Primary Trial Endpoint Research Articles

Event-free survival as a predictor of overall survival and recurrence burden of patients with non–small cell lung cancer receiving neoadjuvant therapy

ObjectivesEvent-free survival has replaced overall survival as a primary end point in many recent and ongoing clinical trials. This study aims to examine the correlation between real-world event-free survival and overall survival and to assess the clinical and economic burden associated with disease recurrence among patients with resected stage II to III non–small cell lung cancer who received neoadjuvant therapy in the United States. MethodsThis retrospective study used the Surveillance, Epidemiology, and End Results Medicare database (2007–2019) to identify patients with newly diagnosed, resected, stage II to IIIB (N2) non–small cell lung cancer who received neoadjuvant therapy. The correlation between real-world event-free survival and overall survival was assessed using the normal scores rank correlation and landmark analysis. Overall survival, all-cause health care resource use and costs, and non–small cell lung cancer–related health care resource use and costs were compared between patients with and without recurrence. ResultsA total of 221 patients met the eligibility criteria (median follow-up time from neoadjuvant treatment initiation: 32.7 months). The mean age was 72.1 years, and 57.0% of patients were male. Real-world, event-free survival and overall survival are positively and significantly correlated (0.68; 95% CI, 0.52-0.79). Patients with recurrence had significantly shorter median overall survival (19.3 vs 116.9 months), 4.59 times increased risk of death (95% CI, 2.56-8.26), and significantly higher all-cause and non–small cell lung cancer–related health care resource use and costs (adjusted mean monthly costs per patient difference: $5758 and $3187, respectively [all P < .001]). ConclusionsThese findings help validate event-free survival as a clinically meaningful end point and strong predictor for overall survival and highlight the need for additional novel therapies that may delay or prevent recurrence in resectable stage II and III non–small cell lung cancer.

A Phase III Clinical Trial Program Investigating the Efficacy and Safety of Ianalumab in Patients with Primary Immune Thrombocytopenia (VAYHIT1 and VAYHIT2) and Warm Autoimmune Hemolytic Anemia (VAYHIA)

Background: Immune thrombocytopenia (ITP) and warm autoimmune hemolytic anemia (wAIHA) are characterized by autoantibody destruction of platelets and red blood cells, respectively. Autoreactive B cells play a role in the pathophysiology of ITP and wAIHA. Serum levels of B-cell activating factor (BAFF) are elevated in these disorders and correlate with increased disease activity. Ianalumab is a novel, fully human immunoglobulin G1 monoclonal antibody that targets BAFF receptor (BAFF-R) and has a unique dual mechanism of action: direct antibody-dependent cellular cytotoxicity-mediated B-cell depletion and inhibition of B-cell differentiation, proliferation and survival via blockade of BAFF-R-mediated signaling. Corticosteroids (CS) are the standard first-line treatment for ITP; however, few patients achieve a long-term response. Additionally, extended and recurrent use of CS is associated with substantial toxicity. Thrombopoietin receptor agonists (TPO-RAs), such as eltrombopag, are commonly used second-line ITP treatments and often achieve a response; however, responses are rarely maintained once treatment ends, so chronic administration is typically required. For wAIHA, few treatments have been approved, and patients rarely achieve durable responses on CS or off-label rituximab. Thus, there are significant unmet needs for patients with ITP or wAIHA. Aim: We report the designs of the randomized, double-blind, multicenter, 3-arm Phase III VAYHIT1 (NCT05653349), VAYHIT2 (NCT05653219) and VAYHIA (NCT05648968) trials. The trials aim to assess whether ianalumab, working with a distinct and complementary mechanism to standard-of-care treatments, can induce durable responses in patients with ITP or wAIHA. Trial designs: VAYHIT1 and VAYHIT2 will assess the efficacy and safety of ianalumab vs placebo in addition to first-line CS and short-term eltrombopag, respectively, in adults with primary ITP. In both trials, patients will be randomized 1:1:1 to intravenous (IV) low-dose ianalumab, high-dose ianalumab or placebo every 4 weeks (wks). The primary endpoint in both trials is the time from randomization to treatment failure, defined as platelet count &amp;lt;30 G/L later than 8 wks from randomization, need for rescue treatment later than 8 wks from randomization, start of a new ITP therapy, or death. In VAYHIT2, ineligibility to taper or inability to discontinue eltrombopag after the completion of treatment with ianalumab or placebo will also be assessed as treatment failure. Secondary endpoints include response rate, complete response rate and safety ( Table). VAYHIA will assess the efficacy and safety of ianalumab vs placebo in adults with wAIHA who have failed ≥1 treatment. Patients will be randomized 1:1:1 to IV low-dose ianalumab, high-dose ianalumab or placebo every 4 wks. Selected supportive care is allowed. The primary endpoint is durable hemoglobin (Hb) response, defined as Hb ≥10 g/dL and an Hb increase of ≥2 g/dL from baseline for ≥8 consecutive wks between Wk 9 and Wk 25 in the absence of rescue or prohibited treatment. The key secondary endpoint is duration of durable Hb response ( Table). An optional open-label crossover period will allow patients who receive placebo and do not achieve a durable Hb response to receive high-dose ianalumab. Patients from all 3 trials will be monitored for efficacy until treatment failure (or up to 39 months after the last patient was randomized, whichever comes first) and safety for up to 2 years. Conclusions: These trials have been designed based on the hypothesis that, when administered early in disease progression, medical therapy targeting complementary physiological pathways may restore self-tolerance in patients with ITP and wAIHA. Ianalumab in combination with standard of care is expected to safely induce a high response rate that will be maintained beyond treatment completion. Ianalumab may address the unmet needs for patients with ITP and wAIHA. Current status: At the time of writing, VAYHIT1, VAYHIT2 and VAYHIA are recruiting. The open-label, single-arm, Phase II VAYHIT3 trial is also assessing ianalumab in patients with primary ITP previously treated with at least 1 CS and 1 TPO-RA (NCT05885555).

