Clinical Trials in the Prodromal Phase of Alzheimer’s Disease – Methodological Challenges and Clinical Outcomes Are Addressed at ISCTM Annual Meeting « ISCTM | The International Society for CNS Clinical Trials and Methodology

Clinical Trials in the Prodromal Phase of Alzheimer’s Disease – Methodological Challenges and Clinical Outcomes Are Addressed at ISCTM Annual Meeting

A half-day session, characterizing the validity and utility of clinical trials designed to assess treatments for prodromal Alzheimer’s Disease (AD), chaired by Michael Davidson, MD, Professor and Chairman of the Department of Psychiatry at Tel Aviv University and George Garibaldi, M.D., Clinical Development, Roche Pharmaceuticals was held on February 24,2010, at the 6th Annual Meeting of the International Society for CNS Clinical Trials and Methodology (ISCTM) in Washington, DC.

Recent advances into AD pathology and accompanying biomarker technology have suggested that early intervention in neurodegenerative diseases prior to the emergence of overt clinical symptoms is advantageous and should result in a greater impact on disease progression. However, assessing the therapeutic index of a prodromal phase of disease is often beset by a number of methodological challenges which were expertly addressed by an expert panel of clinical, industry and regulatory scientists who provided tactical and procedural advice regarding the implementation of these approaches in future clinical trials of prodromal AD.

This session reviewed the many challenges faced when identifying, testing and providing prodromal disease treatments in terms of the sensitivity/specificity of the prodrome; the causal path between the prodrome and the disease, and the use and misuse of biomarkers. Dr. John Morris, MD, Distinguished Professor of Neurology at Washington University in St. Louis provided an overview of the AD prodrome with implications for patient selection and study design. Dr. Morris stated that “prodromal AD typically is distinguished by a failure to meet threshold for dementia, implying a dichotomous condition of no dementia or dementia. However, AD is marked by continuous neuronal deterioration and applying a threshold to determine clinical status is therefore arbitrary and ambiguous. Current definitions of preclinical AD are typically determined by inter-individual comparisons of cognitive test performance (often episodic memory) rather than a decline from previously attained levels leading to both false positive and negative inclusion of patients”. Dr. Morris promoted the inclusion of biomarkers in trials in order to help support accuracy of diagnosis, to enrich the sample, and to confirm the presence of the therapeutic target.

Dr. Marc Cantillon of Merck Research Laboratories confirmed that biomarkers have shown the greatest utility in clinical trials comes when they “are used for entry criteria to confirm diagnosis, as stratification tools, and as covariates; with the five top biomarkers including both markers of neurodegeneration such as CSF tau, FDG-PET and structural MRI, as well as markers of brain abeta deposition such as CSF Aβ42, and PET Aβ imaging, with brain atrophy being the most promising to date for trial application”.

Industry veteran Dr. Ravi Anand concluded the session by reviewing past trials in Mild Cognitive Impairment (MCI) citing their common failure “not from a low rate of conversion to AD but more a matter of inappropriate treatment for the symptomatology, an inappropriate set of outcome measures and the enrollment of inappropriate patients who had disease severity that was virtually unchangeable at the point of intervention”. Dr. Anand opined that “it may be more useful to think of prodromal AD as the transition between healthy aging and MCI with performance deficits being in a single cognitive domain. Supporting this diagnosis would be a lack of functional and behavioral deficits, as well as biomarkers that would be used mainly to exclude patients”. These notions were supported by panel members including Dr. Michael Davidson who agreed “that the clinical construct of MCI as we know it is probably obsolete and if we are to help future patients a new model is needed – one that relies on within subject measures that are sensitive at the earliest point of deflection in prodromal AD. Given the changing population trends and accompanying financial burdens the benefits of delaying the onset of AD for even for a year or two would be of tremendous value”. Presentations and video of the session are currently being posted for viewing by ISCTM Members, accessible through the ISCTM Library.

The ISCTM (www.isctm.org) was founded in 2004 to gather representatives from academic and clinical specialties, the pharmaceutical industry, and regulatory bodies to exchange ideas about important clinical and public-health challenges, to examine the development of novel treatments for major psychiatric and neuropsychiatric disorders, and to support advances in methods of evaluating such treatments that are scientifically sound, ethical, and feasible. To achieve this mission, ISCTM conducts two scientific meetings per year. The Autumn Scientific meeting will be held October 13-14, 2010 at the Hyatt Regency – Inner Harbor, Baltimore, MD. View Preliminary Agenda (Submitted by H. Riordan)

Clinical Trials in the Prodromal Phase of Alzheimer’s Disease – Methodological Challenges and Clinical Outcomes Are Addressed at ISCTM Annual Meeting

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