kumar ◽  
C Perdomo ◽  
...  
Keyword(s):  
Pilot Study ◽  
Extended Release ◽  
Maintenance Phase ◽  
Treatment Phase ◽  
Usage Frequency ◽  
Titration Period ◽  
Falling Asleep ◽  
Insomnia Treatment ◽  
Waking Up

Abstract Introduction Patients who take insomnia medication may change medications for reasons including lack of efficacy, adverse events, and dependence concerns. A pilot study (NCT04009577, E2006-A001-312) assessed a dosing approach for transitioning patients from zolpidem tartrate (ZOL; immediate or extended-release) to lemborexant, a dual orexin receptor antagonist. Here we describe characteristics of subjects who entered the study Screening Period and their reasons for wanting to change medications. Methods This multicenter pilot study was conducted in the U.S. and enrolled subjects age ≥18y with insomnia diagnosed per DSM-5 criteria, and who used ZOL (self-reported intermittently [3-4 nights/week] or frequently [≥5 nights/week]) as their only insomnia treatment. Subjects entered a 3-week Screening Period, during which frequency/dose of ZOL taken was recorded; subjects also wore an actigraph continuously. Eligible subjects thereafter entered the Treatment Phase to determine lemborexant dosing (5 or 10mg during a 2-week Titration Period with assignment to 1 of 3 treatment schedules based on ZOL usage frequency during Screening), followed by a 12-week Extension (Maintenance) Phase and a 4-week Follow-up Period. Results Forty-nine subjects entered the Screening period and completed the Chief Complaint Form through November 2019; mean(SD) age was 57.1(13.8)y, 67.3% were female, 69.4% were white, and 28.6% were black. 31 subjects reported using ZOL frequently and 15 reported using ZOL intermittently (3 missing). The most common sleep complaint was waking up too early (n=33), followed by difficulty staying asleep (n=13), and difficulty falling asleep (n=3). Reasons for wanting to switch from ZOL included: ZOL not working (n=19), concerns about taking ZOL (n=14), wanting to try something new/potentially better (n=6), side effects (n=5), and residual daytime sleepiness (n=4). 43/49 subjects completed screening through this period. Conclusion This study offers the opportunity to understand patients’ current use of insomnia medication and their motivation for wanting to change insomnia medications. Support Eisai Inc.

scholarly journals 0521 Daridorexant (ACT-541468), A Dual Orexin Receptor Antagonist for the Treatment of Insomnia Disorder: Double Blind, Randomized, Phase 3 Studies for Efficacy and Safety in Adult and Elderly Patients

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A199-A200
Author(s):  
G Zammit ◽  
D Seboek Kinter ◽  
C Bassetti ◽  
D Leger ◽  
V Hermann ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Elderly Subjects ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Two Phase ◽  
Pivotal Phase ◽  
Double Blind ◽  
Insomnia Disorder

Abstract Introduction Daridorexant, a potent and selective orally administered dual orexin receptor antagonist (DORA), has shown dose-dependent efficacy and is well tolerated with minimal residual next-morning effects in two phase 2 studies in adult and elderly subjects with insomnia disorder. Following the favorable phase 2 results, clinical development was pursued with two pivotal phase 3 multi-center, double-blind, randomized, placebo-controlled studies to further assess efficacy and safety in adult and elderly subjects with insomnia disorder. Long-term safety and tolerability are being further evaluated in a double-blind placebo-controlled extension study. Methods Each of the pivotal studies include ~900 patients (~40% ≥65y), randomized 1:1:1 to one of two daridorexant arms or placebo. The studies differ in dose only (10 or 25 mg [NCT03545191], 25 or 50 mg [NCT03575104]). Both report objective primary outcomes at 1 and 3 months based on PSG (WASO and LSP). Secondary endpoints include self-reported nighttime benefit with Total Sleep Time (sTST), and daytime benefit using the validated Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). The patients undergo screening (7-13 d) and run-in (7-18 d) periods establishing eligibility and baseline, a 3-month double-blind treatment period, followed by a placebo run-out (7 d) to evaluate rebound insomnia and withdrawal effects and a 30-day safety follow-up. Additionally, subjects completing treatment could enroll in the 40-week double-blinded placebo-controlled extension trial [NCT03679884] to assess long-term safety. Results Enrollment in NCT03575104 (25/50 mg) was successfully completed and involves 76 sites across 10 countries; expected completion March 2020. Recruitment to study NCT03545191 (10/25 mg) is advanced; completion expected June 2020. Conclusion The comprehensive daridorexant phase 3 program includes 3 dose levels and replication of objective and subjective measurements at 1 and 3 months, while assessing self-reported nighttime benefit, and benefit during the day with a validated PRO instrument, as well as safety in insomnia disorder. Support Medical writing Randall Watson, (Idorsia). These studies were sponsored by Idorsia Pharmaceuticals Ltd.

scholarly journals Design and rationale of two phase 3 randomised controlled trials (COUGH-1 and COUGH-2) of gefapixant, a P2X3 receptor antagonist, in refractory or unexplained chronic cough

