# Improving the statistical design and analysis of randomized controlled trials of delirium prevention and treatment for critically ill older adults

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $355,002

## Abstract

Project Summary/Abstract
Among critically ill older adults receiving care in an intensive care unit (ICU), delirium is very common (>70%)
and strongly associated with long-term cognitive impairment similar to Alzheimer's Disease and Related
Dementias (ADRD). With growing recognition of this major problem, there is an increasing number of
randomized controlled trials (RCTs) evaluating preventative and therapeutic interventions for delirium among
critically ill older adults. Efforts are underway to improve the scientific rigor of such trials; specifically, a
NIH/NIA NIDUS collaborative (R24AG054259) and a Canadian CIHR-funded project that aim to harmonize use
of outcome measurement instruments to improve comparability and consistency across delirium RCTs.
However, despite these efforts, guidance regarding delirium endpoint definition and appropriate statistical
methods for evaluating treatment effects in delirium RCTs is lacking. Defining and evaluating a delirium
endpoint is especially challenging for older adults in the ICU as delirium status can vary during the follow-up
period (e.g. 28 days) and measurement may be terminated by patient discharge or death, referred to as
“competing events” in the statistical literature. Both discharge and death are correlated with the risk of
delirium, but likely in opposite directions, and may be affected by the intervention, further complicating
evaluation of delirium endpoints. Thus, our overall objective is to improve the design and statistical
analysis of preventative and therapeutic delirium RCTs in critically ill older adults. To achieve this
objective, we will conduct a systematic review of delirium endpoint definitions and statistical analysis methods,
followed by a rigorous evaluation of their statistical performance (e.g., false positive rate (Type I error) and
statistical power), using simulation studies based on real data from 6 diverse RCT exemplars and 2 large
clinical cohorts (Aim 1). Joint models, that include survival models for both recurring delirium and a single
competing event, have recently been applied in two prominent RCTs of pharmacological interventions for
delirium in the ICU (Aim 2). In this proposal, novel extensions of these joint models will be developed that
better mimic key features of delirium among critically ill older adults by including a recurrent event survival
model for delirium, as well as allowing two survival models, one for each competing event. Thereafter, current
and novel extensions of the joint models will be compared to the endpoint definitions and statistical analysis
methods identified in the preceding systematic review, using simulation studies (Aim 3). Based on these
findings, we will make recommendations for the design and statistical analysis of delirium RCTs, accounting for
the possibility that discharge and death may be affected by the study intervention. We will disseminate these
novel joint models, in addition to our findings and recommendations, throug...

## Key facts

- **NIH application ID:** 10064600
- **Project number:** 5R01AG061384-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Elizabeth Colantuoni
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $355,002
- **Award type:** 5
- **Project period:** 2019-02-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10064600

## Citation

> US National Institutes of Health, RePORTER application 10064600, Improving the statistical design and analysis of randomized controlled trials of delirium prevention and treatment for critically ill older adults (5R01AG061384-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10064600. Licensed CC0.

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