Flortaucipir F 19 was evaluated in a rat micronucleus study and showed no genotoxicity. In this study, flortaucipir F 19 did not increase the number of micronucleated polychromatic erythrocytes at the highest achievable dose level, 1600 μg/kg/day, when given for two consecutive days.
The performance of TAUVID imaging to estimate the density and distribution of aggregated tau neurofibrillary tangles (NFTs) was evaluated in two clinical studies: Study 1 (NCT02516046) and Study 2 (NCT03901092). In each study, TAUVID imaging was interpreted by 5 independent readers who were blinded to clinical information. Readers interpreted TAUVID imaging as positive or negative [see Dosage and Administration (2.6)].
Study 1 enrolled 156 terminally ill patients who agreed to undergo TAUVID imaging and to participate in a postmortem brain donation program. In 64 of these patients, reader interpretation of the TAUVID scan was compared to tau pathology based on scoring provided by independent pathologists, who evaluated the density and distribution of NFTs in the post-mortem brain (see Table 5). Of the 64 patients, the mean age was 83 years (range 55 to 100); 34 were female; 49 had dementia, 1 had mild cognitive impairment, and 14 had no cognitive impairment on clinical evaluation around the time of TAUVID imaging.
Image reader performance for distinguishing B3 (positive) from B0-B2 (negative) tau pathology is shown in Table 6.
The performance of the five TAUVID readers for sensitivity (95% CI) ranged from 92% (80, 97) to 100% (91, 100) and for specificity (95% CI) ranged from 52% (34, 70) to 92% (75, 98). Exploratory analysis evaluated how the same TAUVID interpretations distinguished B2-B3 from B0-B1 tau pathology, a threshold used in integrating tau and amyloid pathology for the neuropathological diagnosis of AD. In this analysis, the performance of the five TAUVID readers for sensitivity (95% CI) ranged from 68% (55, 79) to 86% (74, 93) and for specificity (95% CI) ranged from 63% (31, 86) to 100% (68, 100) [see Warnings and Precautions (5.1)].
Study 2 included the same terminally ill patients as in Study 1 (plus 18 additional terminally ill patients) and 159 patients with cognitive impairment being evaluated for AD (the indicated population). Inter-reader agreement for five new TAUVID readers was evaluated using Fleiss’ kappa statistic (95% CI) and found to be 0.87 (0.83, 0.91) across all 241 patients. Exploratory analysis evaluated inter-reader agreement in two subgroups. In this analysis, Fleiss’ kappa (95% CI) was 0.82 (0.75, 0.88) in the terminally ill patients and 0.90 (0.85, 0.95) in the indicated population.
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