Angiogenic Gene Therapy for Refractory Angina: Results of the EXACT Phase 2 Trial.

BACKGROUND: XC001 is a novel adenoviral-5 vector designed to express multiple isoforms of VEGF (vascular endothelial growth factor) and more safely and potently induce angiogenesis. The EXACT trial (Epicardial Delivery of XC001 Gene Therapy for Refractory Angina Coronary Treatment) assessed the safety and preliminary efficacy of XC001 in patients with no option refractory angina. METHODS: In this single-arm, multicenter, open-label trial, 32 patients with no option refractory angina received a single treatment of XC001 (1×1011 viral particles) via transepicardial delivery. RESULTS: There were no severe adverse events attributed to the study drug. Twenty expected severe adverse events in 13 patients were related to the surgical procedure. Total exercise duration increased from a mean±SD of 359.9±105.55 seconds at baseline to 448.2±168.45 (3 months), 449.2±175.9 (6 months), and 477.6±174.7 (12 months; +88.3 [95% CI, 37.1-139.5], +84.5 [95% CI, 34.1-134.9], and +115.5 [95% CI, 59.1-171.9]). Total myocardial perfusion deficit on positron emission tomography imaging decreased by 10.2% (95% CI, -3.1% to 23.5%), 14.3% (95% CI, 2.8%-25.7%), and 10.2% (95% CI, -0.8% to -21.2%). Angina frequency decreased from a mean±SD 12.2±12.5 episodes to 5.2±7.2 (3 months), 5.1±7.8 (6 months), and 2.7±4.8 (12 months), with an average decrease of 7.7 (95% CI, 4.1-11.3), 6.6 (95% CI, 3.5-9.7), and 8.8 (4.6-13.0) episodes at 3, 6, and 12 months. Angina class improved in 81% of participants at 6 months. CONCLUSIONS: XC001 administered via transepicardial delivery is safe and generally well tolerated. Exploratory improvements in total exercise duration, ischemic burden, and subjective measures support a biologic effect sustained to 12 months, warranting further investigation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04125732.

Berdazimer gel for molluscum contagiosum in patients with atopic dermatitis.

OBJECTIVE: Controlling molluscum contagiosum (MC) infections is critical in atopic dermatitis (AD) management. This post hoc analysis assessed the efficacy and safety of berdazimer gel, 10.3% (topical, antiviral, nitric oxide-releasing medication) versus vehicle in MC patients with or without AD. METHODS: Three Phase 3, multicenter, randomized, double-blind, vehicle-controlled, parallel-group trials (B-SIMPLE[berdazimer sodium in molluscum patients with lesions]1, -2, -4) enrolled patients 6 months and older with 3-70 mollusca. Berdazimer or vehicle was applied once daily to all MC lesions for 12 weeks. Data from three Phase 3 studies were integrated for subgroup efficacy and safety assessments using several weighted meta-analysis approaches. Patients with concurrent AD or a history of AD/eczema were categorized as AD+ subgroup (AD- when absent). Primary efficacy endpoint: complete lesion clearance at Week 12. Safety endpoints included adverse events (AEs) through Week 24 and local skin reactions through Week 12. RESULTS: Of 1598 enrolled patients, 209 (13.1%) were AD+. Baseline mean lesion counts were greater in AD+ (26.4) than AD- (19.3). Complete clearance rates were higher at Week 12 for berdazimer compared with vehicle in AD+ (n = 209; 35.0% vs. 27.4%; odds ratio [OR], 1.3; 95% CI, 0.7-2.5) and AD- (n = 1389; 29.1% vs. 18.9%; OR 1.8; 95% CI 1.4-2.4) subgroups. AEs in AD+ were application-site pain (21.6% with berdazimer vs. 11.9% with vehicle), dermatitis (12.8% vs. 2.4%), and erythema (9.6% vs. 7.1%). CONCLUSIONS: Berdazimer gel showed favorable efficacy regardless of AD status. Berdazimer-induced erythema may be indistinguishable from AD symptoms or with inflammatory response upon resolution of molluscum.

Efficacy and Safety of Topical Nitric Oxide-Releasing Berdazimer Gel in Patients With Molluscum Contagiosum: A Phase 3 Randomized Clinical Trial.

Importance: Molluscum contagiosum (MC) is a highly contagious skin condition. Lesions may persist for months to years, and no US Food and Drug Administration-approved medications are currently available in the US. Objective: To assess the efficacy and safety of berdazimer gel, 10.3%, a novel topical nitric oxide-releasing medication, in the treatment of MC. Design, Setting, and Participants: This was a multicenter, vehicle-controlled, double-blind, phase 3 randomized clinical trial (B-SIMPLE4) conducted in 55 clinics (mostly dermatology and pediatric) in the US from September 1, 2020, to July 21, 2021. Eligible participants were 6 months or older and had from 3 to 70 raised MC lesions. Patients with sexually transmitted MC or with MC only in the periocular area were excluded. Interventions: Patients were randomized to treatment with berdazimer gel, 10.3%, or vehicle gel, applied as a thin layer to all lesions once daily for 12 weeks. Main Outcomes and Measures: The primary efficacy end point was complete clearance of all MC lesions at week 12. Safety and tolerability measures included adverse event frequency and severity, and assessment of local skin reactions and scarring. Data analyses were performed from August 31, 2021, to September 14, 2021. Results: A total of 891 participants were randomized, 444 to berdazimer, 10.3% (mean [range] age, 6.6 [0.9-47.5] years; 228 [51.4%] male; 387 [87.2%] White individuals), and 447 to vehicle (mean [range] age, 6.5 [1.3-49.0] years; 234 [52.3%] female; 382 [85.5%] White individuals). In the intention-to-treat population, 88.5% (393 patients) in the berdazimer group and 88.8% (397 patients) in the vehicle group had a lesion count performed at week 12. At week 12, 32.4% (144 patients) in the berdazimer group achieved complete clearance of MC lesions compared with 19.7% (88 patients) in the vehicle group (absolute difference, 12.7%; odds ratio, 2.0; 95% CI, 1.5-2.8; P < .001) with 14.4% (64 patients) of the berdazimer group discontinuing treatment because of MC clearance compared with 8.9% (40 patients) of the vehicle group. Adverse event rates were low. The most common adverse events were application-site pain and erythema, mostly mild in severity. Adverse events leading to discontinuation affected 4.1% (18 patients) of the berdazimer group and 0.7% (3 patients) of the vehicle group. The most common local skin reaction was mild to moderate erythema. Conclusions and Relevance: Use of berdazimer gel, 10.3%, for MC appears to demonstrate favorable efficacy and safety with low adverse event rates. Trial Registration: ClinicalTrials.gov Identifier: NCT04535531.

