Usage of surrogate endpoints in the design and analysis of clinical trials

There has been a shift in the conduct of early-stage breast cancer trials in recent years from long adjuvant trials with overall or disease-free survival as the efficacy endpoint to shorter neoadjuvant trials with pathological complete response (pCR), a binary marker, at time of surgery as the endpoint. The Food and Drug Administration (FDA) currently embraces this transition and deems evidence in pCR improvement sufficient for drug approval on condition that long-term data are collected to eventually show efficacy in survival. Incorporating data on pCR in the design and analysis of such a trial is therefore of public health interest. Here, we propose one method to assess the power and sample size of such a trial with using observed neoadjuvant data and another method to estimate certain causal treatment effects on survival conditional on pCR. In the first part, we propose an exponential mixture model for survival time with parameters for the response rates and an estimated benefit in survival from achieving response. Under a fixed sample size, we obtain the empirical power through simulations from the proposed mixture model. We also propose a more efficient method than the empirical approach by applying an estimated average hazard ratio to the Schoenfeld formula. The performance of our methods is assessed via simulation studies. Data from two neoadjuvant cancer clinical trials are used to illustrate these methods. Second, we propose a method under the principal stratification framework to estimate the causal effect of treatment on a binary outcome, conditional on a post-treatment binary response marker in randomized controlled clinical trials. Specifically, we estimate the treatment effect among those who would achieve response if given the treatment. We are able to identify this causal effect under two assumptions. First, we model the counterfactual probability of achieving response under treatment given baseline clinical markers and the outcome. Second, we assume a monotonicity condition: a patient who responds under control would respond under treatment as well. We compared the performance of proposed method with other standard approaches in simulation studies. Data from a neoadjuvant breast cancer clinical trial are used to demonstrate the proposed method

Quality of Life in Chronic Pancreatitis is Determined by Constant Pain, Disability/Unemployment, Current Smoking, and Associated Co-Morbidities

OBJECTIVES: Chronic pancreatitis (CP) has a profound independent effect on quality of life (QOL). Our aim was to identify factors that impact the QOL in CP patients. METHODS: We used data on 1,024 CP patients enrolled in the three NAPS2 studies. Information on demographics, risk factors, co-morbidities, disease phenotype, and treatments was obtained from responses to structured questionnaires. Physical and mental component summary (PCS and MCS, respectively) scores generated using responses to the Short Form-12 (SF-12) survey were used to assess QOL at enrollment. Multivariable linear regression models determined independent predictors of QOL. RESULTS: Mean PCS and MCS scores were 36.7+/-11.7 and 42.4+/-12.2, respectively. Significant (P \u3c 0.05) negative impact on PCS scores in multivariable analyses was noted owing to constant mild-moderate pain with episodes of severe pain or constant severe pain (10 points), constant mild-moderate pain (5.2), pain-related disability/unemployment (5.1), current smoking (2.9 points), and medical co-morbidities. Significant (P \u3c 0.05) negative impact on MCS scores was related to constant pain irrespective of severity (6.8-6.9 points), current smoking (3.9 points), and pain-related disability/unemployment (2.4 points). In women, disability/unemployment resulted in an additional 3.7 point reduction in MCS score. Final multivariable models explained 27% and 18% of the variance in PCS and MCS scores, respectively. Etiology, disease duration, pancreatic morphology, diabetes, exocrine insufficiency, and prior endotherapy/pancreatic surgery had no significant independent effect on QOL. CONCLUSIONS: Constant pain, pain-related disability/unemployment, current smoking, and concurrent co-morbidities significantly affect the QOL in CP. Further research is needed to identify factors impacting QOL not explained by our analyses

Differences in Age at Onset of Symptoms, and Effects of Genetic Variants, in Patients With Early- vs Late-Onset Idiopathic Chronic Pancreatitis in a North American Cohort

