ࡱ> =;67>` 2bjbj 8G*8 8 8 8 8 8 8 B t lll8lnlhRo {"||||~ $vh8 ||8 8 ||8 |8 |9D8 8 |Fo йl}P0` ``8 :"=%b :=bL ^> 8 8 8 8 8 8   Table of Contents  TOC \o "1-4" \h \z \u  HYPERLINK \l "_Toc146006015" A Introduction  PAGEREF _Toc146006015 \h 3  HYPERLINK \l "_Toc146006016" A1 Study Abstract  PAGEREF _Toc146006016 \h 3  HYPERLINK \l "_Toc146006017" A2 Primary Hypothesis  PAGEREF _Toc146006017 \h 3  HYPERLINK \l "_Toc146006018" A3 Purpose of the Study Protocol  PAGEREF _Toc146006018 \h 3  HYPERLINK \l "_Toc146006019" B Background  PAGEREF _Toc146006019 \h 3  HYPERLINK \l "_Toc146006020" B1 Prior Literature and Studies  PAGEREF _Toc146006020 \h 3  HYPERLINK \l "_Toc146006021" B2 Rationale for this Study  PAGEREF _Toc146006021 \h 3  HYPERLINK \l "_Toc146006022" C Study Objectives  PAGEREF _Toc146006022 \h 3  HYPERLINK \l "_Toc146006023" C1 Primary Aim  PAGEREF _Toc146006023 \h 3  HYPERLINK \l "_Toc146006024" C2 Secondary Aim  PAGEREF _Toc146006024 \h 3  HYPERLINK \l "_Toc146006025" C3 Rationale for the Selection of Outcome Measures  PAGEREF _Toc146006025 \h 3  HYPERLINK \l "_Toc146006026" D Investigational Agent  PAGEREF _Toc146006026 \h 3  HYPERLINK \l "_Toc146006027" D1 Preclinical Data  PAGEREF _Toc146006027 \h 3  HYPERLINK \l "_Toc146006028" D2 Clinical Data to Date  PAGEREF _Toc146006028 \h 4  HYPERLINK \l "_Toc146006029" D3 Dose Rationale and Risk/Benefits  PAGEREF _Toc146006029 \h 4  HYPERLINK \l "_Toc146006030" E Study Design  PAGEREF _Toc146006030 \h 4  HYPERLINK \l "_Toc146006031" E1 Overview or Design Summary  PAGEREF _Toc146006031 \h 4  HYPERLINK \l "_Toc146006032" E2 Subject Selection and Withdrawal  PAGEREF _Toc146006032 \h 4  HYPERLINK \l "_Toc146006033" 2.a Inclusion Criteria  PAGEREF _Toc146006033 \h 4  HYPERLINK \l "_Toc146006034" 2.a Exclusion Criteria  PAGEREF _Toc146006034 \h 4  HYPERLINK \l "_Toc146006035" 2.b Ethical Considerations  PAGEREF _Toc146006035 \h 4  HYPERLINK \l "_Toc146006036" 2.c Subject Recruitment Plans and Consent Process  PAGEREF _Toc146006036 \h 4  HYPERLINK \l "_Toc146006037" 2.d Randomization Method and Blinding  PAGEREF _Toc146006037 \h 4  HYPERLINK \l "_Toc146006038" 2.e Risks and Benefits  PAGEREF _Toc146006038 \h 4  HYPERLINK \l "_Toc146006039" 2.f Early Withdrawal of Subjects  PAGEREF _Toc146006039 \h 4  HYPERLINK \l "_Toc146006040" 2.g When and How to Withdraw Subjects  PAGEREF _Toc146006040 \h 4  HYPERLINK \l "_Toc146006041" 2.h Data Collection and Follow-up for Withdrawn Subjects  PAGEREF _Toc146006041 \h 4  HYPERLINK \l "_Toc146006042" E3 Study Drug  PAGEREF _Toc146006042 \h 5  HYPERLINK \l "_Toc146006043" 3.a Description  PAGEREF _Toc146006043 \h 5  HYPERLINK \l "_Toc146006044" 3.b Treatment Regimen  PAGEREF _Toc146006044 \h 5  HYPERLINK \l "_Toc146006045" 3.c Method for Assigning Subjects to Treatment Groups  PAGEREF _Toc146006045 \h 5  HYPERLINK \l "_Toc146006046" 3.d Preparation and Administration of Study Drug  PAGEREF _Toc146006046 \h 5  HYPERLINK \l "_Toc146006047" 3.e Subject Compliance Monitoring  PAGEREF _Toc146006047 \h 5  HYPERLINK \l "_Toc146006048" 3.f Prior and Concomitant Therapy  PAGEREF _Toc146006048 \h 5  