Co-primary Endpoints Research Articles

Efficacy and safety of the combination of envafolimab and lenvatinib in unresectable hepatocellular carcinoma: a single-arm, multicentre, exploratory phase II clinical study.

Currently, therapeutic combinations of immune checkpoint inhibitors (ICIs) with anti-angiogenic agents have shown promising outcomes and have the potential to establish a new standard of care. The efficacy and safety of the first-line combination of envafolimab (an ICI) and lenvatinib (an anti-tumor angiogenesis drug) for the treatment of patients with inoperable hepatocellular carcinoma (HCC) have not been demonstrated. Unresectable HCC patients with an Eastern Cooperative Oncology Group (ECOG) physical status score ≤ 1 and a Child-Pugh score ≤ 7 who had not received systemic therapy were included in this single-arm, exploratory, multicentre phase II clinical study. All patients were required to meet the criteria of being at least 18 years of age, having no history of other malignancies, and existing at least one measurable lesion. The patients were treated with envafolimab (150mg, QW, subcutaneous) in combination with lenvatinib (12 mg for patients weighing over 60 kg, 8 mg for patients weighing under 60 kg). The co-primary endpoint of the study was overall survival (OS), while surrogate endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Between March 2022 and April 2023, 36 patients were enrolled, 30 of whom were treated with envafolimab plus lenvatinib. At data cutoff, the median follow-up duration was 20 months (95% CI 18.9-21.1). Among the 30 assessable patients (patients treated according to the trial protocol), the median overall survival (mOS) and median progression-free survival (mPFS) for the therapy comprising envafolimab alongside lenvatinib were 18.5 months (95% CI 13.2-23.8) and 9.4 months (95% CI 1.6-15.6), respectively. The ORR and the DCR (evaluated according to mRECISTcriteria) reached 40% and 80%, respectively. In terms of safety, 23 patients (76.7%) experienced at least one treatment-related adverse event (TRAE), of which the most common was elevated aspartate aminotransferase (AST, 23.3%). Furthermore, grade 3 and higher TRAEs occurred in 30%. This study demonstrates that envafolimab in combination with lenvatinib exhibits favourable anti-cancer activity and a manageable safety profile for the first-line treatment of patients with unresectable HCC.

Safety, effectiveness and immunogenicity of heterologous mRNA-1273 boost after prime with Ad26.COV2.S among healthcare workers in South Africa: The single-arm, open-label, phase 3 SHERPA study.

Limited studies have been conducted on the safety and effectiveness of heterologous COVID-19 vaccine boosting in lower income settings, especially those with high-HIV prevalence., The Sisonke Heterologous mRNA-1273 boost after prime with Ad26.COV2.S (SHERPA) trial evaluated a mRNA-1273 boost after Ad26.COV2.S priming in South Africa. SHERPA was a single-arm, open-label, phase 3 study nested in the Sisonke implementation trial of 500000 healthcare workers (HCWs). Sisonke participants were offered mRNA-1273 boosters between May and November 2022, when Omicron sub-lineages were circulating. Adverse events (AE) were self-reported, and co-primary endpoints (SARS-CoV-2 infections and COVID-19 hospitalizations or deaths) were collected through national databases. We used Cox regression models with booster status as a time-varying covariate to determine the relative vaccine effectiveness (rVE) of the mRNA-1273 booster among SHERPA versus unboosted Sisonke participants. Of 11248 SHERPA participants in the rVE analysis cohort (79.3% female, median age 41), 45.4% had received one and 54.6% two Ad26.COV2.S doses. Self-reported comorbidities included HIV (18.7%), hypertension (12.9%) and diabetes (4.6%). In multivariable analysis including 413161 unboosted Sisonke participants, rVE of the booster was 59% (95%CI 29-76%) against SARS-CoV-2 infection: 77% (95%CI 9-94%) in the one-Ad26.COV2.S dose group and 52% (95%CI 13-73%) in the two-dose group. Severe COVID-19 was identified in 148 unboosted Sisonke participants, and only one SHERPA participant with severe HIV-related immunosuppression. Of 11798 participants in the safety analysis, 228 (1.9%) participants reported 575 reactogenicity events within 7 days of the booster (most commonly injection site pain, malaise, myalgia, swelling, induration and fever). More reactogenicity events were reported among those with prior SARS-CoV-2 infections (adjusted odds ratio [aOR] 2.03, 95%CI 1.59-2.59) and less among people living with HIV (PLWH) (aOR 0.49, 95%CI 0.34-0.69). There were 115 unsolicited adverse events (AEs) within 28 days of vaccination. No related serious AEs were reported. In an immunogenicity sub-study, mRNA-1273 increased binding and neutralizing antibody titres and spike-specific T-cell responses 4 weeks after boosting regardless of the number of prior Ad26.COV2.S doses, or HIV status, and generated Omicron spike-specific cross-reactive responses. mRNA-1273 boosters after one or two Ad26.COV2.S doses were well-tolerated, safe and effective against Omicron SARS-CoV-2 infections among HCWs and PLWH. Trial registration: The SHERPA study is registered in the Pan African Clinical Trials Registry (PACTR): PACTR202310615330649 and the South African National Clinical Trial Registry (SANCTR): DOH-27-052022-5778.

