Results of a randomized double-blind placebo-controlled Phase 2 study propose iptacopan as an alternative complement pathway inhibitor for IgA nephropathy.

Targeting the alternative complement pathway is an attractive therapeutic strategy given its role in the pathogenesis of immunoglobulin A nephropathy (IgAN). Iptacopan (LNP023) is an oral, proximal alternative complement inhibitor that specifically binds to Factor B. Our randomized, double-blind, parallel-group adaptive Phase 2 study (NCT03373461) enrolled patients with biopsy-confirmed IgAN (within previous three years) with estimated glomerular filtration rates of 30 mL/min/1.73 m2 and over and urine protein 0.75 g/24 hours and over on stable doses of renin angiotensin system inhibitors. Patients were randomized to four iptacopan doses (10, 50, 100, or 200 mg bid) or placebo for either a three-month (Part 1; 46 patients) or a six-month (Part 2; 66 patients) treatment period. The primary analysis evaluated the dose-response relationship of iptacopan versus placebo on 24-hour urine protein-to-creatinine ratio (UPCR) at three months. Other efficacy, safety and biomarker parameters were assessed. Baseline characteristics were generally well-balanced across treatment arms. There was a statistically significant dose-response effect, with 23% reduction in UPCR achieved with iptacopan 200 mg bid (80% confidence interval 8-34%) at three months. UPCR decreased further through six months in iptacopan 100 and 200 mg arms (from a mean of 1.3 g/g at baseline to 0.8 g/g at six months in the 200 mg arm). A sustained reduction in complement biomarker levels including plasma Bb, serum Wieslab, and urinary C5b-9 was observed. Iptacopan was well-tolerated, with no reports of deaths, treatment-related serious adverse events or bacterial infections, and led to strong inhibition of alternative complement pathway activity and persistent proteinuria reduction in patients with IgAN. Thus, our findings support further evaluation of iptacopan in the ongoing Phase 3 trial (APPLAUSE-IgAN; NCT04578834).

Interim decision making in seamless trial designs: An application in an adaptive dose-finding study in a rare kidney disease.

Adaptive seamless trial designs, combining the learning and confirming cycles of drug development in a single trial, have gained popularity in recent years. Adaptations may include dose selection, sample size re-estimation and enrichment of the study population. Despite methodological advances and recognition of the potential efficiency gains such designs offer, their implementation, including how to enable efficient decision making on the adaptations in interim analyzes, remains a key challenge in their adoption. This manuscript uses a case study of an adaptive seamless proof-of-concept (Phase 2a)/dose-finding (Phase 2b) to showcase potential adaptive features that can be implemented in trial designs at earlier development stages and the role of simulations in assessing the design operating characteristics and specifying the decision rules for the adaptations. It further outlines the elements needed to support successful interim analysis decision making on the adaptations while safeguarding study integrity, including the role of different stakeholders, interactive simulation-based tools to facilitate decision making and operational aspects requiring preplanning. The benefits of the adaptive Phase 2a/2b design chosen compared to following the traditional two separate studies (2a and 2b) paradigm are discussed. With careful planning and appreciation of their complexity and components needed for their implementation, seamless adaptive designs have the potential to yield significant savings both in terms of time and resources.

Targeting the Alternative Complement Pathway With Iptacopan to Treat IgA Nephropathy: Design and Rationale of the APPLAUSE-IgAN Study.

Introduction: Targeting the alternative complement pathway (AP) is an attractive therapeutic strategy because of its role in immunoglobulin A nephropathy (IgAN) pathophysiology. Iptacopan (LNP023), a proximal complement inhibitor that specifically binds to factor B and inhibits the AP, reduced proteinuria and attenuated AP activation in a Phase 2 study of patients with IgAN, thereby supporting the rationale for its evaluation in a Phase 3 study. Methods: APPLAUSE-IgAN (NCT04578834) is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase 3 study enrolling approximately 450 adult patients (aged ≥18 years) with biopsy-confirmed primary IgAN at high risk of progression to kidney failure despite optimal supportive treatment. Eligible patients receiving stable and maximally tolerated doses of angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs) will be randomized 1:1 to either iptacopan 200 mg or placebo twice daily for a 24-month treatment period. A prespecified interim analysis (IA) will be performed when approximately 250 patients from the main study population complete the 9-month visit. The primary objective is to demonstrate superiority of iptacopan over placebo in reducing 24-hour urine protein-to-creatinine ratio (UPCR) at the IA and demonstrate the superiority of iptacopan over placebo in slowing the rate of estimated glomerular filtration rate (eGFR) decline (total eGFR slope) estimated over 24 months at study completion. The effect of iptacopan on patient-reported outcomes, safety, and tolerability will be evaluated as secondary outcomes. Conclusions: APPLAUSE-IgAN will evaluate the benefits and safety of iptacopan, a novel targeted therapy for IgAN, in reducing complement-mediated kidney damage and thus slowing or preventing disease progression.

