18F-AV-1451-A05 Protocol Amendment 2 An Open Label .
18F-AV-1451-A05 Protocol Amendment 2An Open Label, Multicenter Study, Evaluating the Safety and Imaging Characteristics of 18FAV-1451 in Cognitively Healthy Volunteers, Subjects With Mild Cognitive Impairment, andSubjects With Alzheimer's DiseaseNCT02016560Approval date: 07 Aug 2015
/Protocol 18F-AV-1451-A05ConfidentialProtocol Number:18 F-AV-1451-AOSAn open label, multicenter study, evaluating the safety and imaging characteristics of 18 FAV-1451 in cognitively healthy volunteers, subjects with Mild Cognitive Impairment,and subjects with Alzheimer's diseaseDate and Version:07 August 2015, Amendment 2Name of Compound:18 F-AV-1451([F-18]T807)Sponsor:Avid Radiopha'tmaceuticals, Inc.Philadelphia, Pennsylvania USAApprovals/Signatures and Date:CONFIDENTIALThis material is the property of Avid Radiopharmaceuticals, Inc. (Avid). The information isconfidential and is to be used only in connection with matters authorized by Avid and no part of itis to be disclosed to others without prior written permission from Avi d.LY3191748Page 1 of 53
Protocol 18F-AV-1451-A05ConfidentialSponsor:Name of Compound:Active Ingredient(s):Avid itle of Study: 18F-AV-1451-A05An open label, multicenter study, evaluating the safety and imaging characteristics of 18F-AV1451 in cognitively healthy volunteers, subjects with Mild Cognitive Impairment, and subjectswith Alzheimer’s diseasePlanned number of subjects (Enrolled): 380The first Phase of the study will be divided into three groups:1. Cognitively healthy volunteer subjectsa. Approximately 20 subjects 20 to 40 years of ageb. Approximately 60 subjects 50 years of age2. Mild cognitive impairment (MCI) (n 80)3. Alzheimer’s disease (AD) subjectsa. Approximately 60 subjects with an MMSE 20b. Approximately 10 subjects with an MMSE 10 and 20The second Phase of the study will enroll:4. Approximately 150 subjects with cognitive impairment (MCI or demented subjects witha suspected neurodegenerative cause) and an MMSE 20 and 27. For the purposes ofensuring a distribution of disease severity, a target of at least 1/3 of the enrolled subjects willhave dementia.Name of compound: 18F-AV-1451(also known as [F-18]T807)Dose: 370 MBq (10 mCi)Route of Administration: Intravenous (IV) bolusStudy Phase: IIStudy Centers: Approximately 30 centers in the United StatesTrial Objectives: This study will be conducted in two phases, an exploratory phase and aconfirmatory/validation phase, which will have separate subjects and analyses. The first phaseof this study will be comprised of a cross-sectional component and a longitudinal component.LY3191748Page 2 of 53
Protocol 18F-AV-1451-A05ConfidentialSponsor:Name of Compound:Active Ingredient(s):Avid he second (confirmatory/validation) phase will focus on the relationship of baseline PET tauimages to changes in longitudinal clinical measures.Exploratory Phase, Cross-sectional objectives:The primary objective of the cross-sectional component is: To compare 18F-AV-1451 imaging results in subjects with AD to subjects with MCI andcognitively healthy older individualsThe secondary objective of the cross-sectional component is: To establish a database of cognitively healthy individuals to show the spectrum of 18FAV-1451 imaging results in cognitively healthy individuals across a range of age strataExploratory objectives of the cross-sectional component are: To determine whether greater degrees of cognitive impairment correlate with higher 18FAV-1451 uptake in subjects with an amyloid positive status To explore whether tests of specific cognitive domains correlate with regional 18F-AV1451 uptake To explore the relationships between 18F-AV-1451 uptake and biomarkers ofneurodegeneration and neurological disease (CSF markers including tau, phospho-tauand beta-amyloid (Aβ), genetic markers, PET amyloid imaging, and brain atrophyassessed by volumetric MRI) To expand the 18F-AV-1451 safety databaseExploratory Phase, Longitudinal objectives:The