Safety Analysis Set Research Articles

Safety and Clinical Outcomes of Insulin Degludec in Korean Patients with Diabetes in Real-World Practices: A Prospective, Observational Study.

To investigate the safety and effectiveness of insulin degludec (IDeg) in a real-world population of Korean patients with diabetes requiring insulin therapy. This was a multicenter, prospective, single-arm, open-label, non-interventional study. Patients aged ≥ 12months and treated with previous glucose-lowering medications were eligible to switch to IDeg. The primary endpoint was the incidence of adverse events (AEs), and the secondary endpoints were changes in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial glucose (PPG), and target HbA1c < 7.0%. In total, 3225 and 2450 patients were included in the safety analysis set (SAS) and effectiveness analysis set (EAS), respectively. The mean baseline HbA1c and duration of diabetes were 9.4% and 13.0years, respectively. Adverse events were reported in 740 patients (22.9%); the majority were mild and resolved. Significant improvements were observed in HbA1c, FPG, and PPG at week 26 (all p < 0.0001). The target of HbA1c < 7% was achieved in 22.2% of patients at week 26. In real-world clinical practice, 26weeks of IDeg treatment resulted in significant reductions in glycemic parameters with a low incidence of AEs in Korean patients with diabetes. No new safety signals were observed. This trial is registered under ClinicalTrials.gov (NCT02779413) and the universal trial number is [U1111-1176-2287].

A multicentre, prospective, non-interventional study evaluating the safety of dapagliflozin in patients with type 2 diabetes in routine clinical practice in China (DONATE)

BackgroundThere are few large-scale studies evaluating the safety of the sodium-glucose cotransporter-2 inhibitor, dapagliflozin, in Chinese patients with type 2 diabetes. DONATE, a multicentre, single-arm, prospective, non-interventional study, is the first real-world study evaluating the safety of dapagliflozin in Chinese patients with type 2 diabetes in routine clinical practice.MethodsBetween August 2017 and July 2020, patients with type 2 diabetes who had initiated dapagliflozin therapy and received ≥1 dose were prospectively recruited from 88 hospitals in China. Patients were subsequently followed up for 24 weeks; if patients discontinued dapagliflozin they were followed up for an additional 7 days after treatment discontinuation. The primary outcome was the proportion of patients with adverse events and serious adverse events, particularly key adverse events of special interest (AESI) including urinary tract infection, genital tract infection (typical symptoms with or without microbiological diagnosis) and hypoglycaemia (typical symptoms with or without blood glucose ≤3.9 mmol/L, or blood glucose ≤3.9 mmol/L without symptoms). Exploratory outcomes included the absolute change in metabolic parameters and the proportion of patients with other AESI including volume depletion, abnormal blood electrolytes, polyuria, renal impairment, diabetic ketoacidosis, hepatic impairment and haematuria.ResultsA total of 3000 patients were enrolled, of whom 2990 (99.7%) were included in the safety analysis set. Mean (SD) age was 52.6 (12.0) years, and 65.8% of patients were male. Mean (SD) duration of type 2 diabetes at enrolment was 8.4 (7.1) years. Mean (SD) treatment duration of dapagliflozin was 209.1 (157.6) days. Adverse events were reported in 35.4% (n = 1059) of patients during the 24-week follow-up period. Overall, 9.0% (n = 268) were related to treatment and 6.2% (n = 186) were serious. Urinary tract infection, genital tract infection and hypoglycaemia were reported in 2.3% (n = 70), 1.3% (n = 39) and 1.1% (n = 32) of patients, respectively. The proportion of patients with other AESI was also low: polyuria (0.7%; n = 21), volume depletion (0.3%; n = 9), renal impairment (0.3%; n = 8), hepatic impairment (0.2%; n = 7), haematuria (0.2%; n = 6) and diabetic ketoacidosis (0.1%; n = 2).ConclusionsThis study demonstrated that once-daily dapagliflozin was well tolerated in Chinese patients with type 2 diabetes and the overall safety profile of dapagliflozin in clinical practice in China was consistent with that reported in clinical trials.Trial registrationClinicalTrials.gov, NCT03156985. Registered on 16 May, 2017.

A phase IV study to evaluate the safety of fruquintinib in Chinese real-world clinical practice.

e15568 Background: Fruquintinib is a highly selective, potent, oral tyrosine kinase inhibitor of VEGFR-1, -2, and -3, which was approved in China for 3L mCRC patients based on results of FRESCO study (NCT02314819). In addition, FRESCO-2 (NCT04322539) demonstrated a consistent efficacy and safety profile of Fruquintinib in more heavily treated mCRC worldwide patients. This Phase IV study aims to evaluate the safety of Fruquintinib in real-world clinical practice in China. Methods: This is a prospective, multicenter, phase IV study, to evaluate a real-world safety of Fruquintinib in China. Patients who are within the first cycle of Fruquintinib treatment or plan to use Fruquintinib within 1 week can be enrolled into this study. Three visits are scheduled, including the day of consent, 1 month after consent, and 6 months after consent or 30 days after the last dose (whichever occurs first). The primary endpoint is the collected AE. Results: From April 2019 to Feb 2022, a total of 3005 patients from 96 study sites received at least one dose of fruquintinib and were enrolled in the safety analysis set (SS). The median age of the patients was 60, of which 1053 patients (35.0%) were ≥65.In SS, a total of 1923 patients (64.0%) started Fruquintinib at 5 mg/day. The median relative dose intensity was 85.3%; the median exposure time was 2.7months. In SS, 2291 patients (76.2%) reported TEAEs; 1901 patients (63.3%) reported investigator assessed fruquintinib-related TEAEs.718 patients (23.9%) reported ≥Grade3 TEAEs; 418 patients (13.9%) reported investigator assessed fruquintinib-related ≥Grade3 TEAEs. 330 patients (11.0%) reported SAE; 86 patients (2.9%) reported investigator assessed fruquintinib-related SAE. 169 patients (5.6 %) reported TEAEs leading to death;8 patients (0.3%) reported investigator assessed fruquintinib-related TEAEs leading to death. The most frequent fruquintinib-related TEAEs(＞10%）include palmar-plantar erythrodysesthesia syndrome (PPES,19.4%)，hypertension (15.6%) &amp; fatigue (10.1%); the most frequent Fruquintinib-related≥Grade 3 TEAE (≥1%）include hypertension (6.4%) &amp; PPES (2.2%); The most frequent fruquintinib-related TEAE (≥5%) leading to dose modification was PPES (5.4%). Conclusions: The results are consistent with the fruquintinib safety profile observed in existing clinical studies. No new or significant safety signals were identified. Clinical trial information: NCT04005066 .

