Clinical Endpoint Studies Research Articles

Improvement in precision of counting actinic keratoses

Actinic keratoses (AKs) often serve as a primary endpoint for clinical studies. However, reliability of counting these lesions is poor, even among expert dermatologists. To investigate the reliability of counting AKs before and after a yearly consensus meeting, held annually for 4 years. As part of the Veterans Affairs (VA) Keratinocyte Carcinoma Chemoprevention Trial, board-certified dermatologists convened annually for 4 years to individually count the number of actinic keratoses on three to five test subjects. The dermatologists then met as a group for a consensus discussion on what constituted an AK lesion on each subject. Afterwards, each dermatologist repeated the independent counting exercise on three to five new subjects. The intraclass correlation coefficient (ICC) was used to analyze the reliability of counting AKs among the dermatologists. Eight dermatologists participated in this exercise for 4 consecutive years. Pre-consensus discussion ICCs over 4 years were 0.18, 0.34, 0.38, 0.75, respectively, showing sustained improvement with each consensus discussion. The greatest improvement in reliability of AK counts was shown during the first year of consensus discussions, when the ICC improved from 0.18 to 0.67. There was no improvement by the fourth year of consensus discussion, with pre- and post-consensus ICCs of 0.75 and 0.75, respectively. Annual consensus discussions can lead to improvement in reliability of AK counts. This improvement was sustained over 4 years. By the fourth year, the discussion meeting had no effect on improvement in reliability. A consensus meeting discussion may be helpful for improving reliability in other trials.

Challenges in cardiac device innovation: is neuroimaging an appropriate endpoint? Consensus from the 2013 Yale-UCL Cardiac Device Innovation Summit

BackgroundNeurological events associated with transcatheter aortic valve implantation are major contributors to morbidity and mortality. Choosing an appropriate endpoint to determine neuroprotection device efficacy is a key difficulty inhibiting the translation of the innovation from the laboratory to the bedside. Cost and sample size limitations inhibit the feasibility of using the rate of clinical (such as stroke or other cerebral) events as the primary efficacy endpoint. This paper focuses on consensus opinions from the 2013 Yale-University College London (UCL) Device Innovation Summit.DiscussionNeuroimaging, specifically diffusion-weighted magnetic resonance imaging (DW MRI), may serve as a surrogate endpoint for clinical studies detecting cerebral events in which cost and sample-size limitations prohibit the use of clinical outcomes. A major limitation of using imaging to prove efficacy in cardiac device studies is that no standardized endpoint exists. Ongoing trials investigating cerebral protection devices for transcatheter aortic valve implantation are utilizing and reporting various qualitative and quantitative DW MRI values; however, single lesion volume, number of new lesions, and total lesion volume have been found to be the most reproducible and prognostically important imaging measures.SummaryDW MRI may be a useful surrogate endpoint for clinical studies detecting cerebral events to determine the device’s success in neurological protection. Consensus from the 2013 Yale-UCL Device Innovation Summit specifically recommends the reporting of mean single lesion volume, number of new lesions, and total volume, and encourages European Union (EU)-US regulatory consensus in the guidance of implementing this endpoint.

Outcome Of Patients (pts) With Low and Intermediate-1 Risk Myelodysplastic Syndrome (MDS) After Hypomethylating Agent (HMA) Failure