HYPERLINK \l "_Toc146006049" 3.g Packaging  PAGEREF _Toc146006049 \h 5  HYPERLINK \l "_Toc146006050" 3.h Blinding of Study Drug  PAGEREF _Toc146006050 \h 5  HYPERLINK \l "_Toc146006051" 3.i Receiving, Storage, Dispensing and Return  PAGEREF _Toc146006051 \h 5  HYPERLINK \l "_Toc146006052" F Study Procedures  PAGEREF _Toc146006052 \h 5  HYPERLINK \l "_Toc146006053" F1 Screening for Eligibility  PAGEREF _Toc146006053 \h 5  HYPERLINK \l "_Toc146006054" F2 Schedule of Measurements  PAGEREF _Toc146006054 \h 5  HYPERLINK \l "_Toc146006055" F3 Visit 1  PAGEREF _Toc146006055 \h 5  HYPERLINK \l "_Toc146006056" F4 Visit 2 etc.  PAGEREF _Toc146006056 \h 6  HYPERLINK \l "_Toc146006057" F5 Safety and Adverse Events  PAGEREF _Toc146006057 \h 6  HYPERLINK \l "_Toc146006058" 5.a Safety and Compliance Monitoring  PAGEREF _Toc146006058 \h 6  HYPERLINK \l "_Toc146006059" 5.b Medical Monitoring  PAGEREF _Toc146006059 \h 6  HYPERLINK \l "_Toc146006060" i Investigator only  PAGEREF _Toc146006060 \h 6  HYPERLINK \l "_Toc146006061" ii Independent expert to monitor  PAGEREF _Toc146006061 \h 6  HYPERLINK \l "_Toc146006062" iii Institutional Data and Safety Monitoring Board  PAGEREF _Toc146006062 \h 6  HYPERLINK \l "_Toc146006063" iv Independent Data and Safety Monitoring Board  PAGEREF _Toc146006063 \h 6  HYPERLINK \l "_Toc146006064" 5.c Definitions of Adverse Events  PAGEREF _Toc146006064 \h 6  HYPERLINK \l "_Toc146006065" 5.d Classification of Events  PAGEREF _Toc146006065 \h 6  HYPERLINK \l "_Toc146006066" i Relationship  PAGEREF _Toc146006066 \h 6  HYPERLINK \l "_Toc146006067" ii Severity  PAGEREF _Toc146006067 \h 6  HYPERLINK \l "_Toc146006068" iii Expectedness  PAGEREF _Toc146006068 \h 6  HYPERLINK \l "_Toc146006069" 5.e Data Collection Procedures for Adverse Events  PAGEREF _Toc146006069 \h 6  HYPERLINK \l "_Toc146006070" 5.f Reporting Procedures  PAGEREF _Toc146006070 \h 6  HYPERLINK \l "_Toc146006071" 5.g Adverse Event Reporting Period  PAGEREF _Toc146006071 \h 7  HYPERLINK \l "_Toc146006072" 5.h Post-study Adverse Event  PAGEREF _Toc146006072 \h 7  HYPERLINK \l "_Toc146006073" F6 Study Outcome Measurements and Ascertainment  PAGEREF _Toc146006073 \h 7  HYPERLINK \l "_Toc146006074" G Statistical Plan  PAGEREF _Toc146006074 \h 7  HYPERLINK \l "_Toc146006075" G1 Sample Size Determination and Power  PAGEREF _Toc146006075 \h 7  HYPERLINK \l "_Toc146006076" G2 Interim Monitoring and Early Stopping  PAGEREF _Toc146006076 \h 7  HYPERLINK \l "_Toc146006077" G3 Analysis Plan  PAGEREF _Toc146006077 \h 7  HYPERLINK \l "_Toc146006078" G4 Statistical Methods  PAGEREF _Toc146006078 \h 7  HYPERLINK \l "_Toc146006079" G5 Missing Outcome Data  PAGEREF _Toc146006079 \h 7  HYPERLINK \l "_Toc146006080" G6 Unblinding Procedures  PAGEREF _Toc146006080 \h 7  HYPERLINK \l "_Toc146006081" H Data Handling and Record Keeping  PAGEREF _Toc146006081 \h 7  HYPERLINK \l "_Toc146006082" H1 Confidentiality and Security  PAGEREF _Toc146006082 \h 7  HYPERLINK \l "_Toc146006083" H2 Training  PAGEREF _Toc146006083 \h 7  HYPERLINK \l "_Toc146006084" H3 Case Report Forms and Source Documents  PAGEREF _Toc146006084 \h 7  