Effect of Tarenflurbil on Cognitive Decline and Activities of Daily Living in Patients with Mild Alzheimer Disease a Randomized Controlled Trial
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ORIGINAL CONTRIBUTION Effect of Tarenflurbil on Cognitive Decline and Activities of Daily Living in Patients With Mild Alzheimer Disease A Randomized Controlled Trial Robert C. Green, MD, MPH   Context Amyloid- peptide (A 42) has been implicated in the pathogenesis of Alz-  Lon S. Schneider, MD heimer disease (AD). Tarenflurbil, a selective A 42-lowering agent, demonstrated en- David A. Amato, PhD couraging results on cognitive and functional outcomes among mildly affected pa- tients in an earlier phase 2 trial. Andrew P. Beelen, MD Objective To determine the efficacy, safety, and tolerability of tarenflurbil. Gordon Wilcock, MD Design, Setting, and Patients A multicenter, randomized, double-blind, placebo- Edward A. Swabb, MD, PhD controlled trial enrolling patients with mild AD was conducted at 133 trial sites in the Kenton H. Zavitz, PhD United States between February 21, 2005, and April 30, 2008. Concomitant treat- ment with cholinesterase inhibitors or memantine was permitted. for the Tarenflurbil Phase 3 Study Group Intervention Tarenflurbil, 800 mg, or placebo, administered twice a day. Main Outcome Measures Co-primary efficacy end points were the change from EADING THEORIES ON THE PATHO- baseline to month 18 in total score on the subscale of the Alzheimer Disease Assess- physiology of Alzheimer disease ment Scale−Cognitive Subscale (ADAS-Cog, 80-point version) and Alzheimer Disease (AD) implicate overproduction of Cooperative Studies–activities of daily living (ADCS-ADL) scale. Additional prespeci- amyloid- (A), particularly 42 fied slope analyses explored the possibility of disease modification.  1-3 Lamino acid peptide A 42. Com- Results Of the 1684 participants randomized, 1649 were included in the analysis, and pounds modulating ␥-secretase en- 1046 completed the trial. Tarenflurbil had no beneficial effect on the co-primary outcomes zyme cleaving -amyloid precursor pro- (difference in change from baseline to month 18 vs placebo, based on least squares means: tein (APP) to release various forms of A 0.1 for ADAS-Cog; 95% CI, −0.9 to 1.1; P=.86 and −0.5 for ADCS-ADL; 95% CI, −1.9 are candidates for treatment of AD. One to 0.9; P=.48) using an intent-to-treat analysis. No significant differences occurred in the such compound is tarenflurbil (for- secondary outcomes. The ADAS-Cog score decreased by 7.1 points over 18 months. The  tarenflurbil group had a small increase in frequency of dizziness, anemia, and infections. merly R-flurbiprofen), a selective A 42- lowering agent that has been shown Conclusion Tarenflurbil did not slow cognitive decline or the loss of activities of daily in vitro and in vivo to modulate ␥- living in patients with mild AD.  secretase activity and reduce A 42 pro- Trial Registration clinicaltrials.gov Identifier: NCT00105547 duction in favor of shorter less toxic JAMA. 2009;302(23):2557-2564 www.jama.com    4,5 forms of A (eg, A 38 and A 37). In mouse models of AD, tarenflurbil pre- and that the drug was well tolerated pare tarenflurbil with placebo for 18 vents learning and memory deficits and with few adverse effects.7 On the basis months involving 133 participating trial  4,6 reduces A 42 brain concentrations. of these results, a large phase 3, ran- sites. Written informed consent was ob- A phase 2 trial of tarenflurbil sug- domized, placebo-controlled trial of tained from participants, their legally gested that patients with mild AD and tarenflurbil was conducted in patients authorized representatives, or both. The moderate AD responded differently to with mild AD. treatment, that patients with mild AD Author Affiliations are listed at the end of this article. had a dose-related slower rate of de- METHODS A Complete List of Study Group Investigators is avail- cline than those treated with placebo, able at http//:www.jama.com. Study Design Corresponding Author: Robert C. Green, MD, MPH, A randomized, double-blind, 2-group Neurology, Genetics and Epidemiology, Boston Uni- See also pp 2565 and 2593. versity School of Medicine, 72 E Concord St, L-320, parallel study was conducted to com- Boston, MA 02118 ([email protected]). ©2009 American Medical Association. All rights reserved. (Reprinted) JAMA, December 16, 2009—Vol 302, No. 23 2557 Downloaded from jama.ama-assn.org by guest on November 25, 2011 EFFECT OF TARENFLURBIL AND MILD ALZHEIMER DISEASE institutional review board of partici- vided they had been taking that spe- Eligible participants were random- pating institutions approved the study. cific medication for at least 6 months ized by a central randomization schema Patients were predominantly re- before taking the study drug. Partici- generated by the sponsor. The random- cruited from dementia clinics and were pants taking memantine were en- ization tables were maintained in a enrolled from February 21, 2005, rolled if they had been taking stable locked file room of the head of the Qual- through April 30, 2008. Initial enroll- doses for at