Safety Analysis Set Research Articles

Efficacy and safety of linaclotide in treatment-resistant chronic constipation: A multicenter, open-label study.

This study aimed to evaluate the efficacy and safety of linaclotide in patients with chronic constipation (CC) or irritable bowel syndrome with constipation (IBS-C) who did not respond to treatment with magnesium oxide (MgO). This study was designed as a multicenter, open-label, single-arm, exploratory study. Patients with CC or IBS-C who took MgO and those meeting the medication initiation criteria were administered linaclotide at a daily dosage of 500 μg for 12 weeks. The primary endpoint was a change in the Japanese version of the Patient Assessment of Constipation Quality of Life (JPAC-QOL) score from baseline, which was evaluated by using a paired t-test. The patients' mean age (± standard deviation) was 67.6 ± 13.82 years. The full analysis set included 61 patients. The JPAC-QOL total score was 1.60 at baseline and 0.70 at 12 weeks, with a significant mean change of -0.89 ± 0.721 (p < 0.001). Several secondary endpoints also showed improvement. The frequency of spontaneous bowel movement (SBM) and complete SBM increased by 2.70 ± 7.254 (p < 0.01) and 2.81 ± 5.254 times, respectively (p < 0.001). The Bristol Stool Form Scale, abdominal bloating severity, and straining severity scores improved by 1.33 ± 1.274 (p < 0.001), -0.16 ± 0.563 (p < 0.05), and -0.46 ± 0.795 (p < 0.001) points, respectively. The safety analysis set included 65 patients, 7 of whom had diarrhea, which improved with dose reduction and drug withdrawal. The study was conducted in an older adult population, similar to real clinical practice. Linaclotide may be an option for treating CC that shows an inadequate response to conventional therapy.

Aztreonam-avibactam versus meropenem for the treatment of serious infections caused by Gram-negative bacteria (REVISIT): a descriptive, multinational, open-label, phase 3, randomised trial.

There is a need for additional therapeutic options for serious infections caused by Gram-negative pathogens. In the phase 3, descriptive REVISIT study, we investigated the safety and efficacy of aztreonam-avibactam in the treatment of complicated intra-abdominal infections or hospital-acquired pneumonia or ventilator-associated pneumonia (HAP-VAP) caused, or suspected to be caused, by Gram-negative bacteria. This prospective, multinational, open-label, central assessor-masked study enrolled adults who were hospitalised with a complicated intra-abdominal infection or HAP-VAP. Patients were randomly allocated via block randomisation using interactive response technology stratified by infection type in a 2:1 ratio to aztreonam-avibactam (with metronidazole for complicated intra-abdominal infection) or meropenem with or without colistin for 5-14 days for complicated intra-abdominal infection or 7-14 days for HAP-VAP. The primary endpoint was clinical cure at the test-of-cure visit (within 3 days before or after day 28) in the intention-to-treat (ITT) population. Secondary endpoints included 28-day mortality in the ITT population and safety in patients in the ITT population who received study drug (safety analysis set). No formal hypothesis testing was planned. The study was registered with ClinicalTrials.gov (NCT03329092) and EudraCT (2017-002742-68) and is complete. Between April 5, 2018, and Feb 23, 2023, we screened 461 patients. 422 patients were enrolled and randomly allocated (282 in the aztreonam-avibactam group and 140 in the meropenem group, forming the ITT analysis set), of whom ten patients (seven in the aztreonam-avibactam group and three in the meropenem group) were randomly allocated but did not receive study treatment. 271 (64%) of 422 patients had at least one Gram-negative pathogen from an adequate specimen identified at baseline. The most frequent baseline pathogens were Enterobacterales (252 [93%] of 271). Overall, 19 (24%) of 80 isolates tested for carbapenemases were carbapenemase-positive (serine, metallo-β-lactamase, or both). 193 (68·4%) of 282 patients in the aztreonam-avibactam group and 92 (65·7%) of 140 in the meropenem group had clinical cure at the test-of-cure visit (treatment difference 2·7% [95% CI -6·6 to 12·4]). For patients with complicated intra-abdominal infection, the adjudicated clinical cure rate was 76·4% (159 of 208) for the aztreonam-avibactam group and 74·0% (77 of 104) for the meropenem group. Cure rates in patients with HAP-VAP were 45·9% (34 of 74) for aztreonam-avibactam and 41·7% (15 of 36) for meropenem. 28-day all-cause mortality rates were 4% (12 of 282) for aztreonam-avibactam and 7% (ten of 140) for meropenem; in patients with complicated intra-abdominal infection, mortality was 2% (four of 208) and 3% (three of 104) for aztreonam-avibactam and meropenem, respectively, and in patients with HAP-VAP, mortality was 11% (eight of 74) and 19% (seven of 36), respectively. Aztreonam-avibactam was generally well tolerated, and safety findings were consistent with the known safety profile of aztreonam monotherapy. There were no treatment-related serious adverse events in the aztreonam-avibactam group. These phase 3 efficacy and safety data provide support for aztreonam-avibactam as a potential therapeutic option for complicated intra-abdominal infection or HAP-VAP caused by Gram-negative bacteria. Pfizer.

Long-term safety and effectiveness of romiplostim for chronic idiopathic thrombocytopenic purpura in real-world settings.