Background & Aims Idiopathic chronic pancreatitis (ICP) is the second most common subtype of CP. In 1994, researchers reported the bimodal age at onset of ICP symptoms: early-onset ICP (EO-ICP; median age, 19.2 years) and late-onset ICP (LO-ICP; median age, 56.2 years). Ages of onset and clinical features of ICP differed from those of alcohol-related CP (ACP). However, variants in PRSS1 had not yet been associated with ICP. We reexamined ages of onset of ICP in a large, North American cohort of patients, and investigated the effects of genetic factors and alcohol use in patients with EO-ICP, LO-ICP, or ACP. Methods We performed a cross-sectional analysis of patients with CP of European ancestry enrolled in the North American Pancreatitis Study 2 studies, a prospective study of 1195 patients with CP from 26 centers in the United States from August 2000 through December 2014. We compared age at onset of symptoms for 130 patients with CP who were lifetime abstainers from alcohol (61 patients with early onset and 69 patients with late onset), 308 light to moderate alcohol drinkers with CP, and 225 patients with ACP and heavy to very heavy alcohol use. DNA from available patients was analyzed for variants associated with CP in SPINK1, CFTR, and CTRC. The Kruskal-Wallis test was used to compare continuous variables across groups and based on genetic variants. Results Median ages at onset of symptoms were 20 years for patients with EO-ICP and no alcohol use, 58 years for patients with LO-ICP and no alcohol use, 47 years for light to moderate alcohol drinkers with CP, and 44 years for patients with ACP. A higher proportion of patients with EO-ICP had constant pain (65%) than patients with LO-ICP (31%) (P=.04). A higher proportion of patients with ACP had pseudocysts (43%) than patients with EO-ICP (11%) (P=.001). A higher proportion of patients with EO-ICP had pathogenic variants in SPINK1, CFTR, or CTRC (49%) than patients with LO-ICP (23%), light to moderate alcohol drinking with CP (26%), or ACP (23%) (P=.001). Among patients with variants in SPINK1, those with EO-ICP had onset of symptoms at a median age of 12 years, and light to moderate alcohol drinkers with CP had an age at onset of 24 years. Among patients with variants in CFTR, light to moderate alcohol drinkers had an age at onset of symptoms of 41 years, but this variant did not affect age at onset of EO-ICP or ACP. Conclusions We confirmed previously reported ages at onset of symptoms for EO-ICP and LO-ICP in a North American cohort. We found differences in clinical features among patients with EO-ICP, LO-ICP, and ACP. Almost half of patients with EO-ICP have genetic variants associated with CP, compared to about one-quarter of patients with LO-CP or ACP. Genetic variants affect ages at onset of symptoms in some groups

Chronic pancreatitis: Pediatric and adult cohorts show similarities in disease progress despite different risk factors

Objectives: To investigate the natural history of chronic pancreatitis (CP), patients in the North American Pancreatitis Study2 (NAPS2, adults) and INternational Study group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE, pediatric) were compared. Methods: Demographics, risk factors, disease duration, management and outcomes of 224 children and 1,063 adults were compared using appropriate statistical tests for categorical and continuous variables. Results: Alcohol was a risk in 53% of adults and 1% of children (p<0.0001); tobacco in 50% of adults and 7% of children (p<0.0001). Obstructive factors were more common in children (29% vs 19% in adults, p=0.001). Genetic risk factors were found more often in children. Exocrine pancreatic insufficiency was similar (children 26% vs adult 33%, p=0.107). Diabetes was more common in adults than children (36% vs 4% respectively, p<0.0001). Median emergency room visits, hospitalizations, and missed days of work/school were similar across the cohorts. As a secondary analysis, NAPS2 subjects with childhood onset (NAPS2-CO) were compared to INSPPIRE subjects. These two cohorts were more similar than the total INSPPIRE and NAPS2 cohorts, including for genetic risk factors. The only risk factor significantly more common in the NAPS2-CO cohort compared with the INSPPIRE cohort was alcohol (9% NAPS2-CO vs 1% INSPPIRE cohorts, p=0.011). Conclusions: Despite disparity in age of onset, children and adults with CP exhibit similarity in demographics, CP treatment, and pain. Differences between groups in radiographic findings and diabetes prevalence may be related to differences in risk factors associated with disease and length of time of CP