Multiple Myeloma Disease Model to Predict PFS Outcomes across Lines of Therapy, an Analysis Based on Commpass Observational Study

Introduction Multiple Myeloma (MM) remains incurable despite advances in treatment. Model-based approaches based on tumor dynamics have successfully been used to optimize drug-development in oncology. Model-derived tumor dynamics also called tumor growth inhibition (TGI) metrics capture the treatment effect as tumor biomarkers and are predictive of the overall survival (OS) benefit, based on TGI-OS models, this mathematical framework has been shown to be drug-independent in most cases. M-protein is measured longitudinally during clinical trials, it reflects tumor burden and is one of the criteria used to assess clinical response according to the International Myeloma Working Group Uniform Response Criteria. A drug-independent link between M-protein dynamic metrics and OS was previously established and confirmed for refractory MM patients. The primary endpoint in MM clinical trials is usually progression free survival (PFS). New immunotherapies are currently in development and there is a need for early and robust drug development decision making. Therefore there is strong interest to expand this modeling framework to leverage M-protein dynamics to predict PFS outcomes. Methods CoMMpass (https://www.themmrf.org/finding-a-cure/personalized-treatment-approaches/) is a prospective, longitudinal, observational study in newly diagnosed symptomatic patients with multiple myeloma. It represents a unique source of clinical data to investigate the link between M-protein dynamic and survival outcomes across lines of therapy and treatments. Individual M-protein and PFS Data from 804 patients within the CoMMpass study were used. Given patients are enrolled at their initial treatment regimen and observed over 8 years, they can receive several lines of therapy. Due to the characteristics of the modeling framework, allowing to analyze only one line of therapy for each patient, the latest line of therapy for each subject was selected for which they had at least 2 M-protein assessments available. M-protein dynamic metrics (M-protein ratio to baseline at different time points, time to growth, growth rate, shrinkage rate) derived using an empirical bi-exponential model, 42 prognostic factors and potential treatment effects were first tested in a univariate analysis using a Cox proportional hazards regression model. Statistically significant covariates in the univariate analysis (p&amp;lt;0.05) were included in a full multivariate parametric distribution survival model. A backward deletion stepwise procedure was performed (p&amp;lt;0.01) to retain covariates in the final PFS model. Model qualification was performed using posterior predictive checks based on Kaplan Meier plots. Results Among 804 patients, 490 patients received only 1 line of therapy (LoT), 157 received 2 LoTs, 93 received 3 LoTs, 31 received 4 LoTs,18 received 5 LoTs, 10 received 6 LoTs, finally 7 patients got up to 7 to 11 LoTs. PFS distribution followed a log-normal distribution. Table 1 shows the parameter estimates of the PFS model. Among all tested M-protein dynamic metrics and prognostic factors, the logarithmic value of the growth rate (log(KG)), in red in Table 1, was found to be the best predictor of PFS. Patients with slower growth rate, who received a transplantation, with higher albumin and lower lactate dehydrogenase values had longer PFS. Those findings are consistent with previous modeling works conducted in MM. Also, the PFS model was confirmed to be drug-independent. As shown in Figure 1, prediction intervals derived from model-based simulations well captured observed PFS data for each line of treatment although the line of therapy is not included as a predictor in the PFS model. Similar results were obtained across treatments. In a next step, external validations assessing the model performance to reproduce Phase 3 clinical trial outcomes will be performed. Conclusions A model linking M-protein dynamic to PFS in MM was developed across a wide range of lines of therapy and treatments. The model can support drug development in MM: enabling early predictions of clinical trial outcomes and inform study design e.g. by simulating the probability of success of upcoming pivotal clinical trials.