Symptomatic Improvement in Adults and Adolescents with Eosinophilic Esophagitis Requires Higher Systemic Dupilumab Exposure than Histologic Response.

We assessed potential mechanisms behind the requirement for more frequent dupilumab dosing in eosinophilic esophagitis (EoE) compared with other approved indications. Results for the phase 3 LIBERTY EoE TREET study co-primary endpoints (proportion of patients achieving a peak intraepithelial eosinophil count of ≤6 eosinophils per high-power field and absolute change from baseline in Dysphagia Symptom Questionnaire total score) were pooled in exposure-response analyses. A steep initial relationship then plateau was observed between higher dupilumab steady state trough concentrations (Ctrough) and decreased eosinophilic infiltration at Week 24, while a graded exposure-response relationship was observed for symptomatic improvement at Week 24. Patients with the highest exposures were more likely to achieve greater symptomatic benefit, independent of strictures or history of dilation. The dupilumab 300 mg qw regimen approved for adults and adolescents with EoE weighing ≥40 kg is supported by dose- and exposure-response relationships.

Pharmacokinetics and safety of pirfenidone in individuals with chronic kidney disease (CKD) stage G2 and G3a: a single-dose, Phase I, Bridging study.

Pirfenidone is an inhibitor of transforming growth factor-beta 1 (TGF-β1) and is being developed for the treatment of diabetic kidney disease (DKD). We assessed the pharmacokinetics (PK) and safety of a single dose of pirfenidone in individuals with CKD stages G2/G3a. In this phase I bridging study, patients with CKD stages G2 or G3a, aged 18-70 years, with a body mass index of 18-26 kg/m2, and glomerular filtration rate (eGFR) ranging from 45 to 89 ml/min/1.73m2, received a single oral dose of 400 mg pirfenidone capsules 30 minutes after a standard breakfast. The pharmacokinetic parameters of the two groups were measured and compared after blood and urine collection. The co-primary endpoints were the area under the plasma concentration-time curve from time zero to 36 hours (AUC0-36) and the maximum observed plasma concentration (Cmax) of pirfenidone. Safety was a secondary endpoint. The trial has been registered on ClinicalTrials.gov (ChiCTR2300077297). A total of 20 subjects participated in this study. There were no significant differences between the control group and the patient group (CKD stages G2/G3a) in terms of plasma Cmax, the time to reach the maximum observed concentration (Tmax), and elimination half-life(t1/2). However, the Vz/F of the patient group (CKD G2 stage) was significantly higher than that of the control group. Renal accumulation rate, renal clearance rate (CLr), and urine drug concentration also showed no significant differences. No severe adverse events occurred during the trial. These results indicate that the PK and safety of pirfenidone are not influenced by renal function. Individuals with renal impairment may not require dose adjustments.

Haematopoietic gene therapy of non-conditioned patients with Fanconi anaemia-A: results from open-label phase 1/2 (FANCOLEN-1) and long-term clinical trials

Allogeneic haematopoietic stem-cell transplantation is the standard treatment for bone marrow failure (BMF) in patients with Fanconi anaemia, but transplantation-associated complications such as an increased incidence of subsequent cancer are frequent. The aim of this study was to evaluate the safety and efficacy of the infusion of autologous gene-corrected haematopoietic stem cells as an alternative therapy for these patients. This was an open-label, investigator-initiated phase 1/2 clinical trial (FANCOLEN-1) and long-term follow-up trial (up to 7 years post-treatment) in Spain. Mobilised peripheral blood (PB) CD34+ cells from nine patients with Fanconi anaemia-A in the early stages of BMF were transduced with a therapeutic FANCA-encoding lentiviral vector and re-infused without any cytotoxic conditioning treatment. The primary efficacy endpoint of FANCOLEN-1 was the engraftment of transduced cells, as defined by the detection of at least 0·1 therapeutic vector copies per nucleated cell of patient bone marrow (BM) or PB at the second year post-infusion, without this percentage having declined substantially over the previous year. The safety coprimary endpoint was adverse events during the 3 years after infusion. The completed open-label phase 1/2 and the ongoing long-term clinical trials are registered with ClinicalTrials.gov, NCT03157804; EudraCT, 2011-006100-12; and NCT04437771, respectively. There were eight evaluable treated patients with Fanconi anaemia-A. Patients were recruited between Jan 7, 2016 and April 3, 2019. The primary endpoint was met in five of the eight evaluable patients (62·50%). The median number of therapeutic vector copies per nucleated cell of patient BM and PB at the second year post-infusion was 0·18 (IQR 0·01-0·20) and 0·06 (0·01-0·19), respectively. No genotoxic events related to the gene therapy were observed. Most treatment-emergent adverse events (TEAEs) were non-serious and assessed as not related to therapeutic FANCA-encoding lentiviral vector. Nine serious adverse events (grade 3-4) were reported in six patients, one was considered related to medicinal product infusion, and all resolved without sequelae. Cytopenias and viral infections (common childhood illnesses) were the most frequently reported TEAEs. These results show for the first time that haematopoietic gene therapy without genotoxic conditioning enables sustained engraftment and reversal of BMF progression in patients with Fanconi anaemia. European Commission, Instituto de Salud Carlos III, and Rocket Pharmaceuticals.

