337 A Multicenter Open-label Pilot Study Evaluating Next-Dose Transition From Zolpidem to Lemborexant: Analysis of Female Subgroup

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A134-A135
Author(s):  
Maha Ahmad ◽  
Manoj Malhotra ◽  
Jess Amchin ◽  
Dinesh Kumar ◽  
Carlos Perdomo ◽  
...  
Keyword(s):  
Pilot Study ◽  
Extended Release ◽  
Open Label ◽  
Titration Period ◽  
Post Hoc ◽  
Dose Change ◽  
Extension Period ◽  
Common Teaes ◽  
Female Subjects

Abstract Introduction Dosing paradigms for transitioning patients to lemborexant (LEM) from zolpidem (ZOL: immediate [IR] or extended-release [ER]) were examined in E2006-A001-312 (Study 312; NCT04009577), an open-label pilot study. Given insomnia prevalence in women, post hoc analyses in female subjects were conducted. Methods Study 312 included: 3-week Screening Period (subjects continued ZOL); 2-week Titration Period (TITR); 12-week Extension Period (EXT); 4-week Follow-up. Adults with insomnia taking ZOL-IR or ZOL-ER intermittently (3–4 nights/week) or frequently (≥5 nights/week) were enrolled. Subjects with intermittent, or one week each of intermittent and frequent ZOL use, were assigned to Cohort-1 and started TITR with LEM 5mg (LEM5). Frequent ZOL users (Cohort-2) were randomized 1:1 to LEM5 (Cohort-2A) or LEM 10mg (LEM10; Cohort-2B). Subjects who transitioned to LEM could opt into EXT. Subjects could change LEM dose during TITR (only once) and during EXT. The primary endpoint was the proportion of subjects who transitioned to LEM at end of TITR. Treatment-emergent adverse events (TEAEs) were assessed by dose at time of TEAE. Results Overall, 35 subjects were female and 29/35 (82.9%) transitioned to LEM. In Cohort-1, 7 subjects began TITR; all transitioned to LEM (5 subjects ended TITR on LEM5; 2 ended on LEM10). In Cohort-2A, 14 subjects began TITR with LEM5; 12/14 (85.7%) transitioned (6 subjects each ended TITR on LEM5 or LEM10). In Cohort-2B, 14 subjects began TITR with LEM10; 10/14 (71.4%) transitioned to LEM (3 subjects ended TITR on LEM5 and 7 on LEM10). All 29 transitioned subjects opted into EXT, and 27/29 (93.1%) completed the study. Based on modal dose (most frequent dose taken during TITR and EXT combined) groups, median time to first dose change during EXT was 14.5 and 17.0 days for LEM5 and LEM10, respectively. Overall, most TEAEs were mild/moderate in severity. Across TITR and EXT, more TEAEs occurred with LEM10 than with LEM5; the most common TEAEs were somnolence (n=3) and abnormal dreams (n=3). Conclusion Most female subjects successfully transitioned from intermittent or frequent ZOL-IR/ZOL-ER use to LEM and completed the study. LEM was generally well tolerated. The safety profile was consistent with that observed in Phase 3 studies. Support (if any) Eisai Inc.

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.

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 Plasma exchange with albumin replacement and disease progression in amyotrophic lateral sclerosis: a pilot study

2021 ◽  
Author(s):  
Mónica Povedano ◽  
Andrés Paipa ◽  
Miquel Barceló ◽  
Michael K. Woodward ◽  
Sandra Ortega ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Pilot Study ◽  
Disease Progression ◽  
Plasma Exchange ◽  
Rating Scale ◽  
Open Label ◽  
Primary Endpoints ◽  
Rate Of Decline ◽  
Post Hoc ◽  
Lateral Sclerosis