Correlation between Progression-Free Survival and Overall Survival in Patients with Relapsed Hodgkin Lymphoma: An Analysis of Individual Patient Data from Randomized GHSG Trials

Background: Progression-free survival (PFS) and overall survival (OS) are predominant measures of treatment efficacy in Hodgkin lymphoma (HL). Despite preference for OS from many regulatory authorities, PFS is most relevant to patients and frequently serves as primary endpoint in clinical trials. Recently we found a strong correlation between treatment effects on PFS and OS in the first-line setting (Bröckelmann PJ et al. EHA23/ICML23). However, their relationship in the relapsed setting remains unclear. We aimed to evaluate the correlation of PFS with OS after treatment of relapsed HL. Methods: We evaluated individual patient data of 375 patients with relapsed HL treated within the prospective randomized GHSG trials HDR1 (N= 141) and HDR2 (N= 234) between 02/1993 - 06/2007. Briefly, both trials included patients of 18 to 60 years of age with histologically confirmed relapsed HL after ≥1 prior line of treatment, who had not previously received high-dose chemotherapy and autologous stem-cell transplantation (ASCT). In HDR1 patients received two cycles of Dexa-BEAM (dexamethasone, carmustine, etoposide, cytarabine, and melphalan) and either two further courses of Dexa-BEAM or high-dose BEAM and ASCT. In HDR2, patients were assigned to two cycles of dexamethasone, cytarabine, and cisplatin (DHAP), and thereafter randomly assigned to either BEAM followed by ASCT or sequential cyclophosphamide, methotrexate, and etoposide in high-doses before BEAM followed by ASCT. All patients who received at least one dose of salvage chemotherapy within the respective trial were included in the analysis. We correlated treatment effects and risk factor effects on PFS and OS with the Wei-Lin-Weissfeld (WLW) method and adjusted the analysis for age and sex. Additionally, we applied copula models to correlate the time-to-event variables PFS and OS themselves using their marginal distributions. Results: With a median follow-up of 4.5 years, at least one PFS event, defined as relapse or progression of relapsed HL or death for any reason, was recorded in 146 of 375 patients (38.9%). At least one OS event, defined as death for any reason, was documented in 111 of 375 patients (29.6%). The hazard ratios for treatment effects on PFS and OS were 0.61 (95% confidence interval, CI= 0.38-0.98) and 1.01 (95% CI= 0.63-1.63) for HDR1 and 1.1 (95% CI= 0.69-1.75) and 0.8 (95% CI= 0.44-1.47) for HDR2, respectively. The WLW analysis revealed high correlations of treatment effects on PFS and OS at patient level within the trials. Pearson correlation r of the treatment effects on PFS and OS were r= 0.72 (95% confidence interval CI= 0.66-0.76, P&amp;lt; 0.001) in all 375 patients analyzed, r= 0.72 (95% CI= 0.63-0.79, P&amp;lt;0.001) in the HDR1 trial and r= 0.74 (95% CI= 0.67-0.79, P&amp;lt; 0.001) in the HDR2 trial. The analysis with different risk factors and copula models revealed similarly high correlations, confirming a strong relation between PFS and OS in relapsed HL patients. Conclusions: PFS and OS as well as treatment effects and prognostic effects on PFS and OS are highly correlated in patients treated for relapsed HL. Confirming results in first-line treatment, PFS thereby constitutes a highly relevant endpoint also in the setting of relapsed HL.

A Day 14 Endpoint for Acute Gvhd Clinical Trials

The overall response rate (ORR) 28 days (D28) after treatment has been adopted as the primary endpoint for clinical trials of acute graft versus host disease (GVHD). ORR combines complete response (CR) and partial response (PR) because CR and PR have very similar non relapse mortality (NRM). D28 ORR has some disadvantages: first, physicians usually decide to modify immunosuppression much earlier than D28, and second, NRM does not always correlate well with ORR at D28, particularly for patients who present with intermediate risk or low risk disease. MAGIC serum biomarkers at day 14 (D14) of GVHD treatment have been shown to correlate better with NRM than clinical symptom response (Srinagesh et al, Blood Advances, 2019). We therefore hypothesized that a combination of clinical symptom severity and biomarkers at D14 of treatment would predict NRM at least as well and possibly better than clinical response at D28. We studied 1144 patients from 23 MAGIC sites who were systemically treated with at least 0.25 mg/kg/day of systemic steroids (prednisone equivalents) and had clinical data and serum samples available in the MAGIC database and biorepository. We divided the patients into a training set (n=764) and a validation set (n=380). We used 12-month NRM from the time of acute GVHD onset as the primary outcome of interest. We first trained a recursive partitioning algorithm in the training set to create a response model (MAGIC D14 clinical response) according to overall GVHD grade at both onset and D14 that predicted 12-month NRM and then applied it to the validation set. Patients that either progressed to grade III/IV GVHD, continued having grade III/IV GVHD, or only improved to grade II at D14 from grade III/IV at D0 had high NRM and were classified as non-responders. Patients with grade I/II GVHD at day 0 who had grade 0-II GVHD at day 14 and patients who improved to grade 0/I at day 14 from grade III/IV at day 0 had low NRM and were classified as responders. Although counterintuitive, responders included patients whose GVHD remained at grade II because the 12 month NRM of this group was only 20%. The new clinical model predicted NRM as well as the D28 standard response model in the validation set. When we integrated the D14 MAP biomarker score (low: ≤ 0.290 vs high: &amp;gt;0.290) with the new D14 clinical response (D14 MAGIC integrated response), we observed three response groups of integrated response with strikingly different 12 month NRM (8%, 35%, 76%, p&amp;lt;0.001), in contrast to the D28 standard response (Figure 1A, 1B). D14 complete response required MAGIC clinical response with low MAP; D14 partial response required either MAGIC clinical response with high MAP or MAGIC clinical non-response with low MAP; and D14 non-response required MAGIC clinical non-response with high MAP. The D14 response groups also displayed significant differences in 12 month OS (82%, 58%, 14% respectively, p&amp;lt;0.001) We then compared the D14 integrated response with the D28 standard response for 12 month NRM prediction. This D14 integrated response model was superior for time-dependent AUC (0.78 vs 0.71, P=0.03), sensitivity (0.71 vs 0.54), positive predictive value (0.52 vs 0.48) and negative predictive value (0.92 vs 0.89), with minimal loss in specificity (0.85 vs 0.87) in the prediction of 12-month NRM compared to the D28 standard response model. Using decision curve analysis, the D14 integrated response displayed higher net benefit (correct identification of patients that will experience NRM by 12 months) over the whole range of threshold probabilities/preferences for changing immunosuppression when 12-month NRM was used as the outcome. We conclude first, that the definition of response that uses onset and D14 grades is as accurate as D28 ORR model; and second, that a model using clinical grades and biomarkers on D14 more accurately predicts long term NRM than the standard D28 definition and may be useful as a clinical trial endpoint.