2020 ◽  
Vol 6 (4) ◽  
pp. 00284-2020
Author(s):  
David R. Muccino ◽  
Alyn H. Morice ◽  
Surinder S. Birring ◽  
Peter V. Dicpinigaitis ◽  
Ian D. Pavord ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Chronic Cough ◽  
Phase 1 ◽  
Primary Efficacy ◽  
P2x3 Receptor ◽  
Phase 3 ◽  
Two Phase ◽  
Link Type ◽  
Cough Frequency ◽  
Patient Reported

BackgroundWe present study designs, dose selection and preliminary patient characteristics from two phase 3 clinical trials of gefapixant, a P2X3 receptor antagonist, in refractory chronic cough (RCC) or unexplained chronic cough (UCC).MethodsCOUGH-1 (NCT03449134) and COUGH-2 (NCT03449147) are randomised, placebo-controlled, double-blind, parallel-group trials in subjects with RCC or UCC (age ≥18 years; cough duration ≥1 year; Cough Severity Visual Analogue Scale score ≥40 mm). The primary efficacy study periods are 12 weeks (40-week extension; COUGH-1) and 24 weeks (28-week extension; COUGH-2). Interventions include placebo, gefapixant 15 mg and gefapixant 45 mg (1:1:1 ratio). The primary efficacy endpoints are average 24-h cough frequency at Week 12 (COUGH-1) and Week 24 (COUGH-2). Awake cough frequency, patient-reported outcomes and responder analyses are secondary endpoints.ResultsThe doses of 45 mg (to provide maximal efficacy and acceptable tolerability) and 15 mg (to provide acceptable efficacy and improved tolerability) were selected based on phase 1 and 2 studies. In COUGH-1, 730 participants have been randomised and treated; 74% are female with mean age of 59 years (39% over 65 years), and mean baseline duration of cough of 11.5 years. In COUGH-2, 1314 participants have been randomised and treated; 75% are female with mean age of 58 years (33% over 65 years), and mean baseline duration of cough of 11.1 years.ConclusionsThese global studies include participants with baseline characteristics consistent with previous RCC and UCC studies and will inform the efficacy and safety profile of gefapixant in the treatment of patients with RCC and UCC.

335 Evaluation of Dose Transition From Zolpidem to Lemborexant Across 14 Weeks: Results From a Multicenter Open-label Pilot Study

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A134-A134
Author(s):  
Russell Rosenberg ◽  
Jess Amchin ◽  
Dinesh Kumar ◽  
Carlos Perdomo ◽  
Norman Atkins ◽  
...  
Keyword(s):  
Pilot Study ◽  
Extended Release ◽  
Open Label ◽  
Phase 3 ◽  
Titration Period ◽  
Study Results ◽  
Dose Change ◽  
Extension Period ◽  
Common Teaes

Abstract Introduction E2006-A001-312 (Study 312; NCT04009577) was an open-label pilot study that examined pre-specified dosing paradigms for transitioning patients from zolpidem (ZOL: immediate [IR] or extended-release [ER]) to the dual orexin receptor antagonist lemborexant (LEM; 5mg [LEM5] or 10mg [LEM10]). Methods Study 312 included a 3-week Screening Period (subjects continued ZOL), 2-week Titration Period (TITR), 12-week Extension Period (EXT), and 4-week Follow-up Period. Adults with insomnia who were intermittent (3–4 nights/week) or frequent (≥5 nights/week) ZOL-IR or ZOL-ER users participated. Intermittent ZOL users and subjects with one week each of intermittent and frequent ZOL usage were assigned to Cohort-1 and began TITR with LEM5. Frequent ZOL users were assigned to Cohort-2 and randomized 1:1 to LEM5 or LEM10. Subjects who successfully transitioned to LEM had the option to enter EXT. During TITR and EXT, subjects could change LEM dose (only once during TITR). The primary endpoint was the proportion of subjects who transitioned to LEM at the end of TITR. Treatment-emergent adverse events (TEAEs) were assessed based on dose at time of TEAE. Results Fifty-three subjects enrolled (Cohort-1, n=10; Cohort-2, n=43). Of these, 43/53 (81.1%) transitioned to LEM at the end of TITR; all 43 (100.0%) entered EXT wherein 41/43 subjects received treatment. Three of these subjects discontinued treatment during EXT, so that 38/41 (92.7%) subjects entered EXT, received treatment and completed EXT. At the end of EXT, 25/41 (61.0%) subjects were receiving LEM10 and 16/41 (39.0%) were receiving LEM5. Based on modal dose (most frequent dose taken during TITR and EXT combined) groups, median time to first dose change was 14.5 days and 36.0 days for LEM5 and LEM10, respectively. The majority of TEAEs were mild/moderate in severity. Across the study (TITR and EXT), more TEAEs occurred with LEM10 than LEM5; the most common TEAEs were somnolence (n=4) and abnormal dreams (n=4). Conclusion Study results support the view that patients can successfully transition directly from ZOL to LEM. LEM was generally well tolerated; the safety profile was consistent with that observed in Phase 3 clinical development. Support (if any) Eisai Inc.

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