A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome.

Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is an inborn error of immunity with clinical manifestations including infections, lymphoproliferation, autoimmunity, enteropathy, bronchiectasis, increased risk of lymphoma, and early mortality. Hyperactive PI3Kδ signaling causes APDS and is selectively targeted with leniolisib, an oral, small molecule inhibitor of PI3Kδ. Here, 31 patients with APDS aged ≥12 years were enrolled in a global, phase 3, triple-blinded trial and randomized 2:1 to receive 70 mg leniolisib or placebo twice daily for 12 weeks. Coprimary outcomes were differences from baseline in the index lymph node size and the percentage of naïve B cells in peripheral blood, assessed as proxies for immune dysregulation and deficiency. Both primary outcomes were met: the difference in the adjusted mean change (95% confidence interval [CI]) between leniolisib and placebo for lymph node size was -0.25 (-0.38, -0.12; P = .0006; N = 26) and for percentage of naïve B cells, was 37.30 (24.06, 50.54; P = .0002; N = 13). Leniolisib reduced spleen volume compared with placebo (adjusted mean difference in 3-dimensional volume [cm3], -186; 95% CI, -297 to -76.2; P = .0020) and improved key immune cell subsets. Fewer patients receiving leniolisib reported study treatment-related adverse events (AEs; mostly grades 1-2) than those receiving placebo (23.8% vs 30.0%). Overall, leniolisib was well tolerated and significant improvement over placebo was notable in the coprimary endpoints, reducing lymphadenopathy and increasing the percentage of naïve B cells, reflecting a favorable impact on the immune dysregulation and deficiency seen in patients with APDS. This trial was registered at www.clinicaltrials.gov as #NCT02435173.

Interim analysis: Open-label extension study of leniolisib for patients with APDS.

BACKGROUND: Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS; or p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency) is an inborn error of immunity caused by PI3Kδ hyperactivity. Resultant immune deficiency and dysregulation lead to recurrent sinopulmonary infections, herpes viremia, autoimmunity, and lymphoproliferation. OBJECTIVE: Leniolisib, a selective PI3Kδ inhibitor, demonstrated favorable impact on immune cell subsets and lymphoproliferation over placebo in patients with APDS over 12 weeks. Here, we report results from an interim analysis of an ongoing open-label, single-arm extension study. METHODS: Patients with APDS aged 12 years or older who completed NCT02435173 or had previous exposure to PI3Kδ inhibitors were eligible. The primary end point was safety, assessed via investigator-reported adverse events (AEs) and clinical/laboratory evaluations. Secondary and exploratory end points included health-related quality of life, inflammatory markers, frequency of infections, and lymphoproliferation. RESULTS: Between September 2016 and August 2021, 37 patients (median age, 20 years; 42.3% female) were enrolled. Of these 37 patients, 26, 9, and 2 patients had previously received leniolisib, placebo, or other PI3Kδ inhibitors, respectively. At the data cutoff date (December 13, 2021), median leniolisib exposure was 102 weeks. Overall, 32 patients (87%) experienced an AE. Most AEs were grades 1 to 3; none were grade 4. One patient with severe baseline comorbidities experienced a grade 5 AE, determined as unrelated to leniolisib treatment. While on leniolisib, patients had reduced annualized infection rates (P = .004), and reductions in immunoglobulin replacement therapy occurred in 10 of 27 patients. Other observations include reduced lymphadenopathy and splenomegaly, improved cytopenias, and normalized lymphocyte subsets. CONCLUSIONS: Leniolisib was well tolerated and maintained durable outcomes with up to 5 years of exposure in 37 patients with APDS. CLINICALTRIALS: gov identifier: NCT02859727.

A randomized, double-blind, solifenacin succinate versus placebo control, phase 4, multicenter study evaluating urinary continence after robotic assisted radical prostatectomy.

PURPOSE: Bladder dysfunction influences recovery of urinary continence after radical prostatectomy. We performed a multicenter, randomized, double-blind study evaluating solifenacin vs placebo on return to continence in patients who were still incontinent 7 to 21 days after catheter removal after robot-assisted radical prostatectomy. MATERIALS AND METHODS: A wireless personal digital assistant was given to patients the day of catheter removal. Encrypted answers were transmitted daily to dedicated servers. After a 7 to 21-day treatment-free washout period, patients requiring 2 to 10 pads per day for 7 consecutive days were randomized (1:1) to 5 mg solifenacin daily or placebo. The primary end point was time from first dose to continence defined as 0 pads per day or a dry security pad for 3 consecutive days. Secondary end points included proportion of patients continent at end of study, average change in pads per day number and quality of life assessments. RESULTS: A total of 1,086 screened patients recorded personal digital assistant information. Overall 640 patients were randomized to solifenacin vs placebo and 17 failed to take medication. There was no difference in time to continence (p=0.17). Continence was achieved by study end in 91 of 313 (29%) vs 66 of 309 (21%), respectively (p=0.04). Pads per day change from baseline was -3.2 and -2.9, respectively (p=0.03). Dry mouth was the only common adverse event seen in 6.1% and 0.6%, respectively. Constipation rates were similar. The overall rate of continence in the entire population from screening to end of study was 73%. CONCLUSIONS: There was no effect on primary outcome but some secondary end points benefited the solifenacin arm. The study provides level 1B clinical evidence for continence outcomes after robot-assisted radical prostatectomy.

