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1.  Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer’s disease 
Background
We assessed the impact of retinoid X receptor (RXR) agonist bexarotene on brain amyloid measured by amyloid imaging in patients with Alzheimer’s disease (AD) in a proof-of-concept trial.
Methods
Twenty patients with AD [Mini Mental State Examination (MMSE) score 10–20 inclusive] with positive florbetapir scans were randomized to receive 300 mg of bexarotene or placebo for 4 weeks. The amyloid imaging result was the primary outcome. Whole-population analyses and prespecified analyses by genotype [apolipoprotein E ε4 (ApoE4) carriers and ApoE4 noncarriers] were conducted. Secondary outcomes included scores on the Alzheimer’s Disease Assessment Scale–Cognitive subscale, Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale, MMSE, Clinical Dementia Rating scale, and Neuropsychiatric Inventory. Serum amyloid-β (Aβ) peptide sequences Aβ1–40 and Aβ1–42 measurements were collected as biomarker outcomes.
Results
There was no change in the composite or regional amyloid burden when all patients were included in the analysis. ApoE4 noncarriers showed a significant reduction in brain amyloid on the composite measure in five of six regional measurements. No change in amyloid burden was observed in ApoE4 carriers. There was a significant association between increased serum Aβ1–42 and reductions in brain amyloid in ApoE4 noncarriers (not in carriers). There were significant elevations in serum triglycerides in bexarotene-treated patients. There was no consistent change in any clinical measure.
Conclusions
The primary outcome of this trial was negative. The data suggest that bexarotene reduced brain amyloid and increased serum Aβ1–42 in ApoE4 noncarriers. Elevated triglycerides could represent a cardiovascular risk, and bexarotene should not be administered outside a research setting. RXR agonists warrant further investigations as AD therapies.
Trial registration
ClinicalTrials.gov identifier NCT01782742. Registered 29 January 2013.
Electronic supplementary material
The online version of this article (doi:10.1186/s13195-016-0173-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s13195-016-0173-2
PMCID: PMC4731943  PMID: 26822146
Clinical trial; Alzheimer’s disease; MRI; Amyloid; PET; Bexarotene; ApoE genotype
2.  Alzheimer’s disease drug-development pipeline: few candidates, frequent failures 
Introduction
Alzheimer’s disease (AD) is increasing in frequency as the global population ages. Five drugs are approved for treatment of AD, including four cholinesterase inhibitors and an N-methyl-D-aspartate (NMDA)-receptor antagonist. We have an urgent need to find new therapies for AD.
Methods
We examined Clinicaltrials.gov, a public website that records ongoing clinical trials. We examined the decade of 2002 to 2012, to better understand AD-drug development. We reviewed trials by sponsor, sites, drug mechanism of action, duration, number of patients required, and rate of success in terms of advancement from one phase to the next. We also reviewed the current AD therapy pipeline.
Results
During the 2002 to 2012 observation period, 413 AD trials were performed: 124 Phase 1 trials, 206 Phase 2 trials, and 83 Phase 3 trials. Seventy-eight percent were sponsored by pharmaceutical companies. The United States of America (U.S.) remains the single world region with the greatest number of trials; cumulatively, more non-U.S. than U.S. trials are performed. The largest number of registered trials addressed symptomatic agents aimed at improving cognition (36.6%), followed by trials of disease-modifying small molecules (35.1%) and trials of disease-modifying immunotherapies (18%). The mean length of trials increases from Phase 2 to Phase 3, and the number of participants in trials increases between Phase 2 and Phase 3. Trials of disease-modifying agents are larger and longer than those for symptomatic agents. A very high attrition rate was found, with an overall success rate during the 2002 to 2012 period of 0.4% (99.6% failure).