Association of plasma high-density lipoprotein cholesterol level with risk of incident dementia: a cohort study of healthy older adults

Recent studies have reported associations between high plasma high-density lipoprotein cholesterol (HDL-C) levels and risk of all-cause mortality, age-related macular degeneration, sepsis and fractures, but associations with dementia risk remain unclear. To determine whether high plasma HDL-C levels are associated with increased incident dementia risk in initially-healthy older people. We conducted a post-hoc analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial; a double-blind, randomized, placebo-controlled trial of daily low-dose aspirin in healthy older people. ASPREE recruited 16,703 participants aged ≥70 years (from Australia) and 2411 participants aged ≥65 years (from the US) between 2010 and 2014. Participants had no diagnosed cardiovascular disease, dementia, physical disability, or life-threatening illness at enrolment and were cognitively healthy (3MS score ≥78). All-cause dementia was a primary trial endpoint, and determined by DSM-IV criteria. Cox regression was used to examine hazard ratios between HDL-C categories <40mg/dL, 40-60mg/dL (reference category), 60-80mg/dL, and >80mg/dL and dementia. Restricted cubic spline curves were used to determine nonlinear associations. Data analysis was performed from October 2022 to January 2023. Of the 18,668 participants, 850 (4.6%) cases of incident dementia were recorded over 6.3 (SD 1.8) years. Participants with high HDL-C (>80mg/dL) had a 27% higher risk of dementia (HR 1.27, 95% CI 1.03, 1.58). Age stratified analyses demonstrated that the risk of incident dementia was higher in participants ≥75 years compared to participants <75 years (HR 1.42, 95% CI 1.10, 1.83 vs HR 1.02, 95% CI 0.68, 1.51). Associations remained significant after adjusting for covariates including age, sex, country of enrolment, daily exercise, education, alcohol consumption, weight change over time, non-HDL-C, HDL-C-PRS, and APOE genotype. In a population of initially-healthy older adults aged ≥75 years, high HDL-C levels were associated with increased risk of all-cause dementia. National Institutes of Health, USA; National Health and Medical Research Council Australia; Monash University (Melbourne, VIC, Australia); and the Victorian Cancer Agency (Australia).

Review time of oncology drugs and its underlying factors: an exploration in China.

Introduction: How the launch delay of drugs and other factors of interest can influence the length of the review period by drug agencies is still unknown, and understanding this can help better strike the trade-off related to review speed. Methods: We included all new oncology drug applications submitted to China's National Medical Product Administration (NMPA) between 1 January 2018 and 31 December 2021, and ultimately succeeded in achieving marketing approval. For each drug, the length of the NMPA review process and other major characteristics were collected, including the registration class, approval class, priority review designation, and launch delay relative to the United States, as well as the number of patients enrolled, comparator, and primary endpoint of the pivotal trials supporting the approval. Linear regression model was employed to analyze the effects of factors of interest on the NMPA review time. Results: From 2018 to 2021, NMPA received 137 oncology applications that were ultimately approved. Half of the approvals [76 (55.5%)] were first licensed in the US, leaving a median launch delay of 2.71years (IQR, 1.03-5.59) in China. In the pivotal studies, the median enrollment was 361 participants (IQR, 131-682), and the use of control groups [90 (65.7%)] and surrogate endpoints [101 (73.7%)] was prevalent. The median review time was 304days (IQR, 253-376). Multivariate analysis for log-transformed review time showed that larger enrollment ( 92) was associated with a drop of 20.55% in review time (coefficient = -0.230; 95% CI, -0.404 to -0.055; p = 0.010); and a short delay (0 delay 1.95years) was associated with a drop of 17.63% in review time (coefficient = -0.194; 95% CI, -0.325 to -0.062; p = 0.004). Discussion: The short launch delay relative to the US was one important driver to the review speed of NMPA, which might suggest its latent regulatory reliance on the other global regulator during the post-marketing period when new information on the drug's clinical benefit was still lacking.

Validation of the Medical Research Council prion disease rating scale in France.