Long-term treatment with selective PI3Kδ inhibitor leniolisib in adults with activated PI3Kδ syndrome.

ABSTRACT: Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is an inborn error of immunity that manifests as immune deficiency and dysregulation; symptoms include frequent infections and lymphoproliferation. In our dose-finding and phase 3 placebo-controlled trials, treatment with the selective PI3Kδ inhibitor leniolisib reduced lymphoproliferation and normalized lymphocyte subsets. Here, we present 6 years of follow-up from the 6 adult patients in the original dose-finding trial receiving leniolisib. We used data from the ongoing open-label extension study, which was supplemented at later time points by investigators, including health-related quality of life (HRQoL) assessed through a clinician-reported questionnaire. We observed improvements in HRQoL: 5 of 6 patients experienced an increase in physical capabilities and socialization, and a decrease in prescribed medications. Immune subsets improved in all patients: mean transitional B-cell levels decreased from 38.17% to 2.47% and the CD4:CD8 T-cell ratio normalized to 1.11. Manifestations seen before and within the first year of leniolisib exposure, such as infections and gastrointestinal conditions, attenuated after year 2, with few new conditions emerging out to year 6. Thrombocytopenia or lymphopenia remained present in half of patients at year 6. Of 83 adverse events through year 5, 90.36% were grade 1; none were grade 4/5 nor deemed leniolisib related. Collectively, we saw an enhancement in HRQoL as well as durable changes in lymphocyte subsets and clinical manifestations, further supporting the use of leniolisib as a long-term therapeutic option for the treatment of APDS. This trial was registered at www.ClinicalTrials.gov as #NCT02859727.

Effect of Potentially Inappropriate Use of Antimuscarinic Medications on Healthcare Use and Cost in Individuals with Overactive Bladder.

OBJECTIVES: To examine potentially inappropriate medication (PIM) use in older adults initiating an antimuscarinic medication for the treatment of overactive bladder (OAB). DESIGN: Retrospective database analysis. SETTING: Medical and pharmacy claims data. PARTICIPANTS: Medicare Advantage Prescription Drug Plan members aged 65 and older newly initiated on an antimuscarinic OAB treatment were identified and assigned to PIM and non-PIM comparison groups based on 2012 American Geriatrics Society Beers Criteria and/or the presence of an anticholinergic medication interaction at the time of initiation of treatment (N = 66,275). MEASUREMENTS: Healthcare costs and OAB medication use. RESULTS: Of members initiated on an antimuscarinic OAB medication, 31.1% had a drug-drug or drug-disease or syndrome interaction. Dementia was the most common disease or syndrome interaction (11.3%), followed by constipation (8.6%) and delirium (2.9%). Paroxetine (2.6%), amitriptyline (2.2%), cyclobenzaprine (1.7%), and meclizine (1.6%) were the most common interacting medications. Subjects in the PIM group had greater healthcare costs over 12 months of follow-up ($12,001) than those in the non-PIM group ($9,373) after controlling for baseline characteristics (P < .001). There was no difference between the PIM and the non-PIM groups in odds of discontinuing OAB treatment at 12 months after controlling for baseline characteristics (odds ratio = 0.98, 95% confidence interval = 0.89-1.07, P = .63). CONCLUSION: Potentially inappropriate medication use was highly prevalent and was associated with greater total healthcare costs. Providers should carefully consider medical history and concurrent medication use when initiating antimuscarinic medication for the treatment of OAB. Development of interventions to reduce potentially inappropriate use of antimuscarinics in individuals with OAB is warranted.

Comparative risk of bloodstream infection in hospitalized patients receiving intravenous medication by open, point-of-care, or closed delivery systems.

PURPOSE: The impact of i.v. drug delivery via point-of-care (POC)-activated and closed systems versus traditional manual admixture systems on the risk of hospital-acquired bloodstream infection (BSI) is examined. METHODS: Using data from a proprietary hospital database, a retrospective observational cohort study of patients receiving one or more i.v. drug administrations via POC-activated or closed systems during a three-year period (2007-09) was conducted. Cases of hospital-acquired BSI were identified using diagnosis codes and billing charges for blood cultures and antibiotic use. The risk of BSI in patients with exposure to POC-activated systems, closed systems, or both relative to that of patients exposed to open systems was estimated by odds ratios (ORs) calculated by multivariate logistic regression analysis. RESULTS: The evaluated data indicated that of the 4,073,864 patients included in the study cohort, 0.5% (n = 20,251) experienced hospital-acquired BSI. After adjusting for selected confounding variables, the use of POC-activated systems was associated with a 16% reduction in BSI risk relative to the use of open systems (OR, 0.84; 95% confidence interval [CI], 0.76-0.93), and the use of closed systems correlated with a 12% risk reduction (OR, 0.88; 95% CI, 0.82-0.96). Patients who received i.v. drugs via both POC-activated and closed systems appeared to derive the greatest relative risk reduction benefit (OR, 0.12; 95% CI, 0.06-0.23). CONCLUSION: Use of POC-activated and closed systems for i.v. drug delivery was associated with a significantly reduced risk of hospital-acquired BSI compared with exclusive use of open systems in a large population of hospitalized patients.