Clinical trial NCT02339415
Conditions: Inflammation Coagulation HIV Infection
Sponsor: Hennepin Healthcare Research Institute
Start date: 2015-07-01; Completion date: 2018-09-01
Enrollment: 44 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to evaluate the effects of pharmacologic FXa inhibition (via edoxaban 30 mg daily) on inflammation, as reflected in plasma Interleukin-6 levels.

Detailed description:
We hypothesize that increased generation of activated factor X (FXa) contributes to a systemic elevation in pro-inflammatory cytokine levels (e.g. IL-6) among HIV positive patients. This occurs, in part, via FXa activation of protease activated receptor 2 (PAR-2) on monocytes and tissue macrophages, which perpetuates innate inflammation. We will test our hypothesis with an oral antagonist to FXa (edoxaban), and quantify the immunologic effects of PAR-2 inhibition on systemic inflammation and monocyte activation.

The potential benefits of pharmacologic inhibition of FXa will be studied among HIV positive participants receiving ART with suppressed HIV viral load and a D-dimer \>100 ng/mL. The study design is a cross-over placebo controlled randomized trial of edoxaban 30mg daily versus matched placebo (n=40 total participants). After screening and baseline visits, participants will be randomized to the sequence of drug administration (i.e., edoxaban vs. placebo). After randomization, participants will start study medication #1 and follow-up for visits at months 1, 2, 3 and 4. They will then stop study medication for 3 months, return for visits at months 7 and 8 (analogous to screening and baseline, respectively), then start study medication #2 and follow-up for visits at months 9, 10, 11, and 12.

The treatment effect (i.e., changes from pre-treatment levels) over 4 months will be assessed in measures of inflammation, immune activation, and coagulation. For comparisons with placebo, each participant will then serve as his or her own control in this cross-over design.

Arms: arm 1: Edoxaban 30mg daily arm 2: Matching Placebo
Interventions: intervention 1: Edoxaban 30mg daily intervention 2: Matching placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_ICF_000.pdf: 
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i 
 
 
 
 
Targeted AntiCoagulation Therapy to reduce Inflammation 
and Cellular Activation in Long-term HIV Disease 
(TACTICAL-HIV) 
  
ClinicalTrials.gov Identifier: # 
NCT02339415 
 
Sponsored by:  
Minneapolis Medical Research Foundation 
 
Funding provided by:  
National Heart Lung and Blood Institute (NIH): R01 HL126542 
 
Study drug provided by: Daiichi-Sankyo Pharmaceuticals 
 
Version Number: v2.0 
 
Day Month Year 
1-May-2016 
 
 
Protocol Chair:  Jason Baker, MD, MS 
 
Lead Statistician: Julian Wolfson, PhD 
 
Protocol Manager:  Namo Tetekpor, MPH, MS 
 
Protocol Team Members: Nigel Key, Russell Tracy, Kathleen Brummel-Zeidens, Irini 
Sereti, Micah Mooberry, Jane Kennedy 
 
NOTE: This protocol was developed consistent with ‘Standard Protocol Items: 
Recommendations for Intervention Trials’ (the SPIRIT initiative).1 
 
 


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ii 
Table of Contents 
1 
INTRODUCTION 
1 
1.1 
BACKGROUND AND RATIONALE 
1 
1.1.1 
PREMISE 
1 
1.1.2 
SCIENTIFIC BACKGROUND 
1 
1.2 
HYPOTHESIS AND OBJECTIVES 
4 
2 
METHODOLOGY 
4 
2.1 TRIAL DESIGN 
4 
2.2 STUDY POPULATION 
5 
2.2.1 
INCLUSION CRITERIA 
5 
2.2.2 
EXCLUSION CRITERIA 
5 
2.3 STUDY MEDICATION INTERVENTION 
6 
2.3.1 
EDOXABAN 
6 
2.3.2 
RANDOMIZATION AND BLINDING 
8 
2.3.3 
STUDY DRUG PRODUCTION AND DISTRIBUTION 
8 
2.4 OUTCOMES 
8 
2.4.1 
STUDY VISIT SCHEDULE 
9 
2.4.2 
POWER AND SAMPLE SIZE CONSIDERATIONS 
10 
3 
CLINICAL MANAGEMENT 
11 
3.1 
ADMINISTRATION OF STUDY PROCEDURES 
11 
3.2 
CATEGORIZATION OF BLEEDING EVENTS 
12 
3.2.1 
ISTH DEFINITION OF MAJOR BLEEDING 
12 
3.2.2 
BLEEDING ACADEMIC RESEARCH CONSORTIUM (BARC) DEFINITIONS 
12 
3.3 
STUDY MANAGEMENT OF BLEEDING EVENTS 
12 
3.4 
STUDY DRUG CESSATION 
13 
3.5 
ADHERENCE AND TOLERABILITY 
14 
3.6 
CONCOMITANT MEDICATIONS AND ANTIRETROVIRAL THERAPY 
14 
3.6.1 
CONTRAINDICATED CONCOMITANT MEDICATIONS FOR THIS STUDY INCLUDE: 
14 
3.7 
DATA COLLECTION 
14 
3.8 
BLOOD SPECIMEN PROCESSING 
15 
3.9 
CLINICAL LABS 
15 
4 
SAFETY AND ADVERSE EVENTS 
15 
4.1 
MEASURES TO REDUCE RISK FOR ADVERSE EVENTS 
15 
4.2 
ADVERSE EVENT DEFINITIONS 
15 
4.2.1 
ADVERSE EVENT (AE): 
15 
4.2.2 
SERIOUS ADVERSE EVENT (SAE): 
16 
4.2.3 
UNANTICIPATED PROBLEM (UP): 
16 
4.3 
DOCUMENTING ADVERSE EVENTS AND UNANTICIPATED PROBLEMS 
16 
4.3.1 
ADVERSE EVENT RELATIONSHIP TO STUDY DRUG 
17 
4.4 
REPORTING SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS 
17 
4.5 
PARTICIPANT WITHDRAWAL 
18 


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5 
DATA AND SAFETY MONITORING PLAN 
19 
5.1 
INTERIM ANALYSIS 
19 
5.2 
FREQUENCY AND CONTENT OF DATA AND SAFETY MONITORING 
19 
5.2.1 
SAFETY MONITORING BY DSMB OFFICERS 
19 
5.3 
DSMB (DATA AND SAFETY MONITORING BOARD) 
20 
5.3.1 
DSMB CONFLICT OF INTEREST AND PROTECTION OF CONFIDENTIALITY 
20 
5.3.2 
DSMB RESPONSIBILITIES 
21 
6 
ANALYSIS PLAN 
21 
APPENDIX A:  BLOOD SPECIMEN COLLECTION AND STORAGE 
1 
APPENDIX B:  BLEEDING ACADEMIC RESEARCH CONSORTIUM (BARC) DEFINITIONS 2 
APPENDIX C:  CLINICAL MANAGEMENT OF FACTOR X INHIBITOR BLEEDING EVENTS 3 
APPENDIX D:  DEFINITION AND CRITERIA FOR AIDS EVENT 
4 
APPENDIX E:  ADVERSE EVENTS GRADING TABLES (FROM NIH/DAIDS)  
5 
APPENDIX F: ADVERSE EVENT REPORTING FORM (FOR DSI) 
35 
APPENDIX G: SAMPLE INFORMED CONSENT FORM (ICF)  
1 
 
 
EDOXABAN INVESTIGATOR BROCHURE (PACKAGE INSERT) PROVIDED SEPARATELY 
 
 
 
 


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iv 
List of Abbreviations 
AE 
Adverse Event/Adverse Experience 
AIDS 
Acquired Immune Deficiency Syndrome 
ARB 
Angiotensin Receptor Blocker 
ART 
Antiretroviral Therapy 
BARC 
Bleeding Academic Research Consortium  
BMP 
Basic Metabolic Panel 
BP 
Blood Pressure 
CCC 
Clinical Coordinating Center 
CHD 
Coronary Heart Disease 
CLIA 
Clinical Laboratory Improvement Amendments 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
CVD 
Cardiovascular Disease 
DCC 
Data and Coordinating Center 
DM 
Diabetes Mellitus 
DSMB 
Data and Safety Monitoring Board 
DVT 
Deep vein thrombosis 
ENGAGE AF-TIMI 
Effective anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-
Thrombylysis in Myocardial Infarction 48 
ESPRIT 
Evaluation of Subcutaneous Proleukin® in a Randomized International Trial 
F 
Factor (refering to a coagulation factor, designated by a Roman Numeral; e.g., 
FX) 
FDA 
Food and Drug Administration 
FXa 
Activated Factor X (ten) 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
IL-6 
Interleukin-6 
IND 
Investigational New Drug 
INSIGHT 
International Network for Strategic Initiatives in Global HIV Trials 
IRB 
Institutional Review Board 
MP 
Microparticle 
N 
Number (typically refers to participants) 
NHLBI 
National Heart Lung and Blood Institute, NIH 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
OHSR 
Office for Human Subjects Research 
PAR 
Protease Activated Receptor 
PCA 
Procoagulant Activity 
PD 
Pharmacodynamics 
PBMC 
Peripheral Blood Mononuclear Cells 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
QA 
Quality Assurance 
QIA 
Quantitative Image Analysis 
QC 
Quality Control 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SD 
Standard Deviation 
SILCAAT 
Subcutaneous, Recombinant, Human Interleukin-2 in HIV-Infected Patients with 
Low CD4+ Counts Under Active Antiretroviral Therapy 
SMART 
Strategic Management of AntiRetroviral Therapy 
TF 
Tissue Factor 


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v 
List of Abbreviations 
VTE 
Venous thromboembolism 
 
 
 
 
Protocol Summary 
Full Title 
Targeted Anticoagulation Therapy to Reduce Inflammation and 
Cellular Activation in Long-term HIV Disease 
Short Title 
TACTICAL-HIV 
Clinical Trial Phase Phase 2 
IND Sponsor  
NA 
Conducted By 
Minneapolis Medical Research Foundation and the University 
of Minnesota 
Principal 
Investigator 
Jason Baker, MD, MS 
Lead Statistician 
Julian Wolfson, PhD 
Sample Size 
40 participants 
Study Population 
HIV positive patients on stable ART with HIV RNA level ≤200 
copies/mL, D-dimer level ≥100 mg/L (or ng/mL), and no 
current/anticipated anti-platelet or anti-coagulation treatment 
Accrual Period 
Anticipated enrollment 1 year 
Study Design 
Cross-over placebo-controlled trial, where participants are 
randomized 1:1 to the sequence they receive edoxaban 30mg 
or matched placebo daily (double-blind). 
Study Duration 
12 months; 4 months each of active drug, washout, and 
placebo 
Intervention  
Edoxaban 30mg versus matching placebo taken daily 
Primary Objective 
To evaluate the effects of pharmacologic FXa inhibition (via 
edoxaban) on inflammation, as reflected in plasma IL-6 levels  
Secondary 
Objectives 
Evaluate the effects of edoxaban on monocyte and T-cell 
activation, coagulation and TF activity, other blood markers of 
systemic inflammation, and adherence and tolerability 
 
 
 


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Schematic of Study Design: 
 
 
 
Statement of Compliance 
This trial will be conducted in compliance with the protocol, International Conference on 
Harmonization Good Clinical Practice E6 (ICH-GCP), and the applicable regulatory 
requirements including U.S. Code of Federal Regulations applicable to clinical studies (45 CFR 
46 and 21 CFR 50, 56 and 21 CFR 312), directive 2001/20/EC on the approximation of the 
laws, regulations and administrative provisions of the Member States relating to the 
implementation of good clinical practice in the conduct of clinical trials on medicinal products for 
human use as amended by Commission Directive 2005/28/EC and NIAID Clinical Terms of 
Award.  All key personnel (all individuals responsible for the design and conduct of this study) 
have completed appropriate Human Subjects Protection Training. 
 