Idiopathic thrombocytopenic purpura (ITP), an autoimmune hematologic disorder characterized by severe platelet count reduction, can be treated with romiplostim. However, post-marketing safety and effectiveness data for romiplostim in Japan are scarce. This prospective, observational, post-marketing Specified Use-Results Survey evaluated the real-world safety and effectiveness of romiplostim for 2years. All patients treated with romiplostim during the survey period were eligible. Of the 1622 patients in the safety analysis set, 94.08% (1526/1622) had chronic ITP. The mean single dose of romiplostim was stable after 12weeks and remained < 6μg/kg in approximately 70% of patients until 104weeks. Within 2years, 14.92% of patients discontinued romiplostim because of adverse events, while 6.47% discontinued because of suspected adverse drug reactions. In contrast, 14.00% of patients discontinued romiplostim because of symptom improvement. Before romiplostim initiation, platelet count was < 2.0 × 104/µL in 60.54% of patients, and the mean platelet count was 2.84 ± 5.76 × 104/µL. Platelet count was 9.19 ± 13.01 × 104/µL after 4weeks, and remained between 10.34 ± 10.72 and 12.38 ± 12.63 × 104/µL from 8 to 104weeks of treatment. No specific concerns were revealed regarding the safety and effectiveness of romiplostim in chronic ITP; the findings demonstrated a favorable risk-benefit balance for romiplostim in this population. Trial registration: UMIN000047864 ( www.umin.ac.jp/ctr ).

Clinical efficacy and safety of perampanel monotherapy as primary anti-seizure medication in the treatment of pediatric epilepsy: A single-center, prospective, observational study.

To assess the efficacy and safety of perampanel (PER) as primary monotherapy in patients aged 4-18 years old with epilepsy. A single-center, prospective, observational study was conducted from October 2021 to October 2023, to evaluate PER monotherapy's efficacy and safety as initial therapy for pediatric epilepsy. Changes in seizure frequency, safety, and retention rate were observed at 3, 6, 9, and 12 months after initiating PER primary monotherapy. A total of 124 children aged 4-15 years (mean age = 8.25 ± 2.50 years) were included in the Analysis Sets. The retention rates at 3, 6, 9, and 12 months were 88.71% (110/124), 84.68% (105/124), 78.26% (90/115), and 71.58% (68/95), respectively. Seizure freedom rates at 3, 6, 9, and 12 months were 85.45%, 79.09%, 76.24%, and 75.31%, respectively. The responder rates (≥50% but <100%) at the same endpoints were 9.09%, 14.55%, 12.87%, and 7.41%, respectively. Seizure freedom rate of PER was independent of age at PER initiation, seizure onset age, gender, baseline frequency, seizure types, and family history of epilepsy (p > 0.05) but associated with duration of treatment (p = 0.001) and maintenance dose (p = 0.022). Additionally, 124 patients were included in the safety analysis set. The overall adverse event rate was 38.71% (48/124), with irritability (19 cases, 15.32%) and dizziness (18 cases, 14.52%) being the most common adverse effects. One patient discontinued PER monotherapy within 1 month due to unbearable itching of the skin. PER monotherapy as the primary anti-seizure medication (ASM) for pediatric epilepsy demonstrates high efficacy and safety in real-world clinical treatment. Patients who respond well to this drug and adhere to long-term treatment can achieve favorable seizure control. Furthermore, patients achieving seizure freedom with a relatively lower dose can opt for the same dose as the maintenance dose. This study provided the efficacy and safety of PER monotherapy as the primary ASM for Chinese pediatric epilepsy. In total, 124 patients took part. The seizure freedom rates were over 70% at different observation points (OPs), along with a retention rate of 71.58% at the 12-month OP. Most of adverse effects observed were mild to moderate.

Safety and immunogenicity of a single-dose omicron-containing COVID-19 vaccination in adolescents: an open-label, single-arm, phase 2/3 trial

Most individuals show immunity to SARS-CoV-2 from vaccination or infection, or both. We aimed to determine the safety and immunogenicity of an omicron-containing COVID-19 vaccine (mRNA-1273.222) in vaccine-naive adolescents who were SARS-CoV-2 positive. Part 3 of the phase 2/3 TeenCOVE trial was a phase 3, open-label, single-arm part done in the USA and the Dominican Republic that enrolled healthy, vaccine-naive adolescents (aged 12-17 years) to receive two 50 μg doses of mRNA-1273.222 (ancestral strain Wuhan-Hu-1 and omicron subvariants BA.4 and BA.5), 6 months apart. Primary reactogenicity and safety outcomes included assessment of solicited local or systemic adverse reactions 7 days after vaccination, and unsolicited and prespecified adverse events throughout study participation. Inferred effectiveness (primary immunogenicity outcome) was established by comparing neutralising antibody responses 28 days after dose 1 of mRNA-1273.222 in SARS-CoV-2-positive adolescents with responses 28 days after dose 2 of mRNA-1273 100 μg primary series in SARS-CoV-2-negative young adults (aged 18-25 years) from the COVE trial. This study is registered with ClinicalTrials.gov (NCT04649151). Between Dec 21, 2022, and June 5, 2023, 379 adolescents (378 of whom were SARS-CoV-2 positive) received at least one mRNA-1273.222 dose and were included in the safety analysis set. The reactogenicity profile was favourable compared with the mRNA-1273 primary series, with no new safety concerns identified. Unsolicited adverse events were reported in 49 (13%) of 379 participants; no deaths or adverse events leading to study discontinuation were reported. The immunogenicity set included 245 adolescents from the per-protocol immunogenicity subset who were SARS-CoV-2 positive at baseline and 296 young adults who were SARS-CoV-2 negative. Compared with the mRNA-1273 primary series in SARS-CoV-2-negative young adults, a single dose of mRNA-1273.222 induced superior (geometric mean ratio [GMR] 95% CI lower bound >1) neutralising antibody responses against omicron BA.4 and BA.5 (GMR 48·95 [95% CI 44·21-54·21]) and non-inferior (GMR 95% CI lower bound >0·667) neutralising antibody responses against ancestral SARS-CoV-2 (GMR 4·25 [95% CI 3·69-4·88]) in SARS-CoV-2-positive adolescents. In vaccine-naive, SARS-CoV-2-positive adolescents, single-dose mRNA-1273.222 was effective against COVID-19 based on successful immunobridging to the two-dose mRNA-1273 primary series in young adults. The findings support a simplified single-dose vaccination schedule with variant-containing mRNA vaccines, regardless of previous vaccination status. Moderna.