Abstract Background Plasma exchange (PE) is used to treat a range of neurological disorders. Based on results demonstrated in Alzheimer’s disease, we theorized that PE with albumin replacement (PE-A) might alter the metabolic profile of plasma and cerebrospinal fluid in patients with amyotrophic lateral sclerosis (ALS) by removing disease-inducing molecules. The aim of this study was to evaluate the effect of PE-A on disease progression in ALS. Methods In this open-label, non-controlled, single-arm, prospective pilot study, 13 adults with ALS had 6 months’ treatment with PE-A 5% and 6 months’ follow-up. Primary endpoints were changes from baseline in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score and forced vital capacity (FVC) through 48 weeks. A post hoc analysis compared individual patient data with the expected ALSFRS-R progression slope. Results The median ALSFRS-R score declined throughout the study, although the rate of decline was slower than expected in seven patients at treatment end and in five patients at study end. Six patients remained in the same baseline slope progression category, and four patients improved their slope category at treatment end. Median FVC decreased significantly during the study. Treatment was well tolerated. Of 330 PE-A procedures, 0.9% were associated with potentially related adverse events. Conclusion Although functional impairment progressed, about two-thirds of patients showed a slower than expected rate of decline at treatment end. Most patients had unaltered (54.5%) or reduced (36.4%) ALSFRS-R slope progression at treatment end. Further evaluation of PE-A in controlled studies involving more patients is warranted. EudraCT number 2013-004842-40. Trial registration ClinicalTrials.gov identifier: NCT02479802.

scholarly journals Impact of paliperidone palmitate one-month formulation on relapse prevention in patients with schizophrenia: A post-hoc analysis of a one-year, open-label study stratified by medication adherence

2018 ◽  
Vol 32 (6) ◽  
pp. 691-701 ◽  
Author(s):  
Tianmei Si ◽  
Nan Li ◽  
Huafei Lu ◽  
Shangli Cai ◽  
Jianmin Zhuo ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Hazard Ratio ◽  
Paliperidone Palmitate ◽  
Open Label ◽  
First Relapse ◽  
Continued Use ◽  
One Year ◽  
Long Acting ◽  
Post Hoc

Background: Limited data are available to help identify patients with schizophrenia who are most likely to benefit from long-acting injectable antipsychotics. Aim: To investigate the efficacy of long-acting injectable antipsychotic paliperidone palmitate one-month formulation for preventing relapses, factors influencing time to first relapse, and the effect of different antipsychotic adherence levels on time to first relapse in Chinese patients with schizophrenia. Methods: This was a post-hoc analysis from an open-label, single-arm study of stable patients (Positive and Negative Syndrome Scale total score <70; n=367) receiving paliperidone palmitate one-month formulation at the end of an acute 13-week treatment phase, who entered a naturalistic one-year follow-up period, either continuing with flexibly dosed paliperidone palmitate one-month formulation (75–150 mg eq.) or switching to another antipsychotic(s). Results: There were 362/367 patients (age=31.4±10.75 years) included in the analysis of time to first relapse (primary outcome) and 327/362 patients (39/327, poor antipsychotic adherence (<80%)) willing to receive antipsychotics were included in the exposure/adherence analysis. Overall, 84.6% (95% confidence interval=79.2–88.7) patients remained relapse-free. Poor adherence during follow-up (hazard ratio=2.97, 95% confidence interval=1.48–5.98, p=0.002) and frequent hospitalizations in the previous year (hazard ratio=1.29, 95% confidence interval=1.02–1.62, p=0.03) were associated with a significant risk of shorter time to first relapse in the univariate analysis. In patients with poor adherence, ‘no use’ (hazard ratio=13.13, 95% confidence interval=1.33–129.96, p=0.03) and ‘interrupted use’ (hazard ratio=11.04, 95% confidence interval=1.03–118.60, p=0.047) of paliperidone palmitate one-month formulation (vs continued use) showed a significantly higher risk of relapse; this was not observed in patients with good (≥80%) antipsychotic adherence. No new safety concerns were identified. Conclusion: Continued use of paliperidone palmitate one-month formulation/long-acting injectable antipsychotic was effective in preventing schizophrenia relapses, especially in patients with suboptimal antipsychotic adherence.