Design and Analysis of Studies Based on Hierarchical Composite Endpoints: Insights from the DARE-19 Trial.

BACKGROUND/AIM: DARE-19 (NCT04350593) was a randomized trial studying the effects of dapagliflozin, an SGLT2 inhibitor, in hospitalized patients with COVID-19 pneumonia and cardiometabolic risk factors. The conduct of DARE-19 offered the opportunity to define an innovative and clinically meaningful endpoint in a new disease that would best reflect the known profile of dapagliflozin, accompanied by the statistical challenges of analysis and interpretation of such a novel endpoint. METHODS: Hierarchical composite endpoints (HCEs) are based on clinical outcomes which, unlike traditional composite endpoints incorporate ranking of components according to clinical importance. Design of an HCE requires the clinical considerations specific to the therapeutic area under study and the mechanism of action of the investigational treatment. Statistical aspects for the clinical endpoints include the proper definition of the estimand as suggested by ICH E9(R1) for the precise specification of the treatment effect measured by an HCE. RESULTS: We describe the estimand of the DARE-19 trial, where an HCE was constructed to capture the treatment effect of dapagliflozin in hospitalized patients with COVID-19, and was analyzed using a win odds. Practical aspects of designing new studies based on an HCE are described. These include sample size, power, and minimal detectable effect calculations for an HCE based on the win odds analysis, as well as handling of missing data and the clinical interpretability of the win odds in relation to the estimand. CONCLUSIONS: HCEs are flexible endpoints that can be adapted for use in different therapeutic areas, with win odds as the analysis method. DARE-19 is an example of a COVID-19 trial with an HCE as one of the primary endpoints for estimating a clinically interpretable treatment effect in the COVID-19 setting.

Application of Meta-analysis to Evaluate Relationships Among ARIA-E Rate, Amyloid Reduction Rate, and Clinical Cognitive Response in Amyloid Therapeutic Clinical Trials for Early Alzheimer's Disease.

BACKGROUND: Removal of the extracellular Aß plaques in the brain is one of the mechanisms to treat Alzheimer's disease (AD). Separate clinical trials for several therapeutic compounds that target amyloid plaque reduction have shown noteworthy correlations among plaque removal, the Amyloid-Related Imaging Abnormalities (ARIA) rate, and clinical efficacy of the treatment. The relationships among therapeutic dose levels, the rate of amyloid removal, and the clinical efficacy deserve further investigation across therapeutic agents, particularly for clinical trials to provide insights for strategies to develop amyloid therapies in Alzheimer's disease. METHODS: Published data summaries from clinical trials with amyloid therapies of aducanumab, donanemab, lecanemab, and gantenerumab are evaluated with meta-analyses. Linear mixed models for repeated measurements for visits and random study effects are applied to analyze amyloid centiloid value reduction from baseline and clinical cognition change from baseline for treatment groups according to doses and compounds for the clinical trials. Logistic regression analysis is applied to evaluate the relationship between the amyloid removal rate and the ARIA-Edema (ARIA-E) rate across different dose groups and clinical trials. RESULTS: The extent of amyloid removal varies among therapeutic agents and their dose levels. Across treatment groups and clinical trials, amyloid centiloid value reductions at Weeks 26 and 52 are strongly correlated with both ARIA-E rate over 78 weeks and the clinical efficacy response in the Clinical Dementia-Rating Scale Sum of Boxes (CDR-SB) score change from baseline at Week 78; and the Spearman rank correlations for amyloid reduction at Week 52 are stronger as - 0.79 with the ARIA-E rate over 78 weeks and 0.73 with the Week 78 CDR-SB score change from baseline. CONCLUSION: Aß plaques removal in the brain due to amyloid therapy is strongly correlated with a better clinical response in patients with early Alzheimer's disease and a higher ARIA-E rate for the treatment groups and clinical trials in this meta-analysis. These relationships suggest that the balance between the clinical efficacy response and safety in ARIA-E rate is relevant for the choice of doses for amyloid therapies in confirmatory clinical trials.

Power and sample size calculation for the win odds test: application to an ordinal endpoint in COVID-19 trials.

The win odds is a distribution-free method of comparing locations of distributions of two independent random variables. Introduced as a method for analyzing hierarchical composite endpoints, it is well suited to be used in the analysis of ordinal scale endpoints in COVID-19 clinical trials. For a single outcome, we provide power and sample size calculation formulas for the win odds test. We also provide an implementation of the win odds analysis method for a single ordinal outcome in a commonly used statistical software to make the win odds analysis fully reproducible.