Primary Trial Endpoint Research Articles

Evaluation of the fragility of pivotal trials used to support US Food and Drug Administration approval for plaque psoriasis

Over the last 5years, there has been a rapid growth in the number of clinical trials used to support a US Food and Drug Administration (FDA) approval for systemic therapies with labeled indications for plaque psoriasis. We aim to evaluate the fragility of clinical trial data used to support FDA approval of therapies for psoriasis. We reviewed the primary endpoints of the pivotal trials of all systemic medications with a labeled indication for plaque psoriasis available from Drugs@FDA. Sixty-nine clinical trial primary endpoints met inclusion criteria and were assessed for robustness, yielding a median fragility index of 72 and a median fragility quotient of 0.19. Efficacy and statistical analysis data for several approved medications were not available on the product label or on Drugs@FDA. When compared with randomized controlled trials for FDA approval across various diseases, pivotal trials in psoriasis appear quite robust to changes in outcomes.

Patient-Reported Cognitive Impairment Among Women With Early Breast Cancer Randomly Assigned to Endocrine Therapy Alone Versus Chemoendocrine Therapy: Results From TAILORx.

Cancer-related cognitive impairment (CRCI) is common during adjuvant chemotherapy and may persist. TAILORx provided a novel opportunity to prospectively assess patient-reported cognitive impairment among women with early breast cancer who were randomly assigned to chemoendocrine therapy (CT+E) versus endocrine therapy alone (E), allowing us to quantify the unique contribution of chemotherapy to CRCI. Women with a 21-gene recurrence score of 11 to 25 enrolled in TAILORX were randomly assigned to CT+E or E. Cognitive impairment was assessed among a subgroup of 552 evaluable women using the 37-item Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) questionnaire, administered at baseline, 3, 6, 12, 24, and 36 months. The FACT-Cog included the 20-item Perceived Cognitive Impairment (PCI) scale, our primary end point. Clinically meaningful changes were defined a priori and linear regression was used to model PCI scores on baseline PCI, treatment, and other factors. FACT-Cog PCI scores were significantly lower, indicating more impairment, at 3, 6, 12, 24, and 36 months compared with baseline for both groups. The magnitude of PCI change scores was greater for CT+E than E at 3 months, the prespecified primary trial end point, and at 6 months, but not at 12, 24, and 36 months. Tests of an interaction between menopausal status and treatment were nonsignificant. Adjuvant CT+E is associated with significantly greater CRCI compared with E at 3 and 6 months. These differences abated over time, with no significant differences observed at 12 months and beyond. These findings indicate that chemotherapy produces early, but not sustained, cognitive impairment relative to E, providing reassurance to patients and clinicians in whom adjuvant chemotherapy is indicated to reduce recurrence risk.

The MAGIC Algorithm Probability (MAP) Is a Validated Response Biomarker of Treatment for Acute Graft-Versus-Host Disease

There are no validated biomarkers that measure a patient's response to therapy for acute graft-versus-host disease (GVHD), the leading cause of non-relapse mortality (NRM) after allogeneic hematopoietic cell transplant (HCT). Recent studies from the Mount Sinai Acute GVHD International Consortium (MAGIC) have validated an algorithm probability (MAP) that combines serum concentrations of two biomarkers of GVHD (REG3α and ST2) to generate an estimated probability of 6 month NRM for individual patients. The MAP estimates GVHD-mediated damage to crypts throughout the lower GI tract at single time points (Hartwell et al., JCI Insight, 2017; Major- Monfried et al., Blood, 2018). We hypothesized that the change in MAP between start of treatment and 28 days later could serve as a response biomarker and would compare favorably to clinical response, the gold standard which is widely used as a surrogate for long term survival and is the primary endpoint in most GVHD treatment trials (Martin et al., BBMT, 2009; MacMillan et al., Blood, 2010). We prospectively collected serum samples and clinical staging from 368 sequential HCT patients who received systemic treatment for acute GVHD in one of 20 MAGIC centers between January 2016 and February 2018. We computed MAPs and clinical responses for each patient. MAPs of patients who experienced 6 month NRM increased significantly compared to MAPs of patients who survived (p=0.0004). In patients whose initial MAPs were low (Ann Arbor 1, MAP 0.290), those who survived tended to have the largest decreases in MAP (Fig 1C). We found that patients whose MAPs rose above the previously determined high-risk threshold MAP of 0.290 had significantly worse survival compared to those who remained below it, whereas the large number patients with initially high MAPs that remained above the threshold had a large increase in mortality (Fig 2). When measured at day 28, MAPs predicted NRM more accurately than clinical responses, with areas under the receiver operating characteristic curve (AUC) of 0.86 and 0.70, respectively (p We conclude that the MAP is, to our knowledge, the first laboratory test validated as a response biomarker for acute GVHD treatment and more accurately predicts survival than clinical response after 28 days of treatment. The MAP may serve as a novel endpoint in future trials of GVHD treatment.