Efficacy and safety of tunlametinib in patients with advanced NRAS-mutant melanoma: A multicenter, open-label, single-arm, phase 2 study.

9510 Background: NRAS-mutant melanoma is an aggressive subtype with worse prognosis. However, no targeted therapy has been approved to date worldwide. Tunlametinib (HL-085), a novel, potent, selective, oral small-molecule MEK1/2 inhibitor, has showed a favorable pharmacokinetics profile, acceptable tolerability and encouraging antitumor activity in the phase 1 study (BMC Med. 2023 Jan 4;21(1):2). Methods: This is an ongoing, multicenter, open-label, single-arm, phase 2 pivotal registration study. Patients (pts) with NRAS-mutant unresectable stage III or IV melanoma were enrolled and received tunlametinib 12 mg orally twice daily. A historical control of objective response rate (ORR) of 10% was predefined for sample size estimation (100 pts, assuming loss to follow-up rate of 5%) and efficacy evaluation. The primary endpoint was the confirmed ORR per RECIST v1.1 assessed by independent radiology review committee. Results: A total of 100 pts were enrolled. All pts were included in the safety analysis set and 95 pts were included in the full analysis set (FAS) for efficacy analysis. At cut-off date (August 17, 2022), median follow-up was 7.9 months (95% CI: 6.6, 9.8). In the FAS, the median age was 58.0 years (range: 24 to 84). Sixty-four pts (67.4%) had received prior immunotherapy (PD-1/PD-L1 inhibitor). Fifty-six pts (58.9%) were acral melanoma, 16 (16.8%) mucosal melanoma and 12 (12.6%) skin melanoma. Fourteen pts (14.7%) were stage III and 81 (85.3%) stage IV. The most frequent NRAS mutation types were Q61R (40.0%), Q61K (29.5%) and G12D (9.5%). Confirmed ORR was 34.7% (95%CI: 25.3%, 45.2%). Median progression-free survival was 4.2 months (95%CI: 3.5, 5.6), overall survival was immature, and 1-year survival rates was 57.2% (95% CI, 44.7%, 67.8%). Subgroup analysis showed that, in pts who had previously received immunotherapy, the confirmed ORR was 39.1% (95% CI: 27.1%, 52.1%). The most frequent treatment related adverse events (TRAEs) were increased blood creatine phosphokinase (CK), diarrhea, peripheral oedema, facial oedema and increased aspartate aminotransferase. Grade ≥3 TRAEs occurred in 68 pts (68.0%), of which 38.0% (38/100) were increased blood CK. Most of pts with CK elevation are asymptomatic and can be managed by dose interruption or reduction without permanent treatment discontinuation. No treatment-related death was reported. Conclusions: Tunlametinib was well tolerated and demonstrated encouraging treatment response rate in pts with advanced NRAS-mutant melanoma. These results indicate that tunlametinib could be a promising treatment option for NRAS-mutant melanoma, even for those immunotherapy failed pts. Clinical trial information: NCT05217303 .

Safety and preliminary efficacy of YK-029A, a novel EGFR TKI, in patients with advanced NSCLC harboring ex20ins, T790M or rare mutations.

9014 Background: This study aimed to evaluate the safety and preliminary efficacy of YK-029A, a novel third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in treated or untreated patients with advanced NSCLC. Methods: This dose-escalation and dose-expansion phase 1 trial recruited previously untreated or treated patients with EGFR ex20ins mutant locally advanced or metastatic NSCLC and previously treated patients with EGFR T790M or rare mutations. In dose-escalation phase, patients with EGFR T790M mutation were enrolled. YK-029A was given at doses of 50, 100, 150, 200 to 250 mg/day (3+3 design). In dose-expansion phase, patients with EGFR T790M, EGFR ex20ins, or rare mutations were enrolled. The primary objective was safety. Dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) were explored. In the treatment-naïve cohort of EGFR ex20ins mutant NSCLC, patients were administered oral YK-029A 200 mg once daily in a 28-day cycle, and efficacy was assessed by the independent review committee. The study was registered (chinadrugtrials.org.cn,CTR20180350). Results: A total of 108 were included in the safety analysis set. DLT did not occur in dose-escalation phase. MTD was not reached. Treatment-emergent adverse events (TEAEs) of any grade and grade≥3 occurred in 106 (98.1%) and 41 (38.0%) patients, respectively. Treatment-related adverse events (TRAEs) of any grade and grade≥3 occurred in 102 (94.4%) and 30 (27.8%) patients, respectively. One patient had liver abscess related to YK-029A and died. Three patients terminated the treatment because of TEAEs. The most common TRAEs were diarrhea (46.3%), anemia (38.0%), and rash (32.4%). For the treatment-naïve EGFR ex20ins mutant cohort, 26 patients were included in the efficacy analysis set. Most patients were adenocarcinoma (96.4%) and at stage IV (85.7%). At the cut-off date on October 30, 2022, 19 patients (73.1%) had partial remission, five patients (19.2%) had stable disease, and two patients (7.7%) developed disease progression. The confirmed objective response rate achieved 73.1% (95% confidence interval [CI], 52.21% to 88.43%). The median progression-free survival was 9.3 months (95% CI, 5.85 to not evaluated). Conclusions: YK-029A was well tolerated and showed preliminary efficacy in treatment-naïve EGFR ex20ins mutant patients with locally advanced or metastatic NSCLC. [Table: see text]