Phase 1b/2, open label, multicenter, study of the combination of SD-101 and pembrolizumab in patients with advanced melanoma who are naïve to anti-PD-1 therapy.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9534-9534 ◽  
Author(s):  
Mohammed M. Milhem ◽  
Georgina V. Long ◽  
Christopher J. Hoimes ◽  
Asim Amin ◽  
Christopher D. Lao ◽  
...  
Keyword(s):  
Disease Stage ◽  
Open Label ◽  
Stage Iiic ◽  
Kaplan Meier ◽  
Unresectable Stage ◽  
Treatment Naïve ◽  
Phase 1B ◽  
Grade 3 ◽  
Post Hoc

9534 Background: SD-101 is a synthetic CpG TLR9 agonist. Pembrolizumab is a PD-1 inhibitor. SYNERGY-001/KEYNOTE-184 assesses the safety and preliminary efficacy of the combination of SD-101 and pembrolizumab in patients naïve to anti-PD-1/L1 therapy with unresectable stage IIIC-IV melanoma. Methods: SD-101 was evaluated as 2 mg/lesion injected into 1 to 4 lesions and 8 mg/lesion in 1 lesion as 4 weekly doses followed by 7 doses Q3W. Pembrolizumab was administered as 200 mg IV Q3W. CT scans were performed every 9 weeks. Responses were assessed per investigator using RECIST v1.1. Responses and post-hoc Kaplan-Meier analyses of PFS in the ITT population were compared for patients who received 2 mg/lesion with 8 mg/lesion. Results: 86 patients (2 mg: N = 45; 8 mg: N = 41) have been enrolled with similar baseline characteristics: median age = 66 years; male = 67%; ECOG stage 0 = 67%; disease stage: IIIC = 21%; IVM1a/b = 50%; IVM1c = 28%; LDH ≤ ULN = 71%; treatment naïve = 73%. Median follow up to date is 8.1 months in 2 mg group and 8.3 months in 8 mg group. SD-101 safety profile comprises flu-like symptoms with most frequent grade ≥3 SD-101-related AEs of headache (7%), fatigue (7%), malaise (5%), myalgia (4%), and chills (4%). Immune-related AEs were reported in 19%. ORR in 2 mg group = 71% (95% CI: 57, 82) (CR: 13%) and in 8 mg group = 49% (95% CI: 33, 65) (CR: 7%) with responses in both injected and non-injected lesions, including visceral. DOR = not reached (NR) in either group. ORR by baseline PD-L1 expression in 62 patients, 53% of whom were PD-L1 positive: 2 mg = 80%/79% (PD-L1 positive/negative); 8 mg = 62%/40% (PD-L1 positive/negative). PFS was higher in 2 mg group with median PFS in 2 mg = NR (95% CI: Not estimable [NE], NE) and in 8 mg = 10.4 months (95% CI: 4.2, NE), HR = 0.45 (95% CI: 0.21, 0.98), p = 0.036. 6 month PFS rate in 2 mg = 81% and in 8 mg = 60%. 6 month OS rate in 2 mg = 98% and in 8 mg = 92%. Conclusions: The TLR9 innate immune stimulant, SD-101, in combination with pembrolizumab has been well-tolerated, and is showing promising high response rates and PFS, regardless of PD-L1 expression, particularly in patients who received 2 mg SD-101. Clinical trial information: NCT02521870.

Efficacy and safety of the randomized, open-label, non-inferiority, phase 3 study of subcutaneous (SC) versus intravenous (IV) daratumumab (DARA) administration in patients (pts) with relapsed or refractory multiple myeloma (RRMM): COLUMBA.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8005-8005 ◽  
Author(s):  
Maria-Victoria Mateos ◽  
Hareth Nahi ◽  
Wojciech Legiec ◽  
Sebastian Grosicki ◽  
Vladimir Vorobyev ◽  
...  
Keyword(s):  
Median Duration ◽  
Similar Efficacy ◽  
Open Label ◽  
Phase 3 ◽  
Geometric Means ◽  
Primary Endpoints ◽  
Administration Time ◽  
Phase 1B ◽  
Common Teaes