Efficacy and Safety of Valbenazine in Elderly and Nonelderly Japanese Patients With Tardive Dyskinesia: A Post Hoc Analysis of the J-KINECT Study.

The efficacy and safety of valbenazine, a selective vesicular monoamine transporter 2 inhibitor, has been confirmed for treatment of tardive dyskinesia (TD) in patients aged ≥65 years in non-Asian clinical trials; however, data are lacking in elderly Asian patients. This post hoc analysis of J-KINECT aimed to evaluate the efficacy and safety of valbenazine in elderly Japanese patients with TD. J-KINECT was a randomized, double-blind, placebo-controlled study with a 6-week double-blind, placebo-controlled period; 42-week double-blind, valbenazine extension period; and 4-week posttreatment observation period. Outcomes were summarized by age (≥65 years [elderly] and <65 [nonelderly]) and treatment group. The safety analysis set included 100 and 153 patients aged ≥65 and <65 years, respectively (intention-to-treat set: 98 and 151 patients, respectively). In the elderly group, the difference versus placebo in least-squares mean change from baseline in the Abnormal Involuntary Movement Scale total score at week 6 was -3.1 (95% confidence interval: -4.5, -1.7) and -5.5 (-7.0, -3.9) with valbenazine 40 and 80 mg, respectively; in the nonelderly group, respective differences were -1.5 (-2.6, -0.4) and -2.5 (-3.6, -1.3). Both age groups showed improvement in Clinical Global Impression of Change-Tardive Dyskinesia scores with valbenazine. The incidence of treatment-emergent adverse events (TEAEs) leading to treatment discontinuation was higher in the elderly versus nonelderly group. There was no trend toward higher incidences of TEAEs or related TEAEs in the elderly group. The findings suggest that valbenazine may be used effectively and safely as a treatment for TD, even in elderly patients.

Long-term safety and efficacy of anti-TNF multivalent VHH antibodies ozoralizumab in patients with rheumatoid arthritis

ObjectivesThis study aimed to evaluate the long-term safety and efficacy profiles of ozoralizumab in patients with rheumatoid arthritis (RA) from the OHZORA, NATSUZORA and HOSHIZORA trials.MethodsThis study conducted an integrated...

Safety and effectiveness of tofacitinib in Korean adult patients with ulcerative colitis: post-marketing surveillance study

BackgroundTofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We aimed to identify the safety and effectiveness of tofacitinib in patients with UC in routine clinical settings in Korea.MethodsThis open-label, observational, prospective, post-marketing surveillance study was conducted at 22 hospitals in the Republic of Korea. Patients with moderate to severe active UC who received tofacitinib were included and followed up for up to 52 weeks. Tofacitinib was administered at a dosage of 10 mg twice daily for at least 8 weeks, followed by 5 or 10 mg twice daily at the investigator’s discretion based on clinical evaluation according to the approved Korean label. Safety including adverse events (AEs) and effectiveness including clinical remission, clinical response, and endoscopic mucosal healing were evaluated. Safety analysis set was defined as all patients registered for this study who received at least one dose of tofacitinib according to the approved Korean label and followed up for safety data. Effectiveness analysis set included patients in the safety analysis set who were evaluated for overall effectiveness assessment and excluded patients who had received tofacitinib less than 8 weeks.ResultsA total of 110 patients were enrolled, of whom 106 patients were included in the safety population. The median duration of treatment was 370 days and the treatment duration ranged from 16 to 684 days for the safety population. AEs occurred in 42 patients (39.6%). Serious AEs (SAEs) occurred in 7 patients (6.6%) and of them, there were 2 cases of serious infections. These serious infections were reported as Adverse Event of Special Interest (AESI) in this study and no other AESI were reported. There were no cases of death during the study period. Clinical remission rates were 40.0%, 46.7%, 57.6%, and 55.1% at 8, 16, 24, and 52 weeks, and clinical response rates were 77.8%, 87.9%, 56.6%, and 81.4% at each visit, respectively. Endoscopic mucosal healing rates were 58.7% at 16 weeks and 46.2% at 52 weeks.ConclusionTofacitinib was effective in Korean patients with moderate to severe active UC and the safety findings were consistent with the known safety profile of tofacitinib.SummaryThis study confirmed the safety and effectiveness of tofacitinib in Korean patients with moderate to severe active UC in routine clinical settings.Trial registrationThis study is registered in the ClinicalTrials.gov under the identifier NCT04071405, registered on 28 August 2019.