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Currently there is no consensus on the treatment of relapsed/refractory (r/r) PTCL, and patient prognosis was poor. Golidocitinib is an orally available, JAK1-selective inhibitor currently being evaluated in a multinational, pivotal study in r/r PTCL (JACKPOT8 Part B, NCT04105010). Here we reported the primary analysis of efficacy and safety results of this study. Methods: PTCL patients who had relapsed from or had been refractory/intolerant to ≥1 (but ≤3) prior systemic therapy(ies) were enrolled to receive golidocitinib at 150 mg once daily until disease progression or pre-defined discontinuation criteria were met. The primary endpoint was CT-based objective response rate (ORR) assessed by an independent review committee (IRC) according to Lugano 2014 classification. The efficacy analysis set included patients whose pathological diagnosis of PTCL had been retrospectively confirmed by a central laboratory and who had at least one measurable lesions at baseline. The safety analysis set included all dosed patients. Results: As of 30 November 2022, a total of 104 patients with r/r PTCL were enrolled and dosed with golidocitinib. Baseline characteristics: median age was 58 yrs; 64.4% were male; 20.2% had baseline bone marrow involvement. Major subtypes included NOS (46.2%), AITL (15.4%) and ALCL (9.6%). The median prior lines of therapies were two. All of the patients had been treated with chemotherapies, and 48.1% had been treated with histone deacetylase inhibitors. By the data cut-off (DCO) date, a total of 80 patients had both IRC assessment and central pathology review results available, and thus were included in the efficacy analysis. Among them, 35 patients achieved tumor response (ORR = 43.8%), including 20 patients (25.0%) achieved complete responses. Tumor response was observed in various subtypes, including AITL (56.3%), NOS (45.7%), ALCL (11.1%) and others (44.4%). In patients who relapsed from HDAC inhibitor treatment, 54.8% achieved tumor response. With a median follow-up of 5.5 months for responders, the median duration of response (DoR) has not been reached. Golidocitinib was tolerated in patients with r/r PTCL. By the DCO date, the longest duration on treatment was 15.7 months (still responding). The most common ≥ grade 3 treatment-related adverse events (TRAEs) were hematological in nature, including neutrophil count decreased (26.0%), white blood cell count decreased (25.0%), platelet count decreased (16.3%) and lymphocyte count decreased (16.3%). TRAEs leading to dose interruption, reduction, and discontinuation were 37.5%, 5.8%, and 7.7%, respectively. The majority of TRAEs were reversible or clinically manageable. Conclusions: Golidocitinib demonstrated its potential as a novel targeted therapy for the treatment of r/r PTCL. The updated data will be presented at the conference. Encore Abstract—previously submitted to ASCO 2023 Keywords: aggressive T-cell non-Hodgkin lymphoma, molecular targeted therapies Conflicts of interests pertinent to the abstract W. Yu Employment or leadership position: Employed by Dizal Pharmaceutical

Golidocitinib in treating refractory or relapsed peripheral T-cell lymphoma: Primary analysis of the multinational pivotal study results (JACKPOT8).

7503 Background: Currently there is no consensus on the treatment of relapsed/refractory (r/r) PTCL, and patient prognosis was poor. Golidocitinib is an orally available, JAK1-selective inhibitor currently being evaluated in a multinational, pivotal study in r/r PTCL (JACKPOT8 Part B, NCT04105010). Here we reported the primary analysis of efficacy and safety results of this study. Methods: PTCL patients who had relapsed from or had been refractory/intolerant to ≥ 1 (but ≤ 3) prior systemic therapy(ies) were enrolled to receive golidocitinib at 150 mg once daily until disease progression or pre-defined discontinuation criteria were met. The primary endpoint was CT-based objective response rate (ORR) assessed by an independent review committee (IRC) according to Lugano 2014 classification. The efficacy analysis set included patients whose pathological diagnosis of PTCL had been retrospectively confirmed by a central laboratory and who had at least one measurable lesions at baseline. The safety analysis set included all dosed patients. Results: As of November 30, 2022, a total of 104 patients with r/r PTCL were enrolled and dosed with golidocitinib. Baseline characteristics: median age was 58 years old; 64.4% were male; 20.2% had baseline bone marrow involvement. Major subtypes included NOS (46.2%), AITL (15.4%) and ALCL (9.6%). The median prior lines of therapies were two. All of the patients had been treated with chemotherapies, and 48.1% had also been treated with histone deacetylase inhibitors. By the data cut-off (DCO) date, a total of 80 patients had both IRC assessment and central pathology review results available, and thus were included in the efficacy analysis. Among them, 35 patients achieved tumor response (ORR = 43.8%), including 20 patients (25.0%) achieved complete responses. Tumor response was observed in various subtypes, including AITL (56.3%), NOS (45.7%), ALCL (11.1%) and others (44.4%). In patients who relapsed from HDAC inhibitor treatment, 54.8% achieved tumor response. With a median follow-up of 5.5 months for responders, the median duration of response (DoR) has not been reached. Golidocitinib was tolerated in patients with r/r PTCL. By the DCO date, the longest duration on treatment was 15.7 months (still responding). The most common ≥ grade 3 treatment-related adverse events (TRAEs) were hematological in nature, including neutrophil count decreased (26.0%), white blood cell count decreased (25.0%), platelet count decreased (16.3%) and lymphocyte count decreased (16.3%). TRAEs leading to dose interruption, reduction, and discontinuation were 37.5%, 5.8%, and 7.7%, respectively. The majority of TRAEs were reversible or clinically manageable. Conclusions: Golidocitinib demonstrated its potential as a novel targeted therapy for the treatment of r/r PTCL. The updated data will be presented at the conference. Clinical trial information: NCT04105010 .

Sunvozertinib for the treatment of NSCLC with EGFR Exon20 insertion mutations: The first pivotal study results.

9002 Background: Sunvozertinib(DZD9008) is a rationally designed selective, irreversible EGFR exon20 insertion (exon20ins) inhibitor with wild-type EGFR selectivity. Here we reported the results of WU-KONG6, the first pivotal study of sunvozertinib in previously treated NSCLC patients with EGFR exon20ins. Methods: WU-KONG6 (NCT05712902 and CTR20211009) is a phase II, multi-center pivotal study in NSCLC patients with EGFR exon20ins, whose diseases had progressed on or were after platinum-based chemotherapy. Tumor tissue EGFR exon20ins status was tested by local or central laboratory. The primary and key secondary endpoint were objective response rate (ORR) and duration of response (DoR), respectively, assessed by Blinded Independent Central Review (BICR). Patients received 300 mg sunvozertinib once daily until discontinuation criteria were met. Results: Between July 19, 2021, and May 6, 2022, a total of 104 Chinese patients were enrolled into WU-KONG6 study. The efficacy analysis set included 97 patients, whose EGFR exon20ins status was retrospectively confirmed by a central laboratory. A total of 30 different exon20ins subtypes were enrolled. The median age was 58 years; 59.8% (58/97) were female; 95.9% (93/97) were adenocarcinoma; 95.9% (93/97) had metastatic diseases at study entry; 32% (31/97) had baseline brain metastasis; the median prior lines of therapy were 2. By the data cutoff date (October 17, 2022), the BICR assessed confirmed ORR (cORR) was 60.8% (59/97). In patients with baseline brain metastasis, the cORR was 48.5% (15/31). Anti-tumor efficacy was observed irrespective of age, gender, smoking status, prior lines of therapies, prior onco-immunotherapies, mutation subtypes, and baseline brain metastasis. By the data cut-off date, median follow-up time for responders was 7.1 months, and 64.4% (38/59) of responders were still responding. The longest DoR was &gt; 11 months, and the median DoR has not been reached. The safety analysis set included all enrolled 104 patients. The most common treatment emergent adverse events (TEAEs) were similar as what have been previously reported for sunvozertinib, and also similar as that of other EGFR inhibitors. Majority of the TEAEs were grade 1 or 2, and clinically manageable. Conclusions: The first pivotal study results confirmed sunvozertinib’s superior anti-tumor efficacy than the current available therapy for NSCLC with EGFR exon20ins. The safety profile from WU-KONG6 study was consistent with previously reported findings. The updated data will be presented at the meeting. A multinational phase II pivotal study (WU-KONG1, NCT03974022) with the same study design is ongoing in the USA, Australia, and countries/regions in Asia, Europe and South America. Clinical trial information: NCT05712902 .