Lifetime drinking history of persons with chronic pancreatitis

AIMS: Cumulative consumption of alcohol and variations of alcohol intake by age are unknown in chronic pancreatitis (CP) patients in North America. This study summarizes the lifetime drinking history (LDH) by physician attribution of alcohol etiology, smoking status and sex in persons with CP. METHODS: We analyzed data on 193 CP participants who completed the LDH questionnaire in the North American Pancreatitis Continuation and Validation Study (NAPS2-CV). We collected data on frequency of drinking and drinks per drinking day for each drinking phase of their lives. We examined differences in total number of alcoholic drinks and weight of ethanol consumed by physician\u27s assessment of CP etiology, sex and smoking status. We also compared intensity of drinking in 20, 30 and 40s by timing of CP diagnosis. RESULTS: Persons diagnosed with alcoholic CP consumed median of 34,488 drinks (interquartile range 18,240-75,024) prior to diagnosis of CP, which occurred earlier than in persons with CP of other etiology (47 vs. 52 years). Cumulative drinking was greater in male vs. female patients. Male CP patients with a diagnosis of CP before the age of 45 drank more intensely in their 20s as compared to those with later onset of disease. Current smoking was prevalent (67%) among those diagnosed with alcoholic CP. Twenty-eight percent of patients without physician attribution of alcohol etiology reported drinking heavily in the past. CONCLUSIONS: Lifetime cumulative consumption of alcohol and prevalence of current smoking are high in persons diagnosed with alcoholic pancreatitis. Intense drinking in early years is associated with earlier manifestation of the disease

Tu1482 Common genetic susceptibility factors for recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) in white patients are rare in black patients

Background: RAP and CP affects individuals of all demographics and geographic regions. Genetic factors increasing the susceptibility to pancreatitis in PRSS1, SPINK1, CFTR, and CTRC genes have been reported in many populations. Variations between people of European ancestry and populations from South or East Asia are known. Genetic testing for pancreatitis risks factors is now routinely performed in clinical practice, especially in patients with no obvious cause of pancreatitis. In the North American Pancreatitis Study (NAPS2), ~33% white CP patients were noted to have at least one, and ~10% had more than one variant in these genes. However there are no data on the prevalence of genetic mutations in black patients with pancreatitis. We tested the hypothesis that the genetic risk factors for pancreatitis are similar between black and white patients in the United States. Methods: Controls (n= 253) and subjects with RAP (n=45) or CP (n=230), who identified themselves as AfricanAmerican, enrolled prospectively in the multicenter NAPS2 studies from 2000-2014 were studied. Demographic and phenotypic information was obtained from structured questionnaires completed by the study subjects and the enrolling physician. A blood sample was obtained from each subject, and peripheral blood leukocyte DNA was isolated and purified for analysis. Genotyping for known variants in pancreatitis risk genes PRSS1, SPINK1, CFTR and CTRC was performed by a combination of direct sequencing, restriction fragment length polymorphism (RFLP), multiplex SNP genotyping assays and individual taqman genotyping assays. Results: Mean age of black controls, RAP and CP patients was 47.3±13.4, 45.7±13.6, and 51.9±10.6 years, and 38%, 38% and 63% of them were male, respectively. Physiciandefined alcohol etiology was present in 33% RAP and 77% CP patients. Of all the variants tested, only SPINK1 N34S was overrepresented in CP when compared with controls with borderline significance (CP 1.8%, controls 0%, p=0.051) (Table 1). Two CP patients had a CF mutation found to be specific for blacks with cystic fibrosis (3120+GtoA), one of whom was a compound heterozygote with a CF bicarbonate specific mutation (L967S) on the other allele. None of the pancreatitis patients had disease causing CTRC mutations. One CP patient was found to be carrying deleterious mutations in PRSS1 (R122H). Interestingly, 10/12 CP patients with CF mutations, and all 4 with SPINK1 mutation had physician-defined alcohol etiology. Discussion: Prevalence of mutations in susceptibility genes reported in Caucasians is infrequent among black patients. Genetic sequencing of known susceptibility genes and regulatory elements, plus appropriately powered genetic association studies are needed to understand the risks and mechanisms of pancreatitis in black patients

962: Racial differences in the clinical profile, causes and outcome of chronic pancreatitis

Background: Racial differences in susceptibility and progression of pancreatitis have been reported in epidemiologic studies using administrative or retrospective data. There is little data, however, on the clinical profile, causes and outcome of chronic pancreatitis in black patients. Methods: We analyzed data on black or white patients with chronic pancreatitis prospectively enrolled in the multicenter North American Pancreatitis Studies from 26 US centers during the years 2000-2014. Chronic pancreatitis was defined by definitive evidence on imaging studies or histology. Information on demographics, etiology, risk factors, disease phenotype, treatments and their perceived effectiveness was obtained from responses to detailed questionnaires completed by both patients and physicians. Results:Of the 1159 patients enrolled, 248 (21%) were black. When compared with whites, blacks were significantly (all p Conclusions: Differences were observed between blacks and whites in the underlying cause, morphologic expression, and pain characteristics of chronic pancreatitis, which in part are explained by the underlying risk factor(s) with alcohol and tobacco being much more frequent in black patients