One-year Safety and Effectiveness of Ustekinumab in Patients With Crohn's Disease: The K-STAR Study.

This study investigated the safety and effectiveness of ustekinumab (UST) in Korean patients with Crohn's disease (CD). Adult patients with CD treated with UST were prospectively enrolled in the K-STAR (Post-MarKeting Surveillance for Crohn's Disease patients treated with STelARa) study between April 2018 and April 2022. Both the clinical effectiveness and adverse effects of UST therapy were analyzed. Missing data were handled using nonresponder imputation (ClinicalTrials.gov Identifier: NCT03942120). Of the 464 patients enrolled from 44 hospitals across Korea, 457 and 428 patients (Crohn's disease activity index ≥150) were included in the safety analysis and effectiveness analysis sets, respectively. At weeks 16 to 20 after initiating UST, clinical response, clinical remission, and corticosteroid-free remission rates were 75.0% (321 of 428), 64.0% (274 of 428), and 61.9% (265 of 428), respectively. At week 52 to 66, clinical response, clinical remission, and corticosteroid-free remission rates were 62.4% (267 of 428), 52.6% (225 of 428), and 50.0% (214 of 428), respectively. Combined effectiveness (clinical response + biochemical response) was achieved in 40.0% (171 of 428) and 41.6% (178 of 428) at week 16 to 20 and week 52 to 66, respectively. Biologic-naïve patients exhibited significantly higher rates of combined effectiveness than biologic-experienced patients (50.3% vs 30.7% at week 16-20, P < .001; 47.7% vs 36.0% at week 52-66, P = .014). No additional benefits were observed with the concomitant use of immunomodulators. Ileal location was independently associated with a higher probability of clinical remission compared with colonic or ileocolonic location at week 52 to 66. Adverse and serious adverse events were observed in 28.2% (129 of 457) and 12.7% (58 of 457), respectively, with no new safety signal associated with UST treatment. Ustekinumab was well-tolerated, effective, and safe as induction and maintenance therapy for CD in Korea.

Factors influencing the efficacy and safety of esaxerenone in hypertensive patients: a pooled analysis of five clinical studies on different comorbidities

This study aimed to identify factors associated with a strong home blood pressure (BP)-lowering effect of esaxerenone and the incidence of elevated serum potassium levels in hypertensive patients treated with esaxerenone. A pooled analysis of five multicenter, prospective, open-label single-arm studies was conducted, including 479 patients in the full analysis set (FAS) and 492 patients in the safety analysis set. Multivariate linear regression analysis of morning home systolic BP (SBP) and diastolic BP (DBP) changes from baseline to Week 12 in the FAS (primary endpoint) showed that male sex (estimated change 4.37 mmHg), office pulse rate ≥100 beats/min (25.10 mmHg), and calcium channel blocker (CCB) use as a basal antihypertensive agent (4.53 mmHg) were significantly associated with a positive estimated change (weaker BP-lowering effect) in morning home SBP. CCB use (3.70 mmHg) was associated with a positive estimated change in morning home DBP. Urine albumin‐to‐creatinine ratio 30 to <300 mg/gCr (−4.13 mmHg) was significantly associated with a negative estimated change (stronger BP-lowering effect) in morning home SBP. Based on multivariate logistic regression analysis, elevated baseline serum potassium level (≥4.5 vs < 4.5 mEq/L, odds ratio 13.502) was significantly associated with a high incidence of serum potassium level ≥5.5 mEq/L after esaxerenone treatment. In conclusion, factors associated with a strong BP-lowering effect of esaxerenone were female sex and use of renin–angiotensin system inhibitors as a basal antihypertensive drug. Patients with baseline serum potassium levels ≥4.5 mEq/L had an increased risk of developing elevated serum potassium levels (≥5.5 mEq/L) after esaxerenone treatment.

Phase I/II clinical trial of brentuximab vedotin for pretreated Japanese patients with CD30-positive cutaneous T-cell lymphoma.

Brentuximab vedotin (BV), a conjugate of anti-CD30 antibody and monomethyl auristatin E, has emerged as a promising treatment option for refractory CD30+ mycosis fungoides (MF) and primary cutaneous anaplastic large-cell lymphoma (pcALCL). BV has been shown to be safe and effective in treating Hodgkin's lymphoma and peripheral T-cell lymphoma. This multicenter, prospective, single-arm phase I/II study evaluated the efficacy of BV in Japanese patients with CD30+ cutaneous lymphomas, namely CD30+ cutaneous T-cell lymphoma. Participants were divided into two groups: those with CD30+ MF or pcALCL (cohort 1, n = 13) and those with CD30+ lymphoproliferative disorders other than those in cohort 1 (cohort 2, n = 3). The studied population included the full analysis set (FAS), modified FAS (mFAS), and safety analysis set (SAF). These sets were identified in cohorts 1 and 1 + 2 and labeled FAS1 and FAS2, mFAS1 and mFAS2, and SAF1 and SAF2, respectively. Each treatment cycle lasted 3 weeks, and BV was continued for up to 16 cycles after the third cycle based on treatment response. The primary endpoint was the 4-month objective response rate (ORR4) determined by the Independent Review Forum (IRF). ORR4 was 69.2% for FAS1 and 62.5% for FAS2 (P < 0.0001). Secondary endpoints of ORR, assessed using the global response score (53.8% in FAS1) and modified severity-weighted assessment tool (62.5% in FAS1), using the IRF, provided results comparable to the primary findings. The incidence of ≥grade 3 adverse events (≥15%) in SAF1 was peripheral neuropathy in three patients (23%) and fever and eosinophilia in two patients (15%). In conclusion, BV showed favorable efficacy, tolerability, and safety profile in Japanese patients with relapsed or refractory CD30+ primary cutaneous T-cell lymphoma. The trial was registered with University Hospital Medical Information Network Clinical Trials Registry, Japan (protocol ID: UMIN000034205).

