(r) GILEAU
STATISTICAL ANALYSIS PLAN
Study Title: A Phase 2, Open-label Study to Evaluate the Efficacy and Safety of Switching to Tenofovir Alafenamide (TAF) from Tenofovir Disoproxil Fumarate (TDF) and/or Other Oral Antiviral Treatment (OAV) in Virologically Suppressed Chronic Hepatitis B Subjects with Renal and/or Hepatic Impairment
Name of Test Drug: Tenofovir Alafenamide (TAF)
Study Number: GS-US-320-4035
Protocol Version (Date): Amendment 1 (23 May 2017)
Analysis Type: Week 24 Analysis
Analysis Plan Version: 1.0
Analysis Plan Date: 09 May 2019
Analysis Plan Author(s): PPD
CONFIDENTIAL AND PROPRIETARY INFORMATION Tenofovir Alafenamide GS-US-320-4035 Statistical Analysis Plan – Week 24 Analysis Final
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN...... 1 TABLE OF CONTENTS ...... 2 LIST OF TABLES...... 4 LIST OF ABBREVIATIONS...... 5 1. INTRODUCTION ...... 8 1.1. Study Objectives ...... 8 1.2. Study Design ...... 9 1.2.1. Design Configuration and Subject Population ...... 9 1.2.2. Treatment Groups and Randomization...... 9 1.2.3. Key Eligibility Criteria...... 10 1.2.4. Study Periods and Phases...... 10 1.2.5. Schedule of Assessments...... 11 1.3. Sample Size and Power...... 11 2. TYPE OF PLANNED ANALYSIS ...... 12 2.1. Data Monitoring Committee Analysis ...... 12 2.2. Week 24 Analysis (Primary Analysis) ...... 12 2.3. Week 48 Analysis ...... 12 2.4. Final Analysis ...... 12 3. GENERAL CONSIDERATIONS FOR DATA ANALYSES ...... 13 3.1. Analysis Sets ...... 13 3.1.1. All Enrolled Analysis Set ...... 13 3.1.2. Full Analysis Set ...... 13 3.1.3. Safety Analysis Set...... 13 3.1.4. Per Protocol Analysis Set ...... 14 3.1.5. Pharmacokinetic Analysis Set ...... 14 3.1.6. Serologically Evaluable Full Analysis Set ...... 15 3.1.7. DXA Analysis Set ...... 15 3.2. Subject Grouping ...... 15 3.3. Strata and Covariates...... 16 3.4. Examination of Subject Subgroups ...... 16 3.5. Multiple Comparisons...... 16 3.6. Missing Data and Outliers...... 17 3.6.1. Missing Data ...... 17 3.6.2. Outliers...... 17 3.7. Data Handling Conventions and Transformations ...... 17 3.8. Analysis Visit Windows...... 18 3.8.1. Definition of Study Day 1 and Other Definitions...... 18 3.8.2. Analysis Windows...... 19 3.8.3. Selection of Data in the Event of Multiple Records in an Analysis Visit Window...... 22 4. SUBJECT DISPOSITION ...... 24 4.1. Subject Enrollment and Disposition...... 24 4.2. Extent of Study Drug Exposure and Adherence...... 24 4.2.1. Duration of Exposure to Study Drug...... 25 4.2.2. Adherence with Study Drug Regimen...... 25 4.3. Protocol Deviations...... 26 5. BASELINE CHARACTERISTICS...... 27
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5.1. Demographics and Baseline Characteristics ...... 27 5.2. Medical History...... 28 5.3. Risk Factors for HBV Infections...... 28 6. EFFICACY ANALYSES ...... 29 6.1. Primary Efficacy Endpoint...... 29 6.1.1. Definition of the Primary Efficacy Endpoint ...... 29 6.1.2. Analysis of the Primary Efficacy Endpoint...... 29 6.1.3. Secondary Analyses for the Primary Efficacy Endpoint ...... 29 6.1.4. Subgroup Analysis for the Primary Efficacy Endpoint ...... 30 6.2. Secondary Efficacy Endpoints ...... 30 6.2.1. Definition of Secondary Efficacy Endpoints...... 30 6.2.2. Analysis Methods for Secondary Efficacy Endpoints ...... 31 6.3. Changes From Protocol-Specified Efficacy Analyses...... 32 7. SAFETY ANALYSES...... 33 7.1. Adverse Events...... 33 7.1.1. Adverse Event Dictionary ...... 33 7.1.2. Adverse Event Severity...... 33 7.1.3. Relationship of Adverse Events to Study Drug...... 33 7.1.4. Relationship of Adverse Events to Study Procedures ...... 33 7.1.5. Serious AEs...... 33 7.1.6. Treatment-Emergent Adverse Events...... 33 7.1.7. Summaries of AEs and Deaths...... 34 7.1.8. Potential Cardiovascular Events...... 36 7.2. Laboratory Evaluations ...... 36 7.2.1. Summaries of Numeric Laboratory Results ...... 36 7.2.2. Graded Laboratory Values ...... 38 7.2.3. ALT Elevation...... 39 7.3. Bone Safety Analyses ...... 39 7.3.1. BMD...... 39 7.3.2. Bone Biomarkers...... 40 7.3.3. Fracture Events...... 40 7.3.4. Assessment of Fracture Probability...... 40 7.3.5. Bone Events ...... 41 7.4. Renal Safety Analyses...... 41 7.4.1. Confirmed Renal Abnormalities...... 41 7.4.2. Serum Creatinine...... 42 7.4.3. Estimated Glomerular Filtration Rate ...... 42 7.4.4. Treatment-Emergent Proteinuria...... 43 7.4.5. Urine Creatinine, Urine RBP to Creatinine Ratio and Beta-2-Microglobulin to Creatinine Ratio...... 43 7.4.6. Proteinuria by Quantitative Assessment...... 43 7.4.7. Other Renal Biomarkers...... 44 7.5. Body Weight, Height, BMI, and Vital Signs...... 44 7.6. Prior Hepatitis B Medications...... 45 7.7. Concomitant Medications ...... 45 7.8. Electrocardiogram (ECG) Results...... 45 7.9. Other Safety Measures ...... 45 7.10. Changes From Protocol-Specified Safety Analyses...... 46 8. PATIENT REPORTED OUTCOMES...... 47 8.1. Definition of Patient Reported Outcomes ...... 47 8.1.1. SF-36...... 47 8.1.2. CLDQ...... 49
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8.1.3. WPAI:SHP ...... 49 8.1.4. EuroQol - 5 Dimensions – 3 Levels (EQ-5D-3L) ...... 50 8.2. Analysis Methods for Patient Reported Outcomes...... 51 8.3. Changes from Protocol-Specified Patient Reported Outcomes Analyses ...... 51 9. PHARMACOKINETIC ANALYSES ...... 52 9.1. PK Sample Collection ...... 52 9.1.1. Sparse PK samples ...... 52 9.1.2. Optional Intensive PK Substudy (separate consent required) ...... 52 9.2. PK Analyses Related to Intensive PK Sampling...... 52 9.2.1. Estimation of PK Parameters ...... 52 9.2.2. Pharmacokinetic Parameters ...... 53 9.3. PK Analyses Related to Sparse PK Sampling...... 54 10. REFERENCES ...... 56 11. SOFTWARE ...... 57 12. SAP REVISION...... 58 13. APPENDICES ...... 59
LIST OF TABLES
Table 3-1. Subjects Excluded from the Week 24 PP Analysis Set Due to Premature Discontinuation and/or Missing HBV DNA Assessment in Week 24 Analysis Window ...... 14 Table 3-2. Analysis Windows for HBV DNA, Hematology, Serum Chemistry and Liver Function Tests, Urinalysis, Urine Pregnancy Test, eGFRCG, PTH, FEPO4, FEUA, TmP/GFR, UPCR, UACR, Weight, and Vital Sign Assessments ...... 20 Table 3-3. Analysis Windows for Safety ECG ...... 20 Table 3-4. Analysis Windows for FibroTest, CPT, MELD, and Health-Related QoL Questionnaires...... 20 Table 3-5. Analysis Windows for BMD Results from DXA ...... 21 Table 3-6. Analysis Windows for Complete Physical Examination, Fasting Glucose and Lipid Panel ...... 21 Table 3-7. Analysis Windows for Serum HBsAg (Quantitative) and HBV Serology...... 21 Table 3-8. Analysis Windows for Fasting Renal and Bone Biomarkers...... 22 Table 3-9. Analysis Windows for Post-treatment Assessments...... 22 Table 7-1. Normal, Osteopenia, and Osteoporosis as Defined by T-Score...... 39 Table 9-1. Study Treatments and Associated Analytes ...... 53 Table 9-2. PK Parameters for Each Analyte ...... 53
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LIST OF ABBREVIATIONS
AASLD American Association for the Study of Liver Diseases AE adverse event AFP alpha-fetoprotein ALT alanine aminotransferase Anti-HBe anti-Hepatitis B e-antigen Anti-HBs anti-Hepatitis s-antigen AST aspartate aminotransferase
AUCinf area under the concentration versus time curve extrapolated to infinite time, calculated as AUC0last + (Clast/z)
AUCtau area under the plasma concentration versus time curve over the dosing interval (tau) BMD bone mineral density BMI body mass index CDER Center for Drug Evaluation and Research CHB chronic hepatitis B CI confidence interval CK creatine kinase CKD chronic kidney disease CKD-EPI Chronic Kidney Disease Epidemiology Collaboration
CLCR creatinine clearance CLDQ Chronic Liver Disease Questionnaire
Cmax the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) concentration of drug CPT Child-Pugh-Turcotte CRF/eCRF case report form(s)/electronic case report form(s) CSR clinical study report CTX C-type collagen sequence DMC data monitoring committee DNA deoxyribonucleic acid DXA dual-energy x-ray absorptiometry ECG electrocardiogram ED early discontinuation eGFR estimated glomerular filtration rate
eGFRCG estimated glomerular filtration rate by the Cockcroft-Gault formula EQ-5D-3L EuroQol-5 Dimensions-3 Levels ESRD end-stage renal disease FAS Full Analysis Set FDA (United States) Food and Drug Administration
FEPO4 urine fractional excretion of filtered phosphate FEUA fractional excretion of uric acid
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GFR glomerular filtration rate Gilead, GSI Gilead Sciences, Inc. Hb hemoglobin HBeAb hepatitis B e antibody HBeAg hepatitis B e antigen HBsAb hepatitis B surface antibody HBsAg hepatitis B surface antigen HBV hepatitis B virus HCC hepatocellular carcinoma HCV hepatitis C virus HD hemodialysis HDL high-density lipoprotein HDV hepatitis D virus HLT high-level term HIV human immunodeficiency virus ICF informed consent form IFN interferon INR International Normalized Ratio of Prothrombin time (INR) IRB institutional review board LDL low-density lipoprotein LTT lower-level term LOQ limit of quantitation LLOQ lower Limit of quantitation LOCF last observation carried forward M = E missing = excluded M = F missing = failure MedDRA Medical Dictionary for Regulatory Activities MELD Model for End-stage Liver Disease OAV oral antivirals P1NP procollagen type 1 amino-terminal propeptide PK pharmacokinetic PP per protocol PT preferred term PT/INR prothrombin time/International normalized ratio Q1, Q3 first quartile, third quartile QD once daily (use only in tables) QoL quality of life RBP retinol binding protein SAE serious adverse event SAP statistical analysis plan sCr serum creatinine
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SD standard deviation SF-36 Short Form (36) SI (units) international system of units SOC system organ class TAF Tenofovir Alafenamide, GS-7340 TDF Tenofovir Disoproxil Fumarate TFV Tenofovir TEAE treatment-emergent adverse event TFLs tables, figures, and listings
Tmax the time (observed time point) of Cmax TmP/GFR renal tubular maximum reabsorption rate of phosphate to the glomerular filtration rate
t½ an estimate of the terminal elimination half-life of the drug in serum/plasma/PBMC, calculated by dividing the natural log of 2 by the terminal elimination rate constant (λz) UACR urine albumin-to-creatinine ratio ULN upper limit of the normal range UPCR urine protein-to-creatinine ratio WHO World Health Organization WPAI Work Productivity and Activity Impairment
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1. INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data presentations to be used in the tables, figures, and listings (TFLs) in the Week 24 Clinical Study Report (CSR) for the Phase 2 Study GS -US-320-4035. The primary efficacy and safety analysis will be performed when all subjects have completed the Week 24 assessment or prematurely discontinued from study drug. This SAP is based on the study protocol Amendment 1 dated 23 May 2017 and the electronic case report form (eCRF). The SAP will be finalized before database finalization. Any changes made after the finalization of the SAP will be documented in the CSR.
1.1. Study Objectives
The primary objectives of this study are as follows:
To evaluate the safety and tolerability of tenofovir alafenamide (TAF) 25 mg once daily (QD) at Week 24
To measure the proportion of subjects achieving virologic response (hepatitis B virus [HBV] DNA < 20 IU/mL) at Week 24
The secondary objectives of this study are as follows:
To evaluate the safety and tolerability of TAF 25 mg QD at Weeks 48 and 96
To measure the proportion of subjects achieving virologic response (HBV DNA < 20 IU/mL) at Weeks 48 and 96
To evaluate biochemical (alanine aminotransferase [ALT] normal and ALT normalization) and serological (loss of hepatitis B e antigen [HBeAg] with seroconversion to anti-HBe in HBeAg-positive subjects and loss of hepatitis B s antigen [HBsAg] with seroconversion to anti-HBs) responses at Weeks 24, 48, and 96
o evaluate the effect of TAF 25 mg QD on renal parameters at Weeks 24, 48, and 96 in subjects with moderate or severe renal impairment and hepatically impaired subjects
To evaluate the safety of TAF 25 mg QD as determined by percentage change in hip and spine bone mineral density (BMD) at Weeks 24, 48, and 96
To evaluate the effect of TAF 25 mg QD on fibrosis as assessed by FibroTest at Weeks 24, 48, and 96
To evaluate the effect of TAF 25 mg QD on changes in Child-Pugh-Turcotte (CPT) and Model for End-stage Liver Disease (MELD) scores at Weeks 24, 48, and 96 in hepatically impaired subjects
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The exploratory objectives of this study are as follows: CCI 1.2. Study Design
1.2.1. Design Configuration and Subject Population
This is an open-label, multicenter study to evaluate the safety and efficacy of switching to TAF 25 mg QD from tenofovir disoproxil fumarate (TDF) and/or other OAVs in virologically suppressed subjects who have chronic hepatitis B (CHB) with renal and/or hepatic impairment.
1.2.2. Treatment Groups and Randomization
Approximately 120 subjects will be enrolled into the 2 parts of the study:
Part A (Renally Impaired subjects):
Approximately 90 virologically suppressed (HBV DNA < lower limit of quantitation [LLOQ]) subjects will be enrolled into 2 cohorts of renal impairment. Approximately 50% of subjects (target N = 42 to 46) enrolled into Part A should be virologically suppressed for at least 6 months on TDF or a TDF-containing anti-HBV regimen for CHB at time of screening.
Cohort 1: Moderate or Severe Renal Impairment
Moderate renal impairment (30 mL/min ≤ estimated glomerular filtration rate using the Cockcroft-Gault equation (eGFRCG) ≤ 59 mL/min)
Severe renal impairment (15 mL/min ≤ eGFRCG < 30 mL/min)
eGFRCG is calculated by: (140 – age in years) (actual body weight [kg]) (72) (serum creatinine [mg/dL])
(Note: multiply estimated rate by 0.85 for women)
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Cohort 2: End-stage renal disease (ESRD)
eGFRCG < 15 mL/min and maintained on hemodialysis (HD) at time of screening
Approximately 20% of subjects (target N = 16 to 18) enrolled into Part A will be enrolled into Cohort 2.