Abstract CT005: AEGEAN: A phase 3 trial of neoadjuvant durvalumab + chemotherapy followed by adjuvant durvalumab in patients with resectable NSCLC

Abstract Background: Recent trials have demonstrated the clinical benefit of immunotherapy in either the neoadjuvant or adjuvant resectable (R) NSCLC setting. AEGEAN (NCT03800134) is a randomized, double-blind, placebo (PBO)-controlled trial assessing neoadjuvant durvalumab (D) + chemotherapy (CT) followed by surgery (Sx) and adjuvant D in patients (pts) with R-NSCLC. Methods: Adults with treatment (Tx)-naïve R-NSCLC (stage II-IIIB[N2]; AJCC 8th ed) and ECOG PS 0/1 were randomized (1:1) to receive D 1500 mg or PBO IV + platinum-based CT (every 3 weeks [Q3W] for 4 cycles) before Sx, then further D 1500 mg or PBO IV (Q4W, up to 12 cycles). Pts were stratified by disease stage (II vs III) and PD-L1 tumor cell expression (&amp;lt;1% vs ≥1%, Ventana SP263). Pts with documented EGFR/ALK aberrations were excluded from the modified intent-to-treat (mITT) population for efficacy analyses. The primary endpoints were pathological complete response (pCR), evaluated centrally, and event-free survival (EFS; using RECIST v1.1), evaluated by BICR. Safety was assessed in all pts who received ≥1 study Tx dose. Results: Between Jan 2, 2019, and Apr 19, 2022, 802 pts were randomized to the ITT population (n=740 in the mITT population) of whom 799 received Tx (D arm, n=400; PBO arm, n=399). Baseline characteristics were largely balanced (mITT). Overall, 84.7% in the D arm and 87.2% in PBO arm completed 4 cycles of platinum-doublet CT and 77.6% and 76.7%, respectively, completed Sx (mITT). As of Nov 10, 2022 (data cutoff), median EFS follow-up in censored pts was 11.7 months (mITT). The pCR rate was significantly higher and EFS significantly prolonged in the D vs PBO arms (mITT) (Table). In the safety analysis set, maximum grade 3/4 any-cause AEs occurred in 42.3% vs 43.4% in the D and PBO arms, respectively, during the overall Tx period. Conclusions: The AEGEAN trial met both of its primary endpoints of improved pCR and EFS. Perioperative D plus neoadjuvant CT was associated with a manageable safety profile. Clinical trial identification: NCT03800134 (release date: January 11, 2019) Endpoint D arm PBO arm Tx effect P value pCR n/N: 63/366 (17.2%) n/N: 16/374 (4.3%) Difference in pCR (95% CI), %: 13.0 (8.7-17.6)a 0.000036 (assessed at IA)b EFS n events/N: 98/366 (26.8%) n events/N: 138/374 (36.9%) HR (95% CI): 0.68 (0.53-0.88)d 0.003902e Median (95% CI), months: NR (31.9-NR)c Median (95% CI), months: 25.9 (18.9-NR)c aCIs by stratified Miettinen and Nurminen’s method. bStatistical significance was achieved at the IA (402 pts; data cutoff, Jan 14, 2022); no testing was performed at FA. The statistically significant p-value of 0.000036 was based on a Cochran-Mantel-Haenszel test. cKaplan-Meier method. dStratified Cox proportional hazards model. eStratified log-rank test. CI, confidence interval; FA, final analysis; HR, hazard ratio; IA, interim analysis; NR, not reached. Citation Format: John V. Heymach, David Harpole, Tetsuya Mitsudomi, Janis M. Taube, Gabriella Galffy, Maximilian Hochmair, Thomas Winder, Ruslan Zukov, Gabriel Garbaos, Shugeng Gao, Hiroaki Kuroda, Jian You, Kang-Yun Lee, Lorenzo Antonuzzo, Mike Aperghis, Gary J. Doherty, Helen Mann, Tamer M. Fouad, Martin Reck. AEGEAN: A phase 3 trial of neoadjuvant durvalumab + chemotherapy followed by adjuvant durvalumab in patients with resectable NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT005.

Safety and efficacy of valbenazine for the treatment of chorea associated with Huntington's disease (KINECT-HD): a phase 3, randomised, double-blind, placebo-controlled trial