HYPERLINK \l "_Toc146006085" H4 Records Retention  PAGEREF _Toc146006085 \h 8  HYPERLINK \l "_Toc146006086" H5 Performance Monitoring  PAGEREF _Toc146006086 \h 8  HYPERLINK \l "_Toc146006087" I Study Monitoring, Auditing, and Inspecting  PAGEREF _Toc146006087 \h 8  HYPERLINK \l "_Toc146006088" I1 Study Monitoring Plan  PAGEREF _Toc146006088 \h 8  HYPERLINK \l "_Toc146006089" I2 Auditing and Inspecting  PAGEREF _Toc146006089 \h 8  HYPERLINK \l "_Toc146006090" J Study Administration  PAGEREF _Toc146006090 \h 8  HYPERLINK \l "_Toc146006091" J1 Organization and Participating Centers  PAGEREF _Toc146006091 \h 8  HYPERLINK \l "_Toc146006092" J2 Funding Source and Conflicts of Interest  PAGEREF _Toc146006092 \h 8  HYPERLINK \l "_Toc146006093" J3 Committees  PAGEREF _Toc146006093 \h 8  HYPERLINK \l "_Toc146006094" J4 Subject Stipends or Payments  PAGEREF _Toc146006094 \h 8  HYPERLINK \l "_Toc146006095" J5 Study Timetable  PAGEREF _Toc146006095 \h 8  HYPERLINK \l "_Toc146006096" K Publication Plan  PAGEREF _Toc146006096 \h 8  HYPERLINK \l "_Toc146006097" L Attachments  PAGEREF _Toc146006097 \h 9  HYPERLINK \l "_Toc146006098" L1 Tables  PAGEREF _Toc146006098 \h 9  HYPERLINK \l "_Toc146006099" L2 Informed consent documents  PAGEREF _Toc146006099 \h 9  HYPERLINK \l "_Toc146006100" L3 Patient education brochures  PAGEREF _Toc146006100 \h 9  HYPERLINK \l "_Toc146006101" L4 Special procedures protocols  PAGEREF _Toc146006101 \h 9  HYPERLINK \l "_Toc146006102" L5 Questionnaires or surveys  PAGEREF _Toc146006102 \h 9  HYPERLINK \l "_Toc146006103" M References  PAGEREF _Toc146006103 \h 9  Introduction Study Abstract Primary Hypothesis Purpose of the Study Protocol Background Prior Literature and Studies Rationale for this Study Study Objectives Primary Aim Secondary Aim Rationale for the Selection of Outcome Measures Investigational Agent Preclinical Data Clinical Data to Date Dose Rationale and Risk/Benefits Study Design Overview or Design Summary Subject Selection and Withdrawal Inclusion Criteria Exclusion Criteria Ethical Considerations Subject Recruitment Plans and Consent Process Randomization Method and Blinding Risks and Benefits Early Withdrawal of Subjects When and How to Withdraw Subjects Data Collection and Follow-up for Withdrawn Subjects Study Drug Description Treatment Regimen Method for Assigning Subjects to Treatment Groups Preparation and Administration of Study Drug Subject Compliance Monitoring Prior and Concomitant Therapy Packaging Blinding of Study Drug Receiving, Storage, Dispensing and Return Study Procedures Screening for Eligibility Schedule of Measurements Visit 1 Visit 2 etc. Safety and Adverse Events Safety and Compliance Monitoring Medical Monitoring Investigator only Independent expert to monitor Institutional Data and Safety Monitoring Board Independent Data and Safety Monitoring Board Definitions of Adverse Events Classification of Events Relationship Severity Expectedness Data Collection Procedures for Adverse Events Reporting Procedures Adverse Event Reporting Period Post-study Adverse Event Study Outcome Measurements and Ascertainment Statistical