P267 Validation of the short inflammatory bowel disease questionnaire as an outcome measure in Crohn’s disease patients

Abstract Background Health-related quality-of-life by the self-report, disease-specific Short Inflammatory Bowel Disease Questionnaire (SIBDQ) is increasingly used as an outcome measure in Crohn`s disease (CD) patients in clinical trials. Higher SIBDQ scores indicate better quality-of-life; the range is 10 to 70. However, the construct validity of SIBDQ and its responsiveness to change of disease status require validation. Methods Adult (≥18 years) CD patients (n = 108) with Harvey–Bradshaw Index (HBI) >4 and <16 prospectively filled in the SIBDQ at two time-points (T1, T2) 3 months apart. Medical data at T1 and T2 were collected, and recorded by their physicians in the HBI. Biomarkers of disease activity included Calprotectin and C-reaction protein (CRP), measured at T1 and T2. The construct validity of SIBDQ in relation to biomarkers and HBI was determined by Pearson correlations and group comparisons using Student`s t-test. Statistical significance was taken as p < 0.05. Patients’ medications were prescribed without regard to the study protocol. Results Demographic and medical characteristics (median, %) of the cohort were: age 30 years; females 65%, married/partner 48%; higher education 83%; BMI 22; non-smokers/past-smokers 92%; disease duration 5 years; past Crohn’s disease-related surgery 17%; Montreal classification A2 89%, L2+L3 89%, B1+B2 89%, perianal disease 18%; medications: corticosteroids 4%, 5-ASA 5%, immunomodulators 21%, biologicals 43%. HBI and SIBDQ median scores at T1 and T2 were: HBI: 9 and 4 (p < 0.001); SIBDQ: 43 and 49 (p < 0.001). SIBDQ scores correlated inversely with Calprotectin (r = −0.395, p = .002), CRP (r = −0.208, p = .046), and HBI (r = −0.345, p < 0.001). Baseline HBI scores were used to divide the cohort into two groups for comparison: mild disease (5–7) vs. moderate disease (8–16). Mild disease patients reported higher SIBDQ scores than those with moderate disease (42.7 vs. 39.7, t = 1.96, p = 0.05). Regarding sensitivity of SIBDQ to clinical changes between T1 and T2, we found that change in SIBDQ correlated significantly with change in CRP across these two administrations (r = −0.232, p = 0.042). Finally, defining clinical response in CD as a decrease from baseline HBI score by ≥3 points, SIBDQ change scores were significantly larger in treatment responders (n = 51, M = 6.25) than non-responders (n = 30, M = 1.13, t = −3.042, p = 0.003). Conclusion The SIBDQ measure is a valid assessment of quality-of-life in CD, correlating with biomarkers and sensitive to change of disease activity, with potential for use as a patient-reported outcome in both clinical practice and as a primary end-point in clinical trials.

Clinical efficacy assessment in severe vernal keratoconjunctivitis: preliminary validation of a new penalties-adjusted corneal fluorescein staining score

ABSTRACT Introduction and objective: Vernal keratoconjunctivitis (VKC) is a rare allergic eye condition that occurs in children and is characterised by a combination of debilitating symptoms. Repeated use of topical corticosteroid rescue therapy is often necessary in severe forms. This study aims to assess the validity of a new composite endpoint: the penalties-adjusted corneal staining score (PACS-S) proposed as primary endpoint in VEKTIS trial evaluating the efficacy of a new corticosteroid-sparing treatment, VERKAZIA® (ciclosporin 1 mg/ml eye drops), in severe VKC patients. Methodology: This research comprised a systematic literature review to identify efficacy endpoints being proposed in clinical trials for pediatric patients with severe VKC, followed by a remote expert advisory board assessing the validity of the PACS-S. Results: While no agreed or validated endpoint for assessing efficacy in VKC was identified when VEKTIS trial started, the experts’ board acknowledged a high face validity of PACS-S as a subjective integrated measure matching the current clinical practice. A fair external validity was considered with regards to VEKTIS trial secondary endpoints. Conclusion: PACS-S appears to be a reliable, valid and clinically meaningful primary endpoint that allows significant improvement over existing endpoints in severe VKC trials. Additional research is needed to validate this endpoint.

Profound reductions in first and total cardiovascular events with icosapent ethyl in the REDUCE-IT trial: why these results usher in a new era in dyslipidaemia therapeutics.