Efficacy and safety of an oral combination therapy of niraparib and etoposide in platinum resistant/refractory ovarian cancer: a single arm, prospective, phase II study

ObjectiveNon-platinum chemotherapy is used in platinum resistant/refractory ovarian cancer patients but offers limited efficacy, especially in those who develop platinum resistance after ≤2 lines of platinum based chemotherapy. This phase...

Real-world effectiveness and safety of macitentan in patients with pulmonary artery hypertension: a multicenter, retrospective, observational study in China

Background Macitentan, either as monotherapy or part of combination therapy, improved clinical outcomes in patients with pulmonary artery hypertension (PAH) in clinical trials. Evidence on the effectiveness and safety of macitentan administered in real-world clinical practice in China is limited. Methods This real-world, retrospective, multicenter chart review study was conducted at seven hospitals in China. Adult patients with a diagnosis of PAH who initiated macitentan and had medical assessments at 3–7 months after macitentan initiation were included. The primary outcomes were changes in the World Health Organization functional class (WHO-FC), 6-min walk distance (6MWD), and N-terminal pro-B-type natriuretic peptide (NT-proBNP)/B-type natriuretic peptide from baseline to first follow-up visit (months 3–7). Serious adverse events (SAEs) and adverse drug reactions (ADRs) of macitentan were collected. Results From 30 August 2021 to 31 March 2022, 214 eligible patients were included in the safety analysis set and 105 patients were included in the analysis of effectiveness. At the first follow-up visit compared with baseline, significant changes in WHO-FC were observed (p = .04), 93.5% patients had their WHO-FC improved (25.8%) or maintained (67.7%). 6MWD changed by a mean (standard deviation [SD]) of 45.0 (81.4) meters (p < .001), with 94.7% having their 6MWD improved (34.7%) or maintained (60.0%). The mean (SD) of NT-proBNP decreased from 1667.4 (3233.0) ng/L to 1090.0 (2230.1) ng/L (p < .001). In the safety analysis set, 24 (11.2%) patients experienced at least one ADR and/or SAE. ADRs and SAEs were reported in 11 (5.1%) and 18 (8.4%), respectively. No deaths or unexpected safety events were observed. Conclusion This study provided real-world evidence on the clinical benefits and good tolerance of macitentan in Chinese patients with PAH treated in routine clinical practice.

Foritinib in advanced ROS1-rearranged non-small-cell lung cancer in China: a multicentre, open-label, single-arm, phase 2 study

Currently approved targeted treatment for ROS1-rearranged non-small-cell lung cancer (NSCLC) has either inadequate intracranial activity or CNS-related toxicities. We evaluated the efficacy and safety of foritinib, a novel ALK and ROS1 inhibitor, in patients with advanced ROS1-rearranged NSCLC. This two-part (phase 2a and 2b), multicentre, single-arm, open-label, phase 2 study was done in 29 centres in China. Eligible participants were adults (aged ≥18 years) with histologically or cytologically confirmed ROS1-rearranged, locally advanced or metastatic stage IIIB-IV NSCLC, with an Eastern Cooperative Oncology Group performance status of 2 or less. Patients who had previously received no or one ROS1 inhibitor were enrolled into phase 2a, and patients who were naive to ROS1 inhibitor therapy were enrolled into phase 2b cohort 1. Participants in phase 2a received 80, 120, 160, or 210 mg foritinib succinate (foritinib) orally once daily over 21-day cycles; patients in phase 2b received the recommended phase 2 dose of 160 mg. The primary endpoint was objective response rate, assessed by the independent review committee in the full analysis set (ie, all participants who received at least one dose of study treatment). The safety analysis set included all participants who received at least one dose of study treatment and had available safety assessments. This study is ongoing and is registered with ClinicalTrials.gov, NCT04237805. Between March 26, 2020, and Dec 29, 2022, 104 patients were enrolled and treated. Six patients who had previously received more than one ROS1 inhibitor were enrolled in phase 2a before a protocol amendment stating that patients in this phase should have received no more than one ROS1 inhibitor; these patients were included in the safety analysis but excluded from the efficacy analysis of the ROS1-inhibitor-pretreated cohort. Therefore, the efficacy analysis set (n=98) included 42 patients from phase 2a (17 who were ROS1 inhibitor naive and 25 who had previously received ROS1 inhibitor) and 56 patients from phase 2b cohort 1. In phase 2a, the objective response rate was 94% (95% CI 71-100; 16 of 17 patients) in patients who were ROS1 inhibitor naive and 40% (21-61; ten of 25) in patients who had previously received ROS1 inhibitor. In phase 2b cohort 1, the objective response rate was 88% (95% CI 76-95; 49 of 56 patients). In a prespecified exploratory analysis in 41 patients with CNS metastases at baseline, the objective response rate was 100% (95% CI 48-100; five of five patients) in patients in phase 2a who were ROS1 inhibitor naive, 40% (16-68; six of 15) in patients in phase 2a who had previously received ROS1 inhibitor, and 90% (70-99; 19 of 21) in patients in phase 2b cohort 1. Grade 3-4 treatment-related adverse events occurred in 33 (32%) of 104 patients; the most common were hyperglycaemia (12 [12%] patients) and electrocardiogram prolonged QT interval (six [6%]). Serious treatment-related adverse events occurred in 11 (11%) patients, with hyperglycaemia (six [6%]) being most common. No treatment-related adverse events led to death. Foritinib showed systemic and intracranial antitumour activity and good tolerability in ROS1-inhibitor-naive patients with ROS1-rearranged NSCLC. Foritinib represents a promising treatment for these patients, especially in those with CNS metastases. Fosun Pharma, Wanbang Biopharmaceuticals, and Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer.