The development of assessment tools other than survival time is necessary to conduct therapeutic trials in prion diseases (also known as subacute transmissible encephalopathies). The Medical Research Council Prion Disease Rating Scale published by Thompson et al. (The Medical Research Council prion disease rating scale: A new outcome measure for prion disease therapeutic trials developed and validated using systematic observational studies. Brain. 2013; 136: 1116-27.) is the first attempt at a specific evaluation of prion diseases to avoid the floor effect seen in other scales. Validation of this scale in other countries is essential because, given the rarity of these diseases, therapeutic trials are likely to be multi-centre and international. After translation into French, we assessed by phone 173 cases classified as sporadic Creutzfeldt-Jakob disease out of 852 patients notified to the French national surveillance network between November 2014 and May 2021. Data showed that the natural history of the disease is similar in the UK and France. Patients who have a heterozygous genotype at codon 129 of the prion protein gene have a slower decline than homozygous patients. In rapidly progressing patients, death occurs shortly after reaching a low score or after a 'pre-terminal plateau' at a very low score. The similarities of disease progression profile observed in France and the UK with somewhat different surveillance systems and by distinct procedures highlight the robustness of the Medical Research Council Prion Disease Rating Scale that can be thus used to define primary endpoints of future trials at the international level.

Qualitative Exploration in Exit Interviews of Changes Observed in Clinical Trials for Individuals with Autism Spectrum Disorder Without Intellectual Disability.

To explore, from the perspective of Study Partners (SPs; eg, caregivers) of clinical trial participants with autism spectrum disorder (ASD), any changes experienced in socialization and communication over the clinical trial, how these changes manifested, and the impact these changes had on the autistic individual, the SP, and family. This helps interpret whether changes in trial outcomes were meaningful. Interviews were conducted with the SPs of individuals with ASD, without intellectual disability, from 2 clinical trials: 86 children (aged 5-12 years) or adolescents (aged 13-17 years) who took part in the aV1ation trial (83.7% male), and 41 adults (aged 18+ years) who took part in the V1aduct trial (80.5% male). The primary endpoint for both trials was change from baseline in the VinelandTM-II two-domain composite, consisting of the mean of the Socialization and Communication domains. In these interviews the participants verbally indicated level of change for each of these key domains on 7-point change scales. Improvements in the Socialization domain enabled greater awareness of the feelings of others and allowed for stronger empathy and kindness. Improvements in the Communication domain allowed for the autistic individual to be better at listening and better at self-expression. Together, changes in these two domains, which were considered most important, allowed for richer, deeper relationships. Study Partners noted that improvements in these domains allowed for better integration within the family unit, decreased stress, and increased optimism about the autistic individual's future. The impacts of changes in either domain were synergistic, combining together to create positive experiences which in turn led to further positive impacts in other skills. These qualitative insights provide context to the changes that were observed during the clinical trial and captured using the VinelandTM-II, illustrating the meaning of these changes to the individuals with ASD without intellectual disability and their families, and the impact that they have on people's everyday lives and overall health-related quality of life.

The challenge of clinical end points in sickle cell disease

AbstractAs most patients with sickle cell disease (SCD) do not have access to curative therapies, the availability of drug therapies that can modify disease severity remains highly desirable. Despite an increased understanding of the pathophysiology of SCD, only 4 drugs are approved by the US Food and Drugs Administration. Most drug trials in SCD have involved the use of acute pain episodes as the primary clinical end point. These studies have typically been to prevent or shorten the duration of such episodes. To date, no drug has received regulatory approval for shortening the duration of acute vaso-occlusive complications, likely highlighting the complex pathophysiology of acute pain episodes. Trials to prevent acute pain episodes have largely evaluated those episodes requiring health care use as a surrogate end point. However, with differences in culture and health care practices among countries, health care use may not reliably predict clinically important effects on acute pain episodes. This article discusses issues related to the use of health care use as the primary end point for prevention trials of acute pain episodes and highlights the importance of evaluating patient-reported outcomes as well as other SCD-related complications as outcome measures.

Triglyceride-glucose index, low-density lipoprotein levels, and cardiovascular outcomes in chronic stable cardiovascular disease: results from the ONTARGET and TRANSCEND trials.

The triglyceride-glucose index (TyG) has been proposed as an alternative to insulin resistance and as a predictor of cardiovascular outcomes. Little is known on its role in chronic stable cardiovascular disease and its predictive power at controlled low density lipoprotein (LDL) levels. Our study population consisted of 29 960 participants in the ONTARGET and TRANSCEND trials that enrolled patients with known atherosclerotic disease. Triglycerides and glucose were measured at baseline. TyG was calculated as the logarithmized product of fasting triglycerides and glucose divided by 2. The primary endpoint of both trials was a composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure. The secondary endpoint was all-cause death and the components of the primary endpoint. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) with extensive covariate adjustment for demographic, medical history, and lifestyle factors. During a mean follow-up of 4.3 years, 4895 primary endpoints and 3571 all-cause deaths occurred. In fully adjusted models, individuals in the highest compared to the lowest quartile of the TyG index were at higher risk for the primary endpoint (HR 1.14; 95% CI 1.05-1.25) and for myocardial infarction (HR 1.30; 95% CI 1.11-1.53). A higher TyG index did not associate with the primary endpoint in individuals with LDL levels < 100 mg/dL. A higher TyG index is associated with a modestly increased cardiovascular risk in chronic stable cardiovascular disease. This association is largely attenuated when LDL levels are controlled. www.clinicaltrials.gov: NCT00153101.