Efficacy and safety of lebrikizumab combined with topical corticosteroids in Japanese patients with moderate-to-severe atopic dermatitis: a phase 3, double-blind, placebo-controlled, randomized clinical trial (ADhere-J)

ABSTRACT Objective To evaluate efficacy and safety of lebrikizumab combined with topical corticosteroids (TCS) in Japanese patients with moderate-to-severe atopic dermatitis (AD). Methods Phase 3, randomized, double-blind, placebo-controlled study (ADhere-J; NCT04760314) conducted at 37 centers in Japan (March 2021–February 2023), comprising 16-week induction (reported herein) and 52-week maintenance periods. Overall, 286 patients aged ≥12 years and ≥40 kg were randomized (interactive web response system) to subcutaneous placebo, lebrikizumab 250 mg every 4 weeks (Q4W), or lebrikizumab 250 mg every 2 weeks (Q2W) with TCS (82, 81, and 123 patients, respectively). Coprimary endpoints were proportions of patients achieving (1) Investigator’s Global Assessment score of 0 or 1 (IGA [0,1]) with ≥2-point improvement from baseline, and (2) ≥75% improvement from baseline in Eczema Area and Severity Index (EASI 75) at week 16. Results At week 16, compared with placebo, a significantly greater proportion of the lebrikizumab Q4W and Q2W groups achieved IGA (0,1) (6.1% vs. 29.1% and 33.4%, respectively; both p < 0.001) and EASI 75 (13.4% vs. 47.2% and 51.2%, respectively; both p < 0.001). Serious adverse events (AEs) occurred in 2.4%, 0%, and 0.8% of placebo, lebrikizumab Q4W and Q2W groups, respectively. Common treatment-emergent AEs, including pyrexia (placebo: 15.9%; lebrikizumab Q4W/Q2W: 18.5%/20.3%), conjunctivitis allergic (placebo: 4.9%; lebrikizumab Q4W/Q2W: 12.3%/17.1%), and conjunctivitis (placebo: 2.4%; lebrikizumab Q4W/Q2W: 6.2%/9.8%), were more frequent with lebrikizumab; most were mild or moderate. Conclusion Consistent with global data, lebrikizumab demonstrated clinical improvements with a positive benefit-risk profile in Japanese adults and adolescents with moderate-to-severe AD through 16 weeks.

NivobotulinumtoxinA in the Treatment of Glabellar Lines With or Without Concurrent Treatment of Lateral Canthal Lines in Two Phase 3 Clinical Trials.

Botulinum neurotoxins used in aesthetic medicine require reconstitution before administration, which may be inconvenient and present errors among injectors. Evaluate the efficacy and safety of ready-to-use nivobotulinumtoxinA liquid formulation for the treatment of glabellar lines (GL) with/without treatment of lateral canthal lines (LCL). Two multicenter, phase 3, double-blind, randomized trials enrolled participants with moderate-to-severe GL (Study 001) or moderate-to-severe GL+LCL (Study 005). Participants received double-blind nivobotulinumtoxinA (20U) or placebo (Period 1) then ≤2 open-label nivobotulinumtoxinA GL treatments (Period 2) in Study 001 or double-blind nivobotulinumtoxinA 20U (GL), nivobotulinumtoxinA 44U (GL+LCL), or placebo (Period 1) then ≤2 double-blind injections of the same treatment (Period 2) in Study 005. The composite primary endpoint was the proportion of participants achieving ≥2-grade improvement in Facial Wrinkle Scale (FWS) at maximum frown on investigator and participant assessment; co-primary endpoints were investigator- and participant-assessed FWS "none or mild" rating. At Day 30, significantly higher responder rates were observed for the composite primary endpoint with GL treatment alone (Study 001, 46.1%; Study 005, 45.1%) and GL+LCL (Study 005, 41.3%) versus placebo (0%; all P < 0.001). Responder rates of "none or mild" by investigator and participant assessment, respectively, were significantly higher for GL treatment alone (Study 001, 77.2% and 65.0%; Study 005, 74.3% and 68.8%) and GL+LCL (Study 005, 74.0% and 61.2%) versus placebo (all P < 0.001). Adverse events were similar between treatment groups and placebo. Liquid nivobotulinumtoxinA was effective and well tolerated for treating moderate-to-severe GL alone or with LCL.

Trilaciclib prior to FOLFOXIRI/bevacizumab for patients with untreated metastatic colorectal cancer: phase 3 PRESERVE 1 trial.