Conclusions
The Clinicaltrials.gov database demonstrates that relatively few clinical trials are undertaken for AD therapeutics, considering the magnitude of the problem. The success rate for advancing from one phase to another is low, and the number of compounds progressing to regulatory review is among the lowest found in any therapeutic area. The AD drug-development ecosystem requires support.
doi:10.1186/alzrt269
PMCID: PMC4095696  PMID: 25024750
3.  Advances in designs for Alzheimer’s disease clinical trials 
There is an urgent need to identify new treatments for the rapidly growing population of people with Alzheimer’s disease (AD). Innovations in clinical trial designs many help to reduce development time, provide more definitive answers regarding drug efficacy, and facilitate prioritizing compounds to be advanced to Phase III clinical trials. Standard designs compare drug and placebo changes from baseline on a rating scale. Baysian adaptive clinical trials allow the use of data collected in the trial to modify doses, sample size, trial duration, and entry criteria in an ongoing way as the data are collected. Disease-modification is supported by findings on staggered start and delayed withdrawal designs. Futility designs can use historical controls and may shorten trial duration. Combination therapy designs may allow investigation of additive or synergistic treatment effects. Novel trial selection criteria allow investigation of treatment effects in asymptomatic or minimally symptomatic, prodromal AD populations. The Clinical Dementia Rating-Sum of Boxes (CDR-SOB) can be considered as a single trial outcome in early disease populations. Alternate forms of the Alzheimer’s Disease Assessment Scale-Cognitive Portion (ADAS-cog), computerized measures, and pharmacoeconomic scales provide new and relevant information on drug effects. Comparative dose strategies are used in trials of symptomatic agents, and novel methods including withdrawal designs, symptom emergence analyses, and sequential designs are being utilized to assess the efficacy of putative psychotropic agents. The choice of trial design is driven by the question to be answered by the clinical trial; an increasing number of design approaches are available and may be useful in accelerating and refining AD drug development.
PMCID: PMC3560467  PMID: 23383393
Clinical trials; Alzheimer’s disease; designs; drug development
4.  Globalization of Alzheimer's disease clinical trials 
Alzheimer's disease (AD) therapies are increasingly being tested in global clinical trials. A search of ClincalTrials.gov revealed that of 269 currently active trials, 28% are currently being conducted in the United States; the majority of trials and the majority of trial sites are ex-US. The US has the largest number of trial sites of any single country; cumulatively, nearly half of all sites are outside the US. The US conducts more trials in all phases of drug development but has a greater proportion of phase 3 trials. The increasing importance of global participants in clinical trials emphasizes the importance of considering the ethnic and international factors that may influence trial outcome. The International Conference on Harmonization guidelines divide ethnic factors that may affect drug development into intrinsic and extrinsic influences. These include language, cultural factors, educational levels, the general level of health and standard of care, as well as nutrition and diet. Ethnic influences on pharmacokinetics are known for some metabolic pathways. The biology of AD may also differ among the world's populations. The frequency of the apolipoprotein e4 allele, a major risk factor for AD, differs internationally. Genetic variations might also affect inflammatory, excitotoxic, and oxidative components of AD. Diagnostic standards and experience vary from country to country. Levels of practitioner training and experience, diagnostic approaches to AD, and attitudes regarding aging and AD may differ. Experience and sophistication with regard to clinical trial conduct also vary within and between countries. Experience with conducting the necessary examinations, as well as the linguistic and cultural validity of instrument translations, may affect trial outcomes. Operational and regulatory aspects of clinical trials vary and provide important barriers to seamless conduct of multiregional clinical trials. Collection and testing of biological samples, continuous provision of drug substance, and protection of the integrity of supply lines may be difficult in some international circumstances. Attention to these potential influences on clinical trials will determine the success of global drug development programs and the utility of global trials for developing new AD therapeutics.
doi:10.1186/alzrt86
PMCID: PMC3226279  PMID: 21861855
5.  Agitation in cognitive disorders: International Psychogeriatric Association provisional consensus clinical and research definition 
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
doi:10.1017/S1041610214001963
PMCID: PMC4301197  PMID: 25311499
Alzheimer’s disease; agitation; cognitive impairment; aggression; International Psychogeriatric Association; Food and Drug Administration; clinical trials; intervention; epidemiology

Results 1-5 (5)