Part B (Hepatically Impaired Subjects):
Approximately 30 subjects, all of whom were virologically suppressed for at least 6 months on TDF or a TDF-containing anti-HBV regimen or other OAV(s) for CHB at time of screening will be enrolled with:
Moderate hepatic impairment (CPT Class B; score of 7−9 inclusive) OR
Severe hepatic impairment (CPT Class C; score of 10−12 inclusive)
1.2.3. Key Eligibility Criteria Subjects were to have met all eligibility criteria, including the following key eligibility criteria:
Documented evidence of chronic HBV infection (eg, HBsAg positive for ≥ 6 months)
Maintained on TDF and/or other OAV (s) for CHB for at least 48 weeks and with viral suppression (HBV DNA < LLOQ) for ≥ 6 months prior to screening
Part A Only (renal impairment):
Moderate renal impairment (30 mL/min ≤ eGFRCG ≤ 59 mL/min), severe renal impairment (15 mL/min ≤ eGFRCG < 30 mL/min), or ESRD (eGFRCG < 15 mL/min) maintained on HD
Part B Only (hepatic impairment):
CPT score of 7−12 (inclusive) OR a past history of CPT score ≥ 7 and any CPT score ≤ 12 at screening
eGFRCG ≥ 30 mL/min
1.2.4. Study Periods and Phases The duration of study drug treatment for all subjects is 96 weeks. Subjects in Part A (renally impaired) with HBsAg loss with confirmed seroconversion to anti-HBs should discontinue study drug within 3 to 6 months following confirmation of seroconversion to anti-HBs. Subjects with HBsAg loss with confirmed seroconversion prior to Week 24 are not permitted to discontinue study drug prior to the Week 24 visit. Subjects with HBsAg loss with confirmed seroconversion will be followed off treatment every 4 weeks for 12 weeks and then per the study visit schedule (Appendix 1) through Week 96/early discontinuation (ED). Discontinuation of study drug for subjects experiencing HBsAg loss with confirmed seroconversion who have known bridging fibrosis or compensated cirrhosis should be considered on a case-by-case basis.
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Subjects with moderate or severe hepatic impairment (Part B) who experience HBsAg loss and seroconversion to anti-HBs should not discontinue study drug. Subjects in Part A (renally impaired) who permanently discontinue study drug (either prematurely or after completing 96 weeks of treatment) for reasons other than HBsAg loss with confirmed seroconversion to anti-HBs will be followed every 4 weeks for 24 weeks off treatment or until initiation of appropriate, alternative HBV therapy, whichever occurs first. Use of appropriate, alternative HBV therapy is strongly encouraged.
For subjects in Part B (hepatic impairment) who permanently discontinue study drug, immediate initiation of appropriate, alternative HBV therapy is strongly recommended.
1.2.5. Schedule of Assessments
Laboratory analyses (serum chemistry and liver function tests, hematology, eGFRCG, urinalysis [for all subjects except only where available for subjects in Part A, Cohort 2 (ESRD subjects on HD)], and plasma HBV DNA levels), pregnancy testing [for females of childbearing potential]), vital signs, adverse events (AEs), and concomitant medications will be measured or assessed at screening, baseline, and Weeks 4, 8, 12, 24, 36, 48, 60 ,72, and 96 (and ED).
Dual energy x-ray absorptiometry (DXA) scans of the hip and spine will be performed at baseline and Weeks 24, 48, 72, and 96 (and ED).
Complete physical examinations will be performed at screening, baseline, and Weeks 24, 48, 72, and 96 (and ED). Symptom-driven physical examinations, including body weight assessment, will be conducted at all other visits.
Follow-up assessments will occur every 4 weeks for 12 weeks for subjects in Part A (renally impaired) who discontinue study drug due to HBsAg loss with confirmed seroconversion to anti-HBs on or after the Week 24 visit and then per the visit schedule through Week 96/ED. Subjects with moderate or severe hepatic impairment (Part B) who experience HBsAg loss and seroconversion to anti-HBs should not discontinue study drug. Follow-up assessments include the following: concomitant medications, AEs, body weight, vital signs, symptom-driven physical examinations, laboratory analyses, and HBV serology.
1.3. Sample Size and Power
No formal sample size calculation was performed. A sample size of 120 subjects is based on practical considerations and is considered sufficient to evaluate the primary objectives of the study.
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2. TYPE OF PLANNED ANALYSIS
2.1. Data Monitoring Committee Analysis
After consulting with the data monitoring committee (DMC) members, the DMC data review meeting will be scheduled when the first 20 subjects enrolled have completed 12 weeks of treatment.
The DMC will examine the safety results of the trial and also focus on logistical issues, such as accrual, retention, quality of clinical and laboratory data, and implications of results of external studies. No formal stopping rules will be used by the DMC for safety outcomes. Rather, a clinical assessment will be made to determine if the nature, frequency, and severity of adverse effects associated with study drug warrant the early termination of the study in the best interests of the participants.
The DMC’s role and responsibilities and the scope of analysis to be provided to the DMC are provided in a mutually agreed upon charter that defines the DMC membership, meeting logistics, and meeting frequency.
2.2. Week 24 Analysis (Primary Analysis)
The Week 24 analysis will be conducted after the last subject has completed the Week 24 visit or prematurely discontinued study drug.
2.3. Week 48 Analysis
The Week 48 analysis will be conducted after the last subject has completed the Week 48 visit or prematurely discontinued study drug.
2.4. Final Analysis
The final analysis for the study will be conducted after all subjects have completed the study or prematurely discontinued study drug.
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3. GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the number and percentage of subjects in each category will be presented; for continuous variables, the sample size, mean, standard deviation (SD) or standard error (SE), median, first quartile (Q1), third quartile (Q3), minimum, and maximum will be presented.
If not otherwise specified, subjects will be analyzed according to the study part (and cohort, for Part A) into which they were enrolled. In addition, for Part A, an overall summary of Cohort 1 and Cohort 2 combined will also be provided, expect for renal related endpoints. No combined summary of Part A and Part B will be provided except for enrollment and baseline information.
By-subject listings will be presented for all subjects in the All Enrolled Analysis Set and sorted by subject identification (ID) number, visit date, and time (if applicable). Data collected on log forms, such as AEs, will be presented in chronological order within the subject. The part (and cohort, for Part A) into which subjects were enrolled will be used in the listings. Age, sex at birth, race, and ethnicity will be included in the listings, as space permits.
3.1. Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions are provided in this section. The analysis set will be identified and included as a subtitle of each table, figure, and listing.
A summary of the number and percentage of subjects in each analysis set will be provided.
A by-subject listing of reasons for exclusion from analysis sets will be provided.
3.1.1. All Enrolled Analysis Set
The All Enrolled Analysis Set will include all subjects who received a study subject ID number after screening. This is the primary analysis set for by-subject listings.
3.1.2. Full Analysis Set
The Full Analysis Set (FAS) will include all subjects who were enrolled and received at least 1 dose of study drug. This is the primary analysis set for efficacy analyses.
3.1.3. Safety Analysis Set
The Safety Analysis Set will include all subjects who were enrolled and received at least 1 dose of study drug. This is the primary analysis set for safety analyses.
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3.1.4. Per Protocol Analysis Set
The Week 24 Per Protocol (PP) Analysis Set will include all subjects who (1) were enrolled into the study, (2) received at least 1 dose of study drug, and (3) had not been excluded based on the criteria below. The Week 24 PP Analysis Set is the secondary analysis set for the primary endpoint.
Subjects meeting any of the following criteria will be excluded from the Week 24 PP Analysis Set:
Subjects who do not have an on-treatment HBV DNA assessment in the Week 24 analysis window, except for subjects who discontinued study drug due to lack of efficacy. (Note: Lack of efficacy is defined as having the box for “Lack of Efficacy” checked as the reason for premature study drug discontinuation on the study drug completion eCRF page). The details are summarized in Table 3-1.
Table 3-1. Subjects Excluded from the Week 24 PP Analysis Set Due to Premature Discontinuation and/or Missing HBV DNA Assessment in Week 24 Analysis Window
HBV DNA Data on Treatment Available in Week 24 Analysis Window Discontinuation from Study Drug Prior to or on the Upper Bound of the Week 24 Analysis Window Yes No Yes Due to Lack of Efficacy + + Due to Other Reasons + − No + − + = Inclusion of Subjects in Week 24 PP Analysis Set; - = Exclusion of Subjects in Week 24 PP Analysis Set
Subjects who meet the exclusion criterion for receiving ongoing therapy with any of the prohibited medications listed in the clinical study protocol (Section 5.3, Table 5-1).
Subjects with adherence rate for study drug up to the Week 24 visit below the 2.5th percentile.
3.1.5. Pharmacokinetic Analysis Set
The PK Analysis Set will include all subjects who received at least 1 dose of study drug and for whom concentration data of any analytes of interest are available. The PK Analysis Set will be used for analyses of concentration data.
CCI
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3.1.6. Serologically Evaluable Full Analysis Set
3.1.6.1. Serologically Evaluable Full Analysis Set for HBeAg Loss/Seroconversion
The Serologically Evaluable FAS for HBeAg Loss/Seroconversion will include all subjects who were enrolled and received at least 1 dose of study drug, and with HBeAg positive and HBeAb negative or missing at baseline.
3.1.6.2. Serologically Evaluable Full Analysis Set for HBsAg Loss/Seroconversion
The Serologically Evaluable Full Analysis Set for HBsAg Loss/Seroconversion will include all subjects who were enrolled and received at least 1 dose of study drug, and with HBsAg positive and HBsAb negative or missing at baseline.
3.1.7. DXA Analysis Set
3.1.7.1. Hip DXA Analysis Set
The Hip DXA Analysis Set will include all subjects who were enrolled and received at least 1 dose of study drug and had non-missing baseline hip BMD values.
3.1.7.2. Spine DXA Analysis Set
The Spine DXA Analysis Set will include all subjects who were enrolled and received at least 1 dose of study drug and had non-missing baseline spine BMD values.
3.2. Subject Grouping
This is a single-arm study, thus subjects will be analyzed as a single treatment group, but by different part and cohort as specified below.
If not otherwise specified, subjects will be analyzed according to the study part (and cohort, for Part A) into which they were enrolled. In addition, for Part A, overall summary of Cohort 1 and Cohort 2 combined will also be provided, expect for renal related endpoints. No combined summary of Part A and Part B will be provided except for enrollment and baseline information.
Part A, Cohort 1: Moderate ( 30 mL/min ≤ eGFRCG ≤ 59 mL/min) or severe (15 mL/min ≤ eGFRCG < 30 mL/min) renal impairment
Part A, Cohort 2: ESRD (eGFRCG < 15 mL/min) maintained on HD
Part B: Moderate (CPT Class B; score of 7−9 inclusive) or severe (CPT Class C; score of 10−12 inclusive) hepatic impairment.
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3.3. Strata and Covariates
Subjects will be enrolled into one of 2 parts of the study (Part A [renal impairment], or Part B [hepatic impairment]). For Part A, subjects will be grouped by the level of renal impairment (Cohort 1 moderate or severe renal impairment or Cohort 2 ESRD on HD). For statistical analyses, subjects will be analyzed according to the part (and cohort for Part A). No stratification or covariate adjustments will be made.
3.4. Examination of Subject Subgroups
The primary efficacy endpoint (HBV DNA < 20 IU/mL) will be analyzed for the following subject subgroups:
Age: (a) < 65 years and (b) ≥ 65 years
Sex: (a) male and (b) female
Race: (a) Asian and (b) non-Asian
Region: (a) Asia and (b) Europe and North America
Countries in each region are listed as follows:
■ Asia Pacific: Hong Kong, Korea, Taiwan
■ Europe and North America: Canada, France, Italy, the United Kingdom, and the United States
Study drug adherence: (a) < 95% and (b) ≥ 95% (based on adherence up to the Week 24 visit)
Baseline ALT by 2018 American Association for the Study of Liver Diseases [AASLD] normal range criteria (35 U/L for males and 25 U/L for females): (a) ≤ ULN and (b) > ULN
Baseline FibroTest score (only for Part A): (a) < 0.75 and (b) ≥ 0.75
MELD score (only for Part B): (a) < 10 and (b) ≥ 10
3.5. Multiple Comparisons
Adjustments for multiplicity will not be made because no formal statistical testing will be performed in this study.
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3.6. Missing Data and Outliers
3.6.1. Missing Data
A missing datum for a given study analysis window may be due to any of the following reasons:
A visit occurred in the window, but data were not collected or were unusable
A visit did not occur in the window
A subject permanently discontinued from the study before reaching the window
For the primary endpoint and the secondary efficacy endpoints involving proportions, missing data will be handled using Missing = Failure (M = F) approach. Sensitivity analyses will also be performed including an analysis excluding all missing data.
For missing last dosing date of study drug, imputation rules are described in Section 4.2.1. The handling of missing or incomplete dates for AE onset is described in Section 7.1.6.2 and for concomitant medications in Section 7.7.
For the remaining endpoints, values for missing data will not be imputed, unless specified otherwise.
3.6.2. Outliers Outliers may be identified during the data management and data analysis process, but no sensitivity analyses will be conducted. All available data will be included in the data analysis.
3.7. Data Handling Conventions and Transformations In general, age (in years) on the date of the first dose of study drug will be used for analyses and presentation in listings. If an enrolled subject was not dosed with study drug, the enrollment date will be used instead of the date of the first dose of study drug. For screen failures, the date the informed consent was signed will be used for age calculation. If only the birth year is collected on the eCRF, “01 July” will be used for the unknown birth day and month for the purpose of age calculation. If only birth year and month are collected, “01” will be used for the unknown birth day. Non-PK data that are continuous in nature but are less than the lower limit of quantitation (LOQ) or above the upper LOQ will be imputed as follows except for direct bilirubin, urine creatinine, and serum cystatin C:
A value that is 1 unit less than the LOQ will be used to calculate descriptive statistics if the datum is reported in the form of “ x” (where x is considered the LOQ). For example, if the values are reported as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used to calculate summary statistics. An exception to this rule is any value reported as < 1 or < 0.1, etc. For values reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used to calculate summary statistics.
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A value that is 1 unit above the LOQ will be used to calculate descriptive statistics if the datum is reported in the form of “> x” (where x is considered the LOQ). Values with decimal points will follow the same logic as above.
The LOQ will be used to calculate descriptive statistics if the datum is reported in the form of “≤ x” or “≥ x” (where x is considered the LOQ).
For direct bilirubin, a value of “< 0.1” is imputed as 0.09. For urine creatinine, a value of “< 1” is handled as a missing value in its summary and the calculation of related ratios. For serum cystatin C, a value of “< 0.10” is handled as a missing value in the calculation of eGFR.
Logarithm (base 10) will be used to transform HBV DNA and quantitative HBsAg data.
For HBV DNA, if the value in IU/mL is above the upper LOQ, the corresponding diluted value, if available, will be used. HBV DNA results of “<20 IU/mL HBV DNA detected” or “No HBV DNA detected” will be imputed as 19 IU/mL.
Natural logarithm transformation will be applied to PK concentrations and PK parameters such as Cmax, Ctau, and AUCtau for PK analysis.
PK concentration values below the limit of quantitation (BLQ) will be treated as 0 for the determination of summary and order statistics. Individual values that are BLQ will be presented as “BLQ” in the concentration data listing. For the presentation of summary and order statistics, if at least 1 subject has a concentration value BLQ for the time point, then the minimum value will be displayed as “BLQ”. If more than 50% of the subjects have a concentration data value BLQ for the time point, the minimum and median values will be displayed as “BLQ”. If all subjects have concentration data values BLQ for all the time points, all order statistics (minimum, first quartile [Q1], median, third quartile [Q3], and maximum) will be displayed as “BLQ”.
3.8. Analysis Visit Windows
3.8.1. Definition of Study Day 1 and Other Definitions
Study Day 1 is defined as the day when the first dose of study drug was taken, as recorded on the Study Drug Administration eCRF.
Study days are calculated relative to Study Day 1. For events that occurred on or after the Study Day 1 date, study days are calculated as (visit date – Study Day 1 + 1). For events that occurred prior to Study Day 1, study days are calculated as (visit date − Study Day 1).
Follow-up days are for visits that occurred during the treatment-free follow-up (TFFU) period and are calculated as (visit date – last dose date).
The Last Dose Date is the latest non-missing end date of study drug, recorded on the Study Drug Administration eCRF with the “Study Drug Permanently Discontinued” box checked for subjects who prematurely discontinued study drug. If the last dose date is missing (eg, due to lost to
CONFIDENTIAL Page 18 09 May 2019 Tenofovir Alafenamide GS-US-320-4035 Statistical Analysis Plan – Week 24 Analysis Final follow-up) for subjects who prematurely discontinued study drug, or completed study drug, or for subjects who are still on study drug, the latest of non-missing study drug start dates and end dates, the clinical visit dates, and the laboratory visit dates, excluding the dates during TFFU, will be used to impute the last dose date.
Last Study Date is the latest of non-missing study drug start dates and end dates, the clinical visit dates, and the laboratory visit dates, including the TFFU visit date, for subjects who prematurely discontinued study or who completed study according to the Study Completion eCRF.
3.8.2. Analysis Windows
Subject visits might not occur on protocol-specified days. Therefore, for the purpose of analysis, observations will be assigned to analysis windows.