961 Quality of life (qol) in chronic pancreatitis (cp) is determined by constant pain, disability, current smoking and associated co-morbidities

Background: CP has a profound effect on health related quality of life (HRQOL) when compared with non-disease controls. Most data on QOL among CP patients are limited to assessing the short and long term impact of surgical treatments. Few studies have reported on predictors of QOL in unselected patients with CP. Our aim was to identify factors that determine the HRQOL in a large prospectively ascertained cohort of CP patients. Methods: We used data on 1,024 CP patients enrolled in the North American Pancreatitis Study-2 studies from 26 US centers from 2000-2014. CP was defined by definitive evidence on imaging studies or histology. Information on demographics, alcohol and tobacco use, comorbidities, symptoms, etiology, disease phenotype and treatments was obtained from responses to detailed questionnaires completed by patients and physicians. Patients completed questions on their pain experience (presence, pattern), and QOL (Short Form-12 [SF12 v2] survey). Physical (PCS) and mental (MCS) component summary scores were calculated from responses to SF-12 survey. Mean (sd) PCS and MSC scores in general population is 50±10, and a difference of 3 points is clinically relevant. Multivariable linear regression models determined independent predictors of QOL. Results: Mean age of patients was 50.4±14.6 years, 55% were male, 75% were white, 50% had physician-defined alcohol etiology. Ninety-two percent patients reported pain - as intermittent and mild-moderate by 13%, intermittent and severe by 24%, constant mild-moderate by 6%, and constant mildmoderate with episodes of severe or constant severe by 49%. Disability due to pain was reported by 27% patients. Mean PCS and MCS scores were 36.7±11.7 and 42.4±12.2 respectively. On multivariable analyses, factors with significant and clinically relevant negative impact on both physical and mental QOL were constant pain, disability, current smoking and associated co-morbidities (Table 1). Disability showed an interaction with sex and resulted in an additional 3.72 point decrease in mental QOL in women. The incremental effect of select factors is shown in Figure 1. Variables in the final multivariable models explained 27% of the variance in physical and 17% of the variance in mental QOL scores. Interestingly, pancreatic morphology, exocrine and/or endocrine insufficiency, prior endotherapy, prior pancreatic surgery and duration of CP had no significant independent effect on QOL. Conclusion: Constant pain, pain-related disability, current smoking, and concurrent co-morbidities significantly affect QOL in CP patients. Prior endoscopic or surgical treatments did not have an independent effect on QOL. Further research is needed to identify factors impacting QOL that are not explained by our analyses

Recurrent acute pancreatitis significantly reduces quality of life even in the absence of overt chronic pancreatitis

OBJECTIVES: The impact of recurrent acute pancreatitis (RAP) on quality of life (QOL) is unknown. We hypothesized that RAP would reduce QOL even in the absence of chronic pancreatitis (CP). METHODS: Data were pooled from three prospective, cross-sectional studies conducted across 27 U.S. centers (the North American Pancreatitis Studies); these included subjects with chronic pancreatitis (n = 1086), RAP alone (n = 508), and non-disease controls (n = 1025). QOL was measured using the Short Form 12 (SF-12), generating a Physical Component Summary (PCS) and the Mental Component Summary score (MCS). Multivariable regression models were developed to measure the effect of RAP on QOL, the predictors of lower QOL in those with RAP, and the differential effect QOL predictors between CP and RAP. RESULTS: Compared to controls (51.0 ± 9.4), subjects with RAP (41.1 ± 11.4) and CP (37.2 ± 11.8) had lower PCS (p \u3c 0.01). Subjects with CP had lower PCS compared to those with RAP (p \u3c 0.01). Similarly, MCS was lower among RAP (44.6 ± 11.5) and CP (42.8 ± 12.2) subjects compared to controls (51.7 ± 9.1, p \u3c 0.01). Subjects with CP had lower MCS compared to those with RAP (p \u3c 0.01). After controlling for independent predictors of PCS, RAP was associated with lower PCS (estimate -8.46, p \u3c 0.01) and MCS (estimate -6.45, p \u3c 0.0001) compared to controls. The effect of endocrine insufficiency on PCS was differentially greater among RAP subjects (-1.28 for CP vs. -4.9 for RAP, p = 0.0184). CONCLUSIONS: Even in the absence of CP, subjects with RAP have lower physical and mental QOL. This underscores the importance of identifying interventions to attenuate RAP before the development of overt CP