Valbenazine is a highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor approved for treatment of tardive dyskinesia. To address the ongoing need for improved symptomatic treatments for individuals with Huntington's disease, valbenazine was evaluated for the treatment of chorea associated with Huntington's disease. KINECT-HD (NCT04102579) was a phase 3, randomised, double-blind, placebo-controlled trial, performed in 46 Huntington Study Group sites in the USA and Canada. The study included adults with genetically confirmed Huntington's disease and chorea (Unified Huntington's Disease Rating Scale [UHDRS] Total Maximal Chorea [TMC] score of 8 or higher) who were randomly assigned (1:1) via an interactive web response system (with no stratification or minimisation) to oral placebo or valbenazine (≤80 mg, as tolerated) for 12 weeks of double-blinded treatment. The primary endpoint was a least-squares mean change in UHDRS TMC score from the screening and baseline period (based on the average of screening and baseline values for each participant) to the maintenance period (based on the average of week 10 and 12 values for each participant) in the full-analysis set using a mixed-effects model for repeated measures. Safety assessments included treatment-emergent adverse events, vital signs, electrocardiograms, laboratory tests, clinical tests for parkinsonism, and psychiatric assessments. The double-blind placebo-controlled period of KINECT-HD has been completed, and an open-label extension period is ongoing. KINECT-HD was performed from Nov 13, 2019, to Oct 26, 2021. Of 128 randomly assigned participants, 125 were included in the full-analysis set (64 assigned to valbenazine, 61 assigned to placebo) and 127 were included in the safety-analysis set (64 assigned to valbenazine, 63 assigned to placebo). The full-analysis set included 68 women and 57 men. Least-squares mean changes from the screening and baseline period to the maintenance period in the UHDRS TMC score were -4·6 for valbenazine and -1·4 for placebo (least-squares mean difference -3·2, 95% CI -4·4 to -2·0; p<0·0001). The most commonly reported treatment-emergent adverse event was somnolence (ten [16%] with valbenazine, two [3%] with placebo). Serious treatment-emergent adverse events were reported in two participants in the placebo group (colon cancer and psychosis) and one participant in the valbenazine group (angioedema because of allergic reaction to shellfish). No clinically important ch anges in vital signs, electrocardiograms, or laboratory tests were found. No suicidal behaviour or worsening of suicidal ideation was reported in participants treated with valbenazine. In individuals with Huntington's disease, valbenazine resulted in improvement in chorea compared with placebo and was well tolerated. Continued research is needed to confirm the long-term safety and effectiveness of this medication throughout the disease course in individuals with Huntington's disease-related chorea. Neurocrine Biosciences.

Switching to once-weekly insulin icodec versus once-daily insulin glargine U100 in individuals with basal-bolus insulin-treated type 2 diabetes (ONWARDS 4): a phase 3a, randomised, open-label, multicentre, treat-to-target, non-inferiority trial

Insulin icodec (icodec) is a basal insulin analogue suitable for once-weekly dosing. ONWARDS 4 aimed to assess the efficacy and safety of once-weekly icodec compared with once-daily insulin glargine U100 (glargine U100) in individuals with long-standing type 2 diabetes on a basal-bolus regimen. In this 26-week, phase 3a, randomised, open-label, multicentre, treat-to-target, non-inferiority trial, adults from 80 sites (outpatient clinics and hospital departments) across nine countries (Belgium, India, Italy, Japan, Mexico, the Netherlands, Romania, Russia, and the USA) with type 2 diabetes (glycated haemoglobin [HbA1c] 7·0-10·0%) were randomly assigned (1:1) to receive once-weekly icodec or once-daily glargine U100 combined with 2-4 daily bolus insulin aspart injections. The primary outcome was change in HbA1c from baseline to week 26 (non-inferiority margin of 0·3 percentage points). The primary outcome was evaluated in the full analysis set (ie, all randomly assigned participants). Safety outcomes were evaluated in the safety analysis set (ie, all participants randomly assigned who received at least one dose of trial product). This trial is registered with ClinicalTrials.gov, NCT04880850. Between May 14 and Oct 29, 2021, 746 participants were screened for eligibility, of whom 582 (78%) were randomly assigned (291 [50%] to icodec treatment and 291 [50%] to glargine U100 treatment). Participants had a mean duration of type 2 diabetes of 17·1 years (SD 8·4). At week 26, estimated mean change in HbA1c was -1·16 percentage points in the icodec group (baseline 8·29%) and -1·18 percentage points in the glargine U100 group (baseline 8·31%), showing non-inferiority for icodec versus glargine U100 (estimated treatment difference 0·02 percentage points [95% CI -0·11 to 0·15], p<0·0001). Overall, 171 (59%) of 291 participants in the icodec group and 167 (57%) of 291 participants in the glargine U100 group had an adverse event. 35 serious adverse events were reported in 22 (8%) of 291 participants in the icodec group and 33 serious adverse events were reported in 25 (9%) of 291 participants receiving glargine U100. Overall, combined level 2 and level 3 hypoglycaemia rates were similar between treatment groups. No new safety concerns were identified for icodec. In people with long-standing type 2 diabetes on a basal-bolus regimen, once-weekly icodec showed similar improvements in glycaemic control, with fewer basal insulin injections, lower bolus insulin dose, and with no increase in hypoglycaemic rates compared with once-daily glargine U100. Key strengths of this trial include the use of masked continous glucose monitoring; the high trial completion rate; and the inclusion of a large, diverse, and multinational population. Limitations include the relatively short trial duration and the open-label design. Novo Nordisk.

Perampanel for Treatment of Focal and Generalized Epilepsy in Everyday Clinical Practice: Evidence from PERMIT and PROVE (P11-1.008)

Perampanel for Treatment of Focal and Generalized Epilepsy in Everyday Clinical Practice: Evidence from PERMIT and PROVE (P11-1.008)

Effectiveness of Fremanezumab for the Preventive Treatment of Migraine: Second Interim Analysis of the Observational PEARL Study (P12-12.002)

Effectiveness of Fremanezumab for the Preventive Treatment of Migraine: Second Interim Analysis of the Observational PEARL Study (P12-12.002)

ELEVATE Study 410: Assessment of Cognition (EpiTrack ® ) Following Perampanel (Monotherapy/First Adjunctive) in Patients with Epilepsy and a History of Psychiatric/Behavioral Events (P11-1.011)

