Innovations In Clinical Neuroscience

ISCTM Supplement 2015

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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[ V O L U M E 1 2 , N U M B E R 3 – 4 , S U P P L E M E N T A , M A R C H – A P R I L 2 0 1 5 ] Innovations in CLINICAL NEUROSCIENCE 17S subset of subjects). Exploratory objectives center around the effects of pioglitazone on safety/efficacy of pharmacogenomics to identify genetic l oci associated with drug response and/or conversion to MCI due to AD. To this end, effects of pioglitazone on vMRI over time will also be used in the same subset of subjects enrolled in the ARIA substudy. Retrospective evaluation and optimization of the prognostic characteristics of the biomarker risk algorithm for age of onset of MCI due to AD in non-white subjects will be employed as every six months subjects will undergo assessments. It should be mentioned that routine laboratory tests such as hematology, serum chemistry, and urinalysis will also be taken twice a year. Phase III extension study. This component is to provide a supportive study for the program and entails that subjects who convert to MCI due to AD be continued on the randomized condition (i.e., pioglitazone or placebo) for at least two years following the study. Based on the feedback from the FDA and EMA, this study could provide important supportive evidence for the novel endpoint measurements of MCI due to AD in the potential marketing application. It is expected that the population will largely comprise of converters from cognitively normal to MCI due to AD during the main Phase III study. The design is essentially a double blind extension phase of the main Phase III study and as mentioned the subjects will simply continue on the same treatment (pioglitazone or placebo). The objective of this extension phase is to evaluate the safety and efficacy of pioglitazone in slowing the progression of cognitive decline in subjects with MCI due to AD. The sample size will be approximately 472 subjects (all converters from high-risk 410 Caucasians + 41 non-Caucasian=451; and low risk = 21 subjects) with a number expected to be roughly 316 (67%). The primary endpoint is the change of cognitive impairment from extension study baseline to at least two years post-study completion (composite cognitive test battery score). Important secondary endpoints in this study will be the number of converters from MCI to AD in each group (Figure 2). Lessons learned 1. Regulatory agency. Primary endpoint measures can be devised with the help of industry, academics, and government regulatory agencies. Lessons learned 2. Risk stratification.Using genetic data may help support outcome measures and can be used for risk stratification of enrolling patient populations. Lessons learned 3. Epidemiological trial design. Longitudinal trial design in prevention of disease in healthy volunteers with drug treatment may require lengthy trial time with prolonged follow-up periods. CASE 3: TARGETING VENTRAL STRIATAL ACTIVATION AND ANHEDONIA IN EARLY PHASE CLINICAL TRIALS OF MOOD AND ANXIETY DISORDERS: THE NIMH FAST-MAS PERSPECTIVE Preface. Despite recent basic science breakthroughs in understanding aspects of the pathophysiology of neuropsychiatric disorders, there is a dearth of new therapeutics in the CNS discovery pipeline. FDA approvals of CNS drugs with novel mechanisms are nearly non- existent and presents a great threat to development of new treatments for psychiatric disease. This lack of innovation is, however, not due to a lack of effort and expenditure in the drug development process. To the contrary, the money invested in failed efforts and the overall costs of successful drug development are rising at an alarming rate. Flaws in the traditional methodology of early phase clinical trials (Phase I and Phase IIa) have been identified as among the most important impediments to the successful development of CNS drugs. Outlined herein is an approach to development of early phase clinical trials that is intended to address some of these critical flaws and is currently being implemented in the NIMH supported program: New Experimental Medicine Studies: Fast-Fail Trials in Mood and Anxiety Spectrum Disorders (FAST-MAS). Current Phase IIa issues. Phase IIa clinical trial design and methodology is thought to be the biggest contributor to clinical trial problems and is the gate to the most expensive phase of drug development. Phase IIa is a key point where vital FIGURE 2. Subject flow in the study

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