The aims of this clinical review are to: (i) highlight the importance of elevated baseline triglycerides (TG) in the setting of well-controlled low-density lipoprotein cholesterol (LDL-C) on statins as a major contributor to residual atherosclerotic cardiovascular disease (ASCVD) risk, particularly among patients with type 2 diabetes mellitus, metabolic syndrome, and obesity whose distinctive lipid phenotype cannot be optimally treated with LDL-C reduction therapy alone; (ii) describe the findings and clinical implications of the landmark REDUCE-IT trial in which ethyl eicosapentaenoic acid significantly improved ASCVD outcomes. While many genetic studies have shown that elevated TG are an independent causal factor for ASCVD, prior placebo-controlled trials using niacin, fibrates, omega-3 fatty acids, and dietary supplement fish oil preparations have failed to demonstrate significant CV event reduction when added to statin therapy. In contrast, the REDUCE-IT trial in 8179 participants showed convincingly that the administration of 4 g daily of icosapent ethyl (an ethyl ester of eicosapentaenoic acid) in patients at high risk for ASCVD with increased levels of baseline TG [median value, 2.44 mmol/L (216.0 mg/dL)] but well-controlled LDL-C [median value, 1.94 mmol/L (75.0 mg/dL)] reduced significantly incident events across both the trial primary endpoint and multiple prespecified secondary endpoints, including cardiovascular death, as well as both subsequent and total primary endpoint and key secondary endpoint events. Icosapent ethyl unequivocally contributed to ASCVD event reduction over and above statin therapy. The REDUCE-IT trial results should alter our approach to managing a growing population of hypertriglyceridaemic patients whose lipid phenotype requires more intensive treatment beyond LDL-C lowering alone.

Beyond Performance Metrics: Automatic Deep Learning Retinal OCT Analysis Reproduces Clinical Trial Outcome

To validate the efficacy of a fully automatic, deep learning-based segmentation algorithm beyond conventional performance metrics by measuring the primary outcome of a clinical trial for macular telangiectasia type 2 (MacTel2). Evaluation of diagnostic test or technology. A total of 92 eyes from 62 participants with MacTel2 from a phase 2 clinical trial (NCT01949324) randomized to 1 of 2 treatment groups METHODS: The ellipsoid zone (EZ) defect areas were measured on spectral domain OCT images of each eye at 2 time points (baseline and month 24) by a fully automatic, deep learning-based segmentation algorithm. The change in EZ defect area from baseline to month 24 was calculated and analyzed according to the clinical trial protocol. Difference in the change in EZ defect area from baseline to month 24 between the 2 treatment groups. The difference in the change in EZ defect area from baseline to month 24 between the 2 treatment groups measured by the fully automatic segmentation algorithm was 0.072±0.035 mm2 (P= 0.021). This was comparable to the outcome of the clinical trial using semiautomatic measurements by expert readers, 0.065±0.033 mm2 (P= 0.025). The fully automatic segmentation algorithm was as accurate as semiautomatic expert segmentation to assess EZ defect areas and was able to reliably reproduce the statistically significant primary outcome measure of the clinical trial. This approach, to validate the performance of an automatic segmentation algorithm on the primary clinical trial end point, provides a robust gauge of its clinical applicability.

Reducing Patient Burden in Clinical Trials Through the Use of Historical Controls: Appropriate Selection of Historical Data to Minimize Risk of Bias.

Historical data have been used to augment or replace control arms in some rare disease and pediatric clinical trials. With greater availability of historical data and new methodology such as dynamic borrowing, the inclusion of historical data in clinical trials is an increasingly appealing approach for larger disease areas as well, as this can result in increased power and precision and can minimize the burden on patients in clinical trials. However, sponsors must assess whether the potential biases incurred with this approach outweigh the benefits and discuss this trade-off with the regulatory agencies. This paper discusses important points for the appropriate selection of historical controls for inclusion in the analysis of primary and/or key secondary endpoint(s) in clinical trials. The general steps are as follows: (1) Assess whether a trial is a suitable candidate for this approach. (2) If it is, then carefully identify appropriate historical trials to minimize selection bias. (3) Refine the historical control set if appropriate, for example, by selecting subsets of studies or patients. Identification of trial settings that are amenable to historical borrowing and selection of appropriate historical data using the principles discussed in this paper has the potential to lead to more efficient estimation and decision making. Ultimately, this efficiency gain results in lower patient burden and gets effective drugs to patients more quickly.

Targeting treatable traits in severe asthma: a randomised controlled trial.