The following windows (Table 3-2 to Table 3-8) apply only to baseline and postbaseline on-treatment assessments collected. For summaries and analyses, assessments will first be categorized into baseline and postbaseline on-treatment assessments before applying analysis windows. Baseline value is defined as the last non-missing value obtained on or prior to Study Day 1. For DXA BMD, baseline is defined as the last value on or prior to Study Day 14. For subjects who received study drug, assessments that occurred during the period from Study Day 2 up to and including the Last Dose Date + 3 days, will be considered as postbaseline on- treatment assessments. DXA assessments that occurred during the period from the Study Day 15 up to and including the Last Dose Date + 14 days will be considered as postbaseline on-treatment assessments.
The analysis windows for HBV DNA, hematology, serum chemistry and liver function tests, urinalysis, urine pregnancy test, eGFRCG, bone biomarker serum parathyroid hormone (PTH), urine fractional excretion of filtered phosphate (FEPO4), fractional excretion of uric acid (FEUA), renal tubular maximum reabsorption rate of phosphate to the glomerular filtration rate (TmP/GFR), urine protein to creatinine ratio (UPCR), urine albumin to creatinine ratio (UACR), weight, and vital signs assessments are presented in Table 3-2.
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Table 3-2. Analysis Windows for HBV DNA, Hematology, Serum Chemistry and Liver Function Tests, Urinalysis, Urine Pregnancy Test, eGFRCG, PTH, FEPO4, FEUA, TmP/GFR, UPCR, UACR, Weight, and Vital Sign Assessments
Visit ID Nominal Day Lower Limit Upper Limit Baseline 1 Week 4 28 2 42 Week 8 56 43 70 Week 12 84 71 126 Week 24 168 127 210 Week 36 252 211 294 Week 48 336 295 378 Week 60 420 379 462 Week 72 504 463 588 Week 96 672 589 756
eGFRCG = estimated glomerular filtration rate using the Cockcroft-Gault equation
The analysis windows for electrocardiograms (ECGs) are presented in Table 3-3. No ECG is collected at Week 24. It will be assessed at Week 48 and 96.
Table 3-3. Analysis Windows for Safety ECG
Visit ID Nominal Day Lower Limit Upper Limit Baseline 1 Week 48 336 2 504 Week 96 672 505 840
The analysis windows for CPT score, MELD score, FibroTest and health-related QoL questionnaires are presented in Table 3-4.
Table 3-4. Analysis Windows for FibroTest, CPT, MELD, and Health-Related QoL Questionnaires
Visit ID Nominal Day Lower Limit Upper Limit Baseline 1 Week 24 168 2 252 Week 48 336 253 504 Week 96 672 505 840 QoL = quality of life
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The analysis windows for BMD results from DXA are presented in Table 3-5.
Table 3-5. Analysis Windows for BMD Results from DXA
Visit ID Nominal Day Lower Limit Upper Limit Baseline 14 Week 24 168 15 252 Week 48 336 253 420 Week 72 504 421 588 Week 96 672 589 756
BMD = bone mineral density; DXA = dual energy x-ray absorptiometry The analysis windows for complete physical examination, fasting glucose, fasting lipid panel, including total cholesterol, high-density lipoprotein (HDL), direct low-density lipoprotein (LDL), and triglycerides are presented in Table 3-6. Table 3-6. Analysis Windows for Complete Physical Examination, Fasting Glucose and Lipid Panel
Visit ID Nominal Day Lower Limit Upper Limit Baseline 1 Week 24 168 2 252 Week 48 336 253 420 Week 72 504 421 588 Week 96 672 589 756
The analysis windows for serum HBsAg (quantitative) and HBV serology are presented in Table 3-7. Table 3-7. Analysis Windows for Serum HBsAg (Quantitative) and HBV Serology
Visit ID Nominal Day Lower Limit Upper Limit Baseline 1 Week 12 84 2 126 Week 24 168 127 210 Week 36 252 211 294 Week 48 336 295 378 Week 60 420 379 462 Week 72 504 463 588 Week 96 672 589 756 HBsAg = hepatitis B s antigen
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The analysis windows for fasting renal biomarkers including urine retinol binding protein (RBP):creatinine ratio; urine beta-2-microglobulin:creatinine ratio (evaluated only in Part A, Cohort 1 and Part B subjects); and bone biomarkers, including C-type collagen sequence (CTX) and procollagen type 1 N-terminal propeptide (P1NP) are presented in Table 3-8.
Table 3-8. Analysis Windows for Fasting Renal and Bone Biomarkers
Visit ID Nominal Day Lower Limit Upper Limit Baseline 1 Week 4 28 2 56 Week 12 84 57 126 Week 24 168 127 252 Week 48 336 253 420 Week 72 504 421 588 Week 96 672 589 756
Posttreatment assessments during the TFFU period is defined as assessments that occurred during the period after the Last Dose Date + 3 days up to the Last Study Date, except for post-treatment DXA assessments, which is defined as assessments that occurred during the period after the Last Dose Date + 14 days up to the Last Study Date. The analysis windows for post-treatment assessments are presented in Table 3-9.
Table 3-9. Analysis Windows for Post-treatment Assessments
Visit ID Nominal Day Lower Limit Upper Limit Follow-Up Week 4 28 LDD+4 (LDD+15a) 42 Follow-Up Week 8 56 43 70 Follow-Up Week 12 84 71 98 Follow-Up Week 16 112 99 126 Follow-Up Week 20 140 127 154 Follow-Up Week 24 168 155 182 a Applies to post-treatment DXA assessments only.
3.8.3. Selection of Data in the Event of Multiple Records in an Analysis Visit Window
Depending on the statistical analysis method, single values are required for each analysis window. For example, change from baseline by visit usually requires a single value, whereas a time-to-event analysis would not require 1 value per analysis window. When a single value is needed, the following rule(s) will be used.
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For baseline, the last available record on or prior to the first dose of study drug will be selected. For DXA BMD baseline, the last value on or prior to Study Day 14 will be selected. If there are multiple records with the same time or no time recorded on the same day for numeric observations, the average will be computed for that day; for HBV DNA and quantitative HBsAg the geometric mean will be computed instead. If there are multiple records with the same time or no time recorded on the same day for categorical observations, the most conservative value will be selected (eg, negative will be selected over positive for HBeAg and HBsAg, and positive will be selected over negative for HBeAb and HBsAb).
The following specified rules will be used for post-baseline visits:
ALT: The largest value will be selected for analysis when 2 or more ALT values occur within the same visit window.
BMD: The latest record in the window will be selected.
HBV DNA (IU/mL): The record on the latest day in the window will be selected. If there is more than 1 record on the selected day, the geometric mean will be used.
Quantitative HBsAg (IU/mL): The record closest to the nominal day for that visit will be selected. If there are 2 records equidistant from the nominal day, the latest will be selected. If there is more than 1 record on the selected day, the geometric mean will be used.
Serology: For HBeAg, HBeAb, HBsAg, and HBsAb, the record closest to the nominal day for that visit will be selected. If there are 2 records equidistant from the nominal day, the latest will be selected. If there is more than 1 record on the selected day, the most conservative value will be selected (ie, positive will be selected over negative for HBeAg and HBsAg, and negative will be selected over positive for HBeAb and HBsAb).
For all other laboratory parameters:
If multiple valid non-missing numeric observations exist in a window, records will be chosen as follows:
The record closest to the nominal day for that visit will be selected. If there are 2 records equidistant from the nominal day, the latest will be selected. If there is more than 1 record on the selected day, the average will be used.
If multiple valid non-missing categorical observations (eg, safety ECG results) exist in a window, then records will be chosen as follows:
The most conservative value within the window will be selected (eg, abnormal will be selected over normal for safety ECG). In the event that 2 values within a window are of equal abnormality, the value collected nearest to the nominal date will be selected.
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4. SUBJECT DISPOSITION
4.1. Subject Enrollment and Disposition
The number and percentage of subjects enrolled will be provided by study part and cohort by region, country, investigator, and overall using the All Enrolled Analysis Set. The summary will present the number and percentage of subjects enrolled; the denominator for the percentage calculation will be the total number of subjects enrolled.
A summary of subject disposition will be provided by study part, cohort, and overall for all screened subjects. This summary will present the number of subjects screened, screen failure subjects who were not enrolled, subjects who met all eligibility criteria and were not enrolled, subjects in the All Enrolled Analysis Set, subjects enrolled but never treated, subjects in the FAS, and subjects in the Safety Analysis Set.
Study Drug Completion
Prematurely discontinued study treatment (with summary of reasons for discontinuing treatment)
Completed study treatment
Study Extension Status
Entered 24-week TFFU follow-up period
Willing to start another HBV therapy
Study Completion
Remaining on study
Prematurely discontinued study (with summary of reasons for discontinuing study)
Completed protocol-planned duration of the study
No inferential statistics will be generated. A by-subject listing of reasons for premature study drug/study discontinuation will be provided.
4.2. Extent of Study Drug Exposure and Adherence
The extent of exposure to study drug will be examined by assessing the total duration of exposure to study drug and the level of adherence to the study drug specified in the protocol.
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4.2.1. Duration of Exposure to Study Drug
Total duration of exposure to study drug is defined as the last dosing date minus the first dosing date plus 1, regardless of any temporary interruptions in study drug administration, and will be expressed in weeks using up to 1 decimal place (eg, 4.5 weeks).
The total duration of exposure to study drug will be summarized using descriptive statistics (sample size, mean, SD, median, Q1, Q3, minimum, and maximum) and using the number (ie, cumulative counts) and percentage of subjects exposed through the following time periods for the Safety Analysis Set: ≥ 4 weeks (28 days), ≥ 8 weeks (56 days), ≥ 12 weeks (84 days), ≥ 24 weeks (168 days), ≥ 36 weeks (252 days), ≥ 48 weeks (336 days), ≥ 60 weeks (420 days), ≥ 72 weeks (504 days), and ≥ 96 weeks (672 days).
No formal statistical testing is planned.
4.2.2. Adherence with Study Drug Regimen
Study drug regimen adherence will be computed based on tablet counts. The numbers of tablets of study drug dispensed and returned are captured on the study drug accountability forms.
Adherence (%) of study drug regimen will be calculated as follows:
Number of tablets taken Adherence (%) 100 Number of tablets prescribed
No.of tablets taken at each dispensing period [1] 100 ( No.of tablets prescribed at each dispensing period [2]) 1
[1] Number of tablets taken during a distinct dispensing period for a study drug is calculated as the minimum of (a) the daily number of tablets prescribed for the study drug multiplied by (the duration of treatment +1 day) at the dispensing period of the same dispensing date, and (b) the number of tablets taken for the study drug (number of tablets dispensed minus the number of tablets returned). Total number of tablets taken is determined by summing the number of tablets taken from all evaluable dispensing periods. [2] Number of tablets prescribed at a distinct dispensing period for a study drug is calculated as the daily number of tablets prescribed for the study drug multiplied by the duration of treatment at the dispensing period of the same dispensing date. Total number of tablets prescribed is determined by summing the number of tablets prescribed from all evaluable dispensing periods.
The duration of treatment at a dispensing period for a study drug is calculated as the minimum of the (a) last returned date of the same dispensing period for the study drug, (b) date of premature discontinuation of the study drug, and (c) next dispensing date of the study drug, minus dispensing date of the study drug.
The next dispensing date is the following dispensing date of the study drug regardless of the bottle return date.
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For a record where the number of tablets returned was missing (ie, with “Yes” answered for “Was bottle returned?” question), it is assumed the number of tablets returned was 0. If the number of tablets dispensed was missing, or any study drug bottle was not returned, or the bottle return status was unknown for the same dispensing date, all records for the same dispensing date for that study drug will be excluded from both the denominator and numerator calculations.
Adherence up to the Week 24 visit will be calculated for each subject.
The number and percentage of subjects who return at least 1 bottle and have calculable adherence during the study, descriptive statistics for adherence up to the Week 24 visit for a study drug regimen (sample size, mean, SD, median, Q1, Q3, minimum, and maximum), and the number and percentage of subjects belonging to adherence categories (eg, < 80%, ≥ 80% to < 90%, ≥ 90% to < 95%, ≥ 95%) will be summarized for the Safety Analysis Set. No inferential statistics will be provided.
4.3. Protocol Deviations
A by-subject listing will be provided for subjects who did not meet at least 1 eligibility (inclusion or exclusion) criterion. The listing will present the eligibility criterion (or criteria if more than 1 deviation) that subjects did not meet and related comments, if collected.
Protocol deviations that occurred after subjects entered the study are documented during routine monitoring. The number and percentage of subjects with important protocol deviations by deviation reason (eg, nonadherence to study drug, violation of select inclusion/exclusion criteria) will be summarized for the All Enrolled Analysis Set. A by-subject listing will be provided for subjects with important protocol deviations.
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5. BASELINE CHARACTERISTICS
5.1. Demographics and Baseline Characteristics
Subject demographic data (eg, age, sex, race, and ethnicity) and baseline characteristics (eg, body weight, height, body mass index [BMI], and Vitamin D) will be summarized using descriptive statistics (sample size, mean, SD, median, Q1, Q3, minimum, and maximum) for continuous data and by the number and percentage of subjects for categorical data. Age is calculated as age in years at the first dose of study drug. The summaries of demographic data and baseline subject characteristics will be provided for the Safety Analysis Set.
In addition, the following baseline characteristics and baseline disease characteristics will be summarized:
Age group (< 50 years, ≥ 50 years – and further split into ≥ 50 to < 60 years, ≥ 60 to < 65 years, and > 65 years)
Region (Asia, Europe or North America)
BMI categories (< 18.5 kg/m2 [underweight], ≥ 18.5 to 25.0 kg/m2 [normal], ≥ 25.0 to 30.0 kg/m2 [overweight], and ≥ 30.0 kg/m2 [obese])
HBV DNA categories ( < 20 IU/mL, ≥ 20 to < 69 IU/mL, ≥ 69 IU/mL)
HBsAg (log10 IU/mL)
ALT (U/L)
ALT level based on the central laboratory normal range (≤ ULN, > ULN to 5 × ULN, > 5 × ULN)
ALT level based on the 2018 AASLD normal range with ULN 25 U/L for females and 35 U/L for males (≤ ULN, > ULN to 5 × ULN, > 5 × ULN)
HBeAg and HBeAb status (HBeAg positive/ HBeAb negative, HBeAg positive/ HBeAb positive, HBeAg negative/HBeAb negative, HBeAg negative/HBeAb positive)
Estimated GFR by CG, chronic kidney disease epidemiology collaboration CKD-EPI, and CKD-EPI cystatin C methods
Previous TDF use experience (yes, no) and TDF use at screening
Previous interferon experience (yes, no)
Years positive for HBV
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HBV Genotype (A, B, C, D, Other, Unknown) by history
FibroTest score
Fibrosis stage by FibroTest score (0 to 0.48, 0.49 to 0.74, 0.75 to 1, only for Part A)
CPT and MELD scores (only for Part B)
Cirrhosis history (yes, no, indeterminate/unknown)
Proteinuria by urinalysis (dipstick) (Grades 0, 1, 2, 3)
Clinical BMD status for hip and spine (normal, osteopenia, osteoporosis)
Hip fracture and major osteoporotic fracture probabilities estimated using FRAX (see Section 7.3.4)
Medical history: diabetes mellitus (yes, no), hypertension (yes, no), cardiovascular disease (yes, no), and hyperlipidemia (yes, no)
Diabetes mellitus, hypertension, cardiovascular disease, and hyperlipidemia are determined by medical history, adverse events, and concomitant medication data, which will be reviewed by the Gilead medical monitor based on the finalized database.
5.2. Medical History
Medical history will be collected at screening for disease-specific and general conditions (ie, conditions not specific to CHB). A by-listing of medical history will be provided.
5.3. Risk Factors for HBV Infections
Risk factors for HBV infection will be summarized. A by-subject listing of risk factors for HBV infections will be provided.
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6. EFFICACY ANALYSES
6.1. Primary Efficacy Endpoint
6.1.1. Definition of the Primary Efficacy Endpoint
The primary efficacy endpoint is the proportion of subjects achieving a virologic response of plasma HBV DNA < 20 IU/mL at Week 24.
6.1.2. Analysis of the Primary Efficacy Endpoint
The primary efficacy analysis will be conducted when all enrolled and treated subjects complete their Week 24 visit or prematurely discontinue study drug. Specifically, the analysis window at Week 24 will be defined as Study Day 127 to Study Day 210, inclusive. A M = F approach will be used, where subjects with missing data will be treated as having not achieved the primary endpoint (ie, HBV DNA < 20 IU/mL). The FAS will be used for the primary efficacy analysis.
The number and percentage of subjects who achieved and did not achieve HBV DNA < 20 IU/mL, and reasons for missing HBV DNA data at Week 24 will also be summarized by part and cohort.