▪ BackgroundHMA are standard of care in pts with high-risk MDS and commonly used in pts with lower risk. Pts with high-risk disease post HMA failure have a poor prognosis with a median survival of 4-6 months. The prognosis of pts with low and intermediate-1 risk MDS by the International Prognostic Scoring System (IPSS) after HMA failure is not known. AimsTo assess outcome of pts with low and intermediate-1 risk disease post HMA failure that might benefit from specific strategies or investigational agents. MethodsData from 423 pts with low (n= 141, 33%) and intermediate-1 risk disease (n=282, 67%) by IPSS score treated with HMA at MD Anderson Cancer Center (MDACC; n=144) and Moffitt Cancer Center (MCC; n=279) between 2000 and 2011 were analyzed. ResultsMedian age was 69 years. 294 (69%) pts had a diploid cytogenetic analysis. 63 (15%) pts had therapy-related MDS. 282 (67%) pts received azacitidine, 87 (21%) decitabine, and 54 (12%) both. Median number of cycles of HMA administered was 6 (range, 1-64) for a median duration of therapy of 7 months (range, 1- 74). Best response to HMA was complete response (CR) in 39 (9%) pts, partial response (PR) in 13 (3%), a bone marrow CR in 6 (1%), and hematologic improvement (HI) in 90 (21%) pts. Pts had discontinued HMA because of primary resistance in 198 (47%) pts, loss of response in 141 pts (33%), intolerance in 13 pts (3%) and other reasons in 71 pts (17%). At the time of HMA failure, 81 (19%) pts transformed into acute myeloid leukemia (AML). Of the 302 remaining pts evaluable by IPSS, 67 (22%) pts were of low-risk, 158 (53%) of intermediate-1 risk, 48 (16%) of intermediate-2 risk, and 29 (9%) of high-risk disease. By the revised IPSS (R-IPSS), the percentage of pts with low, very low, intermediate, high, and very high risk disease were 11%, 29%, 30%, 20%, and 10%, respectively. By the MDACC global prognostic scoring system (MDGPSS) 18%, 35%, 29%, and 18%, of the pts were of low-risk, intermediate-1, intermediate-2, and high-risk disease, respectively. After a median follow-up of 16 months from HMA failure, 117 (28%) pts remained alive. The median overall survival (OS) was 15 months (95% CI: 12-18) with estimated 1- and 3-year OS rates of 55% and 27%, respectively. Both, the R-IPSS and the MDGPSS were predictive of survival post HMA failure (Table 1Table 1Survival from HMA failure by risk groupSurvivalRisk groupCategoryPercentageMedian (mos)% 1-year% 3-yearp-valueMDGPSSLow18346848p<0.001Intermediate-135297539Intermediate-229124914High187318R-IPSSVery low11518360p<0.001Low29317638Intermediate30216030High2093912Very high1062511). ConclusionIn the largest cohort of lower risk MDS pts treated with HMA, the outcome after HMA failure is poor. Treatment of those patients remains an unmet medical need. OS is a reasonable primary endpoint for clinical studies targeting this population. Disclosures:Lancet:Celgene: Research Funding. Sekeres:Celgene: Consultancy; Amgen: Consultancy. List:Celgene: Research Funding. Komrokji:Celgene: Research Funding, Speakers Bureau.

A modeling approach for compounds affecting body composition

Body composition and body mass are pivotal clinical endpoints in studies of welfare diseases. We present a combined effort of established and new mathematical models based on rigorous monitoring of energy intake (EI) and body mass in mice. Specifically, we parameterize a mechanistic turnover model based on the law of energy conservation coupled to a drug mechanism model. Key model variables are fat-free mass (FFM) and fat mass (FM), governed by EI and energy expenditure (EE). An empirical Forbes curve relating FFM to FM was derived experimentally for female C57BL/6 mice. The Forbes curve differs from a previously reported curve for male C57BL/6 mice, and we thoroughly analyse how the choice of Forbes curve impacts model predictions. The drug mechanism function acts on EI or EE, or both. Drug mechanism parameters (two to three parameters) and system parameters (up to six free parameters) could be estimated with good precision (coefficients of variation typically <20 % and not greater than 40 % in our analyses). Model simulations were done to predict the EE and FM change at different drug provocations in mice. In addition, we simulated body mass and FM changes at different drug provocations using a similar model for man. Surprisingly, model simulations indicate that an increase in EI (e.g. 10 %) was more efficient than an equal lowering of EI. Also, the relative change in body mass and FM is greater in man than in mouse at the same relative change in either EI or EE. We acknowledge that this assumes the same drug mechanism impact across the two species. A set of recommendations regarding the Forbes curve, vehicle control groups, dual action on EI and loss, and translational aspects are discussed. This quantitative approach significantly improves data interpretation, disease system understanding, safety assessment and translation across species.

