title: Medication development for agitation and aggression in Alzheimer disease: review and discussion of recent randomized clinical trial design.
abstract: BACKGROUND
  The management of disruptive neuropsychiatric symptom (NPS) such as agitation and aggression (A/A) is a major priority in caring for people with Alzheimer's disease (AD). Few effective pharmacological or non-pharmacological options are available. Results of randomized clinical trials (RCTs) of drugs for A/A have been disappointing. This may result from the absence of biological efficacy for medications tested in treating A/A. It may also be related to methodological issues such as the choice of outcomes. The aim of this review was to highlight key methodological issues pertaining to RCTs of current and emerging medications for the treatment of A/A in AD.
  
  
  METHODS
  We searched PubMed/Medline, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for RCTs comparing medications with either placebo or other drugs in the treatment of A/A in AD, between January 2008 and December 2013.
  
  
  RESULTS
  We identified a total of 18 RCTs; of these, 11 were completed and 7 ongoing. Of the ongoing RCTs, only one is in Phase III. Seven of 10 completed RCTs with reported results did not report greater benefit from drug than placebo. Each of the completed RCTs used a different definition of "clinically significant A/A." There was considerable heterogeneity in study design. The primary endpoints were largely proxy-based but a variety of scales were used. The definition of caregiver and scales used to assess caregiver outcomes were similarly heterogeneous. Placebo response was notable in all trials.
  
  
  CONCLUSIONS
  This review highlights a great heterogeneity in RCTs design of drugs for A/A in AD and some key methodological issues such as definition of A/A, choice of outcome measures and caregiver participation that could be addressed by an expert consensus to optimize future trials design.
authors.affiliation: Gerontopôle, INSERM U 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Soto
authors.affiliation: Gerontopôle, INSERM U 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, France.|Department of Epidemiology, Toulouse University Hospital Toulouse, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Andrieu
authors.affiliation: Gerontopôle, INSERM U 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, France.
authors.forename: Fati
authors.initials: F
authors.lastname: Nourhashemi
authors.affiliation: Gerontopôle, INSERM U 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, France.
authors.forename: Pierre Jean
authors.initials: PJ
authors.lastname: Ousset
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College, London, UK.
authors.forename: Clive
authors.initials: C
authors.lastname: Ballard
authors.affiliation: EA CoBTeK / ICMRR University of Nice Sophia Antipolis -CHU, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Robert
authors.affiliation: Gerontopôle, INSERM U 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Vellas
authors.affiliation: Department of Psychiatry, The Johns Hopkins Bayview Medical Center, Baltimore, MD, USA.
authors.forename: Constantine G
authors.initials: CG
authors.lastname: Lyketsos
authors.affiliation: Department of Psychiatry, The Johns Hopkins Bayview Medical Center, Baltimore, MD, USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Rosenberg
keywords: Alzheimer’s; aggression; agitation; behavior; clinical trial; measurement; therapeutics