Carl Chiang

Rosiglitazone Does Not Improve Cognition or Global Function when Used as Adjunctive Therapy to AChE Inhibitors in Mild-to-Moderate Alzheimers Disease: Two Phase 3 Studies

INTRODUCTION Two phase 3 studies evaluated the efficacy and safety of rosiglitazone (RSG), a type 2 diabetes treatment, in an extended release (RSG XR) form as adjunctive therapy to ongoing acetylcholine esterase inhibitor (AChEI) treatment in AD (REFLECT-2, adjunctive to donepezil; REFLECT-3, to any AChEI). An open-label extension study (REFLECT-4) assessed RSG XR long-term safety. METHODS In these two double-blind, placebo-controlled studies, subjects with mild-to-moderate probable AD were randomized within 2 apolipoprotein E (APOE) allelic strata (APOE ε4-positive, APOE ε4-negative) to once daily placebo, 2 mg RSG XR, or 8 mg RSG XR for 48 weeks (REFLECT-2, N=1,496; REFLECT-3, N=1,485). Co-primary efficacy endpoints were change from baseline in Alzheimers Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and Clinical Dementia Rating scale - Sum of Boxes (CDR-SB) scores at week 48. Three populations were analyzed: APOE4-negative, all subjects except APOE ε4 homozygotes, and the full intent-to-treat population. RESULTS No statistically or clinically relevant differences between treatment groups were observed on the a priori primary endpoints in REFLECT-2 or REFLECT-3. Edema was the most frequent adverse event with RSG in each study (14% and 19%, respectively, at 8 mg RSG XR). CONCLUSIONS No evidence of statistically or clinically significant efficacy in cognition or global function was detected for 2 mg or 8 mg RSG XR as adjunctive therapy to ongoing AChEIs. There was no evidence of an interaction between treatment and APOE status. Safety and tolerability of RSG XR was consistent with the known profile of rosiglitazone.

ADJUDICATING MILD COGNITIVE IMPAIRMENT DUE TO ALZHEIMER’S DISEASE AS A NOVEL ENDPOINT EVENT IN THE TOMMORROW STUDY: A DELAY-OF-ONSET PHASE 3 CLINICAL TRIAL

Carl Chiang, PhD1, Robert Alexander, MD2, Kathleen A. Welsh-Bohmer, PhD3,4, Brenda L. Plassman, PhD3,4, Heather Romero, PhD3, Kathleen M. Hayden, PhD3,4, Richard S.E. Keefe, PhD4, 5, Alexandra S. Atkins, PhD5, Patrick Harrigan, BChE6*, Janet O’Neil, MBA6, Meredith Culp, BS6, Ryan Walter, BS7, Jingtao Wu, PhD6, LaDonna Randle, BA7, Stephen Haneline, MS1, Deborah Yarbrough, MS, MBA6, Daniel K. Burns, PhD1, Ann M. Saunders, PhD1, for the TOMMORROW Study Investigators 1Zinfandel Pharmaceuticals, Inc., Durham, NC, USA; 2Takeda Development Center Americas, Inc., Cambridge, MA, USA; 3Duke University Bryan ADRC, Durham, NC, USA; 4Department of Psychiatry, Duke University Medical Center, Durham, NC, USA; 5NeuroCog Trials, Durham, NC, USA; 6Takeda Development Center Americas, Inc., Deerfield, IL, USA; 7PRA Health Science, Deerfield, IL, USA

TOMMORROW neuropsychological battery: German language validation and normative study

Assessment of preclinical Alzheimers disease (AD) requires reliable and validated methods to detect subtle cognitive changes. The battery of standardized cognitive assessments that is used for diagnostic criteria for mild cognitive impairment due to AD in the TOMMORROW study have only been fully validated in English‐speaking countries. We conducted a validation and normative study of the German language version of the TOMMORROW neuropsychological test battery, which tests episodic memory, language, visuospatial ability, executive function, and attention.

CLINICAL TRIALS IN THE PRECLINICAL TO MCI STAGES OF AD: CROSS-CULTURAL VALIDATION AND NORMATIVE STUDY OF THE TOMMORROW NEUROPSYCHOLOGICAL BATTERY

P4-395 CLINICALTRIALS IN THE PRECLINICALTOMCI STAGES OFAD: CROSS-CULTURALVALIDATION AND NORMATIVE STUDYOF THE TOMMORROW NEUROPSYCHOLOGICAL BATTERY Kathleen A.Welsh-Bohmer, Heather R. Romero, Kathleen M. Hayden, Brenda L. Plassman, Alexandra S. Atkins, Nicole Turcotte, Richard SE. Keefe, Oksana A. Makeeva, Natalia G. Zhukova, Andreas U. Monsch, Giovanni B. Frisoni, Zara A. Melikyan, Shyama Brewster, Carl Chiang, Yuka Maruyama, Janet O’Neil, Dominic Fitzsimmons, Grant Runyan, Stephen O. Crawford, Toyoko Oguri, Mark J. Atkinson, Kumar Budur, Elizabeth Merikle, Ferenc Martenyi, Daniel K. Burns, Allen D. Roses, TOMMORROW Study Investigators, Duke University Bryan ADRC, Durham, NC, USA; inVentiv Health, Cary, NC, USA; Wake Forest School of Medicine, Winston-Salem, NC, USA; NeuroCog Trials, Durham, NC, USA; Center for Clinical Trials, Nebbiolo, LLC, Tomsk, Russia; 6 Memory Clinic, University Center for Medicine of Aging, Felix Platter Hospital, Basel, Switzerland; IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; 8 University of NC Wilmington, Wilmington, NC, USA; 9 Zinfandel Pharmaceuticals Inc., Chapel Hill, NC, USA; 10 Zinfandel Pharmaceuticals, Inc., Durham, NC, USA; Zinfandel Pharmaceuticals, Inc., Kamakura, Japan; Takeda Development Center Americas, Inc., Deerfield, IL, USA; 13 Takeda Development Center Americas, Inc., Deerfield, IL, USA; 14 Covance Market Access Services, Inc., Gaithersburg, MD, USA; Covance, Inc., Princeton, NJ, USA; Covance, Inc., Princeton, NJ, USA; TakedaDevelopment Center Americas, Inc., Deerfield, IL, USA. Contact e-mail: kathleen.welshbohmer@duke.edu