Pooled analysis of routine safety parameters observed in healthy participants at baseline and following placebo administration in early phase clinical studies

Abstract

Phase I trials inform on the initial safety profile of a new molecule and impact whether further development is pursued or not. Understanding the effect of non-pharmacological factors on the variability of routine safety parameters could improve decision making in these early clinical trials, helping to separate signals related to the new molecule from background "noise." To understand the impact of non-pharmacological factors on routine safety parameters, we evaluated pooled safety data from over 1000 healthy participants treated with placebo in phase I trials between 2009 and 2018. The phase I participants were predominantly men, less than or equal to 50 years, White, and non-Hispanic; and approximately an equal proportion had body mass index in the normal and overweight/obese range. Following administration of placebo, vital signs, electrocardiogram, and laboratory parameters remained near predose baseline values. Large changes from baseline were observed for many safety parameters, but these occurred in a relatively small number of participants. At least one adverse event (AE) occurred in 49.7% of participants receiving placebo in single ascending dose (SAD) studies and in 72.4% of participants receiving placebo in multiple ascending dose (MAD) studies, with headache being the most commonly reported AE (18.7% in SAD and 28.3% in MAD studies). Overall, these analyses are consistent with non-pharmacological factors having a small impact on routine safety parameters in a phase I trial. The provided supplemental data may be used to contextualize the magnitude and frequency of abnormal safety values and AEs observed in phase I trials.

FIGURE 1

Change from predose baseline in vital signs over time following placebo administration on day 1 in SAD and MAD studies. DBP, diastolic blood pressure; HR, heart rate; MAD, multiple ascending dose; SAD, single ascending dose; SBP, systolic blood pressure. Top edge of the box represents 75% percentile (Q3). Bottom edge of the box represents 25% percentile (Q1). Interquartile Range (IQR) is Q3–Q1. + within the box represents the arithmetic mean. The horizontal line within the box represents median (50% percentile). The lower whisker represents minimum observation above the 1.5 (IQR) from Q1. The upper whisker represents maximum observation below the 1.5 (IQR) from Q3. Open circles represent observations that are more extreme than 1.5 (IQR) from Q1 or Q3.

FIGURE 2

Change from predose baseline in ECG parameters over time following placebo administration on day 1 in SAD and MAD studies. ECG, electrocardiogram; MAD, multiple ascending dose; QTcF, Fridericia's‐corrected QT intervals; SAD, single ascending dose. Top edge of the box represents 75% percentile (Q3). Bottom edge of the box represents 25% percentile (Q1). Interquartile Range (IQR) is Q3–Q1 + within the box represents the arithmetic mean. The horizontal line within the box represents median (50% percentile). The lower whisker represents minimum observation above the 1.5 (IQR) from Q1. The upper whisker represents maximum observation below the 1.5 (IQR) from Q3. Open circles represent observations that are more extreme than 1.5 (IQR) from Q1 or Q3.

FIGURE 3

Change from day 1 predose and 24‐h post last dose for chemistry and hematology parameters. ALT, alanine aminotransferase; AST, aspartate aminotransferase; MAD, multiple ascending dose; SAD, single ascending dose. For Creatinine, change from Day 1 predose was 103.04 mg/dL for one participant in an SAD study. For leukocytes, change from Day 1 predose was 7503.45 10⁹/L for one participant and was 5833.01 10⁹/L for another participant in SAD studies. These values are suspected to be data entry errors and were removed from the plots for visualization purposes. Top edge of the box represents 75% percentile (Q3). Bottom edge of the box represents 25% percentile (Q1). Interquartile Range (IQR) is Q3–Q1. + within the box represents the arithmetic mean. The horizontal line within the box represents median (50% percentile). The lower whisker represents minimum observation above the 1.5 (IQR) from Q1. The upper whisker represents maximum observation below the 1.5 (IQR) from Q3. Open circles represent observations that are more extreme than 1.5 (IQR) from Q1 or Q3.

FIGURE 4

AEs occurring in greater than 2% of participants in (a) SAD and (b) MAD studies. AE, adverse event; MAD, multiple ascending dose; SAD, single ascending dose. Frequency, (number of participants reporting AE/total number of participants) x 100. Number of participants included in the analysis = 787. Adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version in effect at the time of individual study completion. If a participant experienced multiple adverse events with the same preferred term, the participant was counted only once for that preferred term.