primary objective of the first phase longitudinal component is: To assess the rate of change of tau deposition as measured by 18F-AV-1451 uptake overtime.Exploratory objectives of the first phase longitudinal component are: To explore associations between changes in 18F-AV-1451 uptake in the brain and clinicaland functional measures, as well as, biomarkers of neurodegeneration and neurologicaldisease (CSF markers including tau, phospho-tau and beta-amyloid (Aβ), geneticmarkers, PET amyloid imaging, and brain atrophy assessed by volumetric MRI). To expand the 18F-AV-1451 safety databaseConfirmatory Phase, Longitudinal objectives:LY3191748Page 3 of 53
Protocol 18F-AV-1451-A05ConfidentialSponsor:Name of Compound:Active Ingredient(s):Avid he second phase of the study is designed to provide independent validation of the relationshipsobserved in the exploratory analyses of the first phase. In particular, the goal of the secondphase is to confirm the relationship between 18F-AV-1451 uptake in the brain as measured byPET and the subsequent rate of cognitive decline observed over longitudinal follow up.Eligibility:Each of the groups is comprised of specific inclusion and exclusion criteria to determine patienteligibility. See Section 5.3, Selection of Subjects.Study Design:This is a phase 2 cross-sectional and longitudinal observational study that will evaluate imagingcharacteristics of 18F-AV-1451 in control subjects and patients with MCI and AD. This studywill be conducted in two phases, an exploratory/hypothesis generating phase and aconfirmatory/validation phase, which will have separate subjects and analyses.All subjects will provide informed consent before starting any study procedures.For both the Exploratory and Confirmatory Phases, screening assessments may take place overseveral days and will include demographic information, cognitive testing, safety assessment,and MRI, including both volumetric and standard clinical sequences. Raters administering thecognitive testing will be blinded to the 18F-AV-1451 scans for subjects in the ConfirmatoryCohort. Subjects who qualify for the study will return to the clinic at a later date for a florbetapirF 18 PET imaging session and an 18F-AV-1451 PET imaging session. Some subjects, who are 50 years of age, in the exploratory phase may have the option to also participate in cerebrospinalfluid (CSF) collection by lumbar puncture (LP).Subjects who are 50 years of age will return for follow-up visits at 9 ( /-2) and 18 ( /-2)months following the initial 18F-AV-1451 scan. Cognitive assessments and updates toconcomitant medications and medical history will be collected at each follow-up visit. Subjectsin the Exploratory phase will also have follow-up 18F-AV-1451 scans and MRI, including bothvolumetric and standard clinical sequences. A sub-set of subjects in the Exploratory phase mayhave the option to have an additional resting state functional (rsf)MRI sequence scan in additionto the volumetric and standard clinical sequences at both the screening MRI and follow-upMRIs. Subjects or their designated decision maker will be contacted by phone at 5 and 14months following the initial 18F-AV-1451 scan to collect updated concomitant medications andmedical history.LY3191748Page 4 of 53
Protocol 18F-AV-1451-A05ConfidentialSponsor:Name of Compound:Active Ingredient(s):Avid ssessments and Endpoints:Each group will have a screening visit(s), a florbetapir F 18 PET imaging visit, a 18F-AV-1451PET imaging visit, and follow-up phone calls after each imaging visit.Florbetapir F 18 PET Imaging Session:For the florbetapir F 18 PET imaging session, subjects will receive a single IV bolus injectiontarget dose of 370 MBq (10 mCi) of florbetapir F 18. At 50 minutes following injection, acontinuous 10-minute brain scan (2 acquisitions of 5 minute duration) will begin.18F-AV-1451 PET Imaging Session:For the 18F-AV-1451 PET imaging session, subjects will receive a single IV bolus injectiontarget dose of 370 MBq (10 mCi) of 18F-AV-1451 At approximately 80 minutes post dose,scanning will begin. Four 5-minute acquisitions will be taken.For both imaging sessions adverse events will be monitored continuously during the imagingsession. Subjects who experience any adverse event during an imaging session will not bedischarged until the event has resolved or stabilized.A follow-up phone call to the subject, or designated decision maker, will be conducted within 2or 3 business days of the imaging day, but not before 48 hours post-injection, to confirm subjectwell-being and to collect information about any new adverse events. If both of these days arenot business days, the follow-up phone call can occur the following business day.In the Exploratory longitudinal component, subjects who are 50 years of age will have twolongitudinal follow-up visits with 18F-AV-1451 PET imaging, MRI, cognitive assessments andupdated medical history and concomitant medications. In the Confirmatory Cohort, longitudinalfollow-up visits will consist of cognitive assessments and updated medical history andconcomitant medications. No PET imaging or MRI is planned at the follow-up visits in theConfirmatory Cohort. Additional assessments that will be performed at each visit are detailed inSection 7.1.LY3191748Page 5 of 53
Protocol 18F-AV-1451-A05ConfidentialStatistical Methods:In the exploratory study phase, descriptive statistics will be applied to describe the 18F-AV-1451SUVR distribution across age groups among cognitive healthy subjects. ANOVA analysis willbe applied to detect the difference between clinical diagnosis groups. Analyses will beconducted to assess the relationship among 18F-AV-1451 uptake, cognitive functionmeasurements, and other collected biomarkers. Longitudinal data from the exploratory studyphase will be assessed periodically to determine the relationships between various 18F-AV-1451imaging parameters (e.g., composite and regional SUVr, voxel based statistics and visualinterpretation) and the change from baseline in the various cognitive and functional assessments.These data will be used to generate hypotheses regarding the relationship between 18F-AV-1451PET tau imaging and cognitive/functional change that will be formally incorporated into ananalysis plan and tested in the confirmatory phase of the study.LY3191748Page 6 of 53
Protocol 18F-AV-1451-A05ConfidentialTABLE OF CONTENTS1.INTRODUCTION . 122.TRIAL OBJECTIVES . 142.1.Exploratory Phase, Cross-sectional objectives: . 152.2.Exploratory Phase, Longitudinal objectives: . 152.3.Confirmatory Phase, Longitudinal objectives: . 153.SPONSOR, INVESTIGATOR(S) AND OTHER PARTICIPANTS 164.TEST DRUG AND CONTROL AGENTS . 164.1.Descriptive Name:4.2.Descriptive Name: Florbetapir F 18 . 164.3.Radioactive Labeling . 174.4.Decay Characteristics . 174.5.Formulation and Dose Florbetapir F 18 Injection . 174.6.Formulation and Dose 18F-AV-1451 Injection . 184.7.Packaging Florbetapir F 18 Injection . 184.8.Packaging 18F-AV-1451 Injection . 184.9.Storage and Handling Florbetapir F 18 Injection . 184.10.Storage and Handling 18F-AV-1451 Injection . 185.INVESTIGATIONAL PLAN . 195.1.Overall Design and Plan of Trial . 195.2.Planned Dosage and Duration of Treatment . 205.2.1.Dosage and Administration . 205.2.2.Rationale for Dosages . 215.3.Selection of Subjects. 215.3.1.Inclusion Criteria . 215.3.2.Exclusion Criteria . 235.4.Prior and Concomitant Therapy. 245.5.Removal of Subjects from Trial . 245.6.Premature Termination of Trial/Closure of Center . 246.WARNINGS/PRECAUTIONS . 257.PROCEDURES AND METHODS . 257.1.Assessment Periods . 2518F AV-1451 . 16LY3191748Page 7 of 53