Treatable traits have been proposed as a new paradigm for airway disease management. To characterise treatable traits in a severe asthma population and to determine the efficacy of targeting treatments to these treatable traits in severe asthma. Participants (n=140) with severe asthma were recruited to a cross-sectional study and underwent a multidimensional assessment to characterise treatable traits. Eligible participants with severe asthma (n=55) participated in a 16-week parallel-group randomised controlled trial to determine the feasibility and efficacy of management targeted to predefined treatable traits, compared to usual care in a severe asthma clinic. The patient-reported outcome of health-related quality of life was the trial's primary end-point. Participants with severe asthma had a mean±sd of 10.44±3.03 traits per person, comprising 3.01±1.54 pulmonary and 4.85±1.86 extrapulmonary traits and 2.58±1.31 behavioural/risk factors. Individualised treatment that targeted the traits was feasible and led to significantly improved health-related quality of life (0.86 units, p<0.001) and asthma control (0.73, p=0.01). Multidimensional assessment enables detection of treatable traits and identifies a significant trait burden in severe asthma. Targeting these treatable traits using a personalised-medicine approach in severe asthma leads to improvements in health-related quality of life, asthma control and reduced primary care acute visits. Treatable traits may be an effective way to address the complexity of severe asthma.

Identifying and treating high blood pressure in men under 55 years with grade 1 hypertension: the TREAT CASP study and RCT

Background There is uncertainty regarding whether or not younger (i.e. aged &lt; 55 years), low-risk patients with grade 1 hypertension (i.e. a clinic blood pressure of 140–159/90–99 mmHg) should be treated with blood pressure-lowering medication. This is a heterogeneous group of patients because of variation in systolic/pulse pressure amplification from the central aorta to the brachial artery. It is hypothesised that within grade 1 hypertension, patients can be divided into those with high central aortic systolic pressure and those with low central aortic systolic pressure. Objectives The aims of this study were to (1) evaluate whether or not non-invasive central aortic systolic pressure measurement can better identify younger patients with grade 1 hypertension, who are more likely to have an increased left ventricular mass index; and (2) determine whether or not blood pressure lowering regresses early cardiac structural change in patients with high central aortic systolic pressure. Setting A university hospital with satellite primary care recruitment sites. Participants A total of 726 men (aged 18 to &lt; 55 years) were screened to identify 162 men with grade 1 hypertension and low or high central aortic systolic pressure. Blood pressure status was classified according to seated clinic blood pressure, central aortic systolic pressure and 24-hour ambulatory blood pressure. Design (1) Evaluating the strength of the correlation between central aortic systolic pressure, clinic blood pressure and 24-hour ambulatory blood pressure with left ventricular mass index in 162 patients; (2) a 12-month randomised controlled trial in patients with grade 1 hypertension and high central aortic systolic pressure (i.e. a central aortic systolic pressure of ≥ 125 mmHg) (n = 105), using a prospective, open, blinded, end-point design; and (3) a 12-month observational study in 57 patients with grade 1 hypertension and low central aortic systolic pressure (i.e. a central aortic systolic pressure of &lt; 125 mmHg). Interventions Randomised controlled trial – patients with high central aortic systolic pressure randomised to blood pressure lowering medication (50–100 mg of losartan ± 5–10 mg of amlodipine once daily) versus usual care (no treatment) for 12 months. Main outcomes Randomised controlled trial primary end point – change in left ventricular mass index as measured by cardiac magnetic resonance imaging, comparing treatment with no treatment. Results (1) At baseline, left ventricular mass index was higher in men with high central aortic systolic pressure than in those with low central aortic systolic pressure (mean ± standard deviation 67.9 ± 8.8 g/m2 vs. 64.0 ± 8.5 g/m2; difference 4.0 g/m2, 95% confidence interval 1.1 to 6.9 g/m2; p &lt; 0.01). Central aortic systolic pressure was not superior to clinic blood pressure as a determinant of left ventricular mass index. Univariate analysis, regression coefficients and slopes for left ventricular mass index were similar for clinic systolic blood pressure, ambulatory systolic blood pressure and central aortic systolic pressure. (2) In the randomised controlled trial, blood pressure-lowering treatment reduced central aortic systolic pressure (–21.1 mmHg, 95% confidence interval – 24.4 to –17.9 mmHg; p &lt; 0.001) and clinic systolic blood pressure (–20.0 mmHg, 95% confidence interval – 23.3 to –16.6 mmHg; p &lt; 0.001) versus no treatment. Treatment was well tolerated and associated with a greater change (i.e. from baseline to study closeout) in left ventricular mass index versus no treatment [–3.3 g/m2 (95% confidence interval –4.5 to –2.2 g/m2) vs. –0.9 g/m2 (95% confidence interval –1.7 to –0.2 g/m2); p &lt; 0.01], with a medium-to-large effect size (Cohen’s d statistic –0.74). (3) Patients with low central aortic systolic pressure had no significant change in left ventricular mass index after 12 months (mean change –0.5 g/m2, 95% confidence interval –1.2 to 0.2 g/m2; p = 0.18). Conclusions Men with grade 1 hypertension and high central aortic systolic pressure tended to have higher clinic blood pressure and more hypertension-mediated cardiac structural change than those with low central aortic systolic pressure. Central aortic systolic pressure was not superior to clinic blood pressure or ambulatory blood pressure at stratifying risk of increased left ventricular mass index. Blood pressure-lowering treatment led to a regression of left ventricular mass index in men with grade 1 hypertension and high central aortic systolic pressure compared with no treatment. Limitations The study was limited to a moderate sample of men and there was a low prevalence of very high amplification. Future work Evaluating effects of blood pressure lowering on cardiac function. Trial registration Current Controlled Trials ISRCTN09502665. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership and will be published in full in Efficacy and Mechanism Evaluation; Vol. 6, No. 13. See the NIHR Journals Library website for further project information.