least 3 months before tak- ity Assurance department. The clini- ment criteria included community- ing the study drug. Randomization was cal system was used to assign blinded dwelling patients with mild to moder- stratified by use or nonuse of cholin- drug treatment kits. Both dosages ate AD severity (Mini-Mental State esterase inhibitors and memantine. Par- of tarenflurbil were administered as 2 Examination [MMSE] scores of 15-26, ticipants taking antidepressant, anti- tablets twice a day: a single tarenflur- inclusive). Patients were assigned to psychotic, or anxiolytic drugs, vitamin bil tablet for the 400-mg and 2 taren- treatment with tarenflurbil at doses of E, or Ginkgo biloba were eligible, pro- flurbil tablets for the 800-mg groups, either 400 mg or 800 mg twice a day. Af- vided that the dose was stable for at least then after the protocol amendment only ter analysis of phase 2 data indicated that 3 months prior to randomization. at doses of 800 mg twice daily. Partici- patients with mild AD appeared to have Chronic aspirin use for cardioprotec- pants in the placebo group took 2 tab- a more robust response to 800 mg of the tive therapy was allowed. lets identical to the tarenflurbil tablets tarenflurbil twice daily7 and after discus- Participants were excluded if they had twice a day to ensure blinding. Partici- sion with the US Food and Drug Admin- evidence of epilepsy; focal brain lesion; pants were not asked to guess their ran- istration, the enrollment criteria were head injury with loss of consciousness domization group. changed on May 27, 2005, to enroll only or confusion after the injury; DSM- Adverseeventmonitoring,physicalex- patients with mild AD (MMSE score of IV-TR (Text Revision) criteria for any aminationsincludingvitalsignsmeasure- 20-26, inclusive) with treatment modi- major psychiatric disorder including ment, standard resting 12-lead electro- fied by ending the 400-mg group: 42 pa- psychosis, major depression, bipolar cardiograms, and blood and urine sample tients with mild AD were switched to the disorder, or alcohol or substance abuse; collection for clinical laboratory analy- 800-mg group and 32 patients with mod- history of upper gastrointestinal tract sisanddeterminationofplasmatarenflur- erate AD were discontinued from the bleeding requiring surgery, transfu- bil concentration were performed at the trial; thus, the revised analysis plan ex- sion, or both within 3 years or docu- screening visit and at months 1, 3, 6, 9, cluded those with moderate AD. mented evidence of active gastric or 12, 15, and 18. Additional adverse event The remainder of the inclusion and duodenal ulcer disease within 3 months; monitoring was performed via telephone exclusion criteria remained un- history or evidence of active malig- withcaregiversatweek2andeverymonth changed throughout the trial: 55 years nancy, except for prostate cancer, basal between scheduled visits. All participants or older and living in the community, cell carcinoma, or squamous cell car- were assessed 30 days after the last dose meeting criteria for dementia by the cinoma of the skin within 24 months of study medication. A central laboratory Diagnostic and Statistical Manual of of entry; a chronic or acute renal, was used throughout the study. Mental Disorders (Fourth Edition) hepatic, or metabolic disorder; any use (DSM-IV), and having probable AD by of AD immunotherapy or recent use of Outcome Measures National Institute of Neurological and any investigational therapy or major sur- and Power Estimates Communicative Disorders and Stroke– gery; an uncontrolled cardiac condi- Co-primary efficacy outcomes were Alzheimer’s Disease and Related Dis- tion (New York Heart Association class cognition as assessed by the Alzhei- orders Association criteria.8 Addi- III or IV); anticoagulant therapy such mer Disease Assessment Scale– tional inclusion criteria at screening as warfarin within 12 weeks of enroll- Cognitive Subscale (ADAS-Cog, 80- included no clinically significant focal ment; use of any CYP2C9 enzyme point version)10 and functional ability intracranial pathology as assessed by CT inhibitor or the CYP2C9 enzyme sub- as assessed by the Alzheimer Disease or MRI within the previous 12 months, strates losartan, phenytoin, tamoxi- Cooperative Study activities of daily liv- a modified Hachinski ischemic score9 fen, torsemide, and fluvastatin within ing (ADCS-ADL, 78-point scale).11 A of less than 4, at least 6 years of edu- 2 weeks of enrollment; recent history key secondary outcome measure as- cation or sufficient work history to ex- of chronic use of nonsteroidal anti- sessed global function with the Clini- clude mental retardation, adequate vi- inflammatory drugs (NSAIDs) at any cal Dementia Rating (CDR) sum of sion and hearing to participate in study dose or aspirin greater than 325 mg/d; boxes (CDR-sb, 18-point scale).12 Ad- assessments, and a reliable caregiver or history of hypersensitivity to any ditional secondary outcomes included who saw the patient at least 4 days a NSAIDs including cyclooxygenase 2 the MMSE (30-point scale),13 Neuro- week and could accompany the pa- (COX-2)–specific inhibitors.