<h3>Objective:</h3> To assess change from baseline in cognition (EpiTrack^®) scores, efficacy, and safety in a subgroup of patients with a history of psychiatric and behavioral events from the Phase IV ELEVATE Study (Study 410; NCT03288129). <h3>Background:</h3> ELEVATE assessed perampanel monotherapy/first adjunctive therapy in patients aged ≥4 years with focal-onset seizures (FOS), with/without focal to bilateral tonic-clonic seizures (FBTCS), or generalized tonic-clonic seizures (GTCS). <h3>Design/Methods:</h3> The study consisted of Screening, Titration (≤13 weeks), Maintenance (39 weeks), and Follow-up (4 weeks) Periods. During Titration, patients received perampanel at 2 mg/day, which was up-titrated to 4 mg/day (further dose increases [of 2 mg] based on response and tolerability; maximum, 12 mg/day). The primary endpoint was retention rate at 3, 6, 9, and 12 months. Other endpoints included seizure freedom (Maintenance Period), median percent reduction in seizure frequency (Maintenance Period), cognition (assessed using EpiTrack^® [patients ≥6 years of age; baseline, and 3 and 12 months]), and safety. <h3>Results:</h3> In the Safety Analysis Set, 54 patients received perampanel monotherapy/first adjunctive therapy. Of those, 24 patients (FOS, n=17; FBTCS, n=2; GTCS, n=4) had a history of psychiatric and behavioral events and were included in this post hoc analysis. The mean (standard deviation) changes from baseline in EpiTrack^® total score at 12 months and end of treatment were −1.1 (3.14; n=11) and −0.5 (2.61; n=23), respectively (increase=improvement). Median percent reduction in seizure frequency/28 days during the entire Maintenance Period was 73.2% (n=22). The incidence of any treatment-emergent adverse events (TEAEs) in this subgroup was 95.8% (n=23/24). The most common TEAEs were dizziness (25.0%, n=6/24) and vomiting (20.8%, n=5/24). <h3>Conclusions:</h3> Perampanel as monotherapy/first adjunctive therapy was generally safe and efficacious in patients from ELEVATE with a history of psychiatric and behavioral events; EpiTrack^® score in these patients was consistent with that observed in the overall patient population. <b>Disclosure:</b> Dr. Punia has nothing to disclose. Dr. Samad has received personal compensation for serving as an employee of Eisai. Dr. Ngo has received personal compensation for serving as an employee of Eisai Inc.. Dinesh Kumar has received personal compensation for serving as an employee of Eisai. Dr. Malhotra has received personal compensation for serving as an employee of Eisai.

Long-Term Efficacy of Perampanel Monotherapy in Patients with Newly Diagnosed/Currently Untreated Recurrent Focal-Onset Seizures: FREEDOM Study 342 Extension Phase Analysis by Seizure Type (P11-1.005)

<h3>Objective:</h3> To assess efficacy of perampanel monotherapy by seizure type in a post hoc analysis of the FREEDOM Study (Study 342; NCT03201900). <h3>Background:</h3> FREEDOM demonstrated long-term (52 weeks) efficacy and tolerability of perampanel monotherapy (4–8mg/day) in patients aged ≥12 years with newly diagnosed or currently untreated recurrent focal-onset seizures (FOS), with or without focal to bilateral tonic-clonic seizures (FBTCS) in Japan and Korea. <h3>Design/Methods:</h3> The Core Study comprised a 4-week Pretreatment Phase and a 32-week Treatment Phase (6-week Titration; 26-week Maintenance) during which patients received perampanel 4mg/day. Patients who experienced seizure(s) during the 4-mg/day Maintenance Period could be transitioned to an additional 30-week 8-mg/day Treatment Phase (4-week Titration; 26-week Maintenance). Patients could also enter a 26-week Extension Phase to continue treatment with perampanel monotherapy after completion of the Core Study. The 52-week seizure-freedom rates were stratified by prior history of the following subtypes of FOS: focal impaired awareness seizures (FIAS), FBTCS, and FIAS plus FBTCS. <h3>Results:</h3> Overall, 89 patients received ≥1 dose of perampanel (Safety Analysis Set [SAS]) and 73 patients entered the 4-mg/day Maintenance Period (modified Intent-to-Treat [mITT] Analysis Set), of whom 21 patients transitioned to the 8-mg/day Treatment Phase. In the SAS, the mean (standard deviation [SD]) duration of perampanel exposure was 66.5 (52.0) weeks across the Core Study and Extension Phase. In the mITT population, the mean (SD) age was 41.7 (18.5) years, and most patients had newly diagnosed epilepsy (95.9% [n=70/73]). The 52-week seizure-freedom rates were 34.1% for FIAS, 31.3% for FBTCS, and 32.9% for FIAS plus FBTCS; these rates at last evaluated dose (4 or 8mg/day) were 41.5% (FIAS), 43.8% (FBTCS), and 42.9% (FIAS plus FBTCS). <h3>Conclusions:</h3> These results suggest that seizure freedom can be achieved and sustained with perampanel monotherapy treatment (4–8mg/day) long-term (≤52 weeks) regardless of seizure type. <b>Disclosure:</b> Sung Chul Lim has nothing to disclose. Anna Patten, 14934 has received personal compensation for serving as an employee of Eisai Ltd. An immediate family member of Dr. Morita-Sherman has received personal compensation for serving as an employee of Forrester Research. Dr. Morita-Sherman has received personal compensation for serving as an employee of Eisai Inc.. An immediate family member of Dr. Morita-Sherman has stock in Forrester Research. The institution of Dr. Morita-Sherman has received research support from Cleveland Clinic. Dr. Ngo has received personal compensation for serving as an employee of Eisai Inc.. Dr. Yamamoto has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Eisai. Dr. Yamamoto has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Daiichi-Sankyo.

MP29-05 TREATMENT PATTERN AND HEALTH-RELATED QUALITY OF LIFE (HRQOL) OF PATIENTS (PTS) WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER (MCRPC) IN THE UNITED STATES (US)