Point estimates and 2-sided 95% exact confidence intervals (CIs) will be provided for the proportion of subjects with plasma HBV DNA < 20 IU/mL at Week 24 by study part (and cohort).
6.1.3. Secondary Analyses for the Primary Efficacy Endpoint
A modified US FDA-defined snapshot algorithm will be used to summarize HBV DNA outcome at Week 24. The US FDA-defined snapshot algorithm, {U. S. Department of Health and Human Services 2015} developed for HIV-1 clinical trials, has been modified for HBV using on-treatment HBV DNA values of < 20 IU/mL and ≥ 20 IU/mL. Virologic outcome at Week 24 will be defined as the following categories:
HBV DNA < 20 IU/mL: this includes subjects who have the last available on-treatment HBV DNA in the Week 24 analysis window < 20 IU/mL
HBV DNA ≥ 20 IU/mL: this includes subjects who
Have the last available on-treatment HBV DNA in the Week 24 analysis window ≥ 20 IU/mL, or
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Do not have on-treatment HBV DNA data available in the Week 24 analysis window and
1) Discontinue study drug prior to or in the Week 24 analysis window due to lack of efficacy (note: lack of efficacy is defined as having the check-box for ‘Lack of Efficacy’ marked on the Study Drug Completion eCRF), or 2) Discontinue study drug prior to or in the Week 24 analysis window due to reason other than lack of efficacy and have the last available on-treatment HBV DNA ≥ 20 IU/mL
No Virologic Data in the Week 24 Analysis Window: this includes subjects who do not have on-treatment HBV DNA data available in the Week 24 analysis window for any of the following reasons:
1) Discontinuation of study drug prior to or within the Week 24 analysis window due to reasons other than lack of efficacy and the last available on-treatment HBV DNA value is < 20 IU/mL, or 2) Missing data within the window but who are on study drug A Missing = Excluded (M = E) approach will be used as sensitivity analysis to summarize the proportion of subjects with HBV DNA < 20 IU/mL by visit. In the M = E approach, all missing data will be excluded from the computation (ie, missing data points will be excluded from both the numerator and denominator in the proportion computation). Point estimates and 2-sided 95% exact CIs will be provided for the proportion of subjects with plasma HBV DNA < 20 IU/mL by visit and by study part (and cohort).
A secondary analysis using the Week 24 PP Analysis Set will also be performed to evaluate the robustness of the primary analysis of the primary endpoint.
6.1.4. Subgroup Analysis for the Primary Efficacy Endpoint
The primary analysis of the proportion of subjects who had HBV DNA < 20 IU/mL at Week 24 will be repeated using the M=F approach for each subgroup specified in Section 3.4 using the FAS.
6.2. Secondary Efficacy Endpoints
6.2.1. Definition of Secondary Efficacy Endpoints
The secondary efficacy endpoints are:
Proportion of subjects achieving virologic response (plasma HBV DNA < 20 IU/mL ) at Weeks 48 and 96
Proportion of subjects with plasma HBV DNA < 20 IU/mL and target detected/not detected (i.e. < LLOD) at Weeks 24, 48, and 96
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Proportion of subjects with serological response (loss of HBsAg and seroconversion to anti HBs, loss of HBeAg and seroconversion to anti-HBe in HBeAg-positive subjects) at Weeks 24, 48, and 96
Proportion of subjects with biochemical response (normal ALT and normalized ALT) at Weeks 24, 48, and 96
Change in fibrosis as assessed by FibroTest® at Weeks 24, 48, and 96
Change from baseline in CPT score and MELD score at Weeks 24, 48, and 96 in hepatically impaired subjects
The secondary efficacy endpoints at Weeks 48 and 96 will not be summarized using the primary analysis method (M=F) for the Week 24 analysis. Instead, they will be summarized in Week 48 and final analysis.
The following definitions will be used:
HBsAg loss is defined as HBsAg test result changing from HBsAg positive at baseline to HBsAg negative at a postbaseline visit with baseline HBsAb negative or missing.
HBsAg seroconversion is defined as HBsAg loss and HBsAb test result changing from HBsAb negative or missing at baseline to HBsAb positive at a postbaseline visit.
HBeAg loss is defined as HBeAg test result changing from HBeAg positive at baseline to HBeAg negative at a postbaseline visit with baseline HBeAb negative or missing
HBeAg seroconversion is defined as HBeAg loss and HBeAb test result changing from HBeAb negative or missing at baseline to HBeAb positive at a postbaseline visit
ALT normalization is defined as ALT > ULN (by central laboratory normal range or AASLD normal range) at baseline and within normal range at a postbaseline visit
Baseline and postbaseline borderline serology results will be imputed using the following rules:
HBsAg and HBeAg borderline will be considered as HBsAg positive and HBeAg positive.
HBsAb and HBeAb borderline will be considered as HBsAb negative and HBeAb negative
6.2.2. Analysis Methods for Secondary Efficacy Endpoints
The analyses for the secondary efficacy endpoints will be conducted using the FAS. All secondary efficacy endpoints involving proportions will be summarized using M = F by number and percentage of subjects that meet the endpoint by part (and cohort, for Part A). Sensitivity analyses will be performed using the M = E approach as well.
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The change from baseline in log10 (HBsAg) (IU/mL) and ALT (U/L) will be summarized by visit using observed data (ie, missing data will be excluded).
In addition, using the FAS, the proportion of subjects with HBV DNA < 20 IU/mL, the proportion of subjects with normal ALT by the central laboratory and 2018 AASLD criteria (ULN is 35 U/L for males and 25 U/L for females) using the M = F approach, and the mean change from baseline in log10 (HBsAg) (IU/mL) and ALT (U/L) will be plotted with 95% CI over time using observed data.
Fibrosis assessed by FibroTest® by visit, and the change from baseline in FibroTest® score will be summarized using descriptive statistics (sample size, mean, SD, median, Q1, Q3, minimum, and maximum) by part (and cohort, for Part A). A shift table of fibrosis stage based on FibroTest® score by visit will also be provided. Mean change from baseline in FibroTest® score will be plotted with 95% CI over time using observed data for FAS.
By-subject listing of HBV DNA, HBeAg and HBsAg loss/seroconversion, and fibrosis assessment by FibroTest® will also be provided.
The CPT score is calculated as: the sum of the scores related to the 5 items in the table below (if any of the components are missing, the score is not calculated):
Measure 1 point 2 points 3 points Total Bilirubin (mg/dL) < 2 2 - 3 > 3 Serum Albumin (g/dL) > 3.5 2.8 – 3.5 < 2.8 INR < 1.7 1.7 – 2.3 > 2.3 Ascites None Slight Moderate to Severe Hepatic Encephalopathy None Grade 1 - 2 Grade 3 - 4
For summary purposes, the score will be further classified into classes: Class A (5-6 points), Class B (7-9 points), and Class C (10-15 points). The change from baseline in CPT and MELD scores will be summarized by visit using descriptive statistics (sample size, mean, SD, median, Q1, Q3, minimum, and maximum) for FAS Part B subjects. The number and proportion of subjects in each class of CPT score will be summarized in a shift table with the baseline CPT class and the Week 24 CPT class based on FAS Part B subjects.
6.3. Changes From Protocol-Specified Efficacy Analyses
A modified US FDA-defined snapshot algorithm is added to this SAP as secondary analysis to summarize HBV DNA outcome at Week 24.
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7. SAFETY ANALYSES
Safety data during the treatment period will be summarized. All safety data, including data collected during the 24-week TFFU period will be included in data listings.
7.1. Adverse Events
7.1.1. Adverse Event Dictionary
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). System organ class (SOC), high-level group term (HLGT), high-level term (HLT), preferred term (PT), and lower-level term (LLT) will be attached to the clinical database.
7.1.2. Adverse Event Severity
Adverse events are graded by the investigator as Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) or Grade 4 (life threatening) according to toxicity criteria specified in Appendix 4 of the clinical study protocol. The severity grade of events for which the investigator did not record severity will be categorized as “missing” for tabular summaries and data listings, and will be considered the least severe for the purposes of sorting for data presentation.
7.1.3. Relationship of Adverse Events to Study Drug
Study drug-related AEs are those for which the investigator answers “Yes” to the question “Related to Study Treatment?” in the eCRF. Events for which the investigator did not record relationship to study drug will be considered related to study drug for summary purposes. Data listings will show the relationship as missing.
7.1.4. Relationship of Adverse Events to Study Procedures
Adverse events for which ‘Yes’ is marked for question ‘Related to Study Procedures?’ in the eCRF will be identified and included in AE listing.
7.1.5. Serious AEs
Serious adverse events (SAEs) are those identified as serious in the eCRF, where ‘Yes’ was marked for ‘AE serious’. The clinical database will be reconciled with the SAE database of Gilead Pharmacovigilance and Epidemiology (PVE) before database finalization.
7.1.6. Treatment-Emergent Adverse Events
7.1.6.1. Definition of Treatment Emergent
Treatment-emergent adverse events (TEAEs) are defined as:
Any AEs with an onset date on or after the study drug start date and no later than the study drug stop date + 3 days after permanent discontinuation of study drug
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Any AEs with onset date on or after the study drug start date for those who have not permanently discontinued study drug
Any AEs leading to premature discontinuation of study drug
7.1.6.2. Incomplete Dates
If an AE onset date is incomplete or completely missing, the following rules will be used to define TEAE:
Events with Missing Onset Day and/or Month
The event is treatment emergent if the following criteria are met:
The month and year (or year) of onset date is the same as or after the month and year (or year) of the first dose of study drug, and
For those who permanently discontinued study drug only: the month and year (or year) of onset date is the same as or before the month and year (or year) of the date of the last dose of study drug + 3 days, and
AE end date is as follows:
The (complete) end date is on or after the first dose date, or
The month and year (or year) of end date is the same or after the month and year (or year) of the first dose of study drug, or
End date is completely missing
Events with Completely Missing Onset Date
An AE with a completely missing onset date is defined as treatment-emergent AE if end date is as follows:
The (complete) end date is on or after the first dose date, or
The month and year (or year) of the end date is the same or after the month and year (or year) of the first dose of the study drug, or
End date is completely missing
7.1.7. Summaries of AEs and Deaths
A brief summary of AEs (ie, the number and percentage of subjects) will be presented by part (and cohort, for Part A) for the following: (1) any TEAE, (2) any Grade 3 or 4 TEAE, (3) any Grade 2, 3 or 4 TEAE, (4) any TE study drug-related AE, (5) any Grade 3 or 4 TE study
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TE death is defined using the same definition as TEAEs in Section 7.1.6.
Summaries (number and percentage of subjects) of AEs (by SOC, HLT [if specified below], and PT) will be provided by part (and cohort, for Part A) for the Safety Analysis Set as follows:
All TEAEs summarized by SOC, HLT, and PT
Any Grade 3 or 4 TEAEs
Any Grade 2, 3, or 4 TEAEs
All TE nonserious AEs occurring in at least 5% of subjects in either Part A Cohort 1 or Part B (this summary is generated per requirement for reporting in ClinicalTrials.gov), this summary does not apply to Part A Cohort 2 given the small number in this this group
All TE study drug-related AEs summarized by SOC, HLT, and PT
Any Grade 3 or 4 TE study drug-related AEs
Any Grade 2, 3, or 4 TE study drug-related AEs
All TE SAEs
All TE study drug-related SAEs
All TEAEs leading to premature discontinuation from study drug
All TEAEs leading to dose modification or study drug interruption Multiple events will be counted once only per subject in each summary. For data presentation, SOC (and HLT) will be ordered alphabetically, with PT sorted by decreasing total frequency. For summaries by severity grade, the most severe event will be selected.
Data listings will also be provided for the following:
All AEs
Grade 3 and 4 AEs
SAEs
Study drug-related SAEs
Deaths
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AEs leading to premature discontinuation of study drug
AEs leading to dose modification or study drug interruption
7.1.8. Potential Cardiovascular Events
Potential cardiovascular events are defined as events with PT in the selected PT listing, which was provided by Gilead PVE and (see Appendix 4).
A summary (number and percentage of subjects) of potential treatment-emergent cardiovascular events and serious cardiovascular events by PT will be provided by part (and cohort, for Part A) based on the Safety Analysis Set.
A data listing of potential cardiovascular events will be provided.
7.2. Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both quantitative and qualitative methods. Summaries of laboratory data will be provided for the Safety Analysis Set and will include on-treatment data collected for subjects who have permanently discontinued study drug or all available data at the time of the database finalization snapshot for subjects who are still on treatment at the time of analysis. The analysis will be based on values reported in conventional units. When values are below the LOQ, they will be listed as such, and the closest imputed value will be used for the purpose of calculating summary statistics, as specified in Section 3.7.
A by-subject listing for laboratory test results will be provided by subject ID number and visit in chronological order for hematology, serum chemistry, urine chemistry, and urinalysis separately. Values falling outside of the relevant reference range and/or having a severity grade of 1 or higher on the GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities/Antiviral Toxicity Grading Scale will be flagged in the data listings, as appropriate.
No formal statistical testing is planned.
7.2.1. Summaries of Numeric Laboratory Results
Descriptive statistics (sample size, mean, SD, median, Q1, Q3, minimum, and maximum) will be provided by part (and cohort, for Part A) for each laboratory test during the entire study period specified in the study protocol as follows:
Baseline values
Values at each postbaseline analysis window
Change from baseline to each postbaseline analysis window
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Percentage change from baseline to each postbaseline analysis window (if specified)
For serum creatinine and eGFR, summaries will be provided by part (and cohort, for Part A with no Part A total).
A baseline laboratory value is defined as the last measurement obtained on or prior to the date/time of first dose of study drug. Change from baseline to a postbaseline visit is defined as the visit value minus the baseline value. The mean, median, Q1, Q3, minimum, and maximum values will be displayed to the reported number of digits; SD values will be displayed to the reported number of digits plus 1.
Median (Q1, Q3) change from baseline for selected safety endpoints, including the fasting lipid panel parameters and fasting glucose over time, will be plotted by part (and cohort, for Part A).
In the case of multiple values in an analysis window, data will be selected for analysis as described in Section 3.8.2.
7.2.1.1. Metabolic Assessments
For the lipid panel and glucose measurements, only those obtained under fasting status will be summarized.
Fasting lipid data, including total cholesterol, LDL, HDL and triglycerides, will also be analyzed using the following National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III categories {National Cholesterol Education Program (NCEP) 2001}:
Total cholesterol (mg/dL): < 200 (desirable), 200−239 (borderline high), and ≥ 240 (high)
LDL (mg/dL): < 100 (optimal), 100−129 (near optimal/above optimal), 130−159 (borderline high), 160−189 (high), and ≥ 190 (very high)
HDL (mg/dL): < 40 (low), 40−59 (normal), and ≥ 60 (high)
triglycerides (mg/dL): < 150 (normal), 150−199 (borderline high), 200−499 (high), and ≥ 500 (very high)
The number and percentage of subjects in the above categories for each lipid parameter will be summarized by its baseline category by part (and cohort, for Part A) at each visit.
7.2.1.2. Calcium Corrected for Albumin
Calcium corrected for albumin will be calculated and summarized. The following formula will be used when both serum calcium and albumin results for a given blood sample are available and the serum albumin value is < 4.0 g/dL. Calcium corrected for albumin (mg/dL) = serum calcium (mg/dL) + 0.8 × (4.0 – albumin [g/dL])
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When albumin value is ≥ 4.0 g/dL, the actual calcium results will be used. Toxicity grading for calcium will be applied based on the corrected values. 7.2.1.3. Liver Function Tests Liver function tests will be summarized at each visit. PTH will be analyzed at all visits except screening.
7.2.2. Graded Laboratory Values The GSI grading scale will be used to grade laboratory results as Grade 0, Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) or Grade 4 (life threatening). Grade 0 includes all values that do not meet criteria for an abnormality of at least Grade 1. Some laboratory tests have criteria for both increased and decreased levels; analysis for each direction (ie, increased, decreased) will be presented separately. For triglycerides, LDL, and total cholesterol, the GSI grading scale is for fasting test values; nonfasting lipid results (or lipid results with unknown fasting status) will not be graded or summarized by toxicity grade. 7.2.2.1. Treatment-Emergent Laboratory Abnormalities Treatment-emergent laboratory abnormalities are defined as values that increase at least 1 toxicity grade from baseline at any post-baseline time point, up to and including the date of the last dose of study drug + 3 days for subjects who permanently discontinued study drug, or the last available date in the database snapshot for subjects who were still on treatment at the time of analysis. If the relevant baseline laboratory value is missing, any abnormality of at least Grade 1 observed within the time frame specified above will be considered treatment emergent. Fasting glucose and nonfasting glucose (including glucose results with an unknown fasting status) will be graded based on different grading scales as specified in the protocol. Treatment-emergent laboratory abnormalities will be summarized for fasting glucose. Since nonfasting glucose was not assessed at baseline, the maximum post-baseline grade will be summarized. 7.2.2.2. Treatment-Emergent Marked Laboratory Abnormalities
Treatment-emergent marked laboratory abnormalities are defined as values that increase from baseline by at least 3 toxicity grades at any post-baseline time point, up to and including the date of the last dose of study drug + 3 days for subjects who permanently discontinued study drug or the last available date in the database snapshot for subjects who were still on treatment at the time of analysis. If the relevant baseline laboratory value is missing, any Grade 3 or 4 values observed within the time frame specified above will be considered treatment-emergent marked abnormalities.