Exploring mechanisms of action in clinical trials of complex surgical interventions using mediation analysis.

BACKGROUND: Surgical interventions allow for tailoring of treatment to individual patients and implementation may vary with surgeon and healthcare provider. In addition, in clinical trials assessing two competing surgical interventions, the treatments may be accompanied by co-interventions. AIMS: This study explores the use of causal mediation analysis to (1) delineate the treatment effect that results directly from the surgical intervention under study and the indirect effect acting through a co-intervention and (2) to evaluate the benefit of the surgical intervention if either everybody in the trial population received the co-intervention or nobody received it. METHODS: Within a counterfactual framework, relevant direct and indirect effects of a surgical intervention are estimated and adjusted for confounding via parametric regression models, for the situation where both mediator and outcome are binary, with baseline stratification factors included as fixed effects and surgeons as random intercepts. The causal difference in probability of a successful outcome (estimand of interest) is calculated using Monte Carlo simulation with bootstrapping for confidence intervals. Packages for estimation within standard statistical software are reviewed briefly. A step by step application of methods is illustrated using the Amaze randomised trial of ablation as an adjunct to cardiac surgery in patients with irregular heart rhythm, with a co-intervention (removal of the left atrial appendage) administered to a subset of participants at the surgeon's discretion. The primary outcome was return to normal heart rhythm at one year post surgery. RESULTS: In Amaze, 17% (95% confidence interval: 6%, 28%) more patients in the active arm had a successful outcome, but there was a large difference between active and control arms in the proportion of patients who received the co-intervention (55% and 30%, respectively). Causal mediation analysis suggested that around 1% of the treatment effect was attributable to the co-intervention (16% natural direct effect). The controlled direct effect ranged from 18% (6%, 30%) if the co-intervention were mandated, to 14% (2%, 25%) if it were prohibited. Including age as a moderator of the mediation effects showed that the natural direct effect of ablation appeared to decrease with age. CONCLUSIONS: Causal mediation analysis is a useful quantitative tool to explore mediating effects of co-interventions in surgical trials. In Amaze, investigators could be reassured that the effect of the active treatment, not explainable by differential use of the co-intervention, was significant across analyses.

Transcatheter aortic valve implantation via surgical subclavian versus direct aortic access: A United Kingdom analysis.

BACKGROUND: Surgical subclavian (SC) and direct aortic (DA) access are established alternatives to the default transfemoral route for transcatheter aortic valve implantation (TAVI). We sought to find differences in survival and procedure-related outcomes after SC- versus DA-TAVI. METHODS: We performed an observational cohort analysis of cases prospectively uploaded to the UK TAVI registry. To ensure the most contemporaneous comparison, the analysis focused on SC and DA procedures performed from 2013 to 2015. RESULTS: Between January 2013 and July 2015, 82 (37%) SC and 142 (63%) DA cases were performed that had validated 1-year life status. Multivariable regression analysis showed procedure duration was longer for SC cases (SC 193.5 ± 65.8 vs. DA 138.4 ± 57.7 min; p < .01) but length of hospital stay was shorter (SC 8.6 ± 9.5 vs. DA 11.9 ± 10.8 days; p = .03). Acute kidney injury was observed less frequently after SC cases (odds ratio [OR] 0.35, 95% confidence interval [CI 0.12-0.96]; p = .042) but vascular access site-related complications were more common (OR 9.75 [3.07-30.93]; p < .01). Procedure-related bleeding (OR 0.54 [0.24-1.25]; p = .15) and in-hospital stroke rate (SC 3.7% vs. DA 2.1%; p = .67) were similar. There were no significant differences in in-hospital (SC 2.4% vs. DA 4.9%; p = .49), 30-day (SC 2.4% vs. DA 4.2%; p = .71) or 1-year (SC 14.5% vs. DA 21.9%; p = .344) mortality. CONCLUSIONS: Surgical subclavian and direct aortic approaches can offer favourable outcomes in appropriate patients. Neither access modality conferred a survival advantage but there were significant differences in procedural metrics that might influence which approach is selected.

Does the "Weekend Effect" for Postoperative Mortality Stand Up to Scrutiny? Association for Cardiothoracic Anesthesia and Critical Care Cohort Study of 110,728 Cardiac Surgical Patients.

OBJECTIVE: Ongoing debate focuses on whether patients admitted to the hospital on weekends have higher mortality than those admitted on weekdays. Whether this apparent "weekend effect" reflects differing patient risk, care quality differences, or inadequate adjustment for risk during analysis remains unclear. This study aimed to examine the existence of a "weekend effect" for risk-adjusted in-hospital mortality after cardiac surgery. DESIGN: Retrospective analysis of prospectively collected cardiac registry data. SETTING: Ten UK specialist cardiac centers. PARTICIPANTS: A total of 110,728 cases, undertaken by 127 consultant surgeons and 190 consultant anesthetists between April 2002 and March 2012. INTERVENTIONS: Major risk-stratified cardiac surgical operations. MEASUREMENTS AND MAIN RESULTS: Crude in-hospital mortality rate was 3.1%. Multilevel multivariable models were employed to estimate the effect of operative day on in-hospital mortality, adjusting for center, surgeon, anesthetist, patient risk, and procedure priority. Weekend elective cases had significantly lower mortality risk compared to Monday elective cases (odds ratio [OR] 0.64, 95% confidence interval [CI] 0.42, 0.96) following risk adjustment by the logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) and procedure priority; differences between weekend and Monday for urgent and emergency/salvage cases were not significant (OR 1.12, 95% CI 0.73, 1.72, and 1.07, 95% CI 0.79, 1.45 respectively). Considering only the logistic EuroSCORE but not procedure priority yielded 29% higher odds of death for weekend cases compared to Monday operations (OR 1.29, 95% CI 1.08, 1.54). CONCLUSIONS: This study suggests that undergoing cardiac surgery during the weekend does not affect negatively patient survival, and highlights the importance of comprehensive risk adjustment to avoid detecting spurious "weekend effects."

Effect of individual patient risk, centre, surgeon and anaesthetist on length of stay in hospital after cardiac surgery: Association of Cardiothoracic Anaesthesia and Critical Care (ACTACC) consecutive cases series study of 10 UK specialist centres.

OBJECTIVES: To determine the relative contributions of patient risk profile, local and individual clinical practice on length of hospital stay after cardiac surgery. DESIGN: Ten-year audit of prospectively collected consecutive cardiac surgical cases. Case-mix adjusted outcomes were analysed in models that included random effects for centre, surgeon and anaesthetist. SETTING: UK centres providing adult cardiac surgery. PARTICIPANTS: 10 of 36 UK specialist centres agreed to provide outcomes for all major cardiac operations over 10 years. After exclusions (duplicates, cases operated by more than one consultant, deaths and procedures for which the EuroSCORE risk score for cardiac surgery is not appropriate), there were 107 038 cardiac surgical procedures between April 2002 and March 2012, conducted by 127 consultant surgeons and 190 consultant anaesthetists. MAIN OUTCOME MEASURE: Length of stay (LOS) up to 3 months postoperatively. RESULTS: The principal component of variation in outcomes was patient risk (represented by the EuroSCORE and remaining patient heterogeneity), accounting for 95.43% of the variation for postoperative LOS. The impact of the surgeon and centre was moderate (intra-class correlation coefficients ICC=2.79% and 1.59%, respectively), whereas the impact of the anaesthetist was negligible (ICC=0.19%). Similarly, 96.05% of the variation for prolonged LOS (>11 days) was attributable to the patient, with surgeon and centre less but still influential components (ICC=2.12% and 1.66%, respectively, 0.17% only for anaesthetists). Adjustment for year of operation resulted in minor reductions in variation attributable to surgeons (ICC=2.52% for LOS and 2.23% for prolonged LOS). CONCLUSIONS: Patient risk profile is the primary determinant of variation in LOS, and as a result, current initiatives to reduce hospital stay by modifying consultant performance are unlikely to have a substantial impact. Therefore, substantially reducing hospital stay requires shifting away from a one-size-fits-all approach to cardiac surgery, and seeking alternative treatment options personalised to high-risk patients.

Evaluation of the effects of multiple providers in complex surgical interventions.

In contrast to new medicinal products, surgical interventions have many features that complicate their formal assessment through Randomised Clinical Trials. For example, surgery is delivered by multidisciplinary teams; hence, differential effects on the outcome are not solely caused by differences in the leading operator's skill but are also induced by surgical team differences and patient characteristics. This study focuses on how statistical methods can be used to accommodate the multicomponent nature of the delivery of surgical interventions. Hierarchical models with cross-classifications between components of surgery, applied to historic datasets, can be used during the trial planning phase to establish the effects and interactions between different components. Methods are illustrated using two influential components of the intervention, the surgeon and the anaesthetist, in a cohort of cardiac surgery cases. The statistical implications for trial design and analysis are presented. Copyright © 2016 John Wiley & Sons, Ltd.

Assessment of learning curves in complex surgical interventions: a consecutive case-series study.

BACKGROUND: Surgical interventions are complex, which complicates their rigorous assessment through randomised clinical trials. An important component of complexity relates to surgeon experience and the rate at which the required level of skill is achieved, known as the learning curve. There is considerable evidence that operator performance for surgical innovations will change with increasing experience. Such learning effects complicate evaluations; the start of the trial might be delayed, resulting in loss of surgeon equipoise or, if an assessment is undertaken before performance has stabilised, the true impact of the intervention may be distorted. METHODS: Formal estimation of learning parameters is necessary to characterise the learning curve, model its evolution and adjust for its presence during assessment. Current methods are either descriptive or model the learning curve through three main features: the initial skill level, the learning rate and the final skill level achieved. We introduce a fourth characterising feature, the duration of the learning period, which provides an estimate of the point at which learning has stabilised. We propose a two-phase model to estimate formally all four learning curve features. RESULTS: We demonstrate that the two-phase model can be used to estimate the end of the learning period by incorporating a parameter for estimating the duration of learning. This is achieved by breaking down the model into a phase describing the learning period and one describing cases after the final skill level is reached, with the break point representing the length of learning. We illustrate the method using cardiac surgery data. CONCLUSIONS: This modelling extension is useful as it provides a measure of the potential cost of learning an intervention and enables statisticians to accommodate cases undertaken during the learning phase and assess the intervention after the optimal skill level is reached. The limitations of the method and implications for the optimal timing of a definitive randomised controlled trial are also discussed.

Impact of the anesthesiologist and surgeon on cardiac surgical outcomes.

OBJECTIVE: To determine the impact of anesthesiologists, surgeons, and their monthly caseload volume on mortality after cardiac surgery. DESIGN: Ten-year audit of prospectively collected cardiac surgical data. SETTING: Large adult cardiothoracic hospital. PARTICIPANTS: A total of 18,569 cardiac surgical patients in the decade from April 2002 through March 2012, plus 21 consultant surgeons and 29 consultant anesthesiologists. INTERVENTIONS: Major risk-stratified cardiac surgical operations. METHODS: The primary outcome was in-hospital death. Random intercept models for the surgeon and anesthesiologist cluster, respectively, were fitted, achieving risk-adjustment through the logistic EuroSCORE. The intraclass correlation coefficient (ICC) subsequently was used to measure the amount of outcome variation due to clustering. MEASUREMENTS AND MAIN RESULTS: After exclusions (duplicates, very-short-term appointments, and cases performed by more than one consultant), there were 18,426 patients with 581 (3.15%) in-hospital deaths. The overwhelming factor associated with outcome variation was the patient risk profile, accounting for 97.14% of the variation. The impact of the surgeon was small (ICC = 2.78%), and the impact of the anesthesiologist was negligible (ICC = 0.08%). Low monthly surgeon volume of surgery, adjusted for average case mix, was associated with higher risk-adjusted mortality (odds ratio = 0.93, 95% CI 0.87-0.98). CONCLUSIONS: Outcome was determined primarily by the patient. There were small but significant differences in outcome between surgeons. The attending anesthesiologist did not affect patient outcome in this institution. Low average monthly surgeon volume was a significant risk factor. In contrast, low average monthly anesthesiologist volume had no effect.