Real-world safety and effectiveness of intravenous fomepizole in patients with ethylene glycol and methanol poisoning in Japan: results of a 7-year post-marketing surveillance study

ABSTRACT Background Fomepizole is a competitive alcohol dehydrogenase inhibitor used for the treatment of ethylene glycol and methanol poisoning. We evaluated the safety and effectiveness of fomepizole in patients with ethylene glycol or methanol poisoning in Japan. Research design and methods This retrospective post-marketing surveillance study conducted in Japan registered patients who received fomepizole intravenous infusion per the package insert (January 2015−June 2022). Endpoints included adverse drug reactions/infections (ADRs), arterial blood pH, and treatment outcomes. Results Of 147 patients registered (91 institutions), 131 and 126 were included in the safety and effectiveness analysis sets, respectively. Mean age was 43.6 years, and 66.4% were male. Mean time from poison ingestion to treatment was 15.1 hours; 66.4% received concomitant hemodialysis. No serious ADRs were reported. ADRs were reported in seven patients; the most-reported ADR was vomiting (2.3%). Seven patients died, 105 survived without sequelae, and 19 survived with sequelae. Most common sequelae were renal failure or renal dysfunction. Mean arterial blood pH increased to 7.4 by 4 hours of treatment, remaining stable for 24 hours post-treatment. Conclusions Fomepizole is well tolerated and helps improve clinical outcomes in patients with ethylene glycol or methanol poisoning in Japan. Trial registration Japanese Pharmaceutical Information Center (JapicCTI-152817).

Safety and immunogenicity of the intranasal H3N2 M2-deficient single-replication influenza vaccine alone or coadministered with an inactivated influenza vaccine (Fluzone High-Dose Quadrivalent) in adults aged 65–85 years in the USA: a multicentre, randomised, double-blind, double-dummy, phase 1b trial

Older adults (aged ≥65 years) show increased susceptibility to severe disease with influenza virus infection, accounting for 70-85% of annual influenza-related fatalities in the USA. Stimulating mucosal antibodies and T cells might enhance the low vaccine effectiveness seen in older adults for currently licensed inactivated influenza vaccines, which induce mainly serum antibodies. We aimed to evaluate the safety and immunogenicity of the intranasal H3N2 M2-deficient single-replication (M2SR) vaccine, alone or coadministered with a licensed inactivated influenza vaccine (Fluzone High-Dose Quadrivalent; hereafter referred to as Fluzone HD), in older adults. In this multicentre, randomised, double-blind, double-dummy, phase 1b trial, individuals aged 65-85 years who were considered healthy or with stable chronic conditions with no recent (<6 months) influenza vaccinations were recruited from five clinical trial sites in the USA and randomly assigned (3:3:3:1) using a permuted block design to receive the H3N2 M2SR vaccine and Fluzone HD, the H3N2 M2SR vaccine and placebo, Fluzone HD and placebo, or placebo alone. All participants received a single intranasal spray and a single intramuscular injection, whether active or placebo, to maintain masking. The primary outcome was to assess the safety of H3N2 M2SR, administered alone or with Fluzone HD, in the safety analysis set, which included all participants who were randomly assigned and received treatment. Serum and mucosal antibodies were assessed as a secondary endpoint, and cell-mediated immunity as an exploratory endpoint, in participants in the per-protocol population, which included individuals in the safety analysis set without major protocol deviations. This trial is registered with ClinicalTrials.gov, NCT05163847. Between June 14 and Sept 15, 2022, 305 participants were enrolled and randomly assigned to receive the H3N2 M2SR vaccine plus placebo (n=89), H3N2 M2SR vaccine plus Fluzone HD (n=94), Fluzone HD plus placebo (n=92), or placebo alone (n=30). All randomly assigned participants were included in the safety analysis set. The most frequently reported local symptoms up to day 8 in groups that received M2SR were rhinorrhoea (43% [38 of 89] in the H3N2 M2SR plus placebo group and 38% [36 of 94] in the H3N2 M2SR plus Fluzone HD group), nasal congestion (51% [45 of 89] and 35% [33 of 94]), and injection-site pain (8% [seven of 89] and 49% [46 of 94]), and the most frequently reported solicited systemic symptoms were sore throat (28% [25 of 89]) for M2SR and decreased activity (26% [24 of 94]) for the M2SR plus Fluzone HD group. In the Fluzone HD plus placebo group, the most frequently reported local symptom was injection-site pain (48% [44 of 92]) and systemic symptom was muscle aches (22% [20 of 92]). The frequency of participants with any treatment-emergent adverse event related to vaccination was low across all groups (2-5%). One serious adverse event was reported, in a participant in the Fluzone HD plus placebo group. M2SR with Fluzone HD induced seroconversion (≥four-fold increase in haemagglutination inhibition antibodies from baseline to day 29) in 44 (48%) of 91 participants, compared with 28 (31%) of 90 participants who seroconverted in the Fluzone HD plus placebo group (p=0·023). M2SR with Fluzone HD also induced mucosal and cellular immune responses. The H3N2 M2SR vaccine coadministered with Fluzone HD in older adults was well tolerated and provided enhanced immunogenicity compared with Fluzone HD administered alone, suggesting potential for improved efficacy of influenza vaccination in this age group. Additional studies are planned to assess efficacy. US Department of Defense.