7.2.2.3. Summaries of Laboratory Abnormalities
The following summaries (number and percentage of subjects) of laboratory abnormalities will be provided by part (and cohort, for Part A), with subjects categorized according to the most severe abnormality grade):
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Treatment-emergent laboratory abnormalities
Treatment-emergent Grade 3 and 4 laboratory abnormalities
Treatment-emergent marked laboratory abnormalities
The number and percentage of subjects with graded laboratory abnormalities will be provided by part (and cohort, for Part A).
For all summaries of laboratory abnormalities, the denominator is the number of subjects with any non-missing post-baseline value in the given study period. By-subject listings of all graded laboratory abnormalities and of Grade 3 or 4 graded laboratory abnormalities will be provided by subject ID number and visit in chronological order.
7.2.3. ALT Elevation
An ALT elevation is defined as serum ALT > 2 × baseline value and > 10 × ULN, with or without associated symptoms. Confirmed ALT elevation (ie, ALT flare) is defined as ALT elevations at 2 consecutive post-baseline visits. All treatment-emergent ALT elevations, including ALT flares will be summarized by part (and cohort, for Part A). A by-subject listing will be provided for all treatment-emergent and nontreatment-emergent ALT elevations.
7.3. Bone Safety Analyses
7.3.1. BMD
The percentage change from baseline in hip BMD and spine BMD are secondary safety endpoints, and will be summarized by part (and cohort, for Part A) and visit based on observed data using descriptive statistics for subjects in the hip and spine DXA analysis sets, respectively.
For each subject and visit, the clinical BMD status is defined for hip and spine BMD based on the corrected t-score (Table 7-1).
Table 7-1. Normal, Osteopenia, and Osteoporosis as Defined by T-Score
Clinical Status BMD T-Score Normal t-score ≥ −1.0 Osteopenia −2.5 ≤ t-score < −1.0 Osteoporosis t-score < −2.5
The number and percentage of subjects in each clinical BMD status category (normal, osteopenia, and osteoporosis) will be summarized by part (and cohort, for Part A), visit, and baseline clinical status for both hip and spine using observed data.
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The number and percentage of subjects in each category based on percentage change from baseline in hip BMD and spine BMD (> 7% decrease, > 5% to ≤ 7% decrease, > 3% to ≤ 5% decrease, > 1% to ≤ 3% decrease, > 0 to ≤ 1% decrease, 0 to ≤ 1% increase, > 1% to ≤ 3% increase, > 3% to ≤ 5% increase, > 5% to ≤ 7% increase, > 7% increase) will be summarized by part (and cohort, for Part A) and visit using observed data.
Median (Q1, Q3) and mean (95% CIs) of percentage change from baseline in observed hip BMD and spine BMD over time will be plotted by part (and cohort, for Part A) for subjects in the corresponding hip and spine DXA analysis sets.
7.3.2. Bone Biomarkers
Bone biomarkers include serum CTX, P1NP, and PTH.
Baseline, postbaseline, change from baseline, and percentage change from baseline in bone biomarkers will be summarized by part (and cohort, for Part A) and visit using descriptive statistics (sample size, mean, SD, median, Q1, 3, minimum, and maximum) for the Safety Analysis Set.
Median (Q1, Q3) percentage change from the baseline in each bone biomarker by visit will be plotted by part (and cohort, for Part A) for subjects in the Safety Analysis Set.
7.3.3. Fracture Events
The PTs for fracture events were defined based on both Standardised MedDRA Query (SMQ) of Osteoporosis/Osteopenia and HLGT of Fractures from the most current version of MedDRA at the time of the analysis (see Appendix 3). Treatment-emergent fracture events will be summarized based on the identified PTs from SMQ alone and both SMQ and HLGT combined. The number and percentage of subjects who experienced fracture events will be summarized by part (and cohort, for Part A) for the Safety Analysis Set. A data listing of fracture events will be provided.
7.3.4. Assessment of Fracture Probability
Fracture probabilities will be assessed using FRAX, a computer-based algorithm developed by the World Health Organization (WHO; http://www.shef.ac.uk/FRAX).
The FRAX algorithm is based on individual patient models that integrate the risks associated with clinical risk factors, as well as BMD at the femoral neck. The algorithm provides both the 10-year probability of hip fracture and the 10-year probability of a major osteoporotic fracture (clinical spine, forearm, hip, or shoulder fracture).
The FRAX model is constructed from real data in population-based cohorts around the world that have a limited age range. For an age below 40 or above 90 years, the tool will calculate the probability of fracture at the age of 40 or 90 years, respectively. Due to the age limitation, 2 sets of analyses of fracture probabilities will be performed.
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In the first set of analyses, summaries of baseline and change from baseline in the 10-year probabilities of hip fracture, as well as major osteoporotic fracture, will be provided by part (and cohort, for Part A) and visit for subjects aged between 40 and 90 years in the Hip DXA Analysis Set.
In the second set of analyses, the above-specified analysis will be performed to include all subjects, where subjects with an age below 40 or above 90 years will be treated as having an age of 40 or 90 years, respectively, in computing their fracture probabilities.
By-subject listings of fracture risk assessment questionnaire and FRAX fracture probabilities will be provided.
7.3.5. Bone Events
The PTs for bone events are defined based on a search for bone disorder related AEs reviewed by Gilead PVE using the most current version of MedDRA at the time of the analysis (see Appendix 2). The number and percentage of subjects who experienced treatment-emergent bone events will be summarized by part (and cohort, for Part A) for the Safety Analysis Set. A by-subject listing of bone events will be provided.
7.4. Renal Safety Analyses
For all of the renal safety analyses, observed values will be used for subjects in the Safety Analysis Set.
7.4.1. Confirmed Renal Abnormalities
Confirmed renal abnormalities for Part A Cohort 1 subjects are defined as follows:
Confirmed increase from baseline in creatinine of at least 0.3 mg/dL or
Confirmed creatinine clearance (eGFRCG < 30 mL/min for Part A Cohort 1 moderate renal impairment, eGFRCG < 15 mL/min for Part A Cohort 1 severe renal impairment) or
Confirmed phosphorous < 2 mg/dL
Confirmed renal abnormalities for Part B subjects are defined as follows:
Confirmed increase from baseline in creatinine of at least 0.5 mg/dL or
Confirmed creatinine clearance eGFRCG < 50 mL/min or
Confirmed phosphorous < 2 mg/dL
Treatment-emergent confirmed renal abnormalities are defined as renal abnormalities at 2 consecutive post-baseline visits and not present at baseline. Treatment -emergent confirmed renal abnormalities will be summarized for Part A, Cohort 1 and Part B for the Safety Analysis Set. By-subject listings of confirmed renal abnormalities will be provided.
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7.4.2. Serum Creatinine
Baseline and change from baseline in serum creatinine will be summarized for Part A, Cohort 1 and Part B and by visit using descriptive statistics (sample size, mean, SD, median, Q1, Q3, minimum, and maximum).
Median (Q1, Q3) and mean (95% CIs) change from baseline in observed serum creatinine over time will be plotted for Part A, Cohort 1 and Part B for the Safety Analysis Set.
7.4.3. Estimated Glomerular Filtration Rate
The following formulae will be used to calculate eGFR:
Cockcroft-Gault (CG):
eGFRCG (mL/min) = [(140 – age (yrs)) × weight (kg) × (0.85 if female)] / (SCr (mg/dL) × 72),
where weight is actual total body mass in kilograms, and SCr is serum creatinine.
CKD-EPI (creatinine based: )
eGFRCKD-EPI, creatinine (mL/min/1.73 m2) = 141 × min(SCr/κ,1)α × max(SCr/κ,1)-1.209 × 0.993Age ×1.018 (if female) × 1.159 (if black),
where κ is 0.7 for females and 0.9 for males, α is –0.329 for females and –0.411 for males, min indicates the minimum of SCr/κ or 1, and max indicates the maximum of SCr/κ or 1 {Levey 2009}.
CKD-EPI cystatin C:
2 -0.499 -1.328 eGFRCKD-EPI, cysC (mL/min/1.73 m ) = 133 × min(SCys/0.8, 1) × max(SCys/0.8, 1) × 0.996age [× 0.932 if female], where SCys is serum cystatin C.
Change from baseline in eGFRCG and eGFRCKD-EPI, creatinine will be summarized for Part A, Cohort 1 and Part B by visit for the Safety Analysis Set based on observed data. The number and percentage of subjects with a decrease from baseline of ≥ 25% and ≥ 50% in eGFRCG and eGFR CKD-EPI, creatinine will be summarized for Part A, Cohort 1 and Part B. The number and percentage of subjects in the Safety Analysis Set at each stage CKD will be summarized for Part A, Cohort 1 and Part B. The stages of CKD are defined as follows:
Stage 1: eGFRCG ≥ 90 mL/min
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Stage 2: eGFRCG ≥ 60 and < 90 mL/min
Stage 3: eGFRCG ≥ 30 and < 60 mL/min
Stage 3a: eGFRCG ≥ 45 and < 60 mL/min
Stage 3b: eGFRCG ≥ 30 and < 45 mL/min
Stage 4: eGFRCG ≥ 15 and < 30 mL/min
Stage 5: eGFRCG < 15 mL/min
Median (Q1, Q3) change from the baseline in eGFRCG and eGFR CKD-EPI, creatinine by visit will be plotted for Part A, Cohort 1 and Part B.
7.4.4. Treatment-Emergent Proteinuria The number and percentage of subjects in the Safety Analysis Set with treatment-emergent proteinuria by urinalysis (dipstick) will be summarized by Part A, Cohort 1 and Part B. A by-subject listing of subjects with treatment-emergent proteinuria will be provided.
7.4.5. Urine Creatinine, Urine RBP to Creatinine Ratio and Beta-2-Microglobulin to Creatinine Ratio Baseline, postbaseline, and change from baseline in urine creatinine, RBP to creatinine ratio, and beta-2-microglobulin to creatinine ratio will be summarized for Part A, Cohort 1 and Part B by visit using descriptive statistics (sample size, mean, SD, median, Q1, Q3, minimum, and maximum). The median (Q1, Q3) percentage change from baseline in RBP to creatinine ratio, and beta-2-microglobulin to creatinine ratio by visit will be plotted for Part A, Cohort 1 and Part B.
7.4.6. Proteinuria by Quantitative Assessment
Baseline, post-baseline, changes from baseline, and percentage change from baseline in urine protein to creatinine ratio (UPCR) and urine albumin to creatinine ratio (UACR) will be summarized by Part A, Cohort 1 and Part B by visit for the Safety Analysis Set using descriptive statistics (sample size, mean, SD, median, Q1, Q3, minimum, and maximum).
The number and percentage of subjects with UPCR ≤ 200 mg/g versus > 200 mg/g will be summarized by baseline category for each postbaseline visit {KDIGO Guideline Development Staff 2013}.
The number and percentage of subjects with UACR < 30 mg/g versus ≥ 30 mg/g will be summarized by baseline category for each postbasline visit {KDIGO Guideline Development Staff 2013}.
The median (Q1, Q3) percentage change from baseline in UPCR and UACR by visit will be plotted by Part A, Cohort 1 and Part B.
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7.4.7. Other Renal Biomarkers
Other renal biomarkers include TmP/GFR, FEPO4, and FEUA.
TmP/GFR based on serum creatinine {Barth 2000} will be calculated as follows:
TmP / GFR TRP SPO4 if TRP .0 86
TmP GFR TRP TRP)8.0(1/3.0/ SPO4 if TRP .0 86 where TRP (tubular reabsoprtion of phosphate) is calculated by:
UPO SCr TRP 1 4 SPO4 UCr
where SCr is serum creatinine concentration (mg/dL), UPO4 is urine phosphate concentration (mg/dL), SPO4 is serum phosphate concentration, and UCr is urine creatinine concentration (mg/dL).
Urine FEPO4 will be calculated as follows:
FEPO4 (%) = (SCr × UPO4) / (SPO4 × UCr) × 100 (%)
Urine FEUA will be calculated as follows:
FEUA (%) = (SCr × UUa) / (SUa × UCr) × 100 (%)
where UUa and SUa are urine and serum uric acid (mg/dL), respectively.
The baseline, postbaseline, and change from baseline in TmP/GFR, FEPO4, and FEUA will be summarized for Part A, Cohort 1 and Part B and visit using descriptive statistics.
Median (Q1, Q3) change from the baseline in TmP/GFR, FEPO4, and FEUA by visit will be plotted for Part A, Cohort 1 and Part B.
7.5. Body Weight, Height, BMI, and Vital Signs
Descriptive statistics (sample size, mean, SD, median, Q1, Q3, minimum, and maximum) will be provided for the Safety Analysis Set by part (and cohort, for Part A) for body weight (kg), and BMI (kg/m2) as follows:
Baseline value
Values at each postbaseline visit
Change from baseline at each postbaseline visit
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A by-subject listing of vital signs, body weight (kg), height (m), and BMI (kg/m2) will be provided by subject ID number and time point in chronological order.
7.6. Prior Hepatitis B Medications
Prior HBV medications will be summarized by part (and cohort, for Part A). No inferential statistics will be computed. A by-subject listing of prior HBV medications will be provided.
7.7. Concomitant Medications
Concomitant medications (ie, medications other than study drug that are taken while receiving study drug) will be coded using the WHO Drug Dictionary. Use of concomitant medications during the treatment will be summarized (number and percentage of subjects) by Part (and Cohort, for Part A) and preferred name. Multiple drug use (by preferred name) will be counted only once per subject. The summary will be sorted by decreasing total frequency.
If the start or stop date of concomitant medications is incomplete, the month and year (or year alone if month is not recorded) of start or stop date will be used to determine if the medications are concomitant as follows. The medication is concomitant if the month and year of start or stop (or year of the start or stop) of the medication do not meet any of following criteria:
The month and year of start of the medication is after the date of the last dose of study drug
The month and year of stop of the medication is before the date of the first dose of study drug
If the start and stop date of the medications are not missing, and the start date is not after the last dose date and the stop date is not before the first dose date, or the medications are marked as ongoing and start date is on or before the last dose date, the medications are considered concomitant.
Summaries of concomitant medications will be provided for the Safety Analysis Set. No inferential statistics will be provided. Subjects with any concomitant medication use will also be listed.
7.8. Electrocardiogram (ECG) Results
As no ECG is collected at Week 24, it will be assessed at Week 48 and 96. The number and percentage of subjects in the Safety Analysis Set with an investigator’s ECG assessment of normal, abnormal but not clinically significant, or abnormal and clinically significant will be summarized by Part (and Cohort, for Part A) and by baseline result for each visit.
A by-subject listing of safety ECG results will be provided including treatment, assessment date and time, and ECG results.
7.9. Other Safety Measures
By-subject listing of subjects who became pregnant during the study, cirrhosis and hepatocellular carcinoma assessment results will be provided.
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7.10. Changes From Protocol-Specified Safety Analyses
The last-observation-carried-forward (LOCF) method to impute missing data for the secondary safety endpoints of change from baseline in eGFRCG and percent change from baseline in hip and spine BMD was specified in the study protocol. This is removed from the SAP and the analysis for these endpoints will be based on observed data.
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8. PATIENT REPORTED OUTCOMES
The effect of treatment on health-related QoL questionnaires (ie, SF-36, CLDQ, WPAI, and EQ-5D-3L) will be analyzed by visit for the Safety Analysis Set during the treatment period.
8.1. Definition of Patient Reported Outcomes
8.1.1. SF-36
The Short Form-36 (SF-36) includes 11 questions with multiple sub-questions that yield a total of 36 questions. The responses are rated on a 3-point, 5-point, or 6-point scale, and scoring are performed on 8 domains: Physical function (PF), Role physical (RP), Bodily Pain (BP), General health perceptions (GH), Vitality (VT), Social functioning (SF), Role emotional (RE), Mental health (MH).