 Protocol Version 2.0 
 
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1 INTRODUCTION 
1.1 Background and Rationale 
1.1.1 Premise 
Understanding and mitigating persistent inflammation and coagulation activation is 
central to improving the quality and quantity of life for contemporary HIV-positive 
persons. HIV treatment with antiretroviral therapy (ART) effectively and durably 
suppresses viral replication leading to improved survival and profound reductions in risk 
for AIDS, though excess clinical risk remains from non-AIDS-related end-organ 
diseases such as cardiovascular disease (CVD). Findings from multiple epidemiologic 
studies have reported associations between inflammatory (e.g. interleukin-6 [IL-6]) and 
coagulation (e.g., D-dimer) biomarker levels and risk for CVD and all-cause mortality, 
independent of traditional risk factors, HIV factors, and other biomarkers.  Furthermore, 
despite effective treatment with ART, IL-6 and D-dimer levels remain elevated when 
compared to uninfected persons, and predict both short- and long-term mortality over 8 
years of follow-up among treated HIV patients.  Currently, HIV-related alterations in 
coagulation biology that account for strong D-dimer clinical risk associations, including 
strategies to mitigate this risk, remain poorly characterized. 
 
We propose a model where hypercoagulation contributes to disease risk, in part, by 
amplifying inflammatory pathways, in addition to the direct effects of thrombogenesis.  
We hypothesize that increased generation of activated factor X (FXa) contributes to a 
systemic elevation in pro-inflammatory cytokine levels (e.g. interleukin-6 [IL-6]) among 
HIV positive patients.  This occurs, in part, via FXa activation of protease activated 
receptor 2 (PAR-2) on monocytes and tissue macrophages, which perpetuates innate 
inflammation. It is well established that inflammation up-regulates coagulation 
pathways, in part via tissue factor (TF) expression and alterations in key coagulation 
factors—we have shown that both mechanisms contribute to HIV-related 
hypercoagulation. However, the notion that coagulation activity can itself amplify 
inflammatory pathways is a more recent, novel, and testable hypothesis for how low-
level hypercoagulation may contribute to excess disease risk among HIV patients. 
 
Expanding our understanding of these complex pathways is critical given somewhat 
inconsistent observations that: a) a number of hypercoagulable changes are present 
during chronic HIV disease, while, b) clinically apparent clots do not account for most of 
the long-term disease risk predicted by elevated D-dimer levels. The TACTICAL-HIV 
trial is a critical step to advance this field, providing essential information on the 
underlying mechanisms and on candidate immunologic surrogate markers that will 
inform larger clinical trials of anticoagulant treatments for HIV positive patients. 
1.1.2 Scientific Background 
The Changing Spectrum of Morbidity and Mortality Among HIV Positive Patients: 
Antiretroviral therapy (ART) effectively and durably suppresses HIV replication, leads to 
immune recovery (increasing CD4+ T-cell counts) and prolonged life expectancy, and 


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2 
has changed the spectrum of morbidity and mortality among HIV positive persons.2-8 
Among well-treated patients with levels of HIV RNA below the limit of detection, non-
AIDS-related conditions are now a more common cause of morbidity and mortality than 
AIDS.6, 9-11 The most relevant serious non-AIDS-related diseases in current clinical 
practice include atherosclerotic cardiovascular disease (CVD), cancer, liver disease, 
end-stage renal disease, bone disease and subclinical neurocognitive dysfunction. Of 
these, CVD and cancer constitute the vast majority of clinical events.5, 10-13 
 
Reasons for Persistent Inflammation in Persons with ART-treated HIV Infection:  
Chronic inflammation in HIV disease arises from high levels of immune activation. HIV 
treatment with ART reduces activation of the immune response, including levels of 
inflammatory cytokines, though most immunologic abnormalities persist compared to 
HIV uninfected persons.14, 15 HIV infection is classically associated with T-cell activation, 
reflecting adaptive immunity, but recent data demonstrate that innate immune activation 
also contributes to chronic inflammation.16-20 The precise mechanisms driving high level 
immune activation are not entirely clear, but appear to involve both a persistent anti-HIV 
response (even with HIV RNA at low levels) and a more generalized immune activation 
(e.g., cytokine release).15, 21-23 Specifically, innocent bystander activation—in which the 
pro-inflammatory aspects of HIV infection non-specifically drive T-cell and monocyte 
activation—also contributes.22, 24, 25 Other factors unique to HIV disease that may 
contribute to excess inflammation include: a) HIV-mediated destruction of gut 
epithelium, leading to greater translocation of bacterial products, b) dysregulated 
inflammatory responses to co-pathogens (e.g., CMV), and c) irreversible damage to the 
adaptive immune system (including lymphatic tissues).26-31  Treatments that reduce 
persistent inflammation among ART-treated HIV positive patients are lacking, and 
represents an area of extensive research.32 
 
Potential Pathologic Consequences of HIV-related Hypercoagulation: 
We have demonstrated that hypercoagulation in HIV disease arises, in part, from 
increases in tissue factor (TF) procoagulant activity and alterations in the composition of 
coagulation factors.33, 34 Potential mechanisms driving these changes include:  a) non-
specific innate inflammation,35, 36 b) non-specific response to viral infections (e.g., 
interferon gamma release),37, 38 and c) HIV specific damage, e.g., loss of mucosal 
integrity with microbial translocation and TF activation.39 The net-result is 
hypercoagulation; this concept is supported by data from our group and others showing 
that D-dimer levels remain elevated in treated HIV disease.14, 39-41  
Although HIV is associated with increased risk for venous thromboembolic disease, very 
few clinical events predicted by D-dimer levels include large vessel thrombosis.42 One 
explanation provided by non-human primate data suggests that hypercoagulation may 
manifest in end-organ damage via microvascular clotting resulting in thrombotic 
microangiopathy.43 This hypothesis is supported by the well-recognized association 
between HIV and thrombotic thrombocytopenic purpura (TTP).44 Another novel 
explanation entails our innovative aim 1 hypothesis, namely that hypercoagulation 
contributes to clinical risk in treated HIV disease by up-regulating systemic 
inflammation, in part, via TF/VIIa and FXa activation of PAR-2 pathways (Figure).  


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3 
Recent data have established the 
interplay between coagulation and 
inflammation, including bi-
directional feedback.36 Protease 
activated receptors (PARs) play a 
central role in mediating this cross-
talk, as established in conditions 
like acute lung injury, sepsis and 
myocardial infarction.45, 46 PAR-1 is 
activated by various proteases, 
including FXa and thrombin, 
whereas PAR-2 is activated by the 
TF:FVIIa complex, FXa, as well as 
other proteases47-50 In this 
proposal we use an experimental 
approach to test this hypothesis by blocking FXa with low-dose edoxaban. 
 
Outcomes: IL-6 (and D-dimer) Predict Risk for Non-AIDS Defining Clinical Events:  
Excess risk for non-AIDS conditions is due to multiple factors, including a higher burden 
of traditional risk factors, but persistent inflammation despite ART is a key HIV-related 
risk factor. Recent data from a number of epidemiologic studies have shown that 
inflammatory biomarkers well validated in the aging and cardiovascular fields19, 51-54 are 
elevated with untreated and (to a lesser degree) treated HIV infection,14, 40, 55 and 
predict risk for CVD, cancer, and non-AIDS mortality.42, 56-61 Our group conducted a 
series of nested case-control and cohort studies in collaboration with INSIGHT 
investigators, using data from 3 large HIV trials (SMART, ESPRIT, and SILCAAT), and 
determined that associations for risk of CVD, cancer, a composite of serious non-AIDS 
events, and all-cause mortality was most robust for levels of interleukin-6 (IL-6), as well 
as D-dimer (Figure).62-64 These associations are not attenuated by adjusting for HIV or 
traditional CVD risk factors, are several-fold higher than reported in HIV-negative 
studies, and persist over a median of 5.5 years of follow-up.  Importantly, these IL-6 and 
D-dimer associations are independent of each other, making them ideal candidate 
surrogate clinical risk 
markers reflecting the 
potential harm from 
systemic inflammation 
and coagulation.42, 63, 65, 
66 An important 
implication is that any 
treatment candidate that 
down regulates both 
pathways (e.g., 
edoxaban) has 
significant potential for 
corresponding clinical 
benefit. 


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1.2 Hypothesis and Objectives 
We hypothesize that increased generation of activated factor X (FXa) contributes to a 
systemic elevation in pro-inflammatory cytokine levels (e.g. IL-6) among HIV positive 
patients.  This occurs, in part, via FXa activation of protease activated receptor 2 (PAR-
2) on monocytes and tissue macrophages, which perpetuates innate inflammation.  We 
will test our hypothesis with an oral antagonist to FXa (edoxaban), and quantify the 
immunologic effects of PAR-2 inhibition on systemic inflammation and monocyte 
activation.  We will address the following specific objectives: 
 
 Primary Objective:  Evaluate the treatment effects of edoxaban on systemic 
inflammation 
 
 Main Secondary Objectives:  Evaluate the treatment effects of edoxaban on 
monocyte activation, tissue factor activity and coagulation. 
 
2 METHODOLOGY 
2.1 Trial Design 
The potential benefits of pharmacologic inhibition of FXa will be studied among HIV 
positive participants receiving ART with suppressed HIV viral load and a D-dimer >100 
ng/mL.   The study design is a cross-over placebo controlled randomized trial of 
edoxaban 30mg daily versus matched placebo (n=40 total participants).  After screening 
and baseline visits, participants will be randomized to the sequence of drug 
administration (i.e., edoxaban vs. placebo). The full visit sequence is listed below in 
Table 1.  After randomization, participants will start study medication #1 and follow-up 
for visits at months 1, 2, 3 and 4.  They will then stop study medication for 3 months, 
return for visits at months 7 and 8 (analogous to screening and baseline, respectively), 
then start study medication #2 and follow-up for visits at months 9, 10, 11, and 12.  
 
 
 
Table 1: Study Visit Timing and Measures 
Screening 
Baseline 
Month 1 
Month 2 
Month 3 
Month 4 
 Washout 
Month 7 
Month 8 
Month 9 
Month 10 
Month 11 
Month 12 
Study Medication #1 (e.g., edoxaban) 
 
X 
X 
X 
X 
X  
 
 
 
 
 
 
Study Medication #2 (e.g., placebo) 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Blood measurements 
X 
X 
X 
X 
X 
X  
X 
X 
X 
X 
X 
X 
 
This cross-over design will efficiently study short-term treatment effects among a 
smaller sample. The half-life of edoxaban is approximately 6-10 hours and treatment 
related changes in biomarkers such as IL-6 and D-dimer is typically present within 1-2 
months. Thus, the washout period of 3 months extends beyond potential post-treatment 
effects, prior to starting study medication #2.  
The treatment effect (i.e., changes from pre-treatment levels) over 4 months will be 
assessed in measures of inflammation, immune activation, tissue factor (TF) activity 


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5 
and coagulation.  For comparisons with placebo, each participant will then serve as his 
or her own control in this cross-over design. 
 