Applying Data Warehousing to a Phase III Clinical Trial From the Fondazione Italiana Linfomi Ensures Superior Data Quality and Improved Assessment of Clinical Outcomes.

Data collection in clinical trials is becoming complex, with a huge number of variables that need to be recorded, verified, and analyzed to effectively measure clinical outcomes. In this study, we used data warehouse (DW) concepts to achieve this goal. A DW was developed to accommodate data from a large clinical trial, including all the characteristics collected. We present the results related to baseline variables with the following objectives: developing a data quality (DQ) control strategy and improving outcome analysis according to the clinical trial primary end points. Data were retrieved from the electronic case reporting forms (eCRFs) of the phase III, multicenter MCL0208 trial (ClinicalTrials.gov identifier: NCT02354313) of the Fondazione Italiana Linfomi for younger patients with untreated mantle cell lymphoma (MCL). The DW was created with a relational database management system. Recommended DQ dimensions were observed to monitor the activity of each site to handle DQ management during patient follow-up. The DQ management was applied to clinically relevant parameters that predicted progression-free survival to assess its impact. The DW encompassed 16 tables, which included 226 variables for 300 patients and 199,500 items of data. The tool allowed cross-comparison analysis and detected some incongruities in eCRFs, prompting queries to clinical centers. This had an impact on clinical end points, as the DQ control strategy was able to improve the prognostic stratification according to single parameters, such as tumor infiltration by flow cytometry, and even using established prognosticators, such as the MCL International Prognostic Index. The DW is a powerful tool to organize results from large phase III clinical trials and to effectively improve DQ through the application of effective engineered tools.

Patient-reported outcome instruments in clinical trials of systemic sclerosis.

Patient-reported outcome instruments provide valuable insight into disease-related morbidity known only to the patient and complement more objective outcome tools in the clinical trial setting. They are of particular importance in systemic sclerosis owing to the challenges around defining disease activity, the episodic nature of many disease-specific manifestations and the paucity of validated objective surrogate outcome measures for use in clinical trials. Early clinical trials of systemic sclerosis often incorporated legacy patient-reported outcome instruments, but the last 20 years has witnessed the emergence of several scleroderma-specific instruments that are now being routinely used alongside other outcomes in systemic sclerosis clinical trials. More recently, the value of patient-reported outcomes has been highlighted by their prominence in the American College of Rheumatology Combined Response Index for Systemic Sclerosis that has been utilized as the primary endpoint of recent clinical trials of early diffuse systemic sclerosis. This review considers the role and performance of the various patient-reported outcome instruments utilized in systemic sclerosis clinical trials, the current positioning of patient-reported outcome instruments within clinical trial endpoint models across the range of systemic sclerosis disease manifestations and, where applicable, we shall highlight areas for future research.

Effect of Serum Albumin Levels in Patients With Heart Failure With Preserved Ejection Fraction (from the TOPCAT Trial)

Little data are available regarding the determinants and prognostic significance of serum albumin in Heart Failure with Preserved Ejection Fraction (HFpEF). We sought to examine the phenotypic correlates of albumin and its independent prognostic implications in HFpEF. We analyzed data from 3,254 subjects enrolled the TOPCAT trial. We stratified subjects according to tertiles of albumin and examined differences in various phenotypic traits between these strata, including 8 protein biomarkers selected ad hoc and measured from frozen samples available in a subset of participants (n = 372). We also assessed the relationship between albumin and the trial primary endpoint. Lower albumin was associated with older age, black race, and greater prevalence of NYHA class III-IV, peripheral arterial disease, atrial fibrillation and diabetes mellitus. Lower albumin was also associated with increased levels of several inflammatory biomarkers, markers of liver fibrosis, albuminuria, and greater arterial stiffness, diastolic dysfunction and pulmonary hypertension. Albumin was a strong predictor of the primary trial endpoint, even after adjustment for the MAGGIC risk score (hazard ratio [HR] 0.72, confidence interval [CI] 0.67 to 0.78; p <0.0001) and prespecified traditional risk factors (HR 0.78, CI 0.71 to 0.85; p <0.0001). Lower albumin was strongly associated with a worse prognosis even well within normal ranges (>3.5 g/dL), with a sharp increase in risk between 4.6 and 3.6 g/dL. In conclusion, albumin is an integrated marker of various adverse processes in HFpEF, including inflammation, subclinical liver disease, arterial stiffness, and renal disease. Albumin is a powerful risk predictor independent of traditional risk prediction models, even within normal ranges.

A Randomized Trial of EPOCH-Based Chemotherapy with Vorinostat for Highly Aggressive HIV-Associated Lymphomas: Updated Results Evaluating Impact of Diagnosis-to-Treatment Interval (DTI) and Pre-Protocol Systemic Therapy on Outcomes

Introduction: EPOCH-based chemotherapy is considered a preferred first-line treatment for HIV-associated diffuse large B-cell lymphoma (DLBCL) and primary effusion lymphoma in the 2019 NCCN guidelines. We previously reported that adding the HDAC inhibitor vorinostat (VOR) to EPOCH had no impact on complete response (CR) rate, the primary trial endpoint, and similar 1-year survival rates (ASCO 2018, abstract 7573). Here, we report updated results from AMC075 and evaluate the impact of a DTI ≥15 days on clinical outcomes. A DTI ≥15 days has been shown to be associated with a better prognosis in an HIV-negative population treated with R-CHOP (Maurer et al. J Clin Oncol 2018; 36:1603-1610). We also look at the impact of allowing 1 cycle of systemic therapy given prior to study enrollment in order to circumvent logistical challenges in recruiting otherwise eligible trial subjects. Methods: Between 2012 and 2017 we conducted a randomized phase II study of EPOCH (with rituximab in CD20+ tumors) ± VOR 300 mg administered on days 1-5 of each cycle with HIV antiretroviral therapy in 90 participants with aggressive HIV-NHLs. Eligible patients had at least one of the following high-risk features or tumor characteristics: Age-adjusted International Prognostic Index (aa-IPI) of 2-3, Ki-67 ≥ 80%; activated B-cell (ABC) diffuse large B-cell lymphoma(DLBCL); or any other aggressive non-germinal center (non-GCB), non-Burkitt B-cell NHL. Patients who received 1 prior cycle of chemotherapy (CHOP-like or EPOCH) +/- rituximab were allowed to register. The primary endpoint was CR rate. Secondary objectives included determining adverse events, survival rates, and the effect of EPOCH +/- VOR on HIV viral reservoirs. We performed a post-hoc analysis evaluating the impact of time from DTI ≥15 days vs. &amp;lt;15 days on clinical outcomes and that of pre-protocol systemic therapy. Results: Of 86 evaluable patients, 64 had DLBCL (34 GCB-type and 27 ABC-type), 15 plasmablastic lymphoma (PBL), and 7 primary effusion lymphoma (PEL) [Table 1]. Fifty-one (59%) patients were treatment naïve, whereas 35 (41%) had been pre-treated with one cycle of CHOP-like or EPOCH prior to enrollment. Grade 4 neutropenia was more frequent for VOR-EPOCH than for EPOCH (47% vs. 20%), and also grade 4 thrombocytopenia more frequent for VOR-EPOCH (29% vs 2%). The two regimens had similar rates of febrile neutropenia (18% vs. 16%). CR rates were also comparable for the two regimens (68% vs. 74%) [1-sided P=0.72] (Table 1). Median HIV plasma RNA generally decreased in both arms. No significant differences were observed in T-cell subsets or size of the latent HIV reservoir between arms. Treatment outcomes did not differ significantly across NHL subtypes or EBV status (Table 1), nor with pre-protocol systemic therapy (Table 2). Overall CR rates were 45% in patients with CD4+ counts of 50-100 cells/mm3, 63% with 100-199 cells/mm3, and 85% in patients with &amp;gt;200 cells/mm3(Table 1). The 3-year overall survival rates for VOR-EPOCH was 70% and for EPOCH 77% (log-rank P=0.39), and 3-year event-free survival rates were 63% vs. 69%, respectively (log-rank P=0.32) [Figure 1]. Thirty-six patients (86% of n=42) with long DTI (≥15 days) had CR, compared to only 25 (57% of n=44) with short (&amp;lt;15 days) DTI (P=0.0032). The proportion of patients with short DTI was somewhat higher (63%) in the pre-treated group than in the treatment-naïve group (43%; P=0.072) without significant difference in CR or survival rates (Table 2). Conclusion: This prospective trial demonstrated that EPOCH-based chemotherapy was broadly efficacious against aggressive HIV-NHLs, including high risk subtypes (ABC DLBCL, PBL, and PEL). However, a 5-day course of VOR given with each chemotherapy cycle failed to improve outcomes. Consistent with prior reports in HIV-uninfected patients with DLBCL, a DTI of ≥15 days was associated with better clinical outcomes than a shorter DTI. A strategy of permitting pre-protocol therapy was useful in facilitating accrual and was used in about 40% of study participants without compromising clinical outcomes. Disclosures Baiocchi: Prelude: Consultancy. Noy:Janssen: Consultancy; Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. OffLabel Disclosure: Vorinostat is being tested in combination with chemotherapy for HIV-associated B-cell lymphoma