In metastatic colorectal cancer (mCRC), improvements in survival from combining leucovorin/fluorouracil/oxaliplatin/irinotecan (FOLFOXIRI) with bevacizumab have come at the risk of increased rates of high-grade toxicities. Trilaciclib is indicated to decrease the incidence of chemotherapy-induced myelosuppression in patients receiving standard-of-care chemotherapy for extensive-stage small cell lung cancer. Patients with untreated mCRC were randomized 1:1 to trilaciclib (n = 164) or placebo (n = 162) prior to FOLFOXIRI/bevacizumab for up to 12 cycles (induction), followed by trilaciclib or placebo prior to fluorouracil/leucovorin/bevacizumab (maintenance). Co-primary endpoints were duration of severe (grade 4) neutropenia (DSN) in cycles 1-4 and occurrence of severe neutropenia (SN) during induction. Secondary endpoints included antitumor efficacy, survival, and safety. : The study met its co-primary endpoints. Administering trilaciclib prior to FOLFOXIRI/bevacizumab resulted in significant reductions in DSN in cycles 1-4 versus placebo (mean, 0.1 vs. 1.3 days; P < .001) and occurrence of SN during induction (1.3% vs. 19.7%; adjusted relative risk [96% CI], 0.07 [0.0, 0.3]; P < .001). Grade 3/4 adverse events, including neutropenia, diarrhea, and leukopenia, were less frequent with trilaciclib versus placebo (64.8% vs. 73.1%). Trilaciclib was associated with fewer chemotherapy dose reductions and delays, and reduced administration of supportive therapies, compared with placebo. Objective response rate (41.6% vs. 57.1%; P = .009) and median progression-free survival (10.3 vs. 13.1 months; P < .001) were significantly lower with trilaciclib versus placebo. : Administering trilaciclib prior to FOLFOXIRI/bevacizumab protected the neutrophil lineage from the effects of chemotherapy-induced myelosuppression. However, antitumor efficacy endpoints favored placebo.

Efficacy and safety of mirikizumab in patients with moderately-to-severely active Crohn's disease: a phase 3, multicentre, randomised, double-blind, placebo-controlled and active-controlled, treat-through study.

Mirikizumab, a humanised monoclonal antibody that inhibits IL-23p19, is effective in moderate-to-severe ulcerative colitis. We aimed to evaluate the efficacy and safety of mirikizumab in patients with moderately-to-severely active Crohn's disease. VIVID-1 was a global phase 3, randomised, double-blind, double-dummy, placebo-controlled and active-controlled, treat-through study. The study enrolled adult patients at 324 sites (hospitals or medical centres, clinical practices, and clinical research sites) in 33 countries across Europe, Asia, North America, Central America, South America, and Australia. Adult patients with moderately-to-severely active Crohn's disease and previous inadequate response, loss of response, or intolerance to one or more approved biological therapies or conventional therapies were randomly assigned 6:3:2 to receive mirikizumab 900 mg intravenously at weeks 0, 4, and 8, then 300 mg subcutaneously every 4 weeks from weeks 12 to 52; ustekinumab about 6 mg/kg intravenously at week 0, then 90 mg subcutaneously every 8 weeks from weeks 8 to 52; or placebo. The coprimary endpoints assessing superiority of mirikizumab over placebo were composite endpoints: patient-reported outcome (PRO) clinical response at week 12 and endoscopic response at week 52 (endoscopic response-composite), and PRO clinical response at week 12 and Crohn's Disease Activity Index (CDAI) clinical remission at week 52 (CDAI clinical remission-composite). The adjusted risk differences were calculated, and the comparison was performed by the Cochran-Mantel-Haenszel test. Non-responder imputation was used. VIVID-1 was registered on ClinicalTrials.gov, NCT03926130, and is now complete. Between July 23, 2019, and Aug 23, 2023, 1150 patients were randomly assigned and received study treatment (safety population); 1065 patients were included in the efficacy population and received mirikizumab (n=579), ustekinumab (n=287), or placebo (n=199). Both coprimary endpoints were met: endoscopic response-composite was reached in 220 (38·0%) of 579 patients on mirikizumab versus 18 (9·0%) of 199 on placebo (99·5% CI 20·6-36·8; p<0·0001); CDAI clinical remission-composite was reached in 263 (45·4%) of 579 patients on mirikizumab versus 39 (19·6%) of 199 patients on placebo (99·5% CI 15·9-35·6; p<0·0001). The incidence rates of overall adverse events and discontinuations in patients treated with mirikizumab were lower compared with placebo. The most common adverse event across the three groups was COVID-19. Serious adverse events were reported in 65 (10·3%) of 630 patients on mirikizumab, 33 (10·7%) of 309 patients on ustekinumab, and 36 (17·1%) of 211 patients on placebo. There were three deaths during VIVID-1, one in the ustekinumab group, and two in the placebo group, including one in a placebo non-responder who switched to mirikizumab after week 12. None of the deaths were considered related to the study drug. The safety of mirikizumab in Crohn's disease was consistent with its known favourable profile. Mirikizumab was safe and effective as induction and maintenance treatment for patients with moderately-to-severely active Crohn's disease who had intolerance, inadequate response, or loss of response to standard therapy. Eli Lilly and Company.

