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The data safety monitoring board (DSMB), also known the data monitoring committee, is a multidisciplinary team of scientific experts that serve an advisory role within the operation of clinical trials. The principle responsibility of a DSMB is to monitor the conduct of trials for concerns related to participant safety and data quality through the review of interim data analyses, and then to advise trial leadership whether a study is appropriate to continue, needs to modify procedures, or should be terminated. An emphasis is placed on the responsibility of the DSMB to safeguard the rights and well-being of study participants, so it is common to see the incorporation of a DSMB into a study protocol when a trial explores an intervention with high participant risk, a trial is working with a large number of participants, or when a study is working with a particularly vulnerable population, like Alzheimer’s disease (AD) patients. This chapter reviews common DSMB roles and responsibilities as well as highlighting examples of DSMBs in practice in AD clinical research.
Placebo responses raise significant challenges for the design of clinical trials. We report changes in agitation outcomes in the placebo arm of a recent trial of citalopram for agitation in Alzheimer's disease (CitAD).
In the CitAD study, all participants and caregivers received a psychosocial intervention and 92 were assigned to placebo for nine weeks. Outcomes included Neurobehavioral Rating Scale agitation subscale (NBRS-A), modified AD Cooperative Study-Clinical Global Impression of Change (CGIC), Cohen-Mansfield Agitation Inventory (CMAI), the Neuropsychiatric Inventory (NPI) Agitation/Aggression domain (NPI A/A) and Total (NPI-Total) and ADLs. Continuous outcomes were analyzed with mixed-effects modeling and dichotomous outcomes with logistic regression.
Agitation outcomes improved over nine weeks: NBRS-A mean (SD) decreased from 7.8 (3.0) at baseline to 5.4 (3.2), CMAI from 28.7 (6.7) to 26.7 (7.4), NPI A/A from 8.0 (2.4) to 4.9 (3.8), and NPI-Total from 37.3 (17.7) to 28.4 (22.1). The proportion of CGI-C agitation responders ranged from 21 to 29% and was significantly different from zero. MMSE improved from 14.4 (6.9) to 15.7 (7.2) and ADLs similarly improved. Most of the improvement was observed by three weeks and was sustained through nine weeks. The major predictor of improvement in each agitation measure was a higher baseline score in that measure.
We observed significant placebo response which may be due to regression to the mean, response to a psychosocial intervention, natural course of symptoms, or nonspecific benefits of participation in a trial.
Agitation is common across neuropsychiatric disorders and contributes to disability, institutionalization, and diminished quality of life for patients and their caregivers. There is no consensus definition of agitation and no widespread agreement on what elements should be included in the syndrome. The International Psychogeriatric Association formed an Agitation Definition Work Group (ADWG) to develop a provisional consensus definition of agitation in patients with cognitive disorders that can be applied in epidemiologic, non-interventional clinical, pharmacologic, non-pharmacologic interventional, and neurobiological studies. A consensus definition will facilitate communication and cross-study comparison and may have regulatory applications in drug development programs.
The ADWG developed a transparent process using a combination of electronic, face-to-face, and survey-based strategies to develop a consensus based on agreement of a majority of participants. Nine-hundred twenty-eight respondents participated in the different phases of the process.
Agitation was defined broadly as: (1) occurring in patients with a cognitive impairment or dementia syndrome; (2) exhibiting behavior consistent with emotional distress; (3) manifesting excessive motor activity, verbal aggression, or physical aggression; and (4) evidencing behaviors that cause excess disability and are not solely attributable to another disorder (psychiatric, medical, or substance-related). A majority of the respondents rated all surveyed elements of the definition as “strongly agree” or “somewhat agree” (68–88% across elements). A majority of the respondents agreed that the definition is appropriate for clinical and research applications.
A provisional consensus definition of agitation has been developed. This definition can be used to advance interventional and non-interventional research of agitation in patients with cognitive impairment.