Incidence of Postsurgical Intraocular Inflammation 6 Months After Implantation with a Multifocal Intraocular Lens.

This study assessed the incidence of postsurgical intraocular inflammation after cataract extraction by phacoemulsification and implantation with AcrySof IQ ReSTOR intraocular lenses (IOLs) produced using an updated manufacturing process. Incidence rates were compared with historical rates of postsurgical intraocular inflammation. This was a prospective, multicenter, post-approval study at 34 sites. Patients aged ≥22 years received a study lens in at least 1 eye. Postsurgical intraocular inflammation (aqueous cell grade ≥3+ within 14 days after surgery, aqueous cell ≥2+ at 14 to ≤60 days after surgery, or aqueous cell ≥1+ at >60 days) was assessed within a 180-day period after implantation. Rates of toxic anterior segment syndrome (TASS), acute postoperative endophthalmitis, chronic postoperative endophthalmitis, and uncategorized cases of postsurgical intraocular inflammation were assessed. Ocular adverse events (AEs) and ocular adverse device effects (ADEs) were evaluated. Historical rates of postsurgical intraocular inflammation were determined from the 2011-2013 Medicare Limited Data Set files (a 5% sample of the Medicare data set representative of patients aged ≥65 years). Final safety analysis set included 3357 eyes (1792 patients; mean age, 68.6 ± 7.9 years). Postsurgical intraocular inflammation (any type) rate was 5.1 per 1000 attempted IOL implants (95% CI, 2.95, 8.10). TASS, acute postoperative endophthalmitis, and uncategorized inflammation rates were 0.6 (95% CI, 0.07, 2.15), 0.3 (95% CI, 0.01, 1.66), and 4.2 (95% CI, 2.28, 6.99) per 1000 attempted IOL implants, respectively. There were no events of chronic postoperative endophthalmitis. Ocular AEs and ADEs were reported in 17% and 1.5% of eyes, respectively. Most common ADEs were halo (0.63%) and glare (0.51%). The historical postsurgical inflammation rate from 221,519 cataract procedures was 10.3/1000 cataract surgeries, and the endophthalmitis rate was 1.2/1000 surgeries. The updated IOL manufacturing process resulted in postoperative intraocular inflammation rates that were substantially lower than the historic rate.

Switching to tenofovir alafenamide in patients with virologically suppressed chronic hepatitis B and renal or hepatic impairment: final week 96 results from an open-label, multicentre, phase 2 study

Phase 3 studies in patients with chronic hepatitis B have shown tenofovir alafenamide to have non-inferior efficacy to tenofovir disoproxil fumarate, with improved renal and bone safety. We conducted this study to evaluate the safety and efficacy of switching to tenofovir alafenamide in participants with chronic hepatitis B and renal or hepatic impairment. This open-label, multicentre, phase 2 study was done in eight countries or territories at 30 sites. We recruited adults (≥18 years) with chronic hepatitis B who were virally suppressed on nucleoside or nucleotide analogues and had renal impairment (part A: moderate or severe in cohort 1 [estimated glomerular filtration rate by the Cockcroft-Gault formula (eGFRCG) 15-59 mL/min] or end-stage renal disease [eGFRCG <15 mL/min] on haemodialysis in cohort 2) or hepatic impairment including decompensation (part B: Child-Turcotte-Pugh score 7-12). Participants switched to 25 mg of tenofovir alafenamide given orally once daily for 96 weeks. The primary endpoint was the proportion of participants with viral suppression (HBV DNA <20 IU/mL) at week 24 by missing-equals-failure analysis. Efficacy (full analysis set) and safety (safety analysis set) analyses included all enrolled participants who received at least one dose of the study drug. Week 96 safety was assessed, including renal and bone parameters. This trial is registered at ClinicalTrials.gov, NCT03180619, and is completed. 124 participants (93 in part A [78 in cohort 1 and 15 in cohort 2] and 31 in part B) were enrolled between Aug 11, 2017, and Oct 17, 2018, and included in the full and safety analysis sets. 106 (85%) participants completed the study. There were 69 (74%) men and 24 (26%) women in part A and 21 (68%) men and ten (32%) women in part B. At week 24, 91 (97·8%, 95% CI 92·4 to 99·7) of 93 individuals in part A (76 [97·4%, 91·0 to 99·7] of 78 in cohort 1 and 15 [100·0%, 78·2 to 100·0] of 15 in cohort 2) and 31 (100·0%, 88·8 to 100·0) in part B had HBV DNA of less than 20 IU/mL. By week 96, the most common adverse event was upper respiratory tract infection, which occurred in 14 (15%) participants in part A and in six (19%) participants in part B. Serious adverse events occurred in 20 (22%) part A participants and in ten (32%) part B participants; none were related to treatment. No treatment-related deaths occurred. At week 96, median change in estimated glomerular filtration rate (Cockcroft-Gault method) was 1·0 mL/min (IQR -2·8 to 4·5) in cohort 1 and -2·4 mL/min (-11·4 to 10·7) in part B. Mean changes in spine and hip bone mineral density were 1·02% (SD 4·44) and 0·20% (3·25) in part A and -0·25% (3·91) and 0·28% (3·25) in part B. Tenofovir alafenamide might offer continued antiviral efficacy and a favourable safety profile for patients with renal or hepatic impairment and chronic hepatitis B switching from tenofovir disoproxil fumarate or other antivirals. Gilead Sciences.