Efficacy and safety of safinamide in Parkinson's disease patients with motor fluctuations without levodopa dosage escalation over 18 weeks: KEEP study.

This multicentre, prospective, single-arm study evaluated safinamide as add-on therapy to levodopa in Korean patients with Parkinson's disease (PD) with motor fluctuations with≥1.5 h of "off" time daily, who took levodopa≥3 times/day (n = 199). Baseline levodopa and dopamine agonist doses were maintained without escalation during the 18-week treatment period. Participants received safinamide 50 mg/day for 2 weeks and 100 mg/day thereafter. PD diaries and questionnaires (Parkinson's Disease Questionnaire, PDQ-39; Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale, MDS-UPDRS part 3 and part 4; King's Parkinson's Disease Pain Scale, KPPS; Mini-Mental State Examination, MMSE) were assessed at baseline and at week 18. Treatment-emergent adverse events (TEAEs) were recorded. Mean disease duration was 6.6 years, and mean levodopa equivalent daily dose was 721.1 mg/day. At week 18, significant improvements from baseline were seen for the co-primary endpoints, mean daily "off" time (-1.3±2.4 h, p<0.001) and quality of life (QoL) based on PDQ-39 summary index (-2.7±10.3, p<0.001), Moreover, significant improvements were seen in motor symptoms and motor complications (MDS-UPDRS part 3 and 4), daily "on" time without dyskinesia (all p<0.001) and pain (KPPS; p = 0.013). TEAEs occurred in 40.2% of patients, with most being mild in severity. In conclusion, safinamide at a dosage of 100 mg/day significantly improved motor symptoms, QoL, and pain, and demonstrated a favourable safety profile without levodopa dosage escalation during the 18-week treatment period in Korean patients with PD.Trial registration number and date: NCT05312632, First Posted: April 5, 2022.

BIOM-12. ALLIANCE A071401: GENOMICALLY GUIDED PHASE II TRIAL OF ABEMACICLIB IN PATIENTS WITH GRADE 2/3 MENINGIOMAS HARBORING SOMATIC NF2 OR CDK PATHWAY ALTERATIONS

Abstract BACKGROUND Patients with meningiomas that have progressed after surgery and/or radiation have limited treatments. Loss of NF2 and CDKN2A/B are common in higher-grade meningiomas and promote meningioma progression. We evaluated the efficacy of abemaciclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, as part of Alliance A071401, a genomically-driven phase II trial in recurrent or progressive meningiomas. METHODS Eligible patients (pts) with grade 2/3 tumors and NF2 mutations or CDK pathway alterations were treated with abemaciclib 200 mg orally twice daily. Two co-primary endpoints were used: progression-free survival at 6 months (PFS6) and response rate (RR); the trial would be declared positive if either endpoint was met. Twenty-four evaluable pts provided ≥85% power to detect a PFS6 ≥41.5% (vs. null 15%; alpha=0.02), and ≥89% power to detect RR ≥20% (vs. null 2.5%; alpha=0.021). RESULTS Of 83 pts screened while the abemaciclib arm was open between September 15, 2021 and October 3, 2022, 36 eligible pts received abemaciclib. The observed PFS6 rate in the first 24 evaluable pts was 54% (95% CI 33-75%), thus the study met PFS6 endpoint. Of all 35 evaluable pts, median PFS was 7.6 months (95% CI 3.6-17.1 months), estimated 6-month PFS was 55% (95% CI 40-75%) and estimated 6-month OS was 88% (95% CI 77-100%). No objective responses were observed. Of the 36 pts who started treatment, two had a grade 4 adverse event at least possibly related to treatment which included ALT elevation(1), AST elevation(1) and vomiting(1). Patients with NF2 alterations (n=24) had favorable PFS6 outcomes (58%, 95% CI 37-78%) compared to those with CDK (n=4, 25%, 95% CI 1-81%) and CDK+NF2 alterations (n=7, 29% 95% CI 4-71%), (Fisher’s Exact p=0.036). CONCLUSIONS Abemaciclib was well-tolerated and resulted in improved PFS6, meeting the trial’s co-primary endpoint. Abemaciclib warrants further investigation for the treatment of patients with progressive meningiomas.

CTNI-24. WF-1801: SINGLE ARM PILOT STUDY OF RAMIPRIL FOR PREVENTION OF RADIATION-INDUCED COGNITIVE DECLINE IN GLIOBLASTOMA PATIENTS RECEIVING CHEMORADIOTHERAPY