You have accessJournal of UrologyCME1 Apr 2023MP29-05 TREATMENT PATTERN AND HEALTH-RELATED QUALITY OF LIFE (HRQOL) OF PATIENTS (PTS) WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER (MCRPC) IN THE UNITED STATES (US) Neal Shore, Lawrence Karsh, Daniel Shevrin, James Symanowski, Daniel Lin, Jeff Turner, David Russell, Yi Song, James Spalding, Filipa Negreiro, and David Penson Neal ShoreNeal Shore More articles by this author , Lawrence KarshLawrence Karsh More articles by this author , Daniel ShevrinDaniel Shevrin More articles by this author , James SymanowskiJames Symanowski More articles by this author , Daniel LinDaniel Lin More articles by this author , Jeff TurnerJeff Turner More articles by this author , David RussellDavid Russell More articles by this author , Yi SongYi Song More articles by this author , James SpaldingJames Spalding More articles by this author , Filipa NegreiroFilipa Negreiro More articles by this author , and David PensonDavid Penson More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003257.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Therapeutic advances in the management of mCRPC have given clinicians multiple treatment options and the potential for sequencing therapeutic agents, increasing the complexity of treatment decisions. This study aims to describe the treatment patterns and HRQoL of pts with mCRPC in the US from 2015 to 2021. METHODS: This prospective, observational, multicentre study (TRUMPET) enrolled male adult pts who initiated treatment for mCRPC from 147 urology and oncology sites in the US. The data from routine clinic visits and periodic HRQoL questionnaires were collected from Mar 2015 to Apr 2021. The study outcomes assessed patterns of care and HRQoL outcomes (Functional Assessment of Cancer Therapy-Prostate [FACT-P] and Brief Pain Inventory – Short Form [BPI-SF]) associated with mCRPC management. Descriptive analyses were used to evaluate results. RESULTS: Among the enrolled patients, the full analysis set included 832 patients with M1 mCRPC; the safety analysis set included 869 patients with M1 mCRPC. The median duration from initial diagnosis to baseline visit was 4.9 years, median initial prostate-specific antigen (PSA) level at diagnosis was 16.3 ng/mL, and mean (SD) Gleason score was 8.0 (1.18). Novel hormonal therapy (NHT) (enzalutamide and/or abiraterone) and immunotherapy were the most frequent initial treatments (Table). During the follow-up period, 43.8% (n=381) discontinued from the study before the first treatment switch, while 50.1% (n=435) switched treatment, with the majority of pts switching to NHT (n=280, 32.2%). At 1 year follow-up, cumulative first switches were 128 of 158 (81%) from immunotherapy to NHT, 41 of 88 (47%) switched from NHT to a different NHT, 11 of 17 (65%) switched from first-generation anti-androgens (AA) to NHT, 19 of 26 (73%) switched from chemotherapy to NHT, and 6 of 11 (55%) switched from radionuclide therapy to NHT. HRQoL measures showed similar trends (overlapping confidence intervals) of mean change from baseline across different first-line treatment options, irrespective of the initial treatment. CONCLUSIONS: NHT was the preferred first and second-line treatment option in pts with M1 mCRPC. HRQoL was similar regardless of initial treatment. Source of Funding: This study was funded by Astellas Pharma Inc. and Pfizer Inc., the co-developers of enzalutamide. © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e382 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Neal Shore More articles by this author Lawrence Karsh More articles by this author Daniel Shevrin More articles by this author James Symanowski More articles by this author Daniel Lin More articles by this author Jeff Turner More articles by this author David Russell More articles by this author Yi Song More articles by this author James Spalding More articles by this author Filipa Negreiro More articles by this author David Penson More articles by this author Expand All Advertisement PDF downloadLoading ...

Fitusiran prophylaxis in people with severe haemophilia A or haemophilia B without inhibitors (ATLAS-A/B): a multicentre, open-label, randomised, phase 3 trial

Fitusiran, a subcutaneous investigational siRNA therapeutic, targets antithrombin with the goal of rebalancing haemostasis in people with haemophilia A or haemophilia B, regardless of inhibitor status. We aimed to evaluate the efficacy and safety of fitusiran prophylaxis in people with severe haemophilia without inhibitors. This multicentre, open-label, randomised phase 3 study was conducted at 45 sites in 17 countries. Male participants aged at least 12 years with severe haemophilia A or B without inhibitors, who had previously been treated on-demand with clotting factor concentrates, were randomly assigned in a 2:1 ratio to receive 80 mg subcutaneous fitusiran prophylaxis once per month or to continue on-demand clotting factor concentrates for a total of 9 months. Randomisation was stratified by the number of bleeding events in the 6 months before screening (≤10 bleeds and >10 bleeds) and by haemophilia type (haemophilia A or B). The primary endpoint was annualised bleeding rate, analysed in the intention-to-treat analysis set. Safety and tolerability were assessed in the safety analysis set. This trial is registered with ClinicalTrials.gov, NCT03417245, and is complete. Between March 1, 2018, and July 14, 2021, 177 male participants were screened for eligibility and 120 were randomly assigned to receive fitusiran prophylaxis (n=80) or on-demand clotting factor concentrates (n=40). Median follow-up was 7·8 months (IQR 7·8-7·8) in the fitusiran group and 7·8 months (7·8-7·8) in the on-demand clotting factor concentrates group. The median annualised bleeding rate was 0·0 (0·0-3·4) in the fitusiran group and 21·8 (8·4-41·0) in the on-demand clotting factor concentrates group. The estimated mean annualised bleeding rate was significantly lower in the fitusiran prophylaxis group (3·1 [95% CI 2·3-4·3]) than in the on-demand clotting factor concentrates group (31·0 [21·1-45·5]; rate ratio 0·101 [95% CI 0·064-0·159]; p<0·0001). In the fitusiran group, 40 (51%) of 79 treated participants had no treated bleeds compared with two (5%) of 40 participants in the on-demand clotting factor concentrates group. Increased alanine aminotransferase concentration (18 [23%] of 79 participants in the safety analysis set) was the most common treatment-emergent adverse event in the fitusiran group and hypertension (four (10%) of 40 participants) was the most common in the on-demand clotting factor concentrates group. Treatment-emergent serious adverse events were reported in five (6%) participants in the fitusiran group (cholelithiasis [n=2, 3%], cholecystitis [n=1, 1%], lower respiratory tract infection [n=1, 1%], and asthma [n=1, 1%]) and five (13%) participants in the on-demand clotting factor concentrates group (gastroenteritis, pneumonia, suicidal ideation, diplopia, osteoarthritis, epidural haemorrhage, humerus fracture, subdural haemorrhage, and tibia fracture [all n=1, 3%]). No treatment-related thrombosis or deaths were reported. In participants with haemophilia A or B without inhibitors, fitusiran prophylaxis resulted in significant reductions in annualised bleeding rate compared with on-demand clotting factor concentrates and no bleeding events in approximately half of participants. Fitusiran prophylaxis shows haemostatic efficacy in both haemophilia A and haemophilia B, and therefore has the potential to be transformative in the management of all people with haemophilia. Sanofi.

Early GH Treatment Is Effective and Well Tolerated in Children With Turner Syndrome: NordiNet® IOS and Answer Program.

