Data driven evaluation of healthy volunteer characteristics at screening for phase I clinical trials to inform on study design and optimize screening processes

Protocols for clinical trials describe inclusion and exclusion criteria based on general and compound‐specific considerations to ensure subject safety and data quality. In phase I clinical trials, healthy volunteers (HVs) are screened against these criteria that often specify predefined eligibility ranges for vital signs, electrocardiogram, and laboratory tests. HVs are excluded if baseline parameters deviate from these ranges even though this may not indicate underlying pathology, which could delay trial execution. Data from 3365 HVs participating in 9670 screening visits for 94 phase I HV trials, conducted between December 2008 and May 2019 at the Janssen Clinical Pharmacology Unit, were retrospectively analyzed. Commonly predefined protocol ranges were overlaid with HV data to estimate predicted screen failure rates (SFRs). Of the overall population, 91% was White and 64% were men with mean age of 42.8 ± 12.5 years. High predicted SFRs are related to cardiovascular/metabolic (body mass index, heart rate [HR], blood pressure [BP], and corrected QT Fridericia’s formula [QTcF]), renal (estimated glomerular filtration rate [eGFR]), liver (alanine aminotransferase [ALT], and total bilirubin), and coagulation (prothrombin time [PT]) parameters. Predicted SFRs increased with age for high systolic and diastolic BP, QTcF interval, and eGFR. In contrast, lower SFRs in the older age groups were seen for low diastolic BP, liver function test, ALT, PT, and total bilirubin. This analysis can be used to inform on study design, protocol inclusion and exclusion criteria, and to optimize the screening process. Data‐driven critical appraisal of proposed inclusion and exclusion criteria using a risk‐based approach may significantly reduce screen failure rates without compromising subjects’ safety.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

In contrast to those enrolled in phase I trials, healthy volunteer (HV) characteristics at screening are not well‐described.

• WHAT QUESTION DID THIS STUDY ADDRESS?

What baseline characteristics of HVs at screening result in high screen failure rates based on different predefined protocol ranges?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This analysis can be used to inform on study design and protocol inclusion and exclusion criteria and optimizing the screening process.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Data‐driven critical appraisal of proposed inclusion and exclusion criteria using a risk‐based approach may significantly reduce screen failure rates without compromising subjects’ safety.     

Depression and the subsequent risk of Parkinson's disease in the NIH‐AARP Diet and Health Study

We conducted a case‐control study to examine the association between depression and Parkinson's disease (PD). Participants included 992 PD cases diagnosed after 2,000 and 279,958 individuals without PD from the NIH‐AARP Diet and Health Study follow‐up survey. Physician‐diagnosed depression and PD were self‐reported with information on the year of diagnosis in the following categories: before 1985, 1985–1994, 1995–1999, and 2000–present. Only PD cases diagnosed after 2000 were included in the analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were derived from logistic regression models, adjusted for age, gender, educational level, marital status, smoking, and coffee drinking. Individuals with depression diagnosed after 2000 were more likely to report a concurrent diagnosis of PD than those without depression (OR = 4.7, 95% CI = 3.9, 5.7). Depression diagnosed before 2000 was also associated with higher odds of PD diagnosed after 2000 (OR = 2.0, 95% CI = 1.6, 2.4). This association was stronger for depression diagnosed in 1995–1999 (OR = 2.7, 95% CI = 2.0, 3.6), but was also noted for depression diagnosed in 1985–1994 (OR = 1.6, 95% CI = 1.1, 2.3) or even before 1985 (OR = 1.7, 95% CI = 1.3, 2.3). This association was not modified by other factors and persisted in an analysis excluding participants who reported poor health status. The results suggest that depression may either be a very early symptom of PD or share common etiological factors with PD. © 2010 Movement Disorder Society     

A phase II study of the combination of endocrine treatment and bortezomib in patients with endocrine-resistant metastatic breast cancer