Abstract BACKGROUND Patients with glioblastoma (GBM) experience cognitive decline after chemoradiation. Radiation therapy (RT) to the brain creates chronic inflammation believed to contribute to cognitive decline. Ramipril counteracts neuroinflammatory changes in pre-clinical models when given during RT. METHODS This prospective single arm study (WF-1801) coordinated by the Wake Forest NCI Community Oncology Research Program (NCORP) Research Base assessed feasibility, tolerability, and potential efficacy of using ramipril in patients with GBM. Eligibility and treatment paradigms mirrored NRG/RTOG 0825 allowing for outcomes from the placebo arm to be used for comparison. Participants took ramipril during 6 weeks of chemoradiation with temozolomide and for 3 months after RT. Patients completed cognitive testing (HVLT-R, TMT, and COWA) and patient-reported outcomes at baseline, RT completion, and 1 and 4 months after RT. Co-primary endpoints were retention rate (compliance with 75% doses and completion of cognitive testing) and change in cognitive composite score 1 month after RT. RESULTS 75 participants were accrued between 3/25/2019 and 11/14/23: 65% were male, 89% White, median age 63 years. The NRG/RTOG 0825 placebo cohort (n=247) was younger (median 57, p&amp;lt;0.0001) with more White participants (95%, p=0.04). The overall retention rate in WF-1801 was 48% (one-sided 95% CI: 38%-100%); 61% completed &amp;gt;=75% of doses; 57% completed cognitive testing at all time points. The median (range) change in cognitive composite score 1 month after RT was 0.01 (-82.6, 13.0) reflecting an improvement from baseline. However, this was not significantly different from the NRG/RTOG 0825 placebo group median of 0.10 (-48.2, 8.6); p=0.49. CONCLUSION The overall retention rate fell short of our pre-specified endpoint of &amp;gt; 65%; however, medication compliance was high and well-tolerated in retained patients. Future investigations could identify patient subsets who may benefit more from concurrent ramipril. WF-1801 (NCT03475186) funded by UG1CA189824. NRG/RTOG-0825 (NCT00884741) funded by U10CA180868 and U10CA021661.

Effects of Implementing a Heart Failure Order Set to Optimize Guideline-Directed Medical Therapy and Diuresis in Patients with Acute Heart Failure.

Background: Utilization of guideline-directed medical therapy in patients hospitalized for acute heart failure is suboptimal during the hospitalization and after discharge. An inpatient heart failure order set may be a convenient and useful intervention to improve heart failure therapy in the inpatient setting. Methods: This is a retrospective study that assessed the use of an inpatient heart failure order set on pharmacologic therapy in patients hospitalized for acute heart failure from May to August 2022. Patients with heart failure with an ejection fraction less than 50% were included in the analysis. The co-primary endpoints were maintenance or optimization of guideline-directed medical therapy during the hospitalization. Results: Maintenance of guideline-directed medical therapy was significantly greater when providers used the heart failure order set (OR 2.35, 95% CI 1.03-5.33, P = .041). Optimization of guideline-directed medical therapy was also statistically greater with use of the order set (OR 11.31, 95% CI 4.37-29.31, P < .001). Conclusions: An inpatient heart failure order set may be an effective strategy to improve heart failure pharmacotherapy in patients hospitalized with acute heart failure.

Renal Effects of Combination Phosphodiesterase V Inhibition and Low-Dose B-Type Natriuretic Peptide in Acute Heart Failure: A Randomized Clinical Trial.

Cardiorenal dysfunction with impaired cyclic GMP (cGMP) response is common in patients presenting with acute heart failure (HF). Type V phosphodiesterase (PDEV) is known to be upregulated in HF and may explain the dysfunction of renal response. The aim of this study was to determine whether B-type natriuretic peptide (BNP) alone or in combination with PDEV inhibition improves renal function and increases urinary sodium and cGMP excretion in acute HF. This open-label study included 67 patients hospitalized with acute HF and renal dysfunction. Patients were randomized to standard care, low-dose intravenous BNP (0.005 µg/kg per minute), or combination BNP/PDEV inhibition with sildenafil (25 mg q12 hours) for 48 hours. The coprimary end points were the percent change in estimated glomerular filtration rate and blood urea nitrogen from baseline to 48 hours. Treatment with BNP and BNP/PDEV inhibitor significantly increased plasma cGMP at 24 hours (+25.6% [+9.8%, +84.7%] and +60.8% [+32.3%, +103.8%] for BNP and BNP/PDEV versus -13.5% [-29.1%, +14.2%] with standard care; P=0.001). However, there was no significant change in estimated glomerular filtration rate 0 (-10.8%, +12.7%) for standard care versus 0 (-15.3%, +11.8%) for the BNP group versus -8.8% (-14.3%, +8.3%) for the BNP/PDEV group (P=0.60) or blood urea nitrogen -1.4% (-10.7%, +12.0%) for standard care versus -5.9% (-14.6%, +9.4%) for the BNP group versus +6.9% (-5.3%, +18.8%) for the BNP/PDEV group (P=0.38) between groups. Hypotension was more common in the BNP/PDEV inhibitor group. BNP and combination BNP/PDEV inhibition increased plasma cGMP in patients with acute HF but did not improve renal function or urinary sodium/cGMP excretion. Our study does not support the use of intravenous low-dose BNP with or without PDEV inhibition to enhance renal function in patients admitted with acute HF. URL: https://www.clinicaltrials.gov; Unique identifier: NCT00972569.