The MAGIC Algorithm Probability (MAP): A Novel Laboratory Biomarker for the Response to Treatment of Acute Graft-Versus-Host Disease

The MAGIC Algorithm Probability (MAP): A Novel Laboratory Biomarker for the Response to Treatment of Acute Graft-Versus-Host Disease

Evaluation of the m7-FLIPI in Patients with Follicular Lymphoma Treated within the Gallium Trial: EZH2 mutation Status May be a Predictive Marker for Differential Efficacy of Chemotherapy

Evaluation of the m7-FLIPI in Patients with Follicular Lymphoma Treated within the Gallium Trial: EZH2 mutation Status May be a Predictive Marker for Differential Efficacy of Chemotherapy

Enrolment-latency in randomized behavior change trials: individual participant data meta-analysis showed association with attrition but not effect-size

ObjectivesNonresponse can bias prevalence estimates in population surveys. Effects of selective participation in behavior change intervention trials have been little studied. We tested hypotheses that trial participants who are hard to recruit are (1) more likely to be lost-to-follow-up and (2) less responsive to intervention. Study Design and SettingWe undertook a two-stage individual participant data meta-analysis of four alcohol intervention trials involving 9,251 university students in Australia, New Zealand, and Sweden, comparing participants who enrolled “late” (after the final invitation to participate) vs. “early” (before that). Outcomes were whether participants completed assessments at each trial's primary endpoint (late/early) and number of drinks consumed per week (intervention/control) among late enrolees vs. early enrolees. ResultsLate enrolees were more likely to be lost-to-follow-up than early enrolees (OR 2.3, 95% CI: 1.7, 2.9). Intervention effect estimates were smaller for late vs. early enrolees, but not significantly so (RR = 0.93; 95% CI: 0.79, 1.08). ConclusionGreater effort to recruit trial participants was associated with higher attrition, but there was no clear evidence of bias in effect estimation. The possibility that intervention effect estimates do not generalize beyond a relatively compliant minority of trial participants may warrant further study.

Prevalence and Impact of Treatment Crossover in Cardiac Surgery Randomized Trials: A Meta-Epidemiologic Study.

BackgroundCrossover dilutes treatment effect and reduces statistical power of intention‐to‐treat analysis. We examined incidence and impact on cardiac surgery randomized controlled trial (RCT) outcomes of crossover from experimental to control interventions, or vice versa.Methods and Results MEDLINE, EMBASE, and Cochrane Library were searched, and RCTs (≥100 patients) comparing ≥2 adult cardiac surgical interventions were included. Crossover from the initial treatment assignment and relative risks (RRs) for each trial's primary end point and mortality at longest available follow‐up were extracted. All RRs were calculated as >1 favored control group and <1 favored experimental arm. Primary outcome was the effect estimate for primary end point of each RCT, and secondary outcome was all‐cause mortality; both were appraised as RR at the longest follow‐up available. Sixty articles reporting on 47 RCTs (25 440 patients) were identified. Median crossover rate from experimental to control group was 7.0% (first quartile, 2.0%; third quartile, 9.7%), whereas from control to experimental group, the rate was 1.3% (first quartile, 0%; third quartile, 3.6%). RRs for primary end point and mortality were higher in RCTs with higher crossover rate from experimental to control group (RR, 1.01 [95% CI, 0.94–1.07] versus RR, 0.80 [95% CI, 0.66–0.97] and RR, 1.02 [95% CI, 0.95–1.11] versus RR, 0.94 [95% CI, 0.82–1.07], respectively). Crossover from control to experimental group did not alter effect estimates for primary end point or mortality (RR, 0.82 [95% CI, 0.63–1.05] versus RR, 0.95 [95% CI, 0.86–1.04] and RR, 0.88 [95% CI, 0.73–1.07] versus RR, 1.02 [95% CI, 0.95–1.09], respectively).ConclusionsCrossover from experimental to control group is associated with outcomes of cardiac surgery RCTs. Crossover should be minimized at designing stage and carefully appraised after study completion.