Plan Sample Size Determination and Power Interim Monitoring and Early Stopping Analysis Plan Statistical Methods Missing Outcome Data Unblinding Procedures Data Handling and Record Keeping Confidentiality and Security Training Case Report Forms and Source Documents Records Retention Performance Monitoring Study Monitoring, Auditing, and Inspecting Study Monitoring Plan Auditing and Inspecting Study Administration Organization and Participating Centers Funding Source and Conflicts of Interest Committees Subject Stipends or Payments Study Timetable Publication Plan Attachments Tables Informed consent 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PLP^P`LhH.&aES&`clVD M< Vd ~02h#qP#As Q9RkBF<(6 Wi1fOP}S,\2:i'+" U+AHQF=u4[:C!g}N#x lj2$2;v.@z)S,a !JlReSnV&aJ %%                          aT                                   ^IY                                                                                 Z 8$/eR7uE]qDrn4, }!g*ym:_#=]B=I(K|EMegUeV KZB``+c0xel}qw_Toc14600602578_Toc14600602472_Toc1460060237,_Toc1460060227&_Toc1460060217 _Toc1460060207_Toc1460060197_Toc1460060187_Toc1460060177_Toc1460060167_Toc146006015 templateskangc2@nhlbi.nih.gov Kang, Christine (NIH/NHLBI) [C]$  !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcefghijklmnopqrstuvwxyz{|}~      !"#$%'()*+,-./012345:Root Entry F=&<Data dV1TableWordDocument8SummaryInformation(DocumentSummaryInformation8&CompObjq  FMicrosoft Office Word Document MSWordDocWord.Document.89qRoot Entry F0!<Data dV1TableWordDocument8      !"#$%?ABCDEFGHIJKLMNOSummaryInformation(DocumentSummaryInformation8@CompObjq՜.+,D՜.+,H hp  NHLBIL2*d Sample Protocol Template TitleH  \ _PID_HLINKS_NewReviewCycle_EmailSubject _AuthorEmail_AuthorEmailDisplayName_PreviousAdHocReviewCycleID_AdHocReviewCycleIDA6_Toc1460061036 _Toc1460061026_Toc1460061016_Toc1460061007_Toc1460060997_Toc1460060987_Toc1460060977_Toc1460060967_Toc1460060957_Toc1460060947_Toc1460060937_Toc1460060927_Toc1460060917_Toc1460060907_Toc1460060897_Toc1460060887_Toc1460060877_Toc1460060867_Toc1460060857_Toc1460060847_Toc1460060837_Toc1460060827_Toc1460060817_Toc1460060807_Toc1460060797|_Toc1460060787v_Toc1460060777p_Toc1460060767j_Toc1460060757d_Toc1460060747^_Toc1460060737X_Toc1460060727R_Toc1460060717L_Toc1460060707F_Toc1460060697@_Toc1460060687:_Toc14600606774_Toc1460060667._Toc1460060657(_Toc1460060647"_Toc1460060637_Toc1460060627_Toc1460060617_Toc1460060607 _Toc1460060597_Toc1460060587_Toc1460060577_Toc1460060567_Toc1460060557_Toc1460060547_Toc1460060537_Toc1460060527_Toc1460060517_Toc1460060507_Toc1460060497_Toc1460060487_Toc1460060477_Toc1460060467_Toc1460060457_Toc1460060447_Toc1460060437_Toc1460060427_Toc1460060417_Toc1460060407_Toc1460060397_Toc1460060387_Toc1460060377_Toc1460060367z_Toc1460060357t_Toc1460060347n_Toc1460060337h_Toc1460060327b_Toc1460060317\_Toc1460060307V_Toc1460060297P_Toc1460060287J_Toc1460060277D_Toc1460060267>_Toc14600602578_Toc14600602472_Toc1460060237,_Toc1460060227&_Toc1460060217 _Toc1460060207_Toc1460060197_Toc1460060187_Toc1460060177_Toc1460060167_Toc146006015$ New Documentpembertonv@nhlbi.nih.gov$Pemberton, Victoria (NIH/NHLBI) [E]c@o