Uptake of gonadotrophin-releasing hormone agonists for prevention of premature ovarian insufficiency in women undergoing chemotherapy: an Australian single-centre study.

Treatment-related premature ovarian insufficiency (POI) can result in early-onset menopause and infertility. To assess the prevalence of goserelin use for POI prevention in women with cancer since it was listed by the Australian Pharmaceutical Benefits Scheme in 2018 for this indication. This retrospective study included women aged 18-45 years who received curative-intent alkylating chemotherapy for a malignancy between August 2020 and December 2022 at the Peter MacCallum Cancer Centre. The co-primary end-points were (i) documentation of a discussion with the patient regarding goserelin for POI prevention and (ii) prescription of goserelin for POI prevention prior to chemotherapy commencement. Sixty-six patients were eligible. Fifty patients (76%) had a documented discussion regarding goserelin for POI prevention and 53 patients (80%) were prescribed goserelin for POI prevention. Nulliparous women were more likely to have a discussion regarding goserelin (P = 0.004). Younger women, nulliparous women and those referred to a fertility service were more likely to have been prescribed goserelin for POI prevention (P = 0.003, P = 0.001 and P = 0.002 respectively). Twenty-one of 53 patients (40%) who received goserelin had the first dose administered ≥7 days before chemotherapy commencement. One-quarter of eligible patients did not have a documented discussion regarding goserelin, despite the negative consequences of POI. Efforts are needed to increase the discussion and use of goserelin in all premenopausal women regardless of their fertility interests and to ensure timely administration in those who choose to receive it.

Balancing Fertility Preservation and Treatment Efficacy in (Neo)adjuvant Therapy for Adolescent and Young Adult Breast Cancer Patients: a Narrative Review.

Adolescent and young adult (AYA) breast cancer survivors face a significant risk of infertility due to the gonadotoxic effects of (neo)adjuvant therapy, which complicates their ability to conceive post-treatment. While (neo)adjuvant therapy primarily aims to improve recurrence-free and overall survival, fertility preservation strategies should also be considered for young patients. This narrative review explores recent advancements in fertility preservation techniques, such as oocyte, embryo, and ovarian tissue cryopreservation, and evaluates the feasibility of modifying breast cancer (neo)adjuvant therapy to preserve fertility without compromising survival outcomes. Our review highlights that clinical trials with co-primary endpoints of oncological safety and fertility preservation are limited, and substituting standard treatment regimens solely for fertility preservation is currently not recommended. Nevertheless, new clinical studies have emerged that either exclude highly ovarian-toxic agents, such as cyclophosphamide, or omit adjuvant therapy altogether, even if fertility preservation is not their primary endpoint. Unfortunately, many of these trials have not evaluated ovarian toxicity. Notably, since 2020, major oncology organizations, including the American Society of Clinical Oncology (ASCO), the European Society of Medical Oncology (ESMO) have advocated for the routine assessment of ovarian toxicity in all clinical trials. The review underscores the importance of incorporating ovarian toxicity as a standard endpoint in future trials involving premenopausal breast cancer patients to identify treatment regimens that can effectively balance fertility preservation with treatment efficacy.

Preventing Allogeneic Stem Cell Transplant-Related Cardiovascular Dysfunction: ALLO-Active Trial.

Allogeneic stem cell transplantation (allo-SCT) is an efficacious treatment for hematologic malignancies but can be complicated by cardiac dysfunction and exercise intolerance impacting quality of life and longevity. We conducted a randomized controlled trial testing whether a multicomponent activity intervention could attenuate reductions in cardiorespiratory fitness and exercise cardiac function (co-primary end points) in adults undergoing allo-SCT. Sixty-two adults scheduled for allo-SCT were randomized to a 4-month activity program (n=30) or usual care (UC; n=32). Activity comprised multicomponent exercise training (3 days/week) and sedentary time reduction (≥30 min/day) program and was delivered throughout hospitalization (≈4 weeks) and for 12 weeks after discharge. Physiological assessments conducted before admission and at 12 weeks after discharge included cardiopulmonary exercise testing to quantify peak oxygen uptake ([Formula: see text]), exercise cardiac magnetic resonance imaging for peak cardiac volume (CIpeak) and stroke volume (SVIpeak) index, echocardiography-derived left ventricular ejection fraction and global longitudinal strain, and cardiac biomarkers (cTn-I [troponin-I] and BNP [B-type natriuretic peptide]). Fifty-two participants (84%) completed follow-up (25 activity and 27 UC); median (interquartile range [IQR]) adherence to the activity program was 74% (41-96%). There was a marked decline in [Formula: see text] in the UC program (-3.4 mL‧kg-1‧min-1 [95% CI, -4.9 to -1.8]) that was attenuated with activity (-0.9 mL‧kg-1‧min-1 [95% CI, -2.5 to 0.8]; interaction P=0.029). Activity preserved exercise cardiac function, with preservation of CIpeak (0.30 L‧min-1‧m-2 [95% CI, -0.34 to 0.41]) and SVIpeak (0.6 mL/m2 [95% CI, -1.3 to 2.5]), both of which declined with UC (CIpeak, -0.68 L‧min-1‧m-2 [95% CI, -1.3 to -0.32]; interaction P=0.008; SVIpeak, -2.7 mL/m2 [95% CI, -4.6 to -0.9]; interaction P=0.014). There were no treatment effects of activity on cardiac biomarkers or echocardiographic indices. Multicomponent activity intervention during and after allo-SCT is beneficial for preserving patient cardiorespiratory fitness and exercise cardiac function. These results may have important implications for cardiovascular morbidity and mortality after allo-SCT. URL: https://anzctr.org.au/; Unique identifier: ACTRN12619000741189.