8005 Background: In a phase 1b trial, a SC formulation of DARA with recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE drug delivery technology, Halozyme, Inc.) had adequate PK, low rates of infusion-related reactions (IRRs) and similar efficacy to DARA IV. This phase 3 study compared the efficacy, PK, and safety of DARA SC vs IV in pts with RRMM. Methods: DARA SC (1,800 mg DARA + rHuPH20 [2,000 U/mL]) and DARA IV (16 mg/kg IV) were given weekly for C1-2 (28-day cycles), every 2 weeks for C3-6, and every 4 weeks thereafter. DARA SC (15 mL) was given over 3-5 mins at alternating left/right abdominal sites. Pts (≥18 years) must have received ≥3 prior lines of therapy (LOT), including a PI and an IMiD, or were double refractory. Co-primary endpoints were ORR (analyzed by Farrington-Manning test, with non-inferiority = 60% retention of ORR) and pre-dose C3D1 DARA Ctrough (non-inferiority = lower bound of 90% CI for the ratio of the geometric means [GM] ≥80%). Results: 522 pts were randomized (n=263 SC; n=259 IV). Median age was 67 yrs. Median baseline body weight was 73 kg. Pts received a median of 4 LOT and 100% had received both PI and IMiD; 17% had high cytogenetic risk at baseline. Median follow-up was 7.5 mos. ORR was 41% for DARA SC and 37% for DARA IV. DARA SC retained at least 89% of the benefit of DARA IV (97.5% confidence). The ratio of GM of Ctrough for DARA SC over DARA IV was 108% (90% CI, 96%-122%). A significantly lower rate of IRRs was observed with DARA SC vs DARA IV (12.7% vs 34.5%; P<0.0001). Median duration of injection was 5 mins for DARA SC and median duration of infusion was 421/255/205 mins for the first/second/subsequent DARA IV infusions. Median PFS was 5.6 mos DARA SC vs 6.1 mos DARA IV (HR, 0.99; 95% CI, 0.78-1.26). Most common TEAEs (≥15%) were anemia, neutropenia, thrombocytopenia, and diarrhea. Primary reasons for treatment discontinuation included progressive disease (43% SC vs 44% IV) and AEs (7% SC vs 8% IV). Conclusions: Efficacy and PK co-primary endpoints were met, demonstrating non-inferiority of DARA SC to IV. DARA SC significantly decreased IRR rate and administration time, with a comparable safety profile to DARA IV. Clinical trial information: NCT03277105.

scholarly journals Evaluation of the Safety of Deutetrabenazine at Higher Doses to Treat Chorea in Huntington’s Disease

CNS Spectrums ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 162-163
Author(s):  
Samuel Frank ◽  
Christina Vaughan ◽  
David Stamler ◽  
David Oakes ◽  
Mat D. Davis ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Drug Exposure ◽  
Open Label ◽  
Titration Period ◽  
Open Label Extension ◽  
Pharmaceutical Industries ◽  
Post Hoc ◽  
Higher Doses

AbstractBackgroundIn the First-HD pivotal trial, the maximum deutetrabenazine dose evaluated to treat chorea associated with Huntington’s disease (HD chorea) was 48 mg/d, which is the approved maximum dose for this population. In ARC-HD, an open-label extension study evaluating the long-term efficacy and safety of deutetrabenazine to treat HD chorea, dosage ranged from 6 mg/d to 72 mg/d, with doses ≥12 mg/d administered twice daily. Doses in ARC-HD were increased by 6 mg/d per week in a response-driven manner based on efficacy and tolerability until 48 mg/d (Week 8). At the investigator’s discretion, further increases were permitted by 12 mg/d per week to a maximum of 72 mg/d. This post-hoc analysis evaluates the safety and tolerability of deutetrabenazine >48 mg/d compared to ≤48 mg/d to treat HD chorea in ARC-HD.MethodsPatient counts and safety assessments were attributed to patients when they received a dose of either ≤48 mg/d or >48 mg/d. For 9 selected adverse events (AEs), we compared AE rates adjusted for duration of drug exposure (as number of AEs/year) at ≤48 mg/d or >48 mg/d. The AE rates were determined after titration when participants were on stable doses of deutetrabenazine.ResultsAll 113 patients were exposed to doses ≤48 mg/d (177.1 patient-years) and 49 patients were ever exposed to doses >48 mg/d (74.1 patient-years). In patients taking deutetrabenazine >48 mg/d compared to ≤48 mg/d after the titration period, there were no apparent differences in exposure-adjusted AE rates.ConclusionsBased on clinical experience, some patients with HD may benefit from doses higher than 48 mg/d to adequately control chorea. These doses were tolerated without apparent increase in the exposure-adjusted rates of selected AEs after titration. This analysis does not address the occurrence of other AEs or whether adequate efficacy was achieved at lower doses, factors that may have influenced dose increases.FundingTeva Pharmaceutical Industries Ltd., Petach Tikva, Israel

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