Progression-free survival, disease-free survival and other composite end points in oncology: improved reporting is needed.

Composite outcome measures such as progression-free survival and disease-free survival are increasingly used as surrogate end points in oncology research, frequently serving as the primary end point of pivotal trials that form the basis for FDA and EMA approvals. Such outcome measures combine two or more distinct events (for example, tumour (re)growth, new lesions and/or death) into a single, time-to-event end point. The use of a composite end point can increase the statistical power of a clinical trial and decrease the follow-up period required to demonstrate efficacy, thus lowering costs; however, these end points have a number of limitations. Composite outcomes are often vaguely defined, with definitions that vary greatly between studies, complicating comparisons of results across trials. Altering the makeup of events included in a composite outcome can alter study conclusions, including whether treatment effects are statistically significant. Moreover, the events included in a composite outcome often vary in clinical significance, reflect distinct biological pathways and/or are affected differently by treatment. Therefore, knowing the precise breakdown of the component events is essential to accurately interpret trial results and gauge the true benefit of an intervention. In oncology clinical trials, however, such information is rarely provided. In this Perspective, we emphasize this deficiency through a review of 50 studies with progression-free survival as an outcome published in five top oncology journals, discuss the advantages and challenges of using composite end points, and highlight the need for transparent reporting of the component events.

Small Intestinal Permeability and Metabolomic Profiles in Feces and Plasma Associate With Clinical Response in Patients With Active Psoriatic Arthritis Participating in a Fecal Microbiota Transplantation Trial: Exploratory Findings From the FLORA Trial.

We investigated intestinal permeability and fecal, plasma, and urine metabolomic profiles in methotrexate-treated active psoriatic arthritis (PsA) and how this related to clinical response following one sham or fecal microbiota transplantation (FMT). This exploratory study is based on the FLORA trial cohort, in which 31 patients with moderate-to-high peripheral PsA disease activity, despite at least 3 months of methotrexate-treatment, were included in a 26-week, double-blind, 1:1 randomized, sham-controlled trial. Participants were randomly allocated to receive either one healthy donor FMT (n=15) or sham (n=16) via gastroscopy. The primary trial end point was the proportion of treatment failures through 26 weeks. We performed a lactulose-to-mannitol ratio (LMR) test at baseline (n=31) and at week 26 (n=26) to assess small intestinal permeability. Metabolomic profiles in fecal, plasma, and urine samples collected at baseline, weeks 4, 12, and 26 were measured using 1 H Nuclear Magnetic Resonance. Trial failures (n=7) had significantly higher LMR compared with responders (n=19) at week 26 (0.027 [0.017-0.33]) vs. 0.012 [0-0.064], P = 0.013), indicating increased intestinal permeability. Multivariate analysis revealed a significant model for responders (n=19) versus failures (n=12) at all time points based on their fecal (P < 0.0001) and plasma (P = 0.005) metabolomic profiles, whereas urine metabolomic profiles did not differ between groups (P = 1). Fecal N-acetyl glycoprotein GlycA correlated with Health Assessment Questionnaire Disability Index (coefficient=0.50; P = 0.03) and fecal propionate correlated with American College of Rheumatology 20 response at week 26 (coefficient=27, P = 0.02). Intestinal permeability and fecal and plasma metabolomic profiles of patients with PsA were associated with the primary clinical trial end point, failure versus responder.

Transportability of two heart failure trials to a disease registry using individual patient data

ObjectivesRandomized controlled trials are the gold-standard for determining therapeutic efficacy, but are often unrepresentative of real-world settings. Statistical transportation methods (hereafter transportation) can partially account for these differences, improving trial applicability without breaking randomization. We transported treatment effects from two heart failure (HF) trials to a HF registry. Study Design and SettingIndividual-patient-level data from two trials (Carvedilol or Metoprolol European Trial (COMET), comparing carvedilol and metoprolol, and digitalis investigation group trial (DIG), comparing digoxin and placebo) and a Scottish HF registry were obtained. The primary end point for both trials was all-cause mortality; composite outcomes were all-cause mortality or hospitalization for COMET and HF-related death or hospitalization for DIG. We performed transportation using regression-based and inverse odds of sampling weights (IOSW) approaches. ResultsRegistry patients were older, had poorer renal function and received higher-doses of loop-diuretics than trial participants. For each trial, point estimates were similar for the original and IOSW (e.g., DIG composite outcome: OR 0.75 (0.69, 0.82) vs. 0.73 (0.64, 0.83)). Treatment effect estimates were also similar when examining high-risk (0.64 (0.46, 0.89)) and low-risk registry patients (0.73 (0.61, 0.86)). Similar results were obtained using regression-based transportation. ConclusionRegression-based or IOSW approaches can be used to transport trial effect estimates to patients administrative/registry data, with only moderate reductions in precision.