2.2 Study Population 
The target population is HIV positive patients receiving effective ART treatment with 
viral suppression.  These participants are at low risk for AIDS progression, and low 
clinical event risk over the short term.  Health consequences in this population are 
largely due to non-AIDS defining complications over the longer term, related to 
persistent inflammation and coagulation activity (e.g., CVD).  Participants must also not 
have co-morbid diseases known to be pro-inflammatory, or have current use of 
immune-modulatory or anti-coagulant drugs. Participants will be recruited from the 
HCMC HIV clinic, in Minneapolis, which provides care for 2000 HIV positive participants 
(>80% of whom are receiving ART with suppressed viral load). 
A D-dimer threshold of ≥100 ng/mL is used to improve the potential risk-benefit balance, 
by excluding those at the lowest clinical risk with little to no evidence of coagulation 
activation.  This threshold corresponds approximately to the separation between the 1st 
(lowest) and 2nd quartile of D-dimer levels among ART-treated participants (n=3766) in 
our preliminary data (see Figure of Kaplan Meier plots within scientific rationale above).  
Participants with D-dimer levels in the 1st quartile had very low rates of clinical events 
during follow-up. This D-dimer threshold enriches the target population with participants 
most likely to benefit while still studying the treatment effects over a wide range of 
coagulation activity.  Clinical lab measures of D-dimer will be used for screening only; 
outcome analyses will use D-dimer measures from the central core lab. 
2.2.1 Inclusion Criteria 
 HIV infection (verified by previous positive antibody or detectable HIV RNA level) 
 Age ≥18 years 
 Receiving continuous ART for ≥2 years (regimen changes >3 months prior to 
enrollment are acceptable) 
 HIV RNA level ≤200 copies/mL for ≥1 year (1 measure ≥200 allowed if also <500 
and preceded and followed by one or more values ≤200 copies/mL) 
 D-dimer level ≥100 ng/mL in FEU, or ≥50 ng/mL in DDU, measured within 60 days of 
randomization 
 Estimated creatinine clearance ≥50 mL/min 
 Body weight ≥60kg 
 Do not anticipate starting (or stopping) statin or aspirin therapy during the study 
 For women of child bearing potential, agrees to use a reliable form of birth control 
2.2.2 Exclusion Criteria 
 Pregnancy or breast feeding 
 A contra-indication to taking edoxaban 
 A clinical indication for anticoagulation therapy (e.g., atrial fibrillation or DVT/PE) 


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6 
 Treatment with anti-platelet or anti-coagulation therapy; prior treatment with aspirin 
is not itself an exclusion. 
 Daily NSAID use; periodic use (i.e., ≤3 days per week) is not itself an exclusion. 
 Treatment with systemic immune-modulatory therapy within the past 3 months. 
 Grade ≥1 hematology lab abnormality for INR (>1.1 x ULN), hemoglobin (<10.0 g/L), 
platelets (<100,000 cells/L), or WBC (<2,500 cells/mm3) 
 Grade ≥2 lab abnormality for chemistries (i.e., BMP) or liver panel 
 No alcohol or illicit drug abuse/dependency currently, or anticipation of ongoing use 
during study 
 History of prior myocardial infarction or unstable atherosclerotic disease 
 History of prior stroke or transient ischemic attack (TIA) 
 History of active gastrointestinal ulcer or bleeding disorder within the prior year 
 Intent to have surgery during the study period (12 months) 
 
Hepatitis C treatments (e.g., interferon, ribavirin, protease inhibitors) within the past 
3 months 
 
Cirrhosis or hepatic impairment (e.g., Child-Pugh class B or C). 
 Seizure disorder 
 Previous/current CNS space occupying lesion (e.g., Toxoplasmosis, mTB) with 
persistent abnormalities on CNS imaging after completion of treatment. 
 Surgical or invasive procedure anticipated during study period. 
 Invasive cancer in the prior year or receiving cancer treatment (not including 
carcinoma-in-situ or basal cell cancer of the skin) 
 Rheumatologic or inflammatory disease, systemic in nature (e.g., systemic lupus 
erythematosus, rheumatoid arthritis, vasculitis, sarcoidosis, Crohn’s disease) 
 Assessment by the clinical investigator that enrollment into the study could entail 
excess risk to the participant, beyond what is intended or expected. 
 
2.3 Study Medication Intervention 
At baseline, participants will start blinded study medication, either edoxaban or 
matching placebo at 30mg daily.  After 4 months they will stop study medication.  
Participants will remain off study drug between month 4 and month 8.  At the month 8 
visit, participants will again begin blinded study medication, corresponding to the 
comparison drug for that which was taken between baseline and month 4.  Thus, 
participants are randomized to either:  a) active study drug x4 months, washout (no 
drug), matched placebo x4 months, or b) matched placebo x4 months, washout (no 
drug), active study drug x4 months.  Double blinding is maintained. 
Clinical labs, including HIV staging labs and coagulation measures, will be monitored 
prior to initiating each study medication and at 1 and 4 months after starting each study 
medication (see Table 2 of study outcomes and visit schedule below) 
2.3.1 Edoxaban 
Edoxaban is a competitive direct inhibitor of FXa, and will be used to test our central 
hypothesis that FXa activity (via PAR-2) contributes monocyte activation and systemic 


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inflammation.  Edoxaban exhibits >10,000-fold selectivity for FXa relative to thrombin, 
which exhibits immunologic cross-talk via activation of PAR-1.  Edoxaban is currently 
FDA-approved for stroke prevention in patients with non-valvular atrial fibrillation 
(NVAF) and as treatment for deep vein thrombosis (DVT) or pulmonary embolism (PE). 
The recommended dose is 60mg orally once daily for both indications (NVAF and 
DVT/PE).  The dose should be reduced to 30mg once daily for patients with an 
estimated creatinine clearance of 30-50 mL/min.  Finally, for the NVAF indication the 
FDA recommended not using edoxaban among patients with a creatinine clearance >95 
mL/min due to decreased efficacy in the prevention of ischemic stroke; given this was 
not due to an increase risk for bleeding complications, there is no upper limit in 
creatinine clearance as part of the inclusion/exclusion criteria for TACTICAL-HIV. 
In the TACTICAL-HIV study, study drug will be taken as one 30mg dose of edoxaban 
(or matching placebo) daily in the morning (AM), and only participants with a creatinine 
clearance >50 mL/min will be enrolled. 
Pharmacokinetic properties of edoxaban include rapid absorption with attainment of 
peak plasma concentration within 1-2 hours, and a half-life of approximately 6-10 
hours.67  Metabolites are formed largely via hydrolysis with only minor contribution from 
cytochrome P450 (CYP) 3A.  There is little systemic accumulation of edoxaban at 10 
days after administration.67  Edoxaban can be administered with or without food, with 
little effect on bioavailability. Edoxaban is a substrate for the efflux transporter P-
glycoprotein (P-gp), and as a consequence serum levels may increase with concomitant 
administration of strong P-gp inhibitors (e.g., verapamil, quinidine). Renal clearance 
likely involves active secretion.  
Risks associated with edoxaban use include bleeding.  Phase-3 clinical trial safety data 
arises from the ENGAGE AF-TIMI and Hokusai-VTE trials.68, 69 Major bleeding event, 
defined by the International Society on Thrombosis and Haemostasis, was 1.6% with 
edoxaban 30mg daily among those with atrial fibrillation in ENGAGE AF-TIMI, and also 
1.6% among those receiving a higher dose of edoxaban at 60mg for clinical VTE.68-70 In 
addition, in Hokusai-VTE study populations the rate of any clinically relevant bleeding 
was 8.5% for edoxaban (compared to 10.3% for warfarin).  The most common side 
effects overall in these studies were bleeding, rash, abnormal liver tests, and anemia. 
The greatest potential for drug interactions entails the potential need for dose reduction 
with concomitant use of P-gp inhibitors.  Concomitant administration of platelet-
inhibitors or NSAIDs may also increase bleeding risk.  Edoxaban is not safe for use 
during pregnancy. 
Routine clinical lab monitoring of coagulation tests are not indicated during edoxaban 
use.  Anti-factor Xa assay increases proportionally to serum levels of edoxaban.  
INR/PT and aPTT increase with edoxaban use, but to a highly variable degree.  
Episodes of bleeding from direct FXa inhibitors such as edoxaban are managed 
clinically with supportive care and potential use of Prothrombin Concentrate Complex 
(PCC).  


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8 
2.3.2 Randomization and Blinding 
Eligible participants who consent to study procedures will be randomized 1:1 to the 
sequence that they receive edoxaban or matching placebo. Treatment assignments will 
be generated using a permuted block randomization scheme. Sites will use a secure, 
on-line program to obtain treatment assignments.  The program will also verify eligibility 
and the existence of key baseline data. Treatment assignments will be verified and 
recorded in a dataset blinded to view by site staff.  
A bottle ID number (BID) unique to each bottle will be assigned to participants, and 
used by study staff to obtain the correct blinded study drug (active or placebo). Site staff 
will not have access to the treatment assignment linked to each bottle number, and 
bottle numbers will not be assigned in sequence. 
Blinding will occur at 3 levels:  1) treatment assignment will be blinded, 2) interim data 
summaries will blinded to all but the unblinded statistician and 3) core laboratory staff 
will be blinded to treatment group. In the rare event that the blind must be broken, every 
effort will be made to minimize the extent of the unblinding (for staff and participants) 
and an assessment of blinding will occur at the end of the study. 
The blind may be broken in cases of a clinical bleeding event, where reversal of anti-
coagulation is being considered—e.g., with prothrombin concentrate complex (PCC).  
Procedures will be established for the study coordinator to obtain the key/blind for a 
given participant from the dispensing pharmacy. 
2.3.3 Study Drug Production and Distribution   
Active edoxaban 30mg tablets and matching placebo will be provided and distributed by 
Daiichi Sankyo, Inc.  Study drug will be provided in prepackaged bottles that include a 
one-month supply plus additional drug to facilitate a visit window of +/- 2 weeks (n=42).  
Each bottle will have a unique bottle ID number, along with appropriate packaging, 
license and content information per regulations.  Clinical site pharmacy will receive and 
store study drug until dispensing to participants or site staff (who then dispense to 
participants) in the context of study visits. One bottle will be dispensed at baseline, and 
one additional bottle at the 1, 2, and 3-month study visits.  No study drug will be 
dispensed or taken between month 4 and 8, but one bottle will again be dispensed at 
the 8, 9, 10 and 11-month study visit. 
  
The clinical site will communicate directly with the Daiichi Sankyo study team 
representative to ship drug to sites. Daiichi-Sankyo will provide the DCC with the key 
linking the BID (unique to each bottle) with whether the contents are active edoxaban or 
matching placebo.  The DCC will then instruct sites which bottle(s) to dispense to 
patients based on the BID. 
2.4 Outcomes 
Primary Outcome 
 IL-6 plasma levels:  the difference between treatment and control conditions in 
change from pre-treatment to on-treatment values  


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9 
 
Secondary Outcomes 
 Adherence 
 Tolerability and side effects 
 Bleeding episodes:  Major bleeding and those defined as BARC Type 2, 3, 4, 5 
 Monocyte activation:  cellular phenotypes (e.g., CD14+/CD16+), monocyte 
microparticles (MMPs), and plasma biomarkers (e.g., sCD14, sCD163, TNF-α, 
sTNFr-1) 
 Functional TF pro-coagulant activity:  TF-positive microparticle (MPTF), cell-
associated TF, and whole blood TF pro-coagulant activity 
 Coagulation activity (e.g., D-dimer levels, thrombin-antithrombin complex [TAT], and 
functional thrombin potential assay) 
 Endothelial activation:  endothelial cell microparticles (EMPs) 
 T-cell activation and senescence phenotypes in blood 
 Explore the potential impact of edoxaban co-administered with ART on viral 
suppression and the anti-inflammatory treatment effect (via subgroup analyses 
defined by type/class of antiretroviral use) 
 
Important Exploratory Analyses 
 Determine if the treatment effect from Edoxapan differs depending on pre-treatment 
FXa activity (estimated from computational modeling) 
 Estimate the potential effect of Edoxaban treatment on clinical event risk (e.g., 
serious non-AIDS events, CVD, mortality, etc.), as predicted by IL-6 and D-dimer 
associations with clinical risk. 
2.4.1 Study Visit Schedule 
Participants will be screened and, if eligibility criteria are met, will be randomized at the 
baseline visit to start active study drug or matched placebo (blinded).  Randomization 
will occur within 60 days of screening.  
After screening and baseline visits, participants will start edoxaban 30mg once every 
morning (or matched placebo).  They will return for study visits at months 1, 2, 3 and 4, 
after which they will stop study medication.  At month 7 and 8 they will return for repeat 
laboratory and study visit procedures.  After the month 8 study visit is completed, 
participants will resume blinded study medication (either edoxaban 30mg or placebo, 
whichever was not given from baseline to month 4), and then follow-up for study visit 
procedures at months 9, 10, 11 and 12.  The visit schedule is outlined in the table 
below. Patients will be fasting for all blood draws (except screening). 
 
Toxicity labs and a clinical assessment will be ascertained as part of follow-up study 
visits.  If clinical labs (e.g., HIV RNA level, CD4 count, BMP, hepatic panel, and CBC) 
are available as part of routine clinical monitoring during the study visit window, these 
results may be used in place of repeating clinic labs at the study visit. If new symptoms 
develop that may be related to study medications, the site study investigator is to be 


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notified within 24 hours and a clinical determination is to be made whether additional 
toxicity labs and/or adherence requires assessing. 
 