Scale Item Abbreviated Item Content Physical Functioning (PF) 3a Vigorous activities, such as running, lifting heavy objects, or participating in strenuous sports 3b Moderate activities, such as moving a table, pushing a vacuum cleaner, bowling, or playing golf 3c Lifting or carrying groceries 3d Climbing several flights of stairs 3e Climbing one flight of stairs 3f Bending, kneeling, or stooping 3g Walking more than a mile 3h Walking several hundred yards 3i Walking one hundred yards 3j Bathing or dressing oneself Role-Physical (RP) 4a Cut down the amount of time one spent on work or other activities 4b Accomplished less than you would like 4c Limited in kind of work or other activities 4d Had difficulty performing work or other activities (e.g., it took extra effort) Bodily Pain (BP) 7 Intensity of bodily pain 8 Extent pain interfered with normal work
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Scale Item Abbreviated Item Content General Health (GH) 1 Is your health: excellent, very good, good, fair, poor 11a Seem to get sick a little easier than other people 11b As healthy as anybody I know 11c Expect my health to get worse 11d Health is excellent Vitality (VT) 9a Feel full of life 9e Have a lot of energy 9g Feel worn out 9i Feel tired Social Functioning (SF) 6 Extent health problems interfered with normal social activities 10 Frequency health problems interfered with social activities Role-Emotional (RE) 5a Cut down the amount of time spent on work or other activities 5b Accomplished less than you would like 5c Did work or other activities less carefully than usual Mental Health (MH) 9b Been very nervous 9c Felt so down in the dumps that nothing could cheer you up 9d Felt calm and peaceful 9f Felt downhearted and depressed 9h Been happy Health Transition (HT) 2 How health is now compared to before
Two summary scales will be presented based on the domain scores:
Physical component summary (PCS): combines PF, RP, BP, and GH
Mental component summary (MCS): combines VT, SF, RE, and MH
The summary scores aggregate information from the 8 SF-36 domains in a way that captures 80% to 85% of the variance in the 8 domains.
The SF-36 physical component and the mental component scores will be calculated based on the 8 domain scores using the SF-36v2 scoring method (http://www.sf-36.org/demos/SF-36v2.html).
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8.1.2. CLDQ
The Chronic Liver Disease Questionnaire (CLDQ) includes 29 questions which aim to survey how subjects felt during the last two weeks. The responses are rated on a 7-point scale, and translated into 6 domain scores: fatigue, activity, emotional function, abdominal symptoms, systemic symptoms, and worry, and an overall CLDQ score. Specifically,
Abdominal symptoms (AB) = Mean of {R1, R5, R17}
Fatigue (FA) = Mean of {R2, R4, R8, R11, R13}
Systemic (SY) = Mean of {R3, R6, R21, R23, R27}
Activity (AC) = Mean of {R7, R9, R14}
Emotion (EM) = Mean of {R10, R12, R15, R16, R19, R20, R24, R26}
Worry (WO) = Mean of {R18, R22, R25, R28, R29} where R# is the response to question number # (eg, R1 is the response to question 1).
The overall CLDQ score will then be calculated by taking the mean of 6 domain scores.
8.1.3. WPAI:SHP
The Work Productivity and Activity Impairment Questionnaire: Specific Health Hepatitis (WPAI: SHP) includes 6 questions that are summarized into a single overall WPAI:SHP score. The first question is to determine the employment status. Questions 2 through 5 are applicable to employed patients only. Using patient responses to six questions, four scores are derived:
percentage of absenteeism,
percentage of presenteeism (reduced productivity while at work),
an overall work impairment score that combines absenteeism and presenteeism and
percentage of impairment in activities performed outside of work.
Greater scores indicate greater impairment (http://www.reillyassociates.net/WPAI_Scoring.html).
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Score Source Formula Absenteeism Question 2: During the past seven days, how many hours 100 x [Q2/(Q2+Q4)] did you miss from work because of {your health problems}? Question 4: During the past seven days, how many hours did you actually work? Presenteesism Question 5: During the past seven days, how much did 100 x [(Q5)/10] {your health problems} affect your productivity while you were working? Work Question 2: During the past seven days, how many hours 100 x [Q2/(Q2+Q4) + Productivity did you miss from work because of {your health {1 – Q2/(Q2+Q4)}x(Q5)/10] Loss problems}? Question 4: During the past seven days, how many hours did you actually work? Question 5: During the past seven days, how much did {your health problems} affect your productivity while you were working? Activity Question 6: During the past seven days, how much did 100 x [(Q6)/10] Impairment {your health problems} affect your ability to do your regular daily activities, other than work at a job?
For the Work Productivity and Activity Impairment Questionnaire (WPAI-SHP), a single overall score will be calculated based on the results.
8.1.4. EuroQol - 5 Dimensions – 3 Levels (EQ-5D-3L)
The EQ-5D-3L consists of the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The EQ-5D-3L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, extreme problems. The EQ VAS records the respondent’s self-rated health on a vertical, visual analogue scale from 0 (“Worst imaginable health state”) to 100 (“Best imaginable health state”). This information can be used as a quantitative measure of health outcomes as judged by the individual respondent.
The possible responses/scores of the EQ-5D-3L descriptive system are described in the following Table.
Original Response Category Score
No problems 1
Some problems 2
Extreme problems 3
Note: Missing values is to be coded as 9. Ambiguous values (eg, 2 boxes are ticked for a single dimension) should be treated as missing values.
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8.2. Analysis Methods for Patient Reported Outcomes
Descriptive statistics for each of the SF-36 domains, and physical and component scores, CLDQ domain and overall scores, WPAI-SHP overall score, EQ-5D-3L EQ VAS, and change from baseline of these scores will be presented by part (and cohort, for Part A) and visit for the Safety Analysis Set during the treatment period. For EQ-5D-3L, number and percentage of subjects in response categories for each domain by visit will be summarized by part (and cohort, for Part A) for the Safety Analysis Set during the treatment period. -A by subject listing for the scores from each of the questionnaires will be provided by subject ID number and visits in chronological order.
8.3. Changes from Protocol-Specified Patient Reported Outcomes Analyses
There are no deviations from the protocol-specified patient reported outcomes analyses.
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9. PHARMACOKINETIC ANALYSES
9.1. PK Sample Collection
9.1.1. Sparse PK samples
A single PK blood sample will be collected at Baseline and each subsequent on-treatment visit for all subjects except Part A, Cohort 2 (ESRD subjects on HD). An additional PK sample will be collected between 15min-4 h post dose on Week 4, 8, a and 12 for all subjects except Part A, Cohort 2.
4 samples will be collected at each of 4 hemodialysis sessions between Weeks 4 and Week 24 inclusive for subjects in Part A, Cohort 2 (ESRD subjects on HD at selected sites).
9.1.2. Optional Intensive PK Substudy (separate consent required) CCI
9.2. PK Analyses Related to Intensive PK Sampling CCI
9.2.1. Estimation of PK Parameters
PK parameters will be estimated using Phoenix WinNonlin® software using standard noncompartmental methods. The linear/log trapezoidal rule will be used in conjunction with the appropriate noncompartmental model, with input values for dose level, dosing time, plasma concentration, and corresponding real-time values, based on drug dosing times whenever possible.
All predose sample times before time-zero will be converted to zero.
For area under the curve (AUC), samples BLQ of the bioanalytical assays occurring prior to the achievement of the first quantifiable concentration will be assigned a concentration value of 0 to prevent overestimation of the initial AUC. Samples that are BLQ at all other time points will be treated as missing data in WinNonlin. The nominal time point for a key event or dosing
CONFIDENTIAL Page 52 09 May 2019 Tenofovir Alafenamide GS-US-320-4035 Statistical Analysis Plan – Week 24 Analysis Final interval (τ) may be used to permit direct calculation of AUC over specific time intervals. The appropriateness of this approach will be assessed by the PK scientist on a profile-by-profile basis.
PK parameters such as AUCinf, λz and t1/2 are dependent on an accurate estimation of the terminal elimination phase of drug. The appropriateness of calculating these parameters will be evaluated upon inspection of PK data on a profile-by-profile basis by the PK scientist.
9.2.2. Pharmacokinetic Parameters
CCI
Table 9-1. Study Treatments and Associated Analytes
Treatment Group Treatment Analyte Part A Cohort 2: 25 mg TAF TAF and TFV ESRD subjects on HD Part B: Hepatic 25 mg TAF TAF and TFV impairment
The analytes and parameters presented in Table 9-1 and Table 9-2 will be used to evaluate the PK objectives of the study. The primary PK parameters are AUClast, AUC0-24, AUCinf, and Cmax of TAF and TFV. The PK parameters to be estimated in this study are listed and defined in the PK Abbreviations section.
Table 9-2. PK Parameters for Each Analyte
Analyte Parameters
TAF and TFV AUClast, AUC0-24, AUCinf, %AUCexp, Cmax, Tmax, Clast, Tlast, λz, CL/F, Vz/F, and t1/2
Individual subject concentration data and individual subject PK parameters for TAF and TFV will be listed and summarized using descriptive statistics by dose. Summary statistics (n, mean, SD, coefficient of variation [%CV], median, min, max, Q1, and Q3) will be presented for both individual subject concentration data by time point and individual subject PK parameters by dose. Moreover, the geometric mean, 95% CI, and the mean and SD of the natural log-transformed values will be presented for individual subject PK parameter data.
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Individual concentration data listings and summaries will include all subjects with concentration data. The sample size for each time point will be based on the number of subjects with non-missing concentration data at that time point. The number of subjects with concentration BLQ will be presented for each time point. For summary statistics, BLQ values will be treated as 0 at pre-dose and one-half of the LLOQ for post-dose time points.
Individual PK parameter data listings and summaries will include all subjects for whom PK parameters can be derived. The sample size for each PK parameter will be based on the number of subjects with non-missing data for that PK parameter.
The following tables will be provided for TAF and TFV by dose:
Individual subject concentration data and summary statistics
Individual subject plasma PK parameters and summary statistics
The following figures may be provided for TAF and TFV by dose:
Mean (± SD) concentration data versus time (on linear and semilogarithmic scales)
Median (Q1, Q3) concentration data versus time (on linear and semilogarithmic scales)
In addition, a figure may also be provided for individual subject concentration data vs. time (on linear and semilogarithmic scales).
Individual, mean, and median post-dose concentration values that are ≤ LLOQ will not be displayed in the figures and remaining points connected.
CCI
9.3. PK Analyses Related to Sparse PK Sampling
The following will be provided for TAF and TFV:
All subjects (except Part A, Cohort 2):
Pre-dose (baseline) individual subject concentration data will be listed and summarized using descriptive statistics by visit. Summary statistics (n, mean, SD, percent coefficient of variation [%CV], median, min, max, Q1, and Q3) will be presented for individual subject concentration data by visit.
Week 4, 8 and 12 (taken 14min-4 hour post-dose) concentration data will be listed (no summaries will be generated).
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Part A, Cohort 2
Individual subject concentration data will be listed and summarized using descriptive statistics by time point (10 min prior to HD, 1 h before HD concludes, and 10 min after HD). Summary statistics (n, mean, SD, percent coefficient of variation [%CV], median, min, max, Q1, and Q3) will be presented for individual subject concentration data by time point.
Individual concentration data listings and summaries will include all subjects with concentration data. The number of subjects with concentration BLQ will be presented for each time point. For summary statistics, BLQ values will be treated as 0 at predose and one-half of the LLOQ for postdose time points.
For all subjects in the PK Analysis Set, PK sampling details by subject (using concentration data from all sparse and intensive plasma PK sampling), including procedures, differences in scheduled and actual draw times, and sample age will be provided in a listing.
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10. REFERENCES
Barth JH, Jones RG, Payne RB. Calculation of renal tubular reabsorption of phosphate: the algorithm performs better than the nomogram. Ann Clin Biochem 2000;37 ( Pt 1):79-81.
KDIGO Guideline Development Staff. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney international. Supplement 2013;3 (1):v-150.
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150 (9):604- 12.
National Cholesterol Education Program (NCEP). Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Executive Summary. National Institute of Health May, 2001.
U. S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Testicular Toxicity: Evaluation During Drug Development Guidance for Industry: Draft Guidance. 2015.
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11. SOFTWARE
SAS® (SAS Institute Inc., Version 9.4, Cary, NC) is to be used for all programming of tables, listings, and figures.
WinNonlin® (Pharsight Corporation Version 6.3, Mountain View, CA) is to be used for all PK analyses.
FRAX® (WHO Collaborating Center for Metabolic Bone Disease, University of Sheffield, UK) is to be used for the 10-year probabilities of hip fracture or a major osteoporotic fracture.
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12. SAP REVISION
Revision Date (DD MMM YYYY) Section Summary of Revision Reason for Revision
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13. APPENDICES
Appendix 1. Study Procedures Table Appendix 2. Bone Events Appendix 3. Fracture Events Appendix 4 Potential Cardiovascular or Cerebrovascular Events
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Appendix 1. Study Procedures Table
Visit Windowsk ± 3 Days ± 14 Days Screening Baseline Week Week Week Week Week Week Week Week Week Study Procedures (45 days) (Day 1) 4 8 12 24k 36 48k 60 72 96k EDl Follow Upm Informed Consent x Inclusion/Exclusion Criteria x x Medical History (including HBV disease x x and treatment history) Concomitant Medications x xxxxxxxxxxx x Adverse Events x xxxxxxxxxxx x Complete Physical Examination with x x x x x x x weight and vital signsa Height x Body Weight x xxxxxxxxxxx x Vital Signsa x xxxxxxxxxxx x Symptom driven Physical Examination x x x x x x Health Related Quality of Life (CLDQ, x x x x x SF-36, WPAI, EQ-5D-3L)b Health Utilization Assessment x xxxxxxxxxx Serum Chemistry, Hematology, and Liver x xxxxxxxxxxx x Function Testsc Fasting Metabolic Assessmentd x x x x x x urine (+ve test to be confirmed with serum; serum test will also be collected if urine cannot be serum Pregnancy testing (women of child-bearing collected for subjects in Part A, Cohort 2 [ESRD subjects on HD]) potential only) x xxxxxxxxxxx Estimated Glomerular Filtration Rate by x xxxxxxxxxxx x Cockcroft-Gault method (eGFRCG) HBV serology (qualitative HBsAg and x x x x x x x x x x x HBeAg) and quantitative HBsAge
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Visit Windowsk ± 3 Days ± 14 Days Screening Baseline Week Week Week Week Week Week Week Week Week Study Procedures (45 days) (Day 1) 4 8 12 24k 36 48k 60 72 96k EDl Follow Upm HCV, HDV, HIV Testing x α-fetoprotein (AFP)f x Urinalysisg x xxxxxxxxxxx x Urine drug screeng x DXA scans (Hip & Spine)h x x x x x x ECGi x x x x Plasma HBV DNA level x xxxxxxxxxxx x FibroTest® x x x x x CPT and MELD Scores (Part B subjects x x x x x x [hepatic impairment] only)j Serum Cystatin Cn x Fasting Blood for Bone Biomarkers, x x x x x x x x Fasting Urine for Renal Biomarkerso Fracture Risk Assessment (FRAX) x Virology (Sequence analysis of HBV x xxxxxxxxxx pol/RT for resistance surveillance)p Vitamin D x x x Sparse Plasma PK (All subjects except x xxxxxxxxxx Part A, Cohort 2 [ESRD subjects on HD])q Sparse Plasma PK (Part A, Cohort 2 x x x x [ESRD subjects on HD])r CCI
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Visit Windowsk ± 3 Days ± 14 Days Screening Baseline Week Week Week Week Week Week Week Week Week Study Procedures (45 days) (Day 1) 4 8 12 24k 36 48k 60 72 96k EDl Follow Upm CCI x Serum, plasma, and urineg for storage x xxxxxxxxxx (serum only) Study Drug Accountability x x x x x x x x x Study Drug Dispensation x x x x x x x x x In-clinic Dosingt x x x x a Vital signs include blood pressure, pulse, respiration rate and temperature. b Health Related Quality of Life surveys required for Early Discontinuation (ED) visit if not done within the last 24 weeks of the expected ED visit date. c Serum chemistry and Liver Function Tests: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, BUN, calcium, chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric acid, and amylase (reflex lipase testing is performed in subjects with total amylase > 1.5 × ULN), and PTH. PTH analyzed at all visits except for Screening. At Baseline, Weeks 24, 48, 72, and 96/ED, analyses of glucose will be done as part of the fasting metabolic assessments and not as part of the chemistry panel. Liver Function Tests: PT/INR will be done at Screening, Baseline, and Weeks 24, 48, and 96/ED and then as a reflex only test for ALT flares. d Fasting glucose and lipid panel (total cholesterol, HDL, direct LDL, triglycerides). e HBeAb and HBsAb reflex testing will be performed as needed. f An AFP > 50 ng/mL at Screening must have an appropriate evaluation (e.g., CT scan if not performed within the previous 6 months) in order to rule out HCC prior to being permitted to enter the study. g Urine sample collection for all subjects except only where available for subjects in Part A, Cohort 2 (ESRD subjects on HD). h The Baseline DXA can be performed at any time during the Screening period, but should be completed at least 14 days prior to the first dose of study drug to ensure an acceptable pre-dose DXA scan. The Week 24, Week 48, and Week 96 DXA window is −14 days only. DXA required for Early Discontinuation (ED) visit if not done within the last 12 weeks and should be done within ± 14 days of the expected ED visit date. i Subjects must rest quietly in the supine position for a minimum of 5 minutes prior to the recording. j CPT assessment requires: total bilirubin, albumin, PT/INR, Ascites assessment, and Hepatic encephalopathy assessment. MELD assessment requires total bilirubin, serum creatinine, PT/INR, and serum sodium. k The visit window for the Week 24, Week 48, and Week 96 visits is −7 days only. l The Early Discontinuation (ED) visit should be performed within 72 hours of the last study drug dose (+ 3 days) m Subjects in Part A (renally impaired) who discontinue study drug due to HBsAg loss with confirmed seroconversion to anti-HBs on or after the Week 24 visit, will be followed off treatment every 4 weeks for 12 weeks and then per the original study visit schedule through Week 96/ED. Subjects in Part A (renally impaired) who have received at least one dose of study drug and permanently discontinue study drug for reasons other than HBsAg loss with confirmed seroconversion to anti-HBs will be followed every 4 weeks for 24 weeks off treatment or up to initiation of appropriate, alternative HBV therapy, whichever occurs first. Use of appropriate, alternative HBV therapy is strongly encouraged. For subjects in Part B (hepatic impairment) who permanently discontinue study drug, immediate initiation of appropriate, alternative HBV therapy is strongly recommended.
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n Any subject with a post baseline eGFRCG < 15 mL/min must have serum creatinine measured again within 3 calendar days of receipt of results. At the time of this repeat serum creatinine assessment, serum Cystatin C will also be measured and the eGFR by CKD-EPI (cystatin C) will be calculated and compared with the baseline measurement. Any subjects who have an eGFRCG < 15 mL/min that also experience > 20% reduction in eGFR by CKD-EPI (cystatin C) from baseline or who have other clinical and/or laboratory evidence of acute renal failure will be discussed with the Medical Monitor and may discontinue from study drugs. o Blood for selected bone biomarkers and urine for selected renal biomarkers will be collected in a fasted state. The fasting urine sample will be collected for all subjects except Part A, Cohort 2 (ESRD subjects on HD). Required for ED visit if the last sample was not collected within the last 12 weeks. p Resistance sequence analysis may be performed at Baseline for subjects with HBV DNA ≥ 69 IU/mL and may be attempted for viremic (HBV DNA ≥ 69 IU/mL) at Weeks 24, 48, and 96/ED. Phenotypic analysis will be performed for subjects that are subjected to sequence analysis. As it may not be known at the time of the visit whether a subject is viremic or if it will be their last study visit, a virology sample will be collected as each visit. In the event of unconfirmed virologic rebound (HBV DNA ≥ 20 IU/mL), subjects will be asked to return to the clinic for a scheduled or unscheduled blood draw. For virologic rebound occurring within the first 12 weeks of the study, the next scheduled visit will used for follow up. For virologic rebound occurring after Week 12, the subject will return for an unscheduled visit 2-3 weeks after the date of the original test that resulted with HBV DNA virologic rebound for confirmation of virologic rebound. At this follow up visit, a serum blood sample for resistance testing will be obtained. For unscheduled visits, the subject will be required to bring their supply of study drug with them and be assessed for adherence by pill count, and if necessary, the subject will be re-counseled on adherence to study medication. q For all subjects except Part A, Cohort 2 (ESRD subjects on HD): A single PK blood sample will be collected at Baseline and at each subsequent on treatment visit. At the Week 4, 8 and 12 visits, study drug will be administered in clinic, and the single PK blood sample will be collected between 15 minutes and 4 hours post dose. r For Part A, Cohort 2 (ESRD subjects on HD at selected sites): 4 PK blood samples total will be collected at each of 4 hemodialysis sessions between Weeks 4 and Week 24, inclusive: one sample collected within 10 minutes before a hemodialysis session begins, one sample each collected approximately 1 hour prior to conclusion of the hemodialysis session from both the arterial and venous sides of the dialyzer, and one sample collected within 10 minutes after a hemodialysis session concludes. On the day of hemodialysis, study drug should not be administered to subjects until after the completion of hemodialysis and collection of any required post-hemodialysis samples for Part A, Cohort 2. s CCI
t Dosing of study drug will occur in-clinic at the Weeks 4, 8, and 12 visits for subjects in Part A, Cohort 1 (moderate or severe renal impairment) and Part B (hepatic impairment). CCI
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Appendix 2. Bone Events The selected Preferred Terms of bone events based on MedDRA 21.1 are listed as follows:
Selected Preferred Terms Acetabulum fracture Ankle fracture Atypical femur fracture Atypical fracture Avulsion fracture Bone fissure Bone fragmentation Cervical vertebral fracture Chance fracture Clavicle fracture Comminuted fracture Complicated fracture Compression fracture Costal cartilage fracture Craniofacial fracture Epiphyseal fracture Facial bones fracture Femoral neck fracture Femur fracture Fibula fracture Flail chest Foot fracture Forearm fracture Fracture Fracture blisters Fracture delayed union Fracture displacement Fracture infection Fracture malunion Fracture nonunion Fracture of clavicle due to birth trauma
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Selected Preferred Terms Fractured coccyx Fractured ischium Fractured sacrum Fractured skull depressed Greenstick fracture Hand fracture Hip fracture Humerus fracture Ilium fracture Impacted fracture Jaw fracture Limb fracture Lisfranc fracture Lower limb fracture Lumbar vertebral fracture Maisonneuve fracture Metaphyseal corner fracture Multiple fractures Open fracture Osteochondral fracture Osteophyte fracture Osteoporotic fracture Patella fracture Pathological fracture Pelvic fracture Periprosthetic fracture Pseudarthrosis Pseudofracture Pubis fracture Radius fracture Rib fracture Sacroiliac fracture Scapula fracture
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Selected Preferred Terms Scapulothoracic dissociation Skull fracture Skull fractured base Spinal compression fracture Spinal fracture Spinal fusion fracture Sternal fracture Stress fracture Subchondral insufficiency fracture Thoracic vertebral fracture Tibia fracture Torus fracture Traumatic fracture Ulna fracture Upper limb fracture Wrist fracture Bone formation test Bone formation test abnormal Bone metabolism biochemical marker increased Bone resorption test Bone resorption test abnormal C-telopeptide C-telopeptide increased Deoxypyridinoline urine Deoxypyridinoline urine increased N-telopeptide N-telopeptide urine N-telopeptide urine abnormal N-telopeptide urine decreased N-telopeptide urine increased N-telopeptide urine normal Osteocalcin Osteocalcin decreased
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Selected Preferred Terms Osteocalcin increased Osteoprotegerin Osteoprotegerin decreased Osteoprotegerin increased Osteoprotegerin ligand Osteoprotegerin ligand decreased Pyridinoline urine Pyridinoline urine decreased Pyridinoline urine increased Tartrate-resistant acid phosphatase Tartrate-resistant acid phosphatase decreased Tartrate-resistant acid phosphatase increased Alveolar osteitis Aneurysmal bone cyst Bone callus excessive Bone contusion Bone cyst Bone development abnormal Bone disorder Bone erosion Bone fistula Bone formation decreased Bone formation increased Bone hyperpigmentation Bone infarction Bone lesion Bone loss Bone sequestrum Callus formation delayed Cemento osseous dysplasia Cystic angiomatosis Degenerative bone disease Dental alveolar anomaly
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Selected Preferred Terms Dental cyst Enostosis Erdheim-Chester disease Exostosis Exostosis of external ear canal Exostosis of jaw Exposed bone in jaw Extraskeletal ossification Hyperphosphatasaemia Hypertrophic osteoarthropathy Inadequate osteointegration Jaw cyst Jaw disorder Jaw fistula Malacoplakia of bone Medial tibial stress syndrome Melorheostosis Osteitis Osteitis condensans Osteitis deformans Osteonecrosis Osteonecrosis of external auditory canal Osteonecrosis of jaw Osteoradionecrosis Osteorrhagia Osteosclerosis Osteosis Periosteal haematoma Periostitis Periostitis hypertrophic Periostosis Periprosthetic osteolysis Peri-spinal heterotopic ossification
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Selected Preferred Terms Post transplant distal limb syndrome Post-traumatic osteoporosis Radiation osteitis Skeletal injury Spinal column injury Spinal disorder Sternal injury Vertebral column mass Vertebral lesion Vertebral wedging Bone atrophy Bone decalcification Bone metabolism disorder Brown tumour Chronic kidney disease-mineral and bone disorder Craniotabes Gorham's disease Hereditary hypophosphataemic rickets High turnover osteopathy Hungry bone syndrome Hypochondroplasia Hypophosphataemic osteomalacia Idiopathic condylar resorption Itai-itai disease Low turnover osteopathy Osteolysis Osteomalacia Osteopenia Osteoporosis Osteoporosis circumscripta cranii Osteoporosis postmenopausal Osteoporotic fracture Pseudofracture
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Selected Preferred Terms Rachitic rosary Resorption bone decreased Resorption bone increased Rickets Senile osteoporosis Spinal compression fracture Bone marrow oedema Bone marrow oedema syndrome Bone pain Bone swelling Coccydynia Eagle's syndrome Metatarsalgia Os trigonum syndrome Pain in jaw Pubic pain Spinal pain Astragalectomy Bone cyst excision Bone debridement Bone electrostimulation therapy Bone graft Bone graft removal Bone lesion excision Bone operation Bone prosthesis insertion Bone trimming Cementoplasty Cheilectomy Distraction osteogenesis Epiphyseal surgery Epiphysiodesis Femoral derotation osteotomy
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Selected Preferred Terms Orthopaedic procedure Ostectomy Osteomyelitis drainage Osteopathic treatment Osteoporosis prophylaxis Osteotomy Removal of epiphyseal fixation Removal of external fixation Removal of internal fixation Sequestrectomy Sesamoidectomy Calcification metastatic Calciphylaxis Calcium deficiency Calcium intoxication Calcium metabolism disorder Chondrocalcinosis pyrophosphate Chvostek's sign Dent's disease Familial hypocalciuric hypercalcaemia Familial isolated hyperparathyroidism Gastric mucosal calcinosis Hypercalcaemia Hypercalcaemia of malignancy Hypercalcaemic nephropathy Hypercalcitoninaemia Hypercalciuria Hyperparathyroidism Hyperparathyroidism primary Hyperparathyroidism secondary Hyperparathyroidism tertiary Hypocalcaemia Hypocalcaemic seizure
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Selected Preferred Terms Hypocalciuria Hypoparathyroidism Hypoparathyroidism secondary Latent tetany Neonatal hypocalcaemia Parathyroid hyperplasia Periarthritis calcarea Post procedural hypoparathyroidism Primary familial brain calcification Primary hypoparathyroidism Pseudohypercalcaemia Pseudohypoparathyroidism Tetany Tooth demineralisation Trousseau's sign Williams syndrome Congenital syphilitic osteochondritis Epiphyseal disorder Epiphyseal injury Epiphyses delayed fusion Epiphyses premature fusion Epiphysiolysis Epiphysitis Perthes disease Closed fracture manipulation External fixation of fracture Fracture debridement Fracture reduction Fracture treatment Fractured maxilla elevation Fractured zygomatic arch elevation Internal fixation of fracture Intramedullary rod insertion
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Selected Preferred Terms Open reduction of fracture Skeletal traction Surgical fixation of rib fracture Ankle fracture Anterior labroligamentous periosteal sleeve avulsion lesion Atypical femur fracture Bankart lesion Clavicle fracture Epiphyseal fracture Femoral neck fracture Femur fracture Fibula fracture Foot fracture Forearm fracture Fracture of clavicle due to birth trauma Greenstick fracture Hand fracture Hip fracture Humerus fracture Limb fracture Lisfranc fracture Lower limb fracture Maisonneuve fracture Osteochondral fracture Patella fracture Radial head dislocation Radius fracture Scapula fracture Scapulothoracic dissociation Tibia fracture Torus fracture Ulna fracture Upper limb fracture
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Selected Preferred Terms Wrist fracture Amputation Arm amputation Calcanectomy Finger amputation Finger repair operation Foot amputation Foot operation Gluteoplasty Hand amputation Hand repair operation Hip disarticulation Interscapulothoracic amputation Leg amputation Limb amputation Limb immobilisation Limb operation Limb reattachment surgery Limb reconstructive surgery Metacarpal excision Metatarsal excision Microsurgery to hand Rotationplasty Talipes correction Toe amputation Toe operation Trapeziectomy Alveolar bone resorption Bone atrophy Bone decalcification Bone metabolism disorder Brown tumour Chronic kidney disease-mineral and bone disorder
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Selected Preferred Terms Dwarfism High turnover osteopathy Hungry bone syndrome Hypophosphataemic osteomalacia Idiopathic condylar resorption Itai-itai disease Low turnover osteopathy Osteodystrophy Osteolysis Osteomalacia Osteopenia Osteoporosis Osteoporosis circumscripta cranii Osteoporosis postmenopausal Renal rickets Resorption bone decreased Resorption bone increased Rickets Senile osteoporosis Aspiration bursa Aspiration bursa abnormal Aspiration bursa normal Aspiration joint Aspiration joint abnormal Aspiration joint normal Biopsy abdominal wall Biopsy abdominal wall abnormal Biopsy abdominal wall normal Biopsy bone Biopsy bone abnormal Biopsy bone normal Biopsy cartilage Biopsy cartilage abnormal
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Selected Preferred Terms Biopsy cartilage normal Biopsy chest wall Biopsy chest wall abnormal Biopsy chest wall normal Biopsy ligament Biopsy ligament abnormal Biopsy ligament normal Biopsy muscle Biopsy muscle abnormal Biopsy muscle normal Biopsy soft tissue Biopsy tendon Biopsy tendon abnormal Biopsy tendon normal Intervertebral disc biopsy Synovial biopsy Synovial biopsy abnormal Synovial fluid cell count Synovial fluid crystal Synovial fluid crystal present Synovial fluid red blood cells Synovial fluid red blood cells positive Synovial fluid white blood cells Synovial fluid white blood cells positive Arthrogram Arthrogram abnormal Arthrogram normal Arthroscopy Arthroscopy abnormal Arthroscopy normal Bone densitometry Bone density abnormal Bone density decreased
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Selected Preferred Terms Bone density increased Bone scan Bone scan abnormal Bone scan normal Computerised tomogram spine Discogram Discogram abnormal Discogram normal Face and mouth X-ray Face and mouth X-ray abnormal Face and mouth X-ray normal Nuclear magnetic resonance imaging joint Nuclear magnetic resonance imaging neck Orthoroentgenogram Skeletal survey Skeletal survey abnormal Skeletal survey normal Skull X-ray Skull X-ray abnormal Skull X-ray normal Spinal X-ray Spinal X-ray abnormal Spinal X-ray normal Ultrasound joint X-ray limb X-ray limb abnormal X-ray limb normal X-ray of pelvis and hip X-ray of pelvis and hip abnormal X-ray of pelvis and hip normal Acetabulum fracture Fractured ischium Ilium fracture
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Selected Preferred Terms Pelvic fracture Pubis fracture Sacroiliac fracture Acute phosphate nephropathy Hyperphosphataemia Hyperphosphaturia Hypophosphataemia Phosphorus metabolism disorder Pseudohyperphosphataemia Renal rickets Craniofacial fracture Facial bones fracture Fractured skull depressed Jaw fracture Skull fracture Skull fractured base Cervical vertebral fracture Chance fracture Dislocation of vertebra Fractured coccyx Fractured sacrum Intervertebral disc injury Lumbar vertebral fracture Spinal compression fracture Spinal fracture Spinal fusion fracture Thoracic vertebral fracture Ankle arthroplasty Ankle operation Arthrectomy Arthrolysis Arthroscopic surgery Arthrotomy
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Selected Preferred Terms Baker's cyst excision Bone groove deepening Bunion operation Capsulorrhaphy Delayed spinal fusion Elbow operation Epiphyseal injury Flail chest Incomplete spinal fusion Knee arthroplasty Knee operation Ligament operation Maxillonasal dysplasia Meniscus operation Meniscus removal Patella replacement Patellectomy Radiolucency around implant Radiotherapy to joint Removal of foreign body from joint Rheumatoid nodule removal Rotator cuff repair Scapholunate dissociation Shoulder arthroplasty Shoulder operation Stapes fracture Synovectomy Synoviorthesis Temporomandibular joint surgery Tophus removal operation Atypical femur fracture Carpal collapse Osteonecrosis
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Selected Preferred Terms Osteonecrosis of external auditory canal Osteonecrosis of jaw Osteoradionecrosis Perthes disease Abscess jaw Abscess oral Alveolar osteitis Arthrodesis Biopsy bone abnormal Bone abscess Bone debridement Bone graft Bone infarction Bone loss Bone pain Bone scan abnormal Bone sequestrum Candida osteomyelitis Chronic recurrent multifocal osteomyelitis Dental necrosis Exposed bone in jaw Face and mouth X-ray abnormal Groin pain Hip arthroplasty Hip surgery Jaw fistula Jaw lesion excision Jaw operation Joint arthroplasty Joint prosthesis user Joint resurfacing surgery Maxillofacial operation Oral surgery
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Selected Preferred Terms Oroantral fistula Osteitis Osteoarthropathy Osteomyelitis Osteomyelitis acute Osteomyelitis bacterial Osteomyelitis blastomyces Osteomyelitis chronic Osteomyelitis drainage Osteomyelitis fungal Osteomyelitis salmonella Osteomyelitis viral Osteotomy Pain in jaw Periodontal destruction Resorption bone increased Sequestrectomy Staphylococcal osteomyelitis Subperiosteal abscess Tooth abscess Tooth infection X-ray dental abnormal X-ray limb abnormal X-ray of pelvis and hip abnormal Bone density decreased Bone formation decreased Bone loss Bone marrow oedema syndrome Osteopenia Osteoporosis Osteoporosis postmenopausal Osteoporotic fracture Resorption bone increased
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Selected Preferred Terms Senile osteoporosis Acetabulum fracture Atypical femur fracture Body height abnormal Body height below normal Body height decreased Bone density abnormal Bone formation test abnormal Bone metabolism biochemical marker increased Bone metabolism disorder Bone resorption test abnormal Cervical vertebral fracture Closed fracture manipulation C-telopeptide increased Deoxypyridinoline urine increased External fixation of fracture Femoral neck fracture Femur fracture Forearm fracture Fracture Fracture treatment Fractured ischium Fractured sacrum Hip arthroplasty Hip fracture Hip surgery Ilium fracture Internal fixation of fracture Kyphoscoliosis Kyphosis Lumbar vertebral fracture Multiple fractures N-telopeptide urine increased
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Selected Preferred Terms Open reduction of fracture Open reduction of spinal fracture Osteocalcin increased Osteoporosis prophylaxis Pathological fracture Pelvic fracture Post-traumatic osteoporosis Pubis fracture Pyridinoline urine increased Radius fracture Rib fracture Sacroiliac fracture Serum procollagen type I N-terminal propeptide decreased Spinal compression fracture Spinal deformity Spinal fracture Subchondral insufficiency fracture Tartrate-resistant acid phosphatase decreased Thoracic vertebral fracture Vertebral body replacement Vertebroplasty Wrist fracture Wrist surgery
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Appendix 3. Fracture Events The selected Preferred Terms of fracture events from SMQ of Osteoporosis/Osteopenia and HLGT of Fractures based on MedDRA 21.1 are listed as follows:
Selection Type Selected Preferred Term HLGT Fractures Acetabulum fracture HLGT Fractures Ankle fracture HLGT Fractures Atypical femur fracture HLGT Fractures Atypical fracture HLGT Fractures Avulsion fracture HLGT Fractures Bone fissure HLGT Fractures Bone fragmentation HLGT Fractures Cervical vertebral fracture HLGT Fractures Chance fracture HLGT Fractures Clavicle fracture HLGT Fractures Comminuted fracture HLGT Fractures Complicated fracture HLGT Fractures Compression fracture HLGT Fractures Costal cartilage fracture HLGT Fractures Craniofacial fracture HLGT Fractures Epiphyseal fracture HLGT Fractures Facial bones fracture HLGT Fractures Femoral neck fracture HLGT Fractures Femur fracture HLGT Fractures Fibula fracture HLGT Fractures Flail chest HLGT Fractures Foot fracture HLGT Fractures Forearm fracture HLGT Fractures Fracture HLGT Fractures Fracture blisters HLGT Fractures Fracture delayed union HLGT Fractures Fracture displacement HLGT Fractures Fracture infection HLGT Fractures Fracture malunion HLGT Fractures Fracture nonunion
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Selection Type Selected Preferred Term HLGT Fractures Fracture of clavicle due to birth trauma HLGT Fractures Fractured coccyx HLGT Fractures Fractured ischium HLGT Fractures Fractured sacrum HLGT Fractures Fractured skull depressed HLGT Fractures Greenstick fracture HLGT Fractures Hand fracture HLGT Fractures Hip fracture HLGT Fractures Humerus fracture HLGT Fractures Ilium fracture HLGT Fractures Impacted fracture HLGT Fractures Jaw fracture HLGT Fractures Limb fracture HLGT Fractures Lisfranc fracture HLGT Fractures Lower limb fracture HLGT Fractures Lumbar vertebral fracture HLGT Fractures Maisonneuve fracture HLGT Fractures Metaphyseal corner fracture HLGT Fractures Multiple fractures HLGT Fractures Open fracture HLGT Fractures Osteochondral fracture HLGT Fractures Osteophyte fracture HLGT Fractures Osteoporotic fracture HLGT Fractures Patella fracture HLGT Fractures Pathological fracture HLGT Fractures Pelvic fracture HLGT Fractures Periprosthetic fracture HLGT Fractures Pseudarthrosis HLGT Fractures Pseudofracture HLGT Fractures Pubis fracture HLGT Fractures Radius fracture HLGT Fractures Rib fracture HLGT Fractures Sacroiliac fracture HLGT Fractures Scapula fracture
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Selection Type Selected Preferred Term HLGT Fractures Scapulothoracic dissociation HLGT Fractures Skull fracture HLGT Fractures Skull fractured base HLGT Fractures Spinal compression fracture HLGT Fractures Spinal fracture HLGT Fractures Spinal fusion fracture HLGT Fractures Sternal fracture HLGT Fractures Stress fracture HLGT Fractures Subchondral insufficiency fracture HLGT Fractures Thoracic vertebral fracture HLGT Fractures Tibia fracture HLGT Fractures Torus fracture HLGT Fractures Traumatic fracture HLGT Fractures Ulna fracture HLGT Fractures Upper limb fracture HLGT Fractures Wrist fracture SMQ Osteoporosis/Osteopenia Bone density decreased SMQ Osteoporosis/Osteopenia Bone formation decreased SMQ Osteoporosis/Osteopenia Bone loss SMQ Osteoporosis/Osteopenia Bone marrow oedema syndrome SMQ Osteoporosis/Osteopenia Osteopenia SMQ Osteoporosis/Osteopenia Osteoporosis SMQ Osteoporosis/Osteopenia Osteoporosis postmenopausal SMQ Osteoporosis/Osteopenia Osteoporotic fracture SMQ Osteoporosis/Osteopenia Resorption bone increased SMQ Osteoporosis/Osteopenia Senile osteoporosis SMQ Osteoporosis/Osteopenia Acetabulum fracture SMQ Osteoporosis/Osteopenia Atypical femur fracture SMQ Osteoporosis/Osteopenia Body height abnormal SMQ Osteoporosis/Osteopenia Body height below normal SMQ Osteoporosis/Osteopenia Body height decreased SMQ Osteoporosis/Osteopenia Bone density abnormal SMQ Osteoporosis/Osteopenia Bone formation test abnormal SMQ Osteoporosis/Osteopenia Bone metabolism biochemical marker increased
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Selection Type Selected Preferred Term SMQ Osteoporosis/Osteopenia Bone metabolism disorder SMQ Osteoporosis/Osteopenia Bone resorption test abnormal SMQ Osteoporosis/Osteopenia Cervical vertebral fracture SMQ Osteoporosis/Osteopenia Closed fracture manipulation SMQ Osteoporosis/Osteopenia C-telopeptide increased SMQ Osteoporosis/Osteopenia Deoxypyridinoline urine increased SMQ Osteoporosis/Osteopenia External fixation of fracture SMQ Osteoporosis/Osteopenia Femoral neck fracture SMQ Osteoporosis/Osteopenia Femur fracture SMQ Osteoporosis/Osteopenia Forearm fracture SMQ Osteoporosis/Osteopenia Fracture SMQ Osteoporosis/Osteopenia Fracture treatment SMQ Osteoporosis/Osteopenia Fractured ischium SMQ Osteoporosis/Osteopenia Fractured sacrum SMQ Osteoporosis/Osteopenia Hip arthroplasty SMQ Osteoporosis/Osteopenia Hip fracture SMQ Osteoporosis/Osteopenia Hip surgery SMQ Osteoporosis/Osteopenia Ilium fracture SMQ Osteoporosis/Osteopenia Internal fixation of fracture SMQ Osteoporosis/Osteopenia Kyphoscoliosis SMQ Osteoporosis/Osteopenia Kyphosis SMQ Osteoporosis/Osteopenia Lumbar vertebral fracture SMQ Osteoporosis/Osteopenia Multiple fractures SMQ Osteoporosis/Osteopenia N-telopeptide urine increased SMQ Osteoporosis/Osteopenia Open reduction of fracture SMQ Osteoporosis/Osteopenia Open reduction of spinal fracture SMQ Osteoporosis/Osteopenia Osteocalcin increased SMQ Osteoporosis/Osteopenia Osteoporosis prophylaxis SMQ Osteoporosis/Osteopenia Pathological fracture SMQ Osteoporosis/Osteopenia Pelvic fracture SMQ Osteoporosis/Osteopenia Post-traumatic osteoporosis SMQ Osteoporosis/Osteopenia Pubis fracture SMQ Osteoporosis/Osteopenia Pyridinoline urine increased SMQ Osteoporosis/Osteopenia Radius fracture
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Selection Type Selected Preferred Term SMQ Osteoporosis/Osteopenia Rib fracture SMQ Osteoporosis/Osteopenia Sacroiliac fracture SMQ Osteoporosis/Osteopenia Serum procollagen type I N-terminal propeptide decreased SMQ Osteoporosis/Osteopenia Spinal compression fracture SMQ Osteoporosis/Osteopenia Spinal deformity SMQ Osteoporosis/Osteopenia Spinal fracture SMQ Osteoporosis/Osteopenia Subchondral insufficiency fracture SMQ Osteoporosis/Osteopenia Tartrate-resistant acid phosphatase decreased SMQ Osteoporosis/Osteopenia Thoracic vertebral fracture SMQ Osteoporosis/Osteopenia Vertebral body replacement SMQ Osteoporosis/Osteopenia Vertebroplasty SMQ Osteoporosis/Osteopenia Wrist fracture SMQ Osteoporosis/Osteopenia Wrist surgery
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Appendix 4 Potential Cardiovascular or Cerebrovascular Events The selected Preferred Terms of potential cardiovascular or cerebrovascular events based on MedDRA 21.1 are listed as follows:
Selected Preferred Terms Amaurosis fugax Basal ganglia infarction Basal ganglia stroke Basilar artery occlusion Basilar artery stenosis Basilar artery thrombosis Brachiocephalic arteriosclerosis Brachiocephalic artery occlusion Brachiocephalic artery stenosis Brain hypoxia Brain stem embolism Brain stem infarction Brain stem ischaemia Brain stem stroke Brain stem thrombosis Brain stent insertion CADASIL Capsular warning syndrome CARASIL syndrome Carotid angioplasty Carotid arterial embolus Carotid arteriosclerosis Carotid artery bypass Carotid artery disease Carotid artery insufficiency Carotid artery occlusion Carotid artery restenosis Carotid artery stenosis Carotid artery stent insertion Carotid artery stent removal
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Selected Preferred Terms Carotid artery thrombosis Carotid endarterectomy Carotid revascularization Cerebellar artery occlusion Cerebellar artery thrombosis Cerebellar embolism Cerebellar infarction Cerebellar ischaemia Cerebellar stroke Cerebral arteriosclerosis Cerebral artery embolism Cerebral artery occlusion Cerebral artery restenosis Cerebral artery stenosis Cerebral artery thrombosis Cerebral gas embolism Cerebral infarction Cerebral infarction foetal Cerebral ischaemia Cerebral microembolism Cerebral revascularisation Cerebral septic infarct Cerebral small vessel ischaemic disease Cerebral thrombosis Cerebral vascular occlusion Cerebral vasoconstriction Cerebral venous thrombosis Cerebrovascular accident Cerebrovascular disorder Cerebrovascular insufficiency Cerebrovascular stenosis Delayed ischaemic neurological deficit Embolic cerebral infarction
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Selected Preferred Terms Embolic stroke Hypoxic-ischaemic encephalopathy Inner ear infarction Ischaemic cerebral infarction Ischaemic stroke Lacunar infarction Lacunar stroke Lateral medullary syndrome Migrainous infarction Millard-Gubler syndrome Moyamoya disease Perinatal stroke Post cardiac arrest syndrome Post procedural stroke Precerebral arteriosclerosis Precerebral artery occlusion Reversible cerebral vasoconstriction syndrome Reversible ischaemic neurological deficit Spinal artery embolism Spinal artery thrombosis Spinal cord infarction Spinal cord ischaemia Stroke in evolution Subclavian steal syndrome Thalamic infarction Thrombotic cerebral infarction Thrombotic stroke Transient ischaemic attack Vascular encephalopathy Vascular stent occlusion Vascular stent stenosis Vertebral artery occlusion Vertebral artery stenosis
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Selected Preferred Terms Vertebral artery thrombosis Vertebrobasilar insufficiency Acute cardiac event Acute coronary syndrome Acute myocardial infarction Angina unstable Blood creatine phosphokinase MB abnormal Blood creatine phosphokinase MB increased Coronary artery embolism Coronary artery occlusion Coronary artery reocclusion Coronary artery thrombosis Coronary bypass thrombosis Coronary vascular graft occlusion Kounis syndrome Myocardial infarction Myocardial necrosis Myocardial reperfusion injury Myocardial stunning Papillary muscle infarction Periprocedural myocardial infarction Post procedural myocardial infarction Postinfarction angina Silent myocardial infarction Troponin I increased Troponin increased Troponin T increased Blood creatine phosphokinase abnormal Blood creatine phosphokinase increased Cardiac ventricular scarring ECG electrically inactive area ECG signs of myocardial infarction Electrocardiogram Q wave abnormal
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Selected Preferred Terms Electrocardiogram ST segment abnormal Electrocardiogram ST segment elevation Electrocardiogram ST-T segment elevation Electrocardiogram U wave inversion Infarction Myocardial necrosis marker increased Scan myocardial perfusion abnormal Vascular graft occlusion Vascular stent occlusion Vascular stent thrombosis Acute cardiac event Angina pectoris Angina unstable Anginal equivalent Arteriosclerosis coronary artery Arteriospasm coronary Coronary angioplasty Coronary arterial stent insertion Coronary artery bypass Coronary artery compression Coronary artery disease Coronary artery dissection Coronary artery insufficiency Coronary artery restenosis Coronary artery stenosis Coronary artery surgery Coronary brachytherapy Coronary bypass stenosis Coronary endarterectomy Coronary no-reflow phenomenon Coronary ostial stenosis Coronary revascularisation Coronary vascular graft stenosis
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Selected Preferred Terms Diabetic coronary microangiopathy Dissecting coronary artery aneurysm ECG signs of myocardial ischaemia External counterpulsation Haemorrhage coronary artery Ischaemic cardiomyopathy Ischaemic mitral regurgitation Microvascular coronary artery disease Myocardial hypoxia Myocardial ischaemia Percutaneous coronary intervention Prinzmetal angina Stress cardiomyopathy Subclavian coronary steal syndrome Subendocardial ischaemia Wellens' syndrome Arteriogram coronary abnormal Cardiac stress test abnormal Cardiopulmonary exercise test abnormal Cardiovascular event prophylaxis Computerised tomogram coronary artery abnormal Electrocardiogram PR segment depression Electrocardiogram ST segment depression Electrocardiogram ST-T segment abnormal Electrocardiogram ST-T segment depression Electrocardiogram T wave abnormal Electrocardiogram T wave inversion Electrocardiogram U wave inversion Exercise electrocardiogram abnormal Exercise test abnormal
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Selected Preferred Terms Post angioplasty restenosis Stress echocardiogram abnormal Vascular stent stenosis Wall motion score index abnormal
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PPD Biostatistics eSigned 09-May-2019 - 22:15:56