Seasonal vaccination with RTS,S/AS01E vaccine with or without seasonal malaria chemoprevention in children up to the age of 5 years in Burkina Faso and Mali: a double-blind, randomised, controlled, phase 3 trial

Seasonal vaccination with the RTS,S/AS01E vaccine combined with seasonal malaria chemoprevention (SMC) prevented malaria in young children more effectively than either intervention given alone over a 3 year period. The objective of this study was to establish whether the added protection provided by the combination could be sustained for a further 2 years. This was a double-blind, individually randomised, controlled, non-inferiority and superiority, phase 3 trial done at two sites: the Bougouni district and neighbouring areas in Mali and Houndé district, Burkina Faso. Children who had been enrolled in the initial 3-year trial when aged 5-17 months were initially randomly assigned individually to receive SMC with sulphadoxine-pyrimethamine and amodiaquine plus control vaccines, RTS,S/AS01E plus placebo SMC, or SMC plus RTS,S/AS01E. They continued to receive the same interventions until the age of 5 years. The primary trial endpoint was the incidence of clinical malaria over the 5-year trial period in both the modified intention-to-treat and per-protocol populations. Over the 5-year period, non-inferiority was defined as a 20% increase in clinical malaria in the RTS,S/AS01E-alone group compared with the SMC alone group. Superiority was defined as a 12% difference in the incidence of clinical malaria between the combined and single intervention groups. The study is registered with ClinicalTrials.gov, NCT04319380, and is complete. In April, 2020, of 6861 children originally recruited, 5098 (94%) of the 5433 children who completed the initial 3-year follow-up were re-enrolled in the extension study. Over 5 years, the incidence of clinical malaria per 1000 person-years at risk was 313 in the SMC alone group, 320 in the RTS,S/AS01E-alone group, and 133 in the combined group. The combination of RTS,S/AS01E and SMC was superior to SMC (protective efficacy 57·7%, 95% CI 53·3 to 61·7) and to RTS,S/AS01E (protective efficacy 59·0%, 54·7 to 62·8) in preventing clinical malaria. RTS,S/AS01E was non-inferior to SMC (hazard ratio 1·03 [95% CI 0·95 to 1·12]). The protective efficacy of the combination versus SMC over the 5-year period of the study was very similar to that seen in the first 3 years with the protective efficacy of the combination versus SMC being 57·7% (53·3 to 61·7) and versus RTS/AS01E-alone being 59·0% (54·7 to 62·8). The comparable figures for the first 3 years of the study were 62·8% (58·4 to 66·8) and 59·6% (54·7 to 64·0%), respectively. Hospital admissions for WHO-defined severe malaria were reduced by 66·8% (95% CI 40·3 to 81·5), for malarial anaemia by 65·9% (34·1 to 82·4), for blood transfusion by 68·1% (32·6 to 84·9), for all-cause deaths by 44·5% (2·8 to 68·3), for deaths excluding external causes or surgery by 41·1% (-9·2 to 68·3), and for deaths from malaria by 66·8% (-2·7 to 89·3) in the combined group compared with the SMC alone group. No safety signals were detected. Substantial protection against malaria was sustained over 5 years by combining seasonal malaria vaccination with seasonal chemoprevention, offering a potential new approach to malaria control in areas with seasonal malaria transmission. UK Joint Global Health Trials and PATH's Malaria Vaccine Initiative (through a grant from the Bill & Melinda Gates Foundation). For the French translation of the abstract see Supplementary Materials section.

Flow Cytometry Method Validation Protocols.

Analytical method validation provides a means to ensure that data are credible and reproducible. This article will provide a brief introduction to analytical method validation as applied to cellular analysis by flow cytometry, along with practical procedures for four different types of validation. The first, Basic Protocol 1 (the limited validation protocol), is recommended for research and non-regulated laboratories. Next, Basic Protocol 2) presents a reasonable, fit-for-purpose validation approach appropriate for biopharma and research settings. Basic Protocol 3 addresses the type of validation performed in clinical laboratories for moderate-risk tests developed in house. Finally, Basic Protocol 4 describes the process that should be applied whenever a method is being transferred from one facility to another. All four validation plans follow the fit-for-purpose validation approach, in which the validation parameters are selected based on the intended use of the assay. These validation protocols represent the minimal requirement and may not be applicable for every intended use such as high-risk clinical assays or data to be used as a primary endpoint in a clinical trial. The recommendations presented here are consistent with the white papers published by the American Association of Pharmaceutical Scientists and the International Clinical Cytometry Society, as well as with Clinical Laboratory Standards Institute Guideline H62: Validation of Assays Performed by Flow Cytometry (CLSI, 2021). © 2023 Wiley Periodicals LLC. Basic Protocol 1: Limited validation Basic Protocol 2: Fit-for-purpose validation for biopharma and research settings Basic Protocol 3: Validation for moderate clinical risk laboratory developed tests Basic Protocol 4: Transfer validation.

Approach to patient reported outcome measures selection and implementation in a chronic norovirus clinical efficacy trial for patients after solid organ transplant.