Despite having normal growth hormone (GH) secretion, individuals with Turner syndrome (TS) have short stature. Treatment with recombinant human GH is recommended for TS girls with short stature. This work aimed to evaluate the effectiveness and safety of Norditropin (somatropin, Novo Nordisk) with up to 10 years of follow-up in children with TS. Secondary analysis was conducted of Norditropin data from 2 non-interventional studies: NordiNet® IOS (NCT00960128) and the ANSWER program (NCT01009905). A total of 2377 girls with TS were included in the safety analysis set (SAS), with 1513 in the treatment-naive effectiveness analysis set (EAS). At the start of treatment, 1273 (84%) participants were prepubertal (EAS); mean (SD) age was 8.8 (3.9) years. Mean (SD) dose received at the start of GH treatment was 0.045 (0.011) mg/kg/day (EAS). Mean (SD) baseline insulin-like growth factor-1 (IGF-I) SD score (SDS) was -0.86 (1.52), and mean (SD) duration of GH treatment (SAS) was 3.8 (2.8) years.Height SDS (HSDS) increased throughout follow-up, with near-adult HSDS reached by 264 (17%) participants (mean [SD] -1.99 [0.94]; change from baseline +0.90 [0.85]). During the study, 695 (46%) participants (EAS) entered puberty at a mean (SD) age of 12.7 (1.9) years (whether puberty was spontaneous or induced was unknown). Within the SAS, mean IGF-I SDS (SD) at year 10 was 0.91 (1.69); change from baseline +1.48 (1.70). Serious adverse reactions were reported in 10 participants (epiphysiolysis [n = 3]). GH-treated participants with TS responded well, without new safety concerns. Our real-world data are in agreement with previous studies.

Safety and Effectiveness of Molnupiravir (LAGEVRIO®) Capsules in Japanese Patients with COVID-19: Interim Report of Post-marketing Surveillance in Japan.

Molnupiravir is an oral antiviral drug that received special approval for emergency use in Japan on December 24 2021 for infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This post-marketing surveillance (PMS) is underway to investigate the safety and effectiveness of molnupiravir in daily clinical practice in Japan. The interim PMS data collected from December 27 2021 to June 15 2022 are reported in this publication. This survey included adult Japanese patients treated with molnupiravir. For safety, adverse drug reactions (ADR) were assessed by physicians. Effectiveness was assessed by the composite endpoint of (1) hospitalization or (2) death in outpatients and by the composite endpoint of (3) death or (4) initiation of oxygen administration/mechanical ventilation in inpatients hospitalized for any reasons and without oxygen administration at the start of molnupiravir administration. The observation period was through 29days from the start of molnupiravir administration. Of the 1031 patients in the safety analysis set, 68 (6.60%) patients reported ADRs and four (0.39%) patients reported serious ADRs. The main ADRs observed were diarrhoea [26 patients (2.52%)], rash [six patients (0.58%)], dizziness [five patients (0.48%)], and faecessoft [four patients (0.39%)]. In the effectiveness analysis from the start date of molnupiravir administration to day 29, there were 16/612 (2.61%) hospitalizations and no deaths. Oxygen administration was newly initiated in 9/199 (4.52%) inpatients after the initiation of molnupiravir administration; 2/199 (1.01%) inpatients died. This interim analysis of molnupiravir in daily clinical practice use in Japan supports the safety and effectiveness profile of molnupiravir under pandemic conditions in which Omicron was the dominant SARS-CoV-2 variant. The results of this PMS will provide valuable information for daily clinical practice use.

Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study

Neurokinin 3 receptor antagonists are potential non-hormonal therapies for the treatment of vasomotor symptoms in menopausal women as options are scarce for those who cannot or do not want to take hormone therapy. Fezolinetant is one of the first non-hormonal neurokinin 3 receptor antagonists in development for the treatment of vasomotor symptoms due to menopause. This study investigated the safety and efficacy of fezolinetant for the treatment of moderate-to-severe vasomotor symptoms associated with menopause. SKYLIGHT 1 is a randomised, double-blind, placebo-controlled, 12-week, phase 3 trial with a 40-week active treatment extension. This trial was done at 97 facilities across the USA, Canada, Czech Republic, Hungary, Poland, Spain, and the UK. Women aged 40-65 years with an average of seven or more moderate-to-severe hot flashes per day were randomly assigned (1:1:1) to once-daily exact-matched placebo, fezolinetant 30 mg, or fezolinetant 45 mg. Randomisation was done using a web-based interactive response system and investigators, project team members, clinical staff, and participants were masked to treatment assignment. Coprimary endpoints were mean change in frequency and severity of vasomotor symptoms from baseline to weeks 4 and 12. The efficacy and safety analyses comprised all randomly assigned participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT04003155) and is completed. Between July 11, 2019, and Aug 11, 2021, 2205 women were recruited of whom 175 were assigned to placebo, 176 to fezolinetant 30 mg, and 176 to fezolinetant 45 mg (175 in the placebo group, 174 in the fezolinetant 30 mg group, and 173 in the fezolinetant 45 mg received at least one dose [safety analysis set]). One participant randomly assigned to fezolinetant 45 mg received fezolinetant 30 mg in error, so the efficacy analysis set (full analysis set) consisted of 173 in the fezolinetant 30 mg group and 174 in the fezolinetant 45 mg group. 23 participants in the placebo group, 31 in the fezolinetant 30 mg group, and 13 in the fezolinetant 45 mg group discontinued treatment before week 12, mostly due to adverse events or participant withdrawal. Compared with placebo, fezolinetant 30 mg and fezolinetant 45 mg significantly reduced the frequency of vasomotor symptoms at week 4 (difference in change in least squares mean -1·87 [SE 0·42; p<0·001], -2·07 [SE 0·42; p<0·001]) and week 12 (-2·39 [SE 0·44; p<0·001], -2·55 [SE 0·43; p<0·001]). Compared with placebo, fezolinetant 30 mg and 45 mg significantly reduced the severity of vasomotor symptoms at week 4 (-0·15 [0·06; p=0·012], -0·19 [0·06; p=0·002]) and week 12 (-0·24 [0·08; p=0·002], -0·20 [0·08; p=0·007]). Improvements in frequency and severity of vasomotor symptoms were observed after 1 week and maintained over 52 weeks. During the first 12 weeks, treatment-emergent adverse events occurred in 65 (37%) of 174 women in the fezolinetant 30 mg group, 75 (43%) of 173 in the fezolinetant 45 mg group, and 78 (45%) of 175 in the placebo group. The incidence of liver enzyme elevations was low (placebo n=1; fezolinetant 30 mg n=2; fezolinetant 45 mg n=0) and these events were generally asymptomatic, transient, and resolved while on treatment or after treatment discontinuation. Data support the clinical use of fezolinetant as a non-hormonal treatment for vasomotor symptoms associated with menopause. The study was placebo-controlled for 12 weeks followed by a 40-week blinded extension to assess the maintenance of effect. Furthermore, the population studied was diverse and representative of the potential target population for fezolinetant therapy. Further characterisation of the benefit of fezolinetant on quality of life, including on symptoms of mood and sexual wellbeing, merits investigation. Astellas Pharma.