Photoaging

Photoaging

Ezetimibe and bile acid sequestrants

Several lines of evidence indicate that the enterocyte plays a pivotal role in cholesterol homeostasis. The development of the selective inhibitor of cholesterol absorption ezetimibe and bile acid sequestrants (BAS) interrupting the enterohepatic circulation of bile salts has expanded the options for preventing and treating cardiovascular disease. We discuss here a selection of recently published studies that evaluated the effects of ezetimibe and BAS on lipoprotein metabolism. Although significant progress has been made in recent years in elucidating the impacts of ezetimibe and BAS on lipoprotein metabolism, underlying mechanisms are not completely understood. Important new insights have been provided by using in-vivo kinetic studies of apolipoproteins labelled with a stable isotope. Other reports indicated that ezetimibe and BAS modulate the expression of several key genes involved in intestinal lipoprotein metabolism. Many of these effects have been related to the local effects of ezetimibe and BAS on intestinal cholesterol homeostasis. A substantial effort is being made by researchers to fully understand the mechanisms by which ezetimibe and BAS improve lipid profile. The efficacy of combination therapy of statins with ezetimibe or BAS for the prevention of cardiovascular disease remains to be confirmed in clinical endpoint studies.

1083A comparison of sequences to quantitate myocardial salvage following STEMI

Background: Myocardial salvage (MS) is a predictor of prognosis following STEMI and is frequently used as an endpoint in clinical trials. However, the CMR sequence for assessing myocardial oedema, used to calculated MS, following STEMI is controversial. T2-STIR is in widespread clinical use but can lack robustness. The hybrid TSE-SSFP sequence (ACUT2E) has emerging data to support it as a more reproducible method for oedema assessment. A novel T2 mapping method is also available to determine myocardial oedema. More recently, imaging early after gadolinium contrast administration (EGE) has been suggested as an alternative to detect myocardial oedema following STEMI. The aim of this study was to assess which of the CMR sequences for detecting myocardial oedema and, therefore, quantitating MS following STEMI is most robust. Methods: 40 patients day 2 following STEMI were prospectively enrolled into the study. All patients had 2 CMR scans on the same day at least 6 hours apart. 3 slices repeated using all 4 sequences followed by LGE imaging. Images were analysed offline by 2 observers blinded to other sequence analysis results. The images were analysed using semi-automated software, and the MS was expressed as a mass (g). Inter-observer, intra- observer and inter-scan agreement was assessed using the Bland Altman method. Results: Bland Altman plots for inter-observer, inter-scan and intra-observer agreements were acquired for MS calculated by the 4 sequences. ACUT2E appears the least reproducible of the 4 techniques, with T2 mapping with the best intra, inter- observer and inter-scan agreement. Inter-observer (T2-STIR bias -0.9 +/- 9.6; ACUT2E bias -9.8 + /-11.6; T2 map bias -3.8 + /-4.7; EGE bias -5.3 + /-5.9). Inter-scan (T2-STIR bias 0.7 + /-6.4; ACUT2E bias -7.7 + /-11.9; T2 map bias 2.9 + /-4.2; EGE bias 1.1 + /-4.9). Intra-observer (T2-STIR bias 0.6 + /-6.0; ACUT2E bias -6.3 + /-10.1; T2 map bias 2.1 + /-3.3, EGE bias 1.7 + /-2.9). Conclusions: The limitations of T2-STIR are well documented. This is the first study that systematically compared all available techniques to determine the most robust sequence for measuring myocardial oedema and, therefore, quantitate MS following STEMI. This study demonstrates that T2 mapping is a robust methods to be used for surrogate endpoints in clinical studies.

Evolving therapies for liver fibrosis

Fibrosis is an intrinsic response to chronic injury, maintaining organ integrity when extensive necrosis or apoptosis occurs. With protracted damage, fibrosis can progress toward excessive scarring and organ failure, as in liver cirrhosis. To date, antifibrotic treatment of fibrosis represents an unconquered area for drug development, with enormous potential but also high risks. Preclinical research has yielded numerous targets for antifibrotic agents, some of which have entered early-phase clinical studies, but progress has been hampered due to the relative lack of sensitive and specific biomarkers to measure fibrosis progression or reversal. Here we focus on antifibrotic approaches for liver that address specific cell types and functional units that orchestrate fibrotic wound healing responses and have a sound preclinical database or antifibrotic activity in early clinical trials. We also touch upon relevant clinical study endpoints, optimal study design, and developments in fibrosis imaging and biomarkers.

Has the time come for metronomics in low-income and middle-income countries?