Norovirus is the second most common cause of diarrhea among solid organ transplant recipients. There are currently no approved therapies for Norovirus, which can substantially impact quality of life, particularly in an immunocompromised patient population. In order to establish clinical efficacy and support any medication claims related to a patient's symptoms or function, the Food and Drug Administration requires that a trial's primary endpoints be derived from patient reported outcome measures- an outcome that comes directly from the patient, without interpretation of the patient's response by a clinician or anyone else. In this paper, we describe our study team's approach to the definition, selection, measurement and evaluation of patient reported outcome measures as part of establishing clinical efficacy of Nitazoxanide for acute and chronic Norovirus in solid organ transplant recipients. We specifically describe our approach to measuring the primary efficacy endpoint- days to cessation of vomiting and diarrhea after randomization through 160 days, measured through daily symptom diaries as well as the impact of treatment on exploratory efficacy endpoints, particularly change in the impact of norovirus on psychological function and quality of life.

Which trial do we need? Combination antimicrobial therapy for hospital-acquired bacterial pneumonia caused by Pseudomonas aeruginosa

Meropenem therapy will be open-label, while tobramycin or placebo will be administered in a double-blind fashion. The primary trial endpoint will be a composite hierarchical outcome of 1) 28-day all-cause mortality, 2) ventilator-free days, and 3) modified time to clinical stability, evaluated using a win ratio methodology (see below). Secondary trial outcomes will include frequency of safety events (acute kidney injury), resolution of circulatory shock, recurrent HABP, and emergence of meropenem resistance both during treatment and in cases of recurrent infection. Using simulation studies to inform sample size calculations, we estimate that recruitment of 130 patients per treatment arm would provide at least 80% power to detect a win ratio of 1.50 while preserving a two-sided type 1 error rate of 0.05.

Exploring the comparative cardiovascular death benefits of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes: a frequentist and Bayesian network meta-analysis-based scoring.

Cardiovascular death (CV death) is the most objective component of the primary or secondary endpoint in cardiovascular outcome trials (CVOTs) conducted with sodium-glucose cotransporter 2 inhibitors (SGLT-2is). CV death is often incorporated into primary composite outcomes. It is combined with major adverse cardiovascular events (MACEs) in trials with atherosclerotic cardiovascular disease (ASCVD) at baseline and with hospitalization due to heart failure (hHF) in trials with heart failure at baseline. Unlike the primary composites, CV death reduction by itself demonstrated significant variations among the CVOTs with SGLT-2is. Moreover, the impact of the individual agents within the SGLT-2i group on the reduction in CV death has not been explored objectively. This network meta-analysis was undertaken to construct a hierarchy based on indirect pairwise comparisons and rankings among the individual agents within SGLT-2is. A Cochrane library-based web search yielded 13 randomized controlled trials for analysis. Stata/BE 17.0 and RStudio 2022.07.1 Build 554 software were used to conduct a frequentist and Bayesian network meta-analysis. The effect size was assessed based on the risk ratio (RR). Ranking of the individual agents was performed with a frequentist approach (P-score and a multidimensional scaling [MDS] rank system) and a Bayesian ranking (surface under the cumulative ranking [SUCRA]). Regarding the overall data, SGLT-2is reduced the CV death risk by 12% (RR: 0.88, 95% CI 0.80-0.96). All three scoring methods resulted in empagliflozin scoring the highest. There was a 15% RR reduction in CV death (95% CI 0.71-1.02) in the ASCVD and multiple cardiovascular risk factor (MRF) groups and an 11% RR reduction in the HF group, with empagliflozin ranking the highest in the former group and dapagliflozin in the latter. Empagliflozin ranked the highest compared to the other SGLT-2is in the overall population and the trials including type 2 diabetes (T2D) patients with ASCVD or MRF at baseline, while dapagliflozin ranked the highest in the trials of patients with HF at baseline. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022381556, identifier CRD42022381556.

Evolution and optimization of clinical trial endpoints and design in pulmonary arterial hypertension.

Selection of endpoints for clinical trials in pulmonary arterial hypertension (PAH) is challenging because of the small numbers of patients and the changing expectations of patients, clinicians, and regulators in this evolving therapy area. The most commonly used primary endpoint in PAH trials has been 6-min walk distance (6MWD), leading to the approval of several targeted therapies. However, single surrogate endpoints such as 6MWD or hemodynamic parameters may not correlate with clinical outcomes. Composite endpoints of clinical worsening have been developed to reflect patients' overall condition more accurately, although there is no standard definition of worsening. Recently there has been a shift to composite endpoints assessing clinical improvement, and risk scores developed from registry data are increasingly being used. Biomarkers are another area of interest, although brain natriuretic peptide and its N-terminal prohormone are the only markers used for risk assessment or as endpoints in PAH. A range of other genetic, metabolic, and immunologic markers is currently under investigation, along with conventional and novel imaging modalities. Patient-reported outcomes are an increasingly important part of evaluating new therapies, and several PAH-specific tools are now available. In the future, alternative statistical techniques and trial designs, such as patient enrichment strategies, will play a role in evaluating PAH-targeted therapies. In addition, modern sequencing techniques, imaging analyses, and high-dimensional statistical modeling/machine learning may reveal novel markers that can play a role in the diagnosis and monitoring of PAH.