The majority of patients with hormone receptor-positive metastatic breast cancer die from disease progression despite different types of anti-hormonal treatments. Preclinical studies have indicated that resistance to anti-hormonal therapies may be the result of an activated NF-κB signalling pathway in breast cancer. Bortezomib is a proteasome inhibitor that blocks the NF-κB pathway. Recent pharmacodynamic and pharmaco-kinetic xenograft studies have shown that drug exposure may be a crucial factor for the efficacy of bortezomib in solid tumours. The aim was to investigate whether the addition of bortezomib to anti-hormonal therapy would result in regained antitumour activity in patients with progressive and measurable disease being treated with an endocrine agent. Clinical benefit was defined as patients obtaining stable disease, partial response or complete response after 2 cycles, lasting for at least another five weeks. Bortezomib was administered on days 1, 8, 15 and 22 of a 5-week regimen (1.6?mg/m2). Eight patients received an aromatase inhibitor and bortezomib, while one received tamoxifen and bortezomib. There were 3 grade 3 gastrointestinal toxicities. Median time to treatment failure was 69 days (range, 35-140). Two out of the 9 patients had stable disease for more than 10 weeks. Despite an effective target inhibition, suggested in peripheral blood mononuclear cells and available tumour samples, no objective antitumour responses were observed. Addition of a proteasome inhibitor to anti-hormonal therapy resulted in a clinical benefit rate of 22% in a limited number of patients with endocrine resistant and progressive metastatic breast cancer. The demonstrated proteasome inhibition in tumour tissue provides evidence that the lack of clinical responses is not attributed to deficient drug exposure.     

Association of lead exposure with survival in amyotrophic lateral sclerosis

BACKGROUND: Reasons for the variability in survival among ALS cases are unknown but may include exposure to environmental neurotoxicants. OBJECTIVES: We aimed to determine whether lead exposure, assessed by measuring blood and bone lead levels, is associated with survival in amyotrophic lateral sclerosis (ALS). METHODS: We evaluated the relationship of lead exposure to ALS survival in 110 cases from a case-control study conducted in New England in 1993-1996 that included measurements of blood and bone lead. We retrieved information on date and cause of death through 31 December 2003 from the National Death Index Plus and the Social Security Administration Death Index. We evaluated the relationship of survival to lead exposure using Cox proportional hazard analysis, with adjustment for age, sex, and smoking. RESULTS: We found mortality data for 100 of 110 cases; 93 of 100 death certificates mentioned ALS. Median survival from diagnosis to death was 28 months. Shorter survival was associated with older age at diagnosis, female sex, bulbar onset, shorter interval between symptom onset and diagnosis, and reduced lung function. Shorter survival from diagnosis to death had a weak inverse association with blood lead (hazard ratio = 0.9; 95% confidence interval, 0.8-1.0) and a stronger inverse association with patella lead (0.5; 0.2-1.0) and tibia lead (0.3; 0.1-0.7); similar results were found for survival from symptom onset to death. CONCLUSIONS: These results suggest that lead exposure is associated with longer survival in ALS cases and, if confirmed, may shed light on mechanisms involved in disease progression.     

Coping,Stress, and Social Support Associations With Internalizing and Externalizing Behavior Among Urban Adolescents and Young Adults: Revelations From a Cluster Analysis

PurposeTo use cluster analysis to explore how coping, stress, and social support align and intersect with each other and relate to internalizing and externalizing behavior among urban adolescents and young adults disconnected from school and work.MethodsBaseline audio computer assisted self-interview (ACASI) data from a study of 683 urban, low-income, African-American 16–24-year-old youth (mean age = 18.7; SD = 1.8) participating in an employment training program was cluster analyzed. This method reveals how well youth group together based on coping strategies, stress exposure, and social support.ResultsUsing four coping, two support, and two stress subscales, a three-cluster solution best fit the data. One cluster, representing 65% of the sample, was characterized by moderate coping, high support, and low stress. These youth also reported lower weapon carrying compared to youth in the remaining two clusters. Another cluster, representing 17% of the sample, was defined by high coping, moderate support, and high stress. Youth in this cluster reported the highest levels of depressive symptoms and high levels of suicidal ideation as well as high levels of perpetrating intimate partner violence compared to other youth. The final cluster, also representing 17% of the sample, was marked by low coping, low support, and low stress. These youth also reported high levels of suicidal ideation.ConclusionsGiven the varying profiles of stress, support, and coping reported by urban adolescents and young adults, future research and policy should further explore targeted and tailored intervention approaches for these youth.