In 2008, 72% of cancer deaths occurred in low-income and middle-income countries, where, although there is a lower incidence of cancer than in high-income countries, survival rates are also low. Many patients are sent home to die, and an even larger number of patients do not have access to treatment facilities. New constraint-adapted therapeutic strategies are therefore urgently needed. Metronomic chemotherapy--the chronic administration of chemotherapy at low, minimally toxic doses on a frequent schedule of administration, with no prolonged drug-free breaks--has recently emerged as a potential strategy to control advanced or refractory cancer and represents an alternative for patients with cancer living in developing countries. This low-cost, well-tolerated, and easy to access strategy is an attractive therapeutic option in resource-limited countries. Moreover, combined with drug repositioning, additional anticancer effects can be achieved, ultimately resulting in improved cancer control while maintaining minimum cost of treatment. In this Personal View, we will briefly review the rationale behind the combination of metronomic chemotherapy and drug repositioning-an approach we term metronomics. We assess the clinical experience obtained with this kind of anticancer treatment and describe potential new developments in countries with limited resources. We also highlight the need for adapted clinical study endpoints and innovative models of collaboration between for-profit and non-profit organisations, to address the growing problem of cancer in resource-limited countries.

Failure-free survival after second-line systemic treatment of chronic graft-versus-host disease

AbstractThis study attempted to characterize causes of treatment failure, identify associated prognostic factors, and develop shorter-term end points for trials testing investigational products or regimens for second-line systemic treatment of chronic graft-versus-host disease (GVHD). The study cohort (312 patients) received second-line systemic treatment of chronic GVHD. The primary end point was failure-free survival (FFS) defined by the absence of third-line treatment, nonrelapse mortality, and recurrent malignancy during second-line treatment. Treatment change was the major cause of treatment failure. FFS was 56% at 6 months after second-line treatment. Lower steroid doses at 6 months correlated with subsequent withdrawal of immunosuppressive treatment. Multivariate analysis showed that high-risk disease at transplantation, lower gastrointestinal involvement at second-line treatment, and severe NIH global score at second-line treatment were associated with increased risks of treatment failure. These three factors were used to define risk groups, and success rates at 6 months were calculated for each risk group either without or with various steroid dose limits at 6 months as an additional criterion of success. These success rates could be used as the basis for a clinically relevant and efficient shorter-term end point in clinical studies that evaluate agents for second-line systemic treatment of chronic GVHD.

Measuring clinical bleeding using a standardized daily report form and a computer algorithm for adjudication of WHO bleeding grades

Bleeding is increasingly considered an important end point in clinical platelet transfusion studies. Accurate recording and adjudication into well-defined bleeding grades, however, remains a major challenge. We developed a computer algorithm for automatic adjudication. The algorithm's results were compared to those of three independent adjudicators. For one of 1186 bleeding days, the clinical report form (CRF) was filled out incorrectly, and the algorithm therefore missed one grade-1 skin bleed. For two bleeding days, the adjudicators incorrectly classified a grade-2 skin bleed as grade-1 while the algorithm correctly classified these days. The algorithm saved approximately six person-hours of adjudication time for the adjudication of 1186 days from 60 patients. The algorithm can be an invaluable tool for adjudicating large amounts of bleeding data.

Power and Sample Size Determination for the Group Comparison of Patient-Reported Outcomes with Rasch Family Models

BackgroundPatient-reported outcomes (PRO) that comprise all self-reported measures by the patient are important as endpoint in clinical trials and epidemiological studies. Models from the Item Response Theory (IRT) are increasingly used to analyze these particular outcomes that bring into play a latent variable as these outcomes cannot be directly observed. Preliminary developments have been proposed for sample size and power determination for the comparison of PRO in cross-sectional studies comparing two groups of patients when an IRT model is intended to be used for analysis. The objective of this work was to validate these developments in a large number of situations reflecting real-life studies.MethodologyThe method to determine the power relies on the characteristics of the latent trait and of the questionnaire (distribution of the items), the difference between the latent variable mean in each group and the variance of this difference estimated using Cramer-Rao bound. Different scenarios were considered to evaluate the impact of the characteristics of the questionnaire and of the variance of the latent trait on performances of the Cramer-Rao method. The power obtained using Cramer-Rao method was compared to simulations.Principal FindingsPowers achieved with the Cramer-Rao method were close to powers obtained from simulations when the questionnaire was suitable for the studied population. Nevertheless, we have shown an underestimation of power with the Cramer-Rao method when the questionnaire was less suitable for the population. Besides, the Cramer-Rao method stays valid whatever the values of the variance of the latent trait.ConclusionsThe Cramer-Rao method is adequate to determine the power of a test of group effect at design stage for two-group comparison studies including patient-reported outcomes in health sciences. At the design stage, the questionnaire used to measure the intended PRO should be carefully chosen in relation to the studied population.

P275 Clinical response is a meaningful endpoint in ulcerative colitis clinical studies

P275 Clinical response is a meaningful endpoint in ulcerative colitis clinical studies

Design of clinical studies: Adaptive randomization and progression-free survival (PFS) as an endpoint in clinical studies of advanced non-small cell lung cancer (NSCLC)

Design of clinical studies: Adaptive randomization and progression-free survival (PFS) as an endpoint in clinical studies of advanced non-small cell lung cancer (NSCLC)

Quality of life research, it’s only the beginning

Quality of life research, it’s only the beginning

Clinical Response Is a Meaningful Endpoint in Ulcerative Colitis Clinical Studies

Clinical Response Is a Meaningful Endpoint in Ulcerative Colitis Clinical Studies

Safety of CETP inhibition

Cholesteryl ester transfer protein (CETP)-inhibiting drugs effectively raise HDL cholesterol. In 2007, the CETP inhibitor torcetrapib unexpectedly showed increased fatality and cardiovascular events, possibly related to increased blood pressure and aldosterone levels caused by torcetrapib. Since then, novel CETP inhibiting drugs have been investigated. This review will discuss the safety of the CETP-inhibiting drugs. The novel CETP inhibitors dalcetrapib, evacetrapib and anacetrapib did not show harmful effects on blood pressure or aldosterone levels. Ultrasound brachial artery flow-mediated vasodilation, carotid MRI and (18)F-fluordeoxyglucose PET imaging studies, showed that dalcetrapib therapy had neither harmful nor beneficial effects on endothelial function, atherosclerosis progression, or vessel wall inflammation. Recently, the clinical endpoint study investigating dalcetrapib was announced to be terminated early, after the second interim analysis showed that dalcetrapib lacked clinically meaningful efficacy. Dalcetrapib, evacetrapib and anacetrapib did not show the harmful effects on aldosterone and blood pressure that were exhibited by torcetrapib, indicating that CETP inhibition is well tolerated. So far CETP inhibition did not show beneficial effects on clinical outcome. The phase III study with anacetrapib will give final answers on whether CETP inhibition can reduce cardiovascular events.

New Treatments for CKD—New Insights into Pathogenesis

Albuminuria is a standard surrogate endpoint for many clinical studies examining therapies for diabetic nephropathy and other kidney diseases. This standard is based on the assumption that a reduction in albuminuria corresponds to a reduction in glomerular damage and therefore, amelioration of CKD. Albuminuria, however, can also result from decreased proximal tubular uptake. Because proximal tubule reabsorption of albumin is associated with an inflammatory response, inhibition of albumin absorption presents another potential target for therapy of CKDs.

Outcome models in clinical studies: Implications for designing and evaluating trials in clinical nutrition

The selection of appropriate outcome variables in clinical nutrition is particularly challenging, since nutrition is an adjunct therapy in most cases. Therefore, its effect may be confounded with the primary therapy, and classic biomedical outcomes may not reflect the effect of the nutritional intervention. This paper scrutinizes different alternatives to the biomedical perspective. Five different outcome models are proposed and analyzed for their suitability in clinical nutrition studies: biomedical, patient-centered/-reported, health economic, decision-making, and integration of classical and patient-reported endpoints. Most published studies in the field of clinical nutrition make use of biomedical endpoints, but the growing importance of patient-centered/-reported and health economic outcomes is recognized. We recommend avoiding to focus solely on biomedical endpoints in clinical nutrition studies. The availability and value of a broader set of outcome-models should be acknowledged. Patient-centered/-reported, health economic or combined endpoints are particularly useful to assess the effect of nutritional therapies, especially when applied in conjunction with a primary therapy. The proposed outcome models can also contribute to refine clinical nutrition guidelines in assessing the clinical relevance of the study results.

Omega-6 fatty acids and cardiovascular disease

Dietary linoleic acid (LA, an omega-6 fatty acid) is the most abundant polyunsaturated fatty acid (PUFA) in the Western diet. A review of the evidence, including randomised intervention trials of blood cholesterol reduction, observational studies of clinical endpoints and randomized intervention trials of clinical endpoints, indicates that increasing the consumption of PUFAs, including omega-6 fatty acids, from vegetable oils reduces the incidence of coronary heart disease.