Protocol 18F-AV-1451-A05Confidential7.1.1.Screening and Baseline Visit: . 257.1.2.Optional Cerebrospinal fluid (CSF) collection by Lumbar Puncture(LP) (Aβ, p-tau, t-tau); Exploratory Phase only . 267.1.3.Initial PET Imaging Visits: . 277.1.4.First and Second Longitudinal Follow-up Visits . 287.1.5.Longitudinal Follow-Up Phone Calls . 307.2.Observations and Measurements . 307.3.Protocol for Image Collection . 367.4.Good Clinical Practice and Monitoring . 367.5.Informed Consent and Subject Information . 367.6.Documentation . 377.7.Adverse Events (AE) . 377.7.1.Adverse Event Monitoring . 387.7.2.Adverse Event Definitions . 387.7.3.Adverse Event Documentation . 407.7.4.Reporting of Serious Adverse Events . 408.STATISTICAL ANALYSIS . 408.1.General Statistical Considerations . 408.1.1.Sample Size Estimation . 418.1.1.1.Exploratory Phase . 418.1.1.2.Confirmatory Phase . 418.1.2.Exploratory Phase, Cross-sectional Component. 428.1.2.1.Primary Objective Analysis . 428.1.2.2.Secondary Objective Analysis . 428.1.2.3.Exploratory Objective Analyses . 428.1.3.Exploratory Phase, Longitudinal Component. 428.1.3.1.Primary Objective Analysis . 428.1.3.2.Exploratory objective analyses . 438.1.4.Confirmatory Phase . 438.2.Safety Analysis . 438.3.189.USE OF DATA AND PUBLICATION . 4410.INVESTIGATOR’S REGULATORY OBLIGATIONS . 45F-AV-1451 Image Analysis . 44LY3191748Page 8 of 53
Protocol 18F-AV-1451-A05Confidential10.1.Institutional Review Board (IRB) . 4510.2.Informed Consent . 4510.3.Protocol Adherence . 4510.4.Documents Necessary for Initiation of the Trial . 4610.5.Investigational Product Control . 4610.6.Data Collection . 4610.7.Adverse Events . 4710.8.Records Retention . 4711.APPENDICES . 4811.1.References. 4811.2.Trial Flow Chart . 50LY3191748Page 9 of 53
Protocol 18F-AV-1451-A05ConfidentialABBREVIATIONS AND DEFINITIONSAβBeta amyloidADAlzheimer’s diseaseADAS-CogAlzheimer’s Disease Assessment Scale- Cognitive SubscaleAdverse Event(AE)Any untoward medical occurrence in a subject or clinical investigationsubject administered a pharmaceutical product and that does notnecessarily have a causal relationship with this treatment.AuditA systematic and independent examination of the trial-related activitiesand documents to determine whether the evaluated trial-related activitieswere conducted, and the data were recorded, analyzed, and accuratelyreported according to the protocol, applicable standard operatingprocedures (SOPs), good clinical practice (GCP), and the applicableregulatory requirement(s).CHOChinese Hamster OvaryCase Report Form(CRF) andelectronic CaseReport Form(eCRF)A printed or electronic form for recording study participants’ data duringa clinical study, as required by the protocol.CNSCentral Nervous SystemCROContract Research Organization: A person or organization (commercial,academic, or other) contracted by the sponsor to perform one or more ofthe sponsor’s trial-related duties and functions.CTComputed TomographyDSSTDigit Symbol Substitution TestEfficacyEfficacy is the ability of a treatment to achieve a beneficial intendedresult.FDAUS Food and Drug AdministrationFDG18F - FluorodeoxyglucoseLY3191748Page 10 of 53
Protocol 18F-AV-1451-A05ConfidentialGCPGood Clinical PracticeICHInternational Conference on eview Board/IndependentEthics CommitteeA board or committee (institutional, regional, or national) composed ofmedical and nonmedical members whose responsibility is to verify thatthe safety, welfare and human rights of the subjects participating in aclinical study are protected.InvestigatorA person responsible for the conduct of the clinical trial at a trial site. If atrial is conducted by a team of individuals at a trial site, the investigator isthe responsible leader of the team and may be called the principalinvestigator.IVIntravenousKdDissociation ConstantMAOMonoamine OxidaseMBqMegabecquerelmCiMillicurieMCIMild Cognitive ImpairmentMHDMaximum Human DoseMRIMagnetic Resonance ImagingNOAELNo Observable Adverse Effect LevelNOELNo Observable Effect LevelPETPositron Emission TomographySUVRStandard Uptake Value RatioLY3191748Page 11 of 53