Bimekizumab efficacy and safety in Korean patients with moderate to severe plaque psoriasis: A phase 3, randomized, placebo-controlled, double-blinded study.

Bimekizumab treatment has demonstrated significant improvements in clinical outcomes in patients with moderate to severe plaque psoriasis; however, studies so far have focused on predominantly White patient populations from North America and Europe, with one smaller study in a Japanese population. Here, clinical responses, safety, and tolerability of bimekizumab treatment in Korean patients are reported. Korean patients with moderate to severe plaque psoriasis were randomized to bimekizumab 320 mg every 4 weeks (Q4W) or placebo Q4W to week 16. Co-primary efficacy end points were achievement of ≥90% improvement from baseline in the Psoriasis Area and Severity Index (PASI 90) and Investigator's Global Assessment score of 0/1 (clear/almost clear) at week 16. Secondary efficacy end points included achievement of PASI 75 at week 4 and Dermatology Life Quality Index 0/1 at week 16. Safety outcomes were also assessed. Statistical analysis of the co-primary efficacy end points was performed using a type I error rate, at a two-sided α level of 0.05. Overall, 47 Korean patients were randomized to treatment (bimekizumab: 32, placebo: 15). At week 16, bimekizumab-treated patients had significantly higher clinical responses versus placebo-treated patients (PASI 90: 81.3% vs. 0%; IGA 0/1: 87.5% vs. 0%, p < 0.001 for both). Bimekizumab showed a rapid onset of clinical response, with 75.0% of patients achieving PASI 75 by week 4 (0% in placebo patients [nominal p < 0.001]). A higher proportion of bimekizumab-treated patients achieved DLQI 0/1 at week 16 (46.9% vs. 6.7% in placebo patients, nominal p = 0.007), indicating greater improvements in health-related quality of life (HRQoL) following bimekizumab treatment. Bimekizumab was well-tolerated in Korean patients, with no new safety signals identified. Treatment with bimekizumab led to rapid improvements in clinical responses and HRQoL versus placebo in Korean patients, consistent with responses in global populations. These findings suggest that bimekizumab is an effective and well-tolerated treatment option in Korean patients with psoriasis.

Novel vs established cryoballoon ablation system for atrial fibrillation: a systematic review and meta-analysis

BackgroundRecently a novel cryoballoon ablation (CBA) system (POLARx) for the treatment of atrial fibrillation (AF) has been introduced. ObjectiveWe aimed at systematically reviewing the efficacy and safety of the POLARx to the ArcticFront system. MethodsStructured systematic database search for articles published between 2021 and 2024 reporting the efficacy and/or safety of the POLARx system for AF ablation. The co-primary endpoints were the long-term efficacy and safety of the POLARx system ResultsOf the 24 studies with 5364 patients (weighted mean age 62.4 years) included, 15 compared the POLARx system (1746 patients) to the ArcticFront system (2282 patients). Despite significantly lower temperatures at isolation (POLARx -46.3°C, ArcticFront -31.6°C, p <0.01) and nadir temperatures (POLARx -56.5°C ArcticFront -47.8°C p <0.01), the POLARx system did not show a better acute (98.9% and 99.2% successfully ablated patients, 99.5% and 99.8% successfully ablated pulmonary veins in the POLARx and ArcticFront group, respectively) or long-term efficacy (After a weighted mean follow-up of 12.6 months, the success rate was 69.5% with POLARx and 60.2% with ArcticFront (p = 0.98)). While most complications were similar between the POLARx and ArcticFront group, the incidence of phrenic nerve palsies in the pooled cohorts (all POLARx vs all ArcticFront control patients) differed (2.7% vs. 1.6% in the POLARx vs. ArcticFront group, respectively, OR 1.79 [1.14-2.83], p-value = 0.01). ConclusionThe novel POLARx system provided similar efficiency and acute/long-term efficacy, but showed a higher incidence of phrenic nerve palsies compared to the ArcticFront system.

ARCADIA trials: Can nemolizumab be a valid alternative to the therapies currently available?

ARCADIA 1 and ARCADIA 2 were two randomized, placebo-controlled phase 3 trials showing the effectiveness of nemolizumab with concomitant use of low-to-medium potency topical corticosteroids, and/or with or without topical calcineurin inhibitors, in adults and adolescents with moderate-to-severe atopic dermatitis. Coprimary endpoints were met in the nemolizumab plus background therapy groups in both trials, with significant differences versus placebo.