Time to prerandomization seizure count design sufficiently assessed the safety and tolerability of perampanel for the treatment of primary generalized tonic-clonic seizures.

Static assignment of participants in randomized clinical trials to placebo or ineffective treatment confers risk from continued seizures. An alternative trial design of time to exceed prerandomization monthly seizure count (T-PSC) has replicated the efficacy conclusions of traditionally designed trials, with shorter exposure to placebo and ineffective treatment. Trials aim to evaluate efficacy as well as safety and tolerability; therefore, we evaluated whether this T-PSC design also could replicate the trial's safety and tolerability conclusions. We retrospectively applied the T-PSC design to analyze treatment-emergent adverse events (TEAEs) from a blinded, placebo-controlled trial of perampanel for primary generalized tonic-clonic seizures (NCT01393743). The safety analysis set consisted of 81 and 82 participants randomized to perampanel and placebo arms, respectively. We evaluated the incidences of TEAEs, treatment-related TEAEs, serious TEAEs, and TEAEs of special interest that occurred before T-PSC relative to those observed during the full-length trial. Of the 67 and 59 participants who experienced TEAEs in the perampanel and placebo arms during full-length trial, 66 (99%) and 54 (92%) participants experienced TEAEs with onset occurring before T-PSC, respectively. When limited to treatment-related TEAEs, 55 of 56 (98%) and 32 of 37 (86%) participants reported treatment-related TEAEs that occurred before T-PSC in the perampanel and placebo arms, respectively. There were more TEAEs after T-PSC with placebo as compared to perampanel (Fisher exact odds ratio = 8.6, p = .035), which resulted in overestimation of the difference in TEAE rate. There was a numerical reduction in serious TEAEs (3/13 occurred after T-PSC, one in placebo and two in perampanel). Almost all TEAEs occurred before T-PSC. More treatment-related TEAEs occurred after T-PSC for participants randomized to placebo than perampanel, which may be due to either a shorter T-PSC or delayed time to TEAE for placebo.

A single-arm, prospective study on the efficacy and safety of TACE-HAIC combined with lenvatinib and tislelizumab in the treatment of unresectable hepatocellular carcinoma.

e16143 Background: Hepatocellular carcinoma is one of the common tumors in China. In recent years, innovative drugs such as molecular targeted drugs and immune preparations have begun to be used clinically and have achieved good results. Interventional therapy combined with targeted immunotherapy has become a hot topic in HCC treatment research. However, the matching mode, application timing, efficacy and safety of various combination treatment options are still unclear. Therefore, a study of TACE-HAIC combined with lenvatinib and tislelizumab in the treatment of unresectable hepatocellular carcinoma is conducted to evaluate the efficacy and safety. Methods: According to the inclusion and exclusion criteria, 15 patients with unresectable hepatocellular carcinoma were included, all of whom received TACE-HAIC combined with lenvatinib and tislelizumab. The mRECIST criteria is used to evaluate the objective response rate (ORR) and disease control rate (DCR).The CTCAE version 5.0 is used to grade treatment-related adverse events of TACE-HAIC combined with lenvatinib and tislelizumab. Results: Among the 15 patients included in the study, 14 are male and 1 is female. All patients were treated with TACE-HAIC combined with lenvatinib and tislelizumab as planned, and the treatment was well tolerated. The total number of patients for optimal efficacy evaluation is 15, including 5 patients with CR, 8 patients with PR, and 2 patients with SD. The ORR is 86.7%, and DCR is 100% in best efficacy. In the safety analysis set (n = 15), none TEAEs is ≥ grade 3. In the treatment-related adverse events, abdominal pain(8/15, 53.3%), fever(4/15, 26.7%), vomiting(4/15, 26.7%), weight loss(4/15, 26.7%), nausea(2/15, 13.3%), neutropenia(2/15, 13.3%) and liver function damage(1/15, 6.7%) are all ≤ grade 2. Conclusions: TACE-HAIC combined with lenvatinib and tislelizumab has definite efficacy in the treatment of patients with unresectable hepatocellular carcinoma, with high objective response rate, good treatment tolerance, and controllable treatment-related adverse events. This therapy may be a treatment option for patients with unresectable hepatocellular carcinoma. Clinical trial information: ChiCTR2300067362. [Table: see text]