Protocol 18F-AV-1451-A051.ConfidentialINTRODUCTIONMolecular imaging biomarkers have the potential to aid in the diagnosis of patients withcognitive impairment who are being evaluated for Alzheimer’s disease (AD) (Dubois,2010; McKhann, 2011). Positron emission tomography (PET) ligands such as florbetapirF 18 (Wong, 2010) may provide a minimally invasive estimate of cortical beta amyloid(Aβ) neuritic plaque deposition, a hallmark pathology, and a required element for theevaluation of AD neuropathologic diagnosis (Hyman 2012). Multiple studies comparingamyloid PET scans to histopathologic assessment of amyloid burden, in subjects forwhom biopsy samples were available or who came to autopsy after receiving a PETamyloid scan, support the relationship between PET amyloid imaging results and corticalneuritic plaque density (Clark 2011, 2012; Leinonen, 2008; Sojkova, 2011; Kantarci,2011; Burack, 2010). The largest of these studies (Clark 2012) demonstrated a highsensitivity and specificity for florbetapir PET to discriminate subjects with subsequentautopsy findings of no or sparse neuritic plaques (amyloid negative) from those withmoderate to frequent plaques (amyloid positive).The ability to image brain amyloid with compounds such as florbetapir is an importantadvance for diagnosis of neurological disease. An amyloid negative florbetapir PET scanindicates the absence of a hallmark pathology and is inconsistent with a diagnosis of AD.However, because amyloid is believed to accumulate very early in the disease process(Jack et al., 2010) and may be present in other diseases or in clinically normal elderlysubjects (Sperling et al. 2011; Price and Morris, 1999), the density or distribution ofamyloid in subjects with a positive scan is not associated with Alzheimer’s diseaseseverity, has not been established to predict rate of future deterioration and has not beenestablished as a tool to predict or monitor response to therapy.In contrast to Aβ neuritic plaques, the density and distribution of phosphorylated tau,aggregated in neurofibrillary tangles, increases with AD-related cognitive impairmentand correlates with neurodegeneration (Dickson et al., 1997; Duyckaerts et a., 1987).Thus, a PET imaging agent that binds to phosphorylated tau has potential application as abiomarker for disease severity/neurodegeneration and may be useful both for selectingpatients for therapy and for monitoring disease progression in therapeutic trials.18F-AV-1451 (originally named [F-18]T807 by Siemens Molecular Imaging BiomarkerResearch group) has been developed as a positron emitting radiopharmaceutical for invivo imaging of tau protein aggregates (Xia et al., 2013). Autoradiography results usingtissue sections from human brains showed a strong signal in the grey matter of corticalslices from tau positive brains but weak or no binding in tau negative, Aβ positive, or tauand A negative tissue. Scatchard analysis based on this heterogeneous autoradiographyassay yielded an estimated Kd of 15nM. A saturation binding experiment using purifiedPaired Helical Fragment Tau isolated brains of AD patients yielded a Kd value of 0.7 nM.AV-1451 was assessed in competitive binding assays against a panel of 72 of the mostcommon central nervous system (CNS) targets and no clinically relevant inhibition wasseen. AV-1451 was positive in the in vitro hERG assay; however, in vivo cardiovascularsafety pharmacology assessments in dogs showed no evidence of QT prolongation atdoses up to 50x the intended maximum human dose (MHD). Nonetheless, untilLY3191748Page 12 of 53
Protocol 18F-AV-1451-A05Confidentialsufficient human cardiovascular safety data are available, initial clinical studies willexclude subjects with a history of risk factors for Torsades de Pointes and subjects takingdrugs known to prolong the QT interval.In vivo safety pharmacology studies were also conducted in rats to determine potentialeffects on the CNS and respiratory systems. In these studies no clinically relevant effectswere reported at doses exceeding 100x the intended MHD. Additionally, non-radioactiveAV-1451 has been tested in single and repeat-dose toxicology studies in rat and dog. Ineach of these studies the no observable adverse effect levels (NOAELs) were the highestdoses tested (150x MHD for single, 50x MHD for repeat).Potential genotoxicity of non-radioactive AV-1451 was tested in both in vitro and in vivoassays. In the in vitro assays, AV-1451 tested positive for potential genotoxicity.However, in the in vivo rat micronucleus assay at doses up to 750x MHD (scaledallometrically), AV-1451 showed no evidence of genotoxicity. The different results in thein vitro genotoxicity assays and the in vivo micronucleus study are likely related todifferences in the exposure conditions encountered by the target cells in the different testsystems. In vivo, AV-1451 is cleared rapidly; however, the in vitro experiments employstatic, prolonged exposure of cells to high concentrations of the test article. While the invitro data show the potential for genotoxicity, the in vivo data provide assurance thatgenotoxicity is unlikely to occur at clinically-relevant doses for human diagnostic studies.18F-AV-1451 has been evaluated in two human studies under the exploratory IND(Chien, et. al). Adverse events reported have been mild and transient; none have beenconsidered related to 18F-AV-1451 administration. Preliminary evaluation of the PETimages suggest that 18F-AV-1451 is eliminated from normal brain yielding only a diffusepattern of background activity (Figure 1), whereas a regionally-specific gray matterdistribution is observed in subjects with high probability AD (Figure 2).LY3191748Page 13 of 53
Protocol 18F-AV-1451-A05Figure 1:Figure 2:Confidentialcontrol subject (MMSE 29)AD subject (MMSE 18)Human dosimetry has been obtained in nine subjects. Generally, the radiotracerdistribution was consistent among the subjects and showed rapid hepatobiliary clearance.There were three organs that received estimated doses higher than 0.05 mSv/MBq. Theorgan that received the largest estimated dose was the upper large intestinal wall(0.0962 0. 0134 mSv/MBq), followed by the small intestine and the liver. TheEffective Dose was 0.0241 0.0016 mSv/MBq. This results in an estimated EffectiveDose of 8.92 mSv for an anticipated 370 MBq (10 mCi) injection and is comparable tothe effective dose of approved 18F-labeled compounds such as fluorodeoxyglucose (FDG)and florbetapir F 18 injection.The overarching goal of this protocol is to further investigate the spectrum of PETimaging results with 18F -AV-1451 in patients with cognitive decline and healthycontrols. To accomplish this goal, the protocol will investigate 18F-AV-1451 results inyounger and older controls and patients with cognitive complaints ranging from mildcognitive impairment (MCI) to mild and moderate Alzheimer’s disease (AD).Additionally, this protocol will investigate correlations between 18F-AV-1451 PETimaging and other biomarkers associated with AD and will test the relationship between18F-AV-1451 PET imaging and cognitive decline over the 18 month study period.2.TRIAL OBJECTIVESThis study will be conducted in two phases, an exploratory phase and aconfirmatory/validation phase, which will have separate subjects and analyses. The firstphase of this study will be comprised of a cross-sectional component and a longitudinalcomponent. The second (confirmatory/validation) phase will focus on the relationship ofbaseline PET tau images to change in longitudinal clinical measure.LY3191748Page 14 of 53
Protocol 18F-AV-1451-A052.1.ConfidentialExploratory Phase, Cross-sectional objectives:The primary objective of the cross-sectional component is: To compare 18F-AV-1451 imaging results in subjects with AD to subjectswith MCI and cognitively healthy older individualsThe secondary objective of the cross-sectional component is: To establish a database of cognitively healthy individuals to show thespectrum of 18F-AV-1451 imaging results in cognitively healthy individualsacross a range of age strataExploratory objectives of the cross-sectional component are: To determine whether greater degrees of cognitive impairment correlate withhigher 18F-AV-1451 