Study protocol to develop a patient-reported outcome measuring disability associated with unilateral vocal fold paralysis: a mixed-methods approach with the CoPE collaborative

IntroductionPatient-reported outcome (PRO) measures are increasingly developed with multisite, representative patient populations so that they can serve as a primary endpoint in clinical trials and longitudinal studies. Creating multisite infrastructure...

1016P - Surrogate endpoint of progression-free (PFS) and overall survival (OS) for advanced ovarian cancer (AOC) patients (pts) treated with neo-adjuvant chemotherapy (NACT): Results of the CHIVA randomized phase II GINECO study

BackgroundNACT is increasingly used as a model to explore new targeted therapy in combination with CT in AOC. Whether an intermediate endpoint could be used as surrogate of PFS and/or OS in pts treated with NACT remains currently elusive and was explored retrospectively in the CHIVA trial. MethodsPatients (pts) with FIGO stage IIIC-IV AOC considered as unresectable after laparoscopic (Lap) evaluation were treated with 3 to 4 cycles of platinum-taxane NACT + oral nintedanib before interval debulking surgery (IDS). CT (up to 6 cycles in total) and nintedanib were pursued post-operatively. Were measured response rates at the end of NACT according to RECIST (ORR) with CT-scan and to GCIG with CA125, initial Peritoneal Cancer Index (PCI) and its evolution at IDS, complete surgical resection rate (CC0), pathologic complete or near complete response rate (pCR). These covariates in univariate analysis were included together with other prognostic clinical covariates:age, FIGO stage, ECOG, tumor size, ascitis, neutrophil/lymphocyte ratio, platelet and hemoglobin counts and symptoms (pain). ResultsA total of 163/188 pts included in the CHIVA trial were evaluable for the analysis. Median follow-up is 42. 6 mos (95% CI: 39.9-44.8). In the univariate Cox model, ECOG, ascitis, neutrophil/lymphocyte ratio, PCI at baseline, RECIST ORR, CC0 at IDS, pCR and treatment arm were correlated (p<0.05) to PFS and/or OS. In the multivariate Cox model, RECIST ORR (p<0.01) and CC0 at IDS (p<0.01) were the only variables predictive of both PFS and OS. The median PFS was respectively 10.4, 15.1 and 18.3 mos among the 3 groups of pts with 1) No ORR and no CC0; 2)only CC0 or only ORR; 3)ORR and CC0. PFS Hazard Ratio was 0.33 [0.20; 0.52], 0.43 [0.32; 0.70] and 0.68 [0.44; 1.06] for group 3v1, 2vs1 and 2v3 respectively. Median OS was 25.4, 41.0 mos and not reached for group 1, 2, and 3 respectively (p<0.001). ConclusionsResults from the CHIVA trial suggest that the rate of patients who achieve both a RECIST response to NACT and a complete surgical resection (CC0) at IDS could be used as the main primary endpoint for future NACT trials. Clinical trial identification2011-006288-23. Legal entity responsible for the studyARCAGY-GINECO. FundingBoehringer Ingelheim. DisclosureF. Lecuru: Advisory / Consultancy, Board: AstraZeneca; Advisory / Consultancy, Proctoring: Intuitive Surgical. E. Pujade-Lauraine: Honoraria (self), Self: AstraZeneca; Honoraria (self), Self: Tesaro; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: Clovis; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Genmab; Advisory / Consultancy: Incyte; Advisory / Consultancy: MSD; Advisory / Consultancy: Pfizer; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Tesaro; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Tesaro. N. Raban: Travel / Accommodation / Expenses: Roche. P. Pautier: Advisory / Consultancy: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Clovis; Advisory / Consultancy: Genentech; Research grant / Funding (institution): PharmaMar; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Tesaro. J. Alexandre: Honoraria (self): Roche; Honoraria (self): AstraZeneca; Honoraria (self): Ipsen; Honoraria (self): Novartis; Honoraria (self): PharmaMar; Advisory / Consultancy: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Novartis; Research grant / Funding (institution): Janssen; Travel / Accommodation / Expenses: Janssen; Travel / Accommodation / Expenses: Novartis. N. Dohollou: Research grant / Funding (institution): Roche; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Lilly. A. Floquet: Advisory / Consultancy: Tesaro; Advisory / Consultancy: Clovis; Advisory / Consultancy: AstraZeneca; Travel / Accommodation / Expenses: Tesaro; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Roche. C. Louvet: Advisory / Consultancy: MSD; Advisory / Consultancy: Roche; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Servier; Advisory / Consultancy: AstraZeneca; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: MSD. A. Lortholary: Honoraria (self): AstraZeneca; Honoraria (self): Tesaro. G. Ferron: Honoraria (self): Olympus Europe; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Tesaro; Travel / Accommodation / Expenses: Roche. All other authors have declared no conflicts of interest.