 
 
TABLE 2: Visit Timeline 
 
Screening 
Baseline 
Month 1 
Month 2 
Month 3 
Month 4 
Month 7 
Month 8 
Month 9 
Month 10 
Month 11 
Month 12 
ON STUDY DRUG AT VISIT 
-- 
-- 
+ 
+ 
+ 
+ 
-- 
-- 
+ 
+ 
+ 
+ 
Informed consent and eligibility 
criteria 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
Randomization 
-- 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
 
Clinical Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
  Adherence  
-- 
-- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  Side Effect Screen/Assessment 
-- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  Bleeding & Adverse Events 
-- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  Concomitant Medications 
-- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Laboratory Measures  
 
 
 
 
 
 
 
 
 
 
 
 
D-dimer screen 
X* 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
HIV viral load 
X* 
X 
X 
X 
X 
X 
-- 
X 
X 
X 
X 
X 
CD4 count 
-- 
X 
-- 
-- 
-- 
X 
-- 
X 
-- 
-- 
-- 
X 
CBC, INR, aPTT  
X* 
X 
X 
X 
X 
X 
-- 
X 
X 
X 
X 
X 
Anti-Xa 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
BMP, LFTs 
X* 
X 
X 
-- 
-- 
X 
-- 
X 
X 
-- 
-- 
X 
Hep Bs Ag & Hep C Ab  
-- 
X* 
-- 
-- 
-- 
-- 
-- 
X* 
-- 
-- 
-- 
-- 
Lipid Panel 
-- 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
Pregnancy test (for women) 
X 
-- 
X 
X 
X 
X 
-- 
X 
X 
X 
X 
X 
Study Outcomes 
 
 
 
 
 
 
 
 
 
 
 
 
Stored plasma 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Stored PBMCs  
-- 
X 
X 
-- 
-- 
X 
-- 
X 
X 
-- 
-- 
X 
*Lab values from anytime within 30 days of visit can be used; previously positive hepatitis labs (i.e., HBsAg or 
HCV Ab) do not need to be repeated. 
 
2.4.2 Power and Sample Size Considerations 
The study employs a cross-over design, with participants serving as their own 
comparison.  To reduce variability in the primary outcome (log IL-6), we will average the 
2 pre-treatment measures (i.e., screening and baseline or months 7 and 8) as well as 
the 4 follow-up measures (i.e., months 1, 2, 3, and 4, or months 9, 10, 11, and 12). 
2.4.2.1 Primary outcome (IL-6) power and sample size 
We estimate that this cross-over design with n=40 participants will have 80% power at 
level alpha=0.05 to detect a treatment effect of 0.35 SD on log IL-6, corresponding to a 
23% relative difference in (non-log transformed) IL-6 levels between treatment 
conditions. In addition to the study and analysis structure described above, our 
simulation-based power calculation assumes a study attrition rate of 10% (i.e., 90% of 
subjects provide valid follow-up data). Measurements were simulated from the following 
random effects model:  𝑌𝑖𝑗𝑘= 𝛽0 + 𝑏0𝑖+ 𝛽1𝑡𝑟𝑡𝑖𝑗∗𝑓𝑢𝑖𝑗+ 𝜖𝑖𝑗𝑘   , where 𝑡𝑟𝑡𝑖𝑗 is the 
treatment indicator and 𝑓𝑢𝑖𝑗 is the indicator that the measurement is a follow-up 


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11 
measurement. 𝑏0𝑖 is an individual-specific random effect, and 𝜖𝑖𝑗𝑘 is the residual, 
assumed independent of 𝑏0𝑖.  𝑏0𝑖 and 𝜖𝑖𝑗𝑘 are assumed to be normally distributed with 
zero mean and variances chosen to simultaneously satisfy 𝑉𝑎𝑟(𝑌𝑖𝑗𝑘) =  𝑉𝑎𝑟(𝑏0𝑖) +
 𝑉𝑎𝑟(𝜖𝑖𝑗𝑘) = 0.55, and 𝜌(𝑌𝑖𝑗𝑘, 𝑌𝑖𝑗𝑙) =
𝑉𝑎𝑟(𝑏0𝑖)
𝑉𝑎𝑟(𝑏0𝑖)+𝑉𝑎𝑟(𝜖𝑖𝑗𝑘) = 0.4, respectively the cross-
sectional variance and longitudinal correlation of log IL-6 observed in data from the 
SMART study. 
2.4.2.2 Power for secondary objectives and exploratory analyses 
Few pilot data are available to characterize the correlation between multiple 
measurements of monocyte activation and monocyte TF-activity.  However, preliminary 
data provide variance estimates for some of these markers.71 We conducted a 
simulation similar to that described for the primary outcome above, varying the 
between-time correlation of markers from 0.1 (low) to 0.7 (high). Across all cases, the 
given sample size gave at least 80% power to detect a 0.35 SD effect size, which 
corresponds to 22%, 32%, 24%, and 10% relative reductions in CD14+/CD16+, TF+, 
sCD163, and sCD14, respectively. For D-dimer, our study will have approximately 80% 
power to detect a 26% difference in (non-log transformed) levels of this marker between 
treatment conditions. Though data are unavailable on TAT, it is anticipated that the 
between-measurement correlation is likely to be the same and hence a 0.35 SD effect 
will correspond to a difference of approximately 20-30% on this marker. 
Our analysis is also well-powered to detect a difference in treatment effect by degree of 
continuous pre-treatment FXa activity: we estimate >80% power to detect a 0.25 SD log 
IL-6 difference in treatment effect (~22% relative difference on original IL-6 scale) 
between groups differing by 1 SD in FXa activity. 
The effects on IL-6 and D-dimer that we are well-powered to detect with our given 
sample size (i.e., ~25% reductions) correspond to estimated reductions of ~37% in the 
risk for the composite outcome of serious non-AIDS event (CVD, cancer, liver or renal 
event) or death (see Scientific Background 1.1.2), when using a joint model and 
assuming both biomarkers are reduced by the same amount.  If one marker changes 
more than the other, e.g., a 30% reduction in D-dimer levels with a minimal 5-10% 
reduction in IL-6 levels, this would correspond to a predicted 20% reduction in event risk 
(again, see IL-6 and D-dimer data in Scientific Background 1.1.2). 
 
3 CLINICAL MANAGEMENT 
3.1 Administration of Study Procedures 
Study site coordinators will be trained prior to study implementation and will perform all 
study visit procedures during the conduct of the study.  The lead physician investigator 
will conduct clinical and drug toxicity assessments as indicated during the study.  


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12 
3.2 Categorization of Bleeding Events 
All bleeding events will be categorized using the Bleeding Academic Research 
Consortium (BARC) definitions outlined below and in appendix B.  In addition a ‘major 
bleeding’ event will be defined based on definitions established by the International 
Society on Thrombosis and Haemostasis (ISTH). 
3.2.1 ISTH Definition of Major Bleeding  
Major bleeding in non-surgical patients are defined by the following criteria: 
 Fatal bleeding, and/or 
 Symptomatic bleeding in a critical area or organ, such as intracranial, 
intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or 
intramuscular with compartment syndrome, and/or 
 Bleeding causing a fall in hemoglobin level of ≥2 g/dL, or leading to transfusion 
of ≥2 units of whole blood or red cells. 
3.2.2 Bleeding Academic Research Consortium (BARC) Definitions 
BARC definitions are reviewed in detail in Appendix B, but briefly entail: 
 Type 0 – No bleeding 
 Type 1 – Bleeding that is not actionable or requiring healthcare evaluation 
 Type 2 – Overt bleeding beyond what would be expected for a clinical 
circumstance that requires healthcare evaluation but does not meet criteria for 
type 3, 4, or 5. 
 Type 3 – Overt bleeding with hemoglobin drop >3 g/dL, bleeding requiring 
transfusion, intracranial hemorrhage, or bleeding into other designated body 
compartments (e.g., cardiac tamponade) 
 Type 4 – Bleeding related to cardiac surgery 
 Type 5 – Fatal bleeding 
 
3.3 Study Management of Bleeding Events 
The site investigator will review all bleeding events, of any grade or severity, as soon as 
the study team becomes aware of the event.  At that time, the event will be categorized 
in terms of BARC or ISTH classification and a corresponding decision will be made with 
respect to continuation of study drug. 
 
Participants with BARC Type 1 and 2 adverse bleeding episodes will continue with the 
study drug, unless assessment by the study investigator or medical care provider 
indicates that continuing on study drug would be associated with escalation of the 
bleeding event or other excess risk in the clinical context.  
 
Participants with BARC Type 3 or a ‘major bleeding’ event will have the study 
medication permanently discontinued.  Participants must be followed regularly (e.g., 
weekly) until resolution of the adverse event. 
 


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13 
Any participant planning to undergo a surgical procedure during the follow-up period 
should not be enrolled into the study.  If there is a need for a surgical procedure during 
the follow-up period, the study drug should be discontinued permanently.  It is important 
that the treating physician be made aware the participant may have been taking 
edoxaban (and oral FXa inhibitor). 
 
If any participant suffers a fatal bleed the blind for that participant will be broken.  If the 
participant were taking edoxaban at the time of the event, the study will be temporarily 
stopped while the DSMB can review the event in the context of other clinical and safety 
information. 
 
Participants should be referred for acute medical evaluation with any overt clinical 
bleeding, bleeding consistent with BARC Type 2 or above, or a major bleeding event.  
Study team investigators should immediately make the clinical treatment team aware 
that the study participant is potentially taking edoxaban, a factor Xa inhibitor; this should 
include a direct phone call as well as documentation in the electronic health record.  
Clinical management will include standard of care along with cessation of study 
medication.  See APPENDIX C for an approach to bleeding complications related to 
Factor Xa-inhibition with edoxaban.  NOTE:  Prothrombin concentrate complex (PCC), 
such as K-Centra (i.e., replacement of factors II, VII, IX, and X), may be effective in 
management of bleeding in the context of FXa inhibition, but there is no current antidote 
and dialysis is not effective. 
 
3.4 Study Drug Cessation 
At baseline, participants will start blinded study medication consisting of edoxaban or 
matching placebo at 30mg every morning. No dose adjustment can be made during 
the study. Tolerability, side effects, adverse events and clinical laboratory monitoring 
will be assessed at each study visit (via participant report and clinical labs), and at 
anytime during the study per the discretion of the clinical site investigator.   
 
If an adverse event of grade ≥3 is assessed as related to study drug, study medication 
should be stopped. If a grade 2 rash is persistent, study medication may also be 
stopped at the discretion of the site investigator.  Medication may also be stopped for 
grade <3 adverse events if the study investigator determines that the participant may be 
at risk for an escalation of the adverse event, persistent toxicity, or at risk in excess of 
what would be expected due to other contextual circumstances. If study medication was 
discontinued due to an adverse event of grade <3 that is not expected to recur, the 
study investigator may recommend re-initiating study medication. 
 
Any of the following will also result in stopping study medication (see section 3.1.2): 
i. 
Major bleeding event 
ii. 
BARC Type 3 bleeding event  
iii. 
Any surgical procedure with bleeding risk 
iv. 
Investigator or participant wishes to stop study medication 
 


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14 
3.5 Adherence and Tolerability 
Adherence will be assessed via participant self-report and pill count (by study 
coordinators) during each follow-up visit.  Tolerability will also be assessed via self-
report, with additional laboratory assessments performed for toxicity. 
 
3.6 Concomitant Medications and Antiretroviral Therapy 
Any antiretroviral medication and ART regimen may be used that is recommended as a 
potential option in the US DHHS guidelines on use of ART for adults with HIV 
infection.72  
 
Concomitant medications will be assessed at every study visit.  Medications 
contraindicated for this study include those that may increase risk of bleeding and/or 
substantially increase the effective exposure or serum drug levels of edoxaban (e.g., 
substrates for P-gp). NOTE:  There are numerous medications that are substrates for P-
glycoprotein (P-gp), and therefore have potential to influence edoxaban levels (and 
vice-a-versa). Concomitant medications associated with potential drug-drug interactions 
that are anticipated to be modest/minimal will not necessarily be contra-indicated for this 
short-term study (e.g., atorvastatin, digoxin). 
3.6.1 Contraindicated concomitant medications for this study include: 
i. 
Aspirin (daily use >3 days) 
ii. 
Platelet inhibitor (e.g., clopidogrel) 
iii. 
NSAIDs (daily use >3 days) 
iv. 
Fibrinolytic therapy (within 1 month) 
v. 
Verapamil 
vi. 
Quinidine 
vii. 
Amiodarone 
viii. 
Dronedarone 
ix. 
Ketaconazole and other azoles 
x. 
Erythromycin and other macrolides 
xi. 
Illicit drug use (e.g., cocaine)  
xii. 
Medications or drugs that may be associated with unacceptable increase 
risk to participants, as determined by the study investigator. 
 
3.7 Data Collection 
All data will be entered into web-based case report forms and transferred to servers at 
the data coordinating center (DCC) at University of Minnesota School of Public Health 
using REDCap software.  Paper source documentation will also be kept in a secure, 
locked location at each clinical site.  Study coordinators and/or other qualified research 
technicians will perform all blood draws and blood specimen processing.  
  


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15 
3.8 Blood Specimen Processing 
The blood specimen collection tubes and processing protocols are outlined in the study 
laboratory manual.  Participants will be fasting for all study visit blood draws (optional for 
screening visit).  Plasma and serum specimens will need to be processed from whole 
blood within 1 hour of collection. Peripheral blood mononuclear cell (PBMC) specimens 
will be processed locally at the University of Minnesota and stored until analyzed by 
core immunology laboratory at the end of follow-up. 
3.9 Clinical Labs 
All clinical labs will be measured on fresh blood specimens the day of the study visit, at 
the HCMC clinical lab using CLIA approved standards.  D-dimer levels at screening will 
be assessed at HCMC using HemosIL D-Dimer HS, a latex-enhanced turbidimetric 
immunoassay, on the ACL TOP automated analyzer (from Instrumentation Laboratory).  
Normal range for D-dimer levels using these methods are 0-229 ng/mL.  Plasma HIV 
RNA level will be estimated using COBAS® AmpliPrep/COBAS® TaqMan® HIV-1 Test, 
v2.0.   
 
The following clinical labs will be assessed to monitor for toxicity per Table 2 above: 
i. Complete Blood Count (CBC, with platelet count and differential) 
ii. Basic Metabolic Panel (BMP) 
iii. Coagulation panel (INR/PT, aPTT, anti-FXa)  
iv. Hepatic Function panel (ALT, AST, Total bilirubin) 
 
4  SAFETY AND ADVERSE EVENTS 
4.1 Measures to reduce risk for adverse events 
Risks related to edoxaban are principally related to bleeding events.  To reduce this 
risk, participants will be counseled to avoid concomitant medications that may increase 
risk for bleeding and be made aware of potential signs/symptoms that may be 
associated with occult bleeding (e.g., dyspepsia, black stools, weakness, fatigue). 
 
4.2 Adverse Event Definitions 
4.2.1 Adverse Event (AE):  
Any untoward medical occurrence in a clinical research participant administered 
an investigational product, which may or may not have a causal relationship with 
the investigational product. As such, an AE can be an unfavorable or unintended 
sign (including an abnormal laboratory finding, for example), symptom or disease 
temporally associated with the use of an investigational product, whether or not 
considered related to the product.  
 


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16 
If a preexisting condition worsens post-enrollment (frequency increases and/or 
severity grade increases), it should be reported as an adverse event. 
 
A symptom check-list will be included in the CRF (detailed in the protocol 
implementation manual) that includes common symptoms or side effects typically 
related to edoxaban therapy. 
 
Appendix E provides a table of adverse events, with grading criteria, adopted 
from the DAIDS 2009 Table for Grading the Severity of Adult and Pediatric 
Adverse Events 
 
4.2.2 Serious Adverse Event (SAE):  
Any adverse event occurring at any dose that results in any of the following 
outcomes:  
i. 
Death,  
ii. 
A life-threatening condition,  
iii. 
A congenital anomaly/birth defect, 
iv. 
Inpatient hospitalization or prolongation of existing hospitalization,  
v. 
Persistent or significant disability/incapacity,  
vi. 
An important medical event that, based upon appropriate medical judgment, 
may jeopardize the patient or subject and may require intervention to 
prevent one of the outcomes listed above. 
4.2.3 Unanticipated Problem (UP): 
Any event that is: 
i. 
Unexpected, AND  
ii. 
Related to study participation in this study, AND  
iii. 
Increase the risk of harm to the participant or others (or be an SAE) 
 
4.3 Documenting Adverse Events and Unanticipated Problems 
All serious adverse events (SAE) and unanticipated problems (UP), regardless of the 
assessed relationship with study drug, will be ascertained and recorded on study visit 
CRFs (through the online REDCAP interface).  
 
All new non-serious adverse events of grade ≥3 or deemed related to study drug will be 
ascertained and recorded on study visit CRFs (through the online REDCAP interface). 
Criteria for assigning a grade of severity of adverse events are summarized in 
Appendix E.   
 
NOTE:  adverse events based on laboratory criteria will only be 
ascertained/recorded if ≥ grade 3, and no adverse events will be 
ascertained/recorded based on CD4+ T-cell count criteria. 
 


 Protocol Version 2.0 
 
17 
There are five severity grades that can be assigned to adverse events, which are 
defined as follows:  
i. 
Grade 1 = Mild  
ii. 
Grade 2 = Moderate  
iii. 
Grade 3 = Severe  
iv. 
Grade 4 = Potentially life-threatening  
v. 
Grade 5 = Death 
 
Additional information ascertained for each adverse event includes:  a) date of onset, b) 
relationship to study drug (see section 4.3.1 below), c) any action taken on study drug, 
and d) whether the adverse event qualifies as an SAE (including the criteria fulfilled). 
 
Source documentation (in addition to the CRF variables for AEs) will be collected by 
research coordinators at the clinical site for all AEs of grade ≤3, SAEs or UPs. 
4.3.1 Adverse Event Relationship to Study Drug 
For all adverse events grade ≥3, SAEs or UPs that occur after randomization, 
study investigator(s) will assess the potential relationship of the event to the 
study medication.  One of the following designations will be used:  
 
i. Related: There is a reasonable possibility that the AE may be related to the 
study agent(s). 
 
ii. Not related: There is not a reasonable possibility that the AE may be related 
to the study agent(s). Alternative etiology, diagnosis or, explanation for the AE 
should be provided. 
 
4.4 Reporting Serious Adverse Events and Unanticipated Problems 
The IRB (or Human Subjects Committee) and the Data Safety Monitoring Board 
(DSMB, see section 5 below) will receive notification of all SAEs that are deemed 
protocol related, or a UP.  NOTE: an adverse event (of any grade) that is unexpected, is 
reasonably believed to be related to study participation, and involves risk to the 
participant or others should be captured as a UP (per definitions above 4.2).   
 
The site will enter information about the SAE/UP event into the appropriate case report 
form (via REDCap reporting).  The data center can generate a summary of individual, or 
a series of, AE events upon request from the site. 
 
Daiichi Sankyo will receive notification of all SAEs and/or UPs within 5 business days of 
learning of the event.  Reporting of all SAE/UP events will be made to Daiichi Sankyo, 
the FDA (voluntary submission) and the NHLBI Program Official using the same 
reporting information (FDA Form 3500 per below).  Specifically, sites must: 
 
a) Inform local IRB per institutional guidelines and timelines 
b) fill out an SAE/UP case report form, via REDCap online reporting 


 Protocol Version 2.0 
 
18 
c) fill out an SAE/UP Form provided by Daiichi Sankyo (APPENDIX F)  
d) email the completed to Daiichi Sankyo representative  
e) voluntary reporting to FDA, via either submitting MedWatch Form FDA 3500 or 
complete voluntary reporting online via FDA MedWatch (see below for link)  
 
FDA MedWatch reporting forms may be found at: 
http://www.fda.gov/safety/medwatch/howtoreport/downloadforms/default.htm 
 
FDA MedWatch online voluntary reporting process can be performed at: 
https://www.accessdata.fda.gov/scripts/medwatch/ 
 
The table below summarizes SAE and UP reporting timelines that will be implemented. 
 
Table 3: NHLBI SAE and UP reporting Timelines  
 
What event is 
reported 
 
When is Event 
reported 
By whom is event 
reported 
To whom is Event 
reported 
Fatal or life-
threatening 
unexpected, 
suspected serious 
adverse reactions 
Within 7 calendar 
days of initial receipt 
of information 
Investigator 
Local IRB 
NHLBI and/or Data 
Coordinating Center 
DSMB 
DSI 
 
Non-fatal, non-life-
threatening 
unexpected, 
suspected serious 
adverse reactions 
Within 15 calendar 
days of initial receipt 
of information 
Investigator 
Local IRB 
NHLBI and/or DCC 
DSMB 
DSI 
Unanticipated 
Problem that is not an 
SAE 
Within 14 days of the 
investigator becoming 
aware of the problem 
Investigator 
Local IRB 
NHLBI and/or DCC 
DSMB 
 
All Unanticipated 
Problems1 Related or 
Unrelated to study 
 
Within 30 days of the 
IRB’s receipt of the 
report of the UP from 
the investigator. 
IRB 
OHRP2 
NHLBI 
 
1. 
Per OHRP guidance: only when a particular AE or series of AEs is determined to meet the criteria for an UP should a 
report of the AE(s) be submitted to the IRB at each institution under the HHS regulations at 45 CFR part 46. Such reports 
to the IRB will be submitted by the investigator. 
2. 
Office for Human Research Protections  
 
4.5 Participant Withdrawal 
Participants may withdraw from the study at any time at their request, as described in 
the consent.  All randomized participants will be encouraged to complete a final study 
visit, including all visit procedures. 
 


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19 
5 Data and Safety Monitoring Plan 
The Principal Investigator (PI) will be responsible for ensuring participants’ safety on a 
daily basis. A Data and Safety Monitoring Board (DSMB) will be formed with Dr. 
Wolfson as the un-blinded statistician; other members will not be part of the study team. 
Committee members will have experience with HIV/AIDS clinical research and 
thrombosis and anticoagulation therapy.  
5.1 Interim Analysis 
Most of the primary blood and tissue outcomes will not be available until after visits are 
completed, as samples will be batch processed at our participating laboratory site. 
Hence, there will be no formal interim analyses for efficacy or futility related to the main 
study outcomes. 
5.2 Frequency and Content of Data and Safety Monitoring  
To ensure compliance and data are reported correctly and completely, CRF data will be 
monitored monthly for completeness and compliance with the study protocol.  Queries 
for clarification or data completion will be communicated from the data center to the 
clinical site.  
 
Prior to enrollment the DSMB will review the protocol and data analysis plan.  During 
the study the DSMB will meet at every 6 months, and on an ad-hoc bases as 
necessitated for adverse events. An initial DSMB meeting will be scheduled as soon as 
any of the following occurs: 
i. 
Six months have elapsed since enrollment of the first patient 
ii. 
50% of goal enrollment is achieved 
iii. 
15 participants have completed 1st study drug period (i.e., 4 months) 
  
The data and safety monitoring report will include data on: enrollment (including 
progress), visit attendance, completeness of data, completeness and quality of 
specimen collection, baseline characteristics, adherence and discontinuation of 
medication, and side effects and adverse events.   
 
5.2.1 Safety Monitoring by DSMB Officers 
The PI will be informed of all SAEs deemed protocol related, UPs, or significant 
bleeding events as soon as they occur and will notify the DSMB for review within 7 
business days of notification.  The two clinicians (one HIV/Medicine and one 
Hematology) on the DSMB will also serve as medical officers and will perform 
independent safety monitoring for the study.  Independent safety monitoring will 
occur for any of the following: 
 SAE or UP deemed related to protocol/study drug 
 Major bleeding event (ISTH definition in 3.2) 
 Bleeding event of BARC type ≥3 (definition in 3.2 and appendix B) 
 


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20 
Independent safety monitoring will entail a review of a summary report of (de-identified) 
clinical data via email.  The DSMB will then determine whether the study should:  
a) continue and conduct the next scheduled DSMB meeting as planned, or 
b) continue but conduct an additional DSMB call to re-evaluate study safety, or 
c) temporarily stop enrollment, but continue follow-up of randomized participants, until 
an additional DSMB meeting can be performed, or 
d) provide more clinical information on the adverse event to properly inform a decision. 
 
As a result of this review a determination will then be made whether:  a) continuing the 
study without change and without additional DSMB review (beyond scheduled meetings 
as planned), b) continue the study but conduct an additional DSMB meeting/call to re-
evaluate study safety, c) temporarily stop enrollment in the study, but continue follow-up 
of randomized participants, until an additional DSMB meeting can be performed to re-
evaluate study safety and appropriateness to continue, d) more clinical information is 
needed on the adverse event to properly inform a decision. 
5.3 DSMB (Data and Safety Monitoring Board) 
The following individual(s) has/have accepted position(s) as part of the DSMB. Should 
there be any questions regarding the independence of the DSMB, it will be addressed 
and corrected if necessary at that time.  Julian Wolfson (lead statistician) will produce 
data reports and represent the protocol team as part of both open and closed sessions 
for the DSMB.   
 
 Biostatistician: Holly Janes, PhD (hjanes@fhcrc.org) 
 HIV/General Medicine: Matthew Freiberg, MD 
(matthew.s.freiberg@vanderbilt.edu) 
 Hematology Medicine: Sam Schulman, MD (schulms@mcmaster.ca) 
 Hematology Medicine: David Garcia, MD (davidg99@uw.edu) 
 
 
The DSMB will monitor progress of the study and safety of the intervention while the 
study is still blinded to the investigators. The frequency of the DSMB monitoring is 
listed above in 5.2. As part of this responsibility, DSMB members must be satisfied that 
the timeliness, completeness, and accuracy of the data submitted to them for review are 
sufficient for evaluation of the safety and welfare of study participants.  The DSMB will 
also assess the performance of the overall study operations and any other relevant 
issues as necessary. 
5.3.1 DSMB Conflict of Interest and Protection of Confidentiality 
DSMB members should have no direct involvement with the study investigators 
or intervention. Each DSMB member will sign a Conflict of Interest Statement 
which includes current affiliations, if any, with pharmaceutical and biotechnology 
companies (e.g., stockholder, consultant), and any other relationship that could 
be perceived as a conflict of interest related to the study and / or associated with 
commercial interests pertinent to study objectives.  


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21 
 
Data will be presented in a blinded manner during the open sessions of the 
DSMB that include the study PI. At DSMB meetings, data and discussion are 
confidential. Participant identities will not be known to the DSMB members. 
 
5.3.2 DSMB Responsibilities 
The DSMB Charter provides a detailed list of the DSMB responsibilities. They 
include: 
 Review the research protocol, informed consent documents and plans for data 
safety and monitoring; 
 Recommend subject recruitment be initiated after receipt of a satisfactory 
protocol; 
 Evaluate the progress of the trial, accrual and retention, periodic assessments 
of data quality and timeliness, participant risk versus benefit, and other factors 
that can affect study outcome; 
 Evaluation of all SAE/UPs, bleeding events of BARC type ≥3, and/or major 
bleeding Event (ISTH definition), will be reviewed by the designed medical 
officers on the DSMB within 1 week of report.  An assessment will be made at 
that time if a full DSMB meeting is required before then next schedule meeting; 
 Consider factors external to the study when relevant information becomes 
available, such as scientific or therapeutic developments that may have an 
impact on the safety of the participants or the ethics of the trial; 
 Review study performance, make recommendations and assist in the 
resolution of problems reported by the Principal Investigator; 
 Protect the safety of the study participants. 
 
6 ANALYSIS PLAN 
The primary analyses involving the main effect of treatment will be performed in an 
intent-to-treat framework using a random effects model with random subject-specific 
intercepts and fixed effects for treatment period and pre-treatment IL-6 (average of two 
measures, from screening and baseline). Separate models with an interaction term 
between treatment and pre-treatment FXa activity will used to test whether the effect of 
treatment differs by the degree of FXa activity (as estimated from computational 
modeling). The coefficients of the period indicator will be tested to check for evidence of 
treatment sequencing and/or carry-over effects. The characteristics of any patients who 
drop out of the study will be compared to the characteristics of those who do not to 
ascertain whether drop-out was informative.  Secondary outcomes will be analyzed in a 
similar fashion to analysis of changes in IL-6. In secondary exploratory analyses, we will 
also perform per-protocol (‘on treatment’) analyses, as well as imputation and (if 


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22 
necessary) sensitivity analyses to account for missing data. If medication adherence is 
sub-optimal, we will also consider compliance-adjusted analyses.  
We will also use the IL-6 and D-dimer associations with clinical risk (Scientific 
Background in 1.1.2.),63 to estimate the predicted risk reductions for both a composite 
outcome (serious non-AIDS events) as well as individual events such as cardiovascular 
disease (CVD) events. Statistical tests will include a significance level of alpha=0.05.


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23 
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71. 
Baker JV, Huppler Hullsiek K, Singh A, Wilson EM, Henry K, LIchtenstein K, Onen N, 
Kojic E, Patel P, Brooks JT, Hodis H, Budoff M, Sereti I, for the CDC SUN Study 
Investigators. Immunologic predictors of coronary artery calcium progression in a 
contemporary hiv cohort. Aids. 2014;28 
72. 
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of 
anti-retroviral agents in hiv-1-infected adults and 
adolescents. 2013;Available at:  
http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf 
 
 


 Protocol Version 2.0 
 
1 
APPENDIX A:  BLOOD SPECIMEN COLLECTION AND STORAGE  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Updated: April 2015 
 
 
CLINICAL 
Blood Collection Tube 
Blood Volume 
S 
B 
M1 
M2 
M3 
M4 
M7 
M8 
M9 
M10 
M11 
M12 
HCMC Labs Processing 
HIV RNA 
(1) 4ml EDTA  Lavender 
2-3mL 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CD4 Count + CBC 
(1) 4ml EDTA  Lavender 
4mL 
X 
X 
X 
X 
CBC 
2-3mL 
X* 
X 
X 
X 
X 
X 
X 
BMP, Hepatic Panel 
(1) 5mL Green 
4mL 
X* 
X 
X 
X 
X 
X 
X 
Lipid Panel 
X 
INR, aPTT 
(1) 5mL NaCitrate Blue 
4mL 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
D-Dimer 
X* 
Anti-Xa 
X 
X 
X 
X 
HBsAg & HCV Ab 
(1) 5mL SST Red 
4mL 
X* 
X* 
X 
X 
X 
X 
 
 
Pregnancy, Urine 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Core 
Labs 
BLOOD FOR 
STORAGE 
 
Blood 
Vol 
Cryo 
Vials 
** 
S 
B 
M1 
M2 
M3 
M4 
M7 
M8 
M9 
M10 
M11 
M12 
 
Study Lab Processing 
NIH 
PBMC 
(Processing at UMN) 
(4) 10mL CPT Tiger Top 
36mL 
3 
 
X 
X 
 
 
X 
 
X 
X 
 
 
X 
UNC 
Platelet Free Plasma 
(3) 5mL NaCitrate Blue 
15mL 
4 
X 
 
 
 
 
 
X 
 
 
 
 
 
15mL 
8 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Whole blood 
storage 
[5mL Na-Citrate Blue] 
5mL 
4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
UVT 
Serum 
5mL SST Red 
5mL 
1 
X 
 
 
 
 
 
X 
 
 
 
 
 
5mL 
3 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Platelet Poor Plasma 
10mL EDTA Lavender 
10mL 
3 
X 
 
 
 
 
 
X 
 
 
 
 
 
10mL 
7 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
*Labs values from anytime within 30days of screening can be used; previously positive hepatitis labs (i.e., HBsAg or HCV Ab) do not need to be 
repeated 
**Vials  are to be 500μl Full 
[ ] Aliquot  prior to plasma processing 


 Protocol Version 2.0 
 
2 
APPENDIX B:  BLEEDING ACADEMIC RESEARCH CONSORTIUM 
(BARC) DEFINITIONS  
 
Type 0  
no bleeding  
Type 1  
bleeding that is not actionable and does not cause the patient to seek 
unscheduled performance of studies, hospitalization, or treatment by a 
healthcare professional; may include episodes leading to self-discontinuation of 
medical therapy by the patient without consulting a healthcare professional  
Type 2  
any overt, actionable sign of hemorrhage (e.g., more bleeding than would be 
expected for a clinical circumstance, including bleeding found by imaging 
alone) that does not fit the criteria for type 3, 4, or 5 but does meet at least one 
of the following criteria: (1) requiring nonsurgical, medical intervention by a 
healthcare professional, (2) leading to hospitalization or increased level of care, 
or (3) prompting evaluation  
Type 3  
Type 3a  
 
Overt bleeding plus hemoglobin drop of 3-<5 g/dL (provided hemoglobin 
drop is related to bleed)  
 
Any transfusion with overt bleeding 
 
Type 3b  
 
Overt bleeding plus hemoglobin drop ≥5 g/dL (provided hemoglobin 
drop is related to bleed)  
 
Cardiac tamponade 
 
Bleeding requiring surgical intervention for control (excluding 
dental/nasal/skin/hemorrhoid)  
 
Bleeding requiring intravenous vasoactive agents 
 
Type 3c  
 
Intracranial hemorrhage (does not include microbleeds or hemorrhagic 
transformation, does include intraspinal)  
 
Subcategories confirmed by autopsy or imaging or lumbar puncture 
 
Intraocular bleed compromising vision  
 
Type 4  
CABG-related bleeding (cardiac surgery) 
 
Perioperative intracranial bleeding within 48 hours 
 
Reoperation after closure of sternotomy for the purpose of controlling 
bleeding 
 
Transfusion of ≥5 U whole blood or packed red blood cells within a 48-
hour period 
 
Chest tube output ≥2 L within a 24 hour period 
 
 
 
 


 Protocol Version 2.0 
 
3 
APPENDIX C:  CLINICAL MANAGEMENT OF FACTOR X INHIBITOR 
BLEEDING EVENTS 
 
NOTE:  TACTICAL-HIV participants the present with acute or active bleeding complication during 
the course of the study should be referred for clinical evaluation at the appropriate or nearby health 
care facility.  Management of clinical bleeding complications will not be directed by the TACTICAL-
HIV study team, and will be supported by the participant’s health insurance or third-party payer. 
 
There is no specific reversal agent or pharmacologic antidote to edoxaban-related bleeding, thus 
management of hemorrhagic complications is primarily supportive. Edoxaban is moderately protein 
bound (e.g., 50-60%) and is not dialyzable. If patients require pharmacologic therapy to manage 
hemorrhagic complications, a Hematology/Coagulation consult is advised.   
 
A FXa-activity level can is available by most clinical labs (and at HCMC), which can provide 
information quickly on the degree of FXa inhibition.  The table below summarizes one approach to 
management of Factor Xa inhibitor-related bleeding events, adapted from University of North 
Carolina Anticoagulation Reversal Guidelines: 
www.med.unc.edu/emergmed/files/emergent-anticoagulation-reversal-in-the-ed 
 
Bleeding Severity 
Management Approach 
Mild 
Delay next dose or discontinue Factor Xa inhibitor 
Moderate 
Consider any of the following based on bleeding severity:  
 Symptomatic treatment  
 Mechanical compression  
 Surgical intervention  
 Fluid replacement and hemodynamic support  
 Blood product transfusion  
 Oral activated charcoal (if previous dose ingested within 2 hours)  
   Dose: Liquid charcoal with sorbitol 50 g PO x 1 dose  
 
If hemostasis is not achieved with the strategies outlined above, proceed to 
the steps below and obtain a Hematology/Coagulation consult for further 
recommendations 
Severe or Life-
Threatening 
 
Consider any of the strategies outlined above based on bleeding severity. 
No agent currently available in the US has been shown to successfully 
reverse the anticoagulant effects of Factor Xa inhibitor-related bleeding 
events. However, the strategy below may be considered based on the 
currently available evidence. Therefore, the pharmacologic interventions 
below may be considered, but are not required in the management of 
Factor Xa inhibitor-related bleeding.  
A Hematology/Coagulation consult should be obtained after the following:  
1) Administer KCentra (4-factor PCC) 50 units/kg IV x 1 (max 5000 units)  
2) For persistent refractory bleeding, pursue formal Heme/Coag consult.  
3) To investigate potential causes of the bleeding event, obtain the 
following: serum creatinine, PT, aPTT, anti-Xa activity (send-out lab), CBC 
(platelets).  
4) If PT prolonged, administer vitamin K 10mg IV x one dose (as there may 
be vitamin K deficiency present). 
 
Table adapted from Eerenberg, Circulation 2011 (Oct 4);124(14):1573-1579 
 
 
 


 Protocol Version 2.0 
 
4 
 
APPENDIX D:  DEFINITION AND CRITERIA FOR AIDS EVENT 
The following list encompass the CDC's 1993 surveillance case definition of AIDS (without 
the CD4+ criterion), with the addition of several diagnoses increasingly felt to be associated 
with severe immunosuppression in participants infected with HIV.  
 
Modified CDC Category C 1993 Definition 
• Candidiasis of bronchi, trachea or lungs 
• Candidiasis, esophageal 
• Cervical cancer, invasive 
• Coccidioidomycosis, disseminated or extrapulmonary 
• Cryptococcosis, extrapulmonary 
• Cryptosporidiosis, chronic intestinal (> 1 month’s duration) 
• CMV disease (other than liver, spleen, or nodes) 
• CMV retinitis (with loss of vision) 
• Encephalopathy, HIV-related (including AIDS Dementia Complex) 
• Herpes simplex, chronic ulcers (> 1 mo); or bronchitis, pneumonitis or esophagitis 
• Histoplasmosis, disseminated or extrapulmonary 
• Isosporiasis, chronic intestinal (> 1 month’s duration) 
• Kaposi’s sarcoma (mucocutaneous or visceral) 
• Lymphoma, Burkitt’s (or equivalent term) 
• Lymphoma, primary, of brain 
• Mycobacterium avium complex or M. kansasii, disseminated or extrapulmonary 
• M. tuberculosis, any site (pulmonary or extrapulmonary) 
• Mycobacterium, other species or unidentified species, disseminated or extrapulmonary 
• Pneumocystis carinii pneumonia (pneumocystic jiroveci) 
• Pneumonia, recurrent bacterial (2 episodes within 1 yr of each other, after randomization) 
• Progressive multifocal leukoencephalopathy 
• Salmonella sepsis, recurrent (2 episodes within 1 year of each other, after randomization) 
• Toxoplasmosis of brain 
• Wasting syndrome due to HIV 
 
Additions to CDC Definition 
• Aspergillosis, invasive 
• Bartonellosis 
• Chagas disease (American trypanosomiasis) of the CNS 
• Herpes zoster, multi-dermatomal (≥10 lesions in a non-contiguous site) 
• Leishmaniasis, visceral (kala-azar) 
• Lymphoma, Hodgkin’s 
• Lymphoma, non-Hodgkin's, all cell types 
• Microsporidiosis (> 1 month’s duration) 
• Nocardiosis 
• Penicillium marneffii, disseminated 
• Pneumocystis carinii, extrapulmonary 
• Rhodococcus equi disease 
 
 


 Protocol Version 2.0 
 
5 
 
APPENDIX E:  ADVERSE EVENTS GRADING TABLES (FROM 
NIH/DAIDS)  


 
 
 
 
 
 
 
 
 
Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and 
             Pediatric Adverse Events  
 
  
 
 
Version 2.0 
November 2014 
 
 
MODIFIED FOR TACTICAL-HIV STUDY (PCC008) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Division of AIDS 
National Institute of Allergy and Infectious Diseases 
National Institutes of Health 
US Department of Health and Human Services


 
 
Table of Contents 
 
Glossary and Acronyms .................................................................................................................. 1 
 
Introduction..................................................................................................................................... 3 
 
Instructions for Use ......................................................................................................................... 4 
Major Clinical Conditions............................................................................................................... 7 
 
Cardiovascular .......................................................................................................................... 7 
 
Dermatologic............................................................................................................................. 9 
Endocrine and Metabolic ........................................................................................................ 10 
 
Gastrointestinal ....................................................................................................................... 11 
 
Musculoskeletal ...................................................................................................................... 13 
Neurologic............................................................................................................................... 14 
 
Pregnancy, Puerperium, and Perinatal .................................................................................... 16 
 
Psychiatric ............................................................................................................................... 17 
Respiratory .............................................................................................................................. 18 
 
Sensory.................................................................................................................................... 19 
 
Systemic .................................................................................................................................. 20 
Urinary .................................................................................................................................... 22 
 
Site Reactions to Injections and Infusions .................................................................................... 23 
Laboratory Values......................................................................................................................... 24 
 
Chemistries ............................................................................................................................. 24 
 
Hematology............................................................................................................................. 27 
Urinalysis ................................................................................................................................ 29 
 
Appendix A.  Total Bilirubin Table for Term and Preterm Neonates .......................................... 30


DAIDS AE Grading Table Version 2.0- November 2014 
Page 1 
 
 
Glossary and Acronyms 
 
AE 
Adverse event; Any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medical treatment or procedure regardless 
of whether it is considered related to the medical treatment or 
procedure. 
ALT (SGPT)                                                  Alanine aminotransferase (serum glutamic pyruvic transaminase) 
 ANC                                                               Absolute neutrophil count  
 
AST (SGOT)                                                  Aspartate aminotransferase (serum glutamic-oxaloacetic transaminase) 
 AV                                                                  Atrioventricular  
 
Basic Self-care Functions                              Adult 
Activities such as bathing, dressing, toileting, transfer or movement, 
continence, and feeding. 
 
Young Children 
Activities that are age and culturally appropriate, such as feeding one’s 
self with culturally appropriate eating implements. 
BMI z-score                                                   Body mass index z- score; A body reference norm. Specifically, the 
number of standard deviations a participant's BMI differs from the 
average BMI for their age, sex, and ethnicity. 
BMD t-score                                                  Bone mineral density t-score; The number of standard deviations above 
or below the mean bone mineral density of a healthy 30 year old adult 
of the same sex and ethnicity as the participant. 
BMD z-score                                                  Bone mineral density z-score; The number of standard deviations a 
participant's BMD differs from the average BMD for their age, sex, and 
ethnicity. 
BPAP                                                             Bilevel positive airway pressure; A mode used during noninvasive 
positive pressure ventilation. 
Chemical Pregnancy                                      A pregnancy in which a positive pregnancy test is followed by a 
negative pregnancy test without evidence of a clinical pregnancy loss. 
CNS                                                                Central nervous system 
CPAP                                                             Continuous positive airway pressure 
DAERS                                                          DAIDS Adverse Experience Reporting System; An internet-based 
system developed for clinical research sites to report Expedited 
Adverse Events (EAEs) to DAIDS. It facilitates timely EAE report 
submission and serves as a centralized location for accessing and 
processing EAE information for reporting purposes. 
Disability                                                        A substantial disruption of a person’s ability to conduct normal life 
functions. 
ECG                                                               Electrocardiogram 
 eGFR                                                              Estimated glomerular filtration rate  
 
Hospitalization                                                Does not include the following hospital admissions: under 24 hours, 
unrelated to an adverse event (e.g., for labor and delivery, cosmetic 
surgery, social or administrative for temporary placement [for lack of a 
place to sleep]), protocol-specified, and for diagnosis or therapy of a 
condition that existed before the receipt of a study agent and which has 
not increased in severity or frequency. 
 INR                                                                 International normalized ratio  


DAIDS AE Grading Table Version 2.0- November 2014 
Page 2 
 
 
Glossary and Acronyms  
 
 
Intervention                                                    Medical, surgical, or other procedures recommended or provided by a 
healthcare professional for the treatment of an adverse event. 
 IV                                                                   Intravenous  
 
IVIG                                                                Intravenous immune globulin 
 LDL                                                                Low density lipoprotein  
 
LLN                                                                Lower limit of normal 
Life-threatening AE                                       Any adverse event that places the participant, in the view of the 
investigator, at immediate risk of death from the reaction when it 
occurred (i.e., it does not include a reaction that would have caused 
death if it had occurred in a more severe form). 
NA                                                                  Not applicable 
Participant ID                                                 The identification number assigned to a study participant which is used 
to track study-related documentation, including any reported AEs. 
PR Interval                                                     The interval between the beginning of the P wave and the beginning of 
the QRS complex of an electrocardiogram that represents the time 
between the beginning of the contraction of the atria and the beginning 
of the contraction of the ventricles. 
 PT                                                                   Prothrombin time  
 
PTT                                                                 Partial thromboplastin time 
QTc Interval                                                  The measure of time between the onset of ventricular depolarization 
and completion of ventricular repolarization corrected for ventricular 
rate. 
RBC                                                               Red blood cell 
 SI                                                                    Standard international unit  
 
ULN                                                                Upper limit of normal 
Usual Social & Functional Activities            Activities which adults and children perform on a routine basis and 
those which are part of regular activities of daily living, for example: 
 
Adult 
Adaptive tasks and desirable activities, such as going to work, 
shopping, cooking, use of transportation, or pursuing a hobby. 
 
Young Children 
Activities that are age and culturally appropriate, such as social 
interactions, play activities, or learning tasks. 
WBC                                                              White blood cell 
 WHO                                                              World Health Organization  
 
WNL                                                               Within normal limits


DAIDS AE Grading Table Version 2.0- November 2014 
Page 3 
 
 
Introduction 
 
The Division of AIDS (DAIDS) oversees clinical trials throughout the world which it sponsors 
and supports.  The clinical trials evaluate the safety and efficacy of therapeutic products, 
vaccines, and other preventive modalities.  Adverse event (AE) data collected during these 
clinical trials form the basis for subsequent safety and efficacy analyses of pharmaceutical 
products and medical devices.  Incorrect and inconsistent AE severity grading can lead to 
inaccurate data analyses and interpretation, which in turn can impact the safety and well-being of 
clinical trial participants and future patients using pharmaceutical products. 
 
The DAIDS AE grading table is a shared tool for assessing the severity of AEs (including 
clinical and laboratory abnormalities) in participants enrolled in clinical trials.  Over the years as 
scientific knowledge and experience have expanded, revisions to the DAIDS AE grading table 
have become necessary. 
 
This document is for use in PCC008 (TACTICAL-HIV).  Instructions and information related to 
pediatric events and microbicide studies have been removed from the 2014 clarification of the 
DAIDS Table for Grading AE’s.  Thus, all definitions pertain to adults (≥ß18 years old) 


DAIDS AE Grading Table Version 2.0- November 2014 
Page 4 
 
 
Instructions for Use 
 
General Considerations 
The Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Version 2.0 consists of parameters, or AEs, with severity grading guidance that are to be 
used in DAIDS clinical trials for safety data reporting to maintain accuracy and consistency in 
the evaluation of AEs.  The term “severe” is not the same as the term “serious” in classifying 
AEs.  The severity of a specific event describes its intensity, and it is the intensity which is 
graded.  Seriousness, which is not graded, relates to an outcome of an AE and is a regulatory 
definition. 
 
Clinical sites are encouraged to report parameters in the DAIDS AE grading table as they are 
written to maintain data consistency across clinical trials.  However, since some parameters can 
be reported with more specificity, clinical sites are encouraged to report parameters that convey 
additional clinical information.  For example, diarrhea could be reported as neonatal diarrhea; 
seizures, as febrile seizures; and pain, as jaw pain. 
 
The DAIDS AE grading table provides an AE severity grading scale ranging from grades 1 to 5 
with descriptions for each AE based on the following general guidelines: 
•   Grade 1 indicates a mild event 
•   Grade 2 indicates a moderate event 
•   Grade 3 indicates a severe event 
•   Grade 4 indicates a potentially life-threatening event 
• Grade 5 indicates death (Note: This grade is not specifically listed on each page of the 
grading table). 
 