uptake in subjects with an amyloid positive status To explore whether tests of specific cognitive domains correlate with regional18F-AV-1451 uptake To explore the relationships between 18F-AV-1451 uptake and biomarkers ofneurodegeneration and neurological disease (CSF markers including tau,phospho-tau and beta-amyloid (Aβ), genetic markers, PET amyloid imaging,and brain atrophy assessed by volumetric MRI) To expand the 18F-AV-1451 safety database2.2.Exploratory Phase, Longitudinal objectives:The primary objective of the first phase of the longitudinal component is: To assess the rate of change of tau deposition as measured by 18F-AV-1451uptake over time.The exploratory objectives of the first phase of the longitudinal component are:2.3. To explore associations between changes in 18F-AV-1451 uptake in the brainand clinical and functional measures, as well as, biomarkers ofneurodegeneration and neurological disease (CSF markers including tau,phospho-tau and beta-amyloid (Aβ), genetic markers, PET amyloid imaging,and brain atrophy assessed by volumetric MRI) To expand the 18F-AV-1451 safety databaseConfirmatory Phase, Longitudinal objectives:The second phase of the study is designed to provide independent validation of therelationships observed in the exploratory analyses of the first phase. In particular, thegoal of the second phase is to confirm the relationship between 18F-AV-1451 uptake inthe brain as measured by PET and the subsequent rate of cognitive
18F-AV-1451 ([F-18]T807) Sponsor: Avid Radiopha'tmaceuticals, Inc. Philadelphia, Pennsylvania USA Approvals/Signatures and Date: CONFIDENTIAL This material is the property of Avid Radiopharmaceuticals, Inc. (Avid). The information is confidential and is to be used only in connection with matters authorized by Avid and no part of it
18F-AV-1451-A05 SAP Exploratory v1.0 An Open Label, Multicenter Study, Evaluating the Safety and Imaging Characteristics of 18F- . Approval date: 27 Nov 2017. Avid Radiopharmaceuticals Protocol 18F-AV1451-A05 Statistical Analysis Plan Final Version 1.0 Chiltern International Inc. 1 of 48
[Study A05]) Assess intra-reader reliability for scans read twice by each reader. Statistical Analysis Plan for 18F-AV-1451-FR01 8 4. STUDY DESIGN All training and reads will be conducted by an imaging contract research organization (CRO)as described in the imaging review charter (IRC). Five readers will be trained in-person on the flortaucipir F 18PET scan read methodology using the .
Commissioner for Trademarks . United States Patent and Trademark Office . P.O. Box 1451. Alexandria, VA 22313-1451 . Ms. Amy Cotton . Acting Deputy Commissioner for Trademark Examination Policy . United States Patent and Trademark Office . P.O. Box 1451. Alexandria, VA 22313-1451 . Re: Comments Regarding Implementation of the Trademark .
the positron emission tomography tracer 18F-florbetapir. Positron emission tomography agents have shown great promise in mapping fibrillar amyloid deposition in the brain. 18F-florbetapir [(E)-4-(2-(6-(2-(2-(2-18F-fluoroethoxy) e] is a novel imaging agent that binds with high affinity (Kd
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Transducer Interface for Sensors and Actuators - Mixed-Mode Communication Protocols and Transducer Electronic Data Sheet (TEDS) Formats, until final publication, planned for the second half of 2004. IEEE 1451.4- In General . IEEE 1451.4 defines a physical connection (Mixed-Mode Interface, or MMI) that is
In Tables 18F-1 through 18F-11, information and control needs for each operation instruction or action are presented in fourteen (14) columns of information. . 1.97 INSTRUMENT . Manual starting and resetting of safety systems.
American Math Competition 8 Practice Test 8 89 American Mathematics Competitions Practice 8 AMC 8 (American Mathematics Contest 8) INSTRUCTIONS 1. DO NOT OPEN THIS BOOKLET UNTIL YOUR PROCTOR TELLS YOU. 2. This is a twenty-five question multiple choice test. Each question is followed by