Other points to consider include: 
•   Use parameters defined by age and sex values as applicable. 
•   Male and female sex are defined as sex at birth. 
• Unless noted, laboratory values are for term neonates.  Preterm neonates should be assessed 
using local laboratory normal ranges. 
•   Where applicable, Standard International (SI) units are included in italics. 
 
Selecting and Reporting a Primary AE Term 
When selecting a primary AE term to report, sites should select the term that best describes what 
occurred to the participant.  For example, a participant may present with itching, urticaria, 
flushing, angioedema of the face, and dyspnea.  If the underlying diagnosis is determined to be 
an acute allergic reaction, sites should report “Acute Allergic Reaction” as the primary AE term. 
 
Primary AE terms should be reported using the DAIDS Adverse Experience Reporting System 
(DAERS) only if they meet expedited reporting criteria.  However, all primary AE terms should 
be reported using protocol-specific case report forms (CRFs).  Because the reported information 
is stored in different databases (i.e., safety and clinical), sites should report primary AE terms 
using the same terminology for data consistency.


DAIDS AE Grading Table Version 2.0- November 2014 
Page 5 
Instructions for Use  
 
 
 
 
When reporting using DAERS, other clinically significant events associated with a primary AE 
term that more fully describe the nature, severity, or complications of the primary AE term 
should be entered in the “Other Events” section.  However, the severity grade for these events 
must be lower than or equal to the severity grade of the primary AE term.  In the example above, 
dyspnea and angioedema of the face may be entered in the “Other Events” section, because they 
are more descriptive and provide additional information on the severity of the acute allergic 
reaction.  However, their severity grades must be lower than or equal to the severity grade of the 
primary AE term of “Acute Allergic Reaction”. 
 
Differences exist in the reporting and recording of information (e.g., signs and symptoms, 
clinically significant events) in DAERS and CRFs.  Therefore, sites should refer to their 
protocols and CRF requirements for further instructions. 
 
Grading Adult and Pediatric AEs 
When a single parameter is not appropriate for grading an AE in both adult and pediatric 
populations, separate parameters with specified age ranges are provided.  If no distinction 
between adult and pediatric populations has been made, the listed parameter should be used for 
grading an AE in both populations. 
 
Reporting Pregnancy Outcomes 
In the Pregnancy, Puerperium, and Perinatal section, all parameters are pregnancy outcomes 
and should be reported using the mother's participant ID.  If an infant is not enrolled in the same 
study as the mother, any identified birth defects should be reported using the mother's participant 
ID.  However, if an infant is enrolled in the same study as the mother or in another study, any 
identified birth defects should be reported using the infant's participant ID.  Sites should refer to 
the applicable network standards for reporting abnormal pregnancy outcomes on the CRFs. 
 
Determining Severity Grade for Parameters between Grades 
If the severity of an AE could fall in either one of two grades (i.e., the severity of an AE could be 
either grade 2 or grade 3), sites should select the higher of the two grades. 
 
Laboratory Values 
General. An asymptomatic, abnormal laboratory finding without an accompanying AE should 
not be reported to DAIDS in an expedited timeframe unless it meets protocol-specific reporting 
requirements.  Sites should refer to the applicable network standards for reporting abnormal 
laboratory findings on the CRFs. 
 
Values below Grade 1.  Any laboratory value that is between the ULN and grade 1 (for high 
values) or the LLN and grade 1 (for low values) should not be graded or reported as an AE. 
Sites should consult the Manual for Expedited Reporting of Adverse Events to DAIDS, Version 
2.0 and their protocol when making an assessment of the need to report an AE. 
 
Overlap of Local Laboratory Normal Values with Grading Table Ranges.  When local laboratory 
normal values fall within grading table laboratory ranges, the severity grading is based on the 
ranges in the grading table unless there is a protocol-specific grading criterion for the laboratory


DAIDS AE Grading Table Version 2.0- November 2014 
Page 6 
Instructions for Use  
 
 
 
 
value.  For example, “Magnesium, Low" has a grade 1 range of 1.2 to < 1.4 mEq/L, while a 
particular laboratory’s normal range for magnesium may be 1.3 to 2.8 mEq/L.  If a study 
participant’s magnesium laboratory value is 1.3 mEq/L, the laboratory value should be graded as 
grade 1. 
 
  
Estimating Severity Grade for Parameters Not Identified in the Grading Table 
The functional table below should be used to grade the severity of an AE that is not specifically 
identified in the grading table.  In addition, all deaths related to an AE are to be classified as 
grade 5. 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
Clinical adverse 
event  NOT 
identified 
elsewhere in the 
grading table 
Mild symptoms 
causing no or 
minimal interference 
with usual social & 
functional activities 
with intervention not 
indicated 
Moderate symptoms 
causing greater than 
minimal interference 
with usual social & 
functional activities 
with intervention 
indicated 
Severe symptoms 
causing inability to 
perform usual social & 
functional activities with 
intervention or 
hospitalization indicated 
Potentially life-threatening 
symptoms causing inability to 
perform basic self-care 
functions with intervention 
indicated to prevent 
permanent impairment, 
persistent disability, or death 


DAIDS AE Grading Table Version 2.0- November 2014 
Page 7 
Major Clinical Conditions 
Cardiovascular 
 
 
  
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Arrhythmia 
(by ECG or physical 
examination) 
Specify type, if applicable 
No symptoms AND 
No intervention 
indicated 
No symptoms AND 
Non-urgent 
intervention indicated 
Non-life-threatening 
symptoms  AND 
Non-urgent 
intervention indicated 
Life-threatening 
arrhythmia OR Urgent 
intervention indicated 
Blood Pressure 
Abnormalities 1 
Hypertension (with the 
lowest reading taken 
after repeat testing 
during a visit) 
≥ 18 years of age 
140 to < 160 mmHg 
systolic 
OR 
90 to < 100 mmHg 
diastolic 
≥ 160 to < 180 
mmHg systolic 
OR 
≥ 100 to < 110 
mmHg diastolic 
≥ 180 mmHg systolic 
OR 
≥ 110 mmHg diastolic 
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated 
< 18 years of age 
> 120/80 mmHg 
≥ 95th to < 99th 
percentile + 5 mmHg 
adjusted for age, 
height, and gender 
(systolic and/or 
diastolic) 
≥ 99th percentile 
+ 5 mmHg adjusted 
for age, height, and 
gender (systolic 
and/or diastolic) 
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated 
Hypotension 
No symptoms 
Symptoms corrected 
with oral fluid 
replacement 
Symptoms AND IV 
fluids indicated 
Shock requiring use of 
vasopressors or 
mechanical assistance to 
maintain blood pressure 
Cardiac Ischemia or 
Infarction 
Report only one 
NA 
NA 
New symptoms with 
ischemia (stable 
angina) OR New 
testing consistent with 
ischemia 
Unstable angina OR 
Acute myocardial 
infarction 
Heart Failure 
No symptoms AND 
Laboratory or 
cardiac imaging 
abnormalities 
Symptoms with mild 
to moderate activity 
or exertion 
Symptoms at rest or 
with minimal activity 
or exertion (e.g., 
hypoxemia) OR 
Intervention indicated 
(e.g., oxygen) 
Life-threatening 
consequences OR Urgent 
intervention indicated 
(e.g., vasoactive 
medications, ventricular 
assist device, heart 
transplant) 
Hemorrhage 
(with significant acute 
blood loss) 
NA 
Symptoms AND  No 
transfusion indicated 
Symptoms AND 
Transfusion of ≤ 2 
units packed RBCs 
indicated 
Life-threatening 
hypotension OR 
Transfusion of > 2 units 
packed RBCs (for 
children, packed RBCs 
> 10 cc/kg) indicated 
 
1 Blood pressure norms for children < 18 years of age can be found in: Expert Panel on Integrated Guidelines for Cardiovascular Health and 
Risk 
Reduction in Children and Adolescents. Pediatrics 2011;128;S213; originally published online November 14, 2011; DOI: 10.1542/peds.2009- 
2107C.


DAIDS AE Grading Table Version 2.0- November 2014 
Page 8 
Cardiovascular 
 
 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Prolonged PR Interval 
or AV Block 
Report only one 
> 16 years  of age 
PR interval 0.21 to < 
0.25 seconds 
PR interval ≥ 0.25 
seconds OR Type I 
2nd degree AV block 
Type II 2nd degree 
AV block OR 
Ventricular pause ≥ 
3.0 seconds 
Complete AV block 
≤ 16 years of age 
1st degree AV block 
(PR interval 
> normal for age and 
rate) 
Type I 2nd degree AV 
block 
Type II 2nd degree 
AV block OR 
Ventricular pause ≥ 
3.0 seconds 
Complete AV block 
Prolonged QTc 
Interval 2 
0.45 to 0.47 seconds 
> 0.47 to 0.50 
seconds 
> 0.50 seconds OR 
≥ 0.06 seconds above 
baseline 
Life-threatening 
consequences (e.g., 
Torsade de pointes, other 
associated serious 
ventricular dysrhythmia) 
Thrombosis or 
Embolism 
Report only one 
NA 
Symptoms AND No 
intervention indicated 
Symptoms AND 
Intervention indicated 
Life-threatening embolic 
event (e.g., pulmonary 
embolism, thrombus) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 As per Bazett’s formula.


Dermatologic 
3 For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions section 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 9 
 
 
 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Alopecia (scalp only) 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal interference 
with usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities 
NA 
NA 
Bruising 
Localized to one 
area 
Localized to more 
than one area 
Generalized 
NA 
Cellulitis 
NA 
Non-parenteral 
treatment indicated 
(e.g., oral antibiotics, 
antifungals, 
antivirals) 
IV treatment indicated 
(e.g., IV antibiotics, 
antifungals, antivirals) 
Life-threatening 
consequences (e.g., 
sepsis, tissue necrosis) 
Hyperpigmentation 
Slight or localized 
causing no or 
minimal interference 
with usual social & 
functional activities 
Marked or 
generalized causing 
greater than minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Hypopigmentation 
Slight or localized 
causing no or 
minimal interference 
with usual social & 
functional activities 
Marked or 
generalized causing 
greater than minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Petechiae 
Localized to one 
area 
Localized to more 
than one area 
Generalized 
NA 
Pruritus 3 
(without skin lesions) 
Itching causing no 
or minimal 
interference with 
usual social & 
functional activities 
Itching causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Itching causing 
inability to perform 
usual social & 
functional activities 
NA 
Rash 
Specify type, if applicable 
Localized rash 
Diffuse rash OR 
Target lesions 
Diffuse rash AND 
Vesicles or limited 
number of bullae or 
superficial ulcerations 
of mucous membrane 
limited to one site 
Extensive or generalized 
bullous lesions OR 
Ulceration of mucous 
membrane involving two 
or more distinct mucosal 
sites OR Stevens- 
Johnson syndrome OR 
Toxic epidermal 
necrolysis 


Endocrine and Metabolic 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 10 
 
 
 
 
  
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Diabetes Mellitus 
Controlled without 
medication 
Controlled with 
medication OR 
Modification of 
current medication 
regimen 
Uncontrolled despite 
treatment 
modification OR 
Hospitalization for 
immediate glucose 
control indicated 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non- 
ketotic coma, end organ 
failure) 
Gynecomastia 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal interference 
with usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing pain with 
greater than minimal 
interference with 
usual social & 
functional activities 
Disfiguring changes 
AND Symptoms 
requiring intervention 
or causing inability to 
perform usual social 
& functional activities 
NA 
Hyperthyroidism 
No symptoms AND 
Abnormal laboratory 
value 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
suppression therapy 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (e.g., 
thyroid storm) 
Hypothyroidism 
No symptoms AND 
Abnormal laboratory 
value 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR  Thyroid 
replacement therapy 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (e.g., 
myxedema coma) 
Lipoatrophy 4 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal interference 
with usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities 
Disfiguring changes 
NA 
Lipohypertrophy 5 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal interference 
with usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities 
Disfiguring changes 
NA 
 
4 Definition: A disorder characterized by fat loss in the face, extremities, and buttocks. 
5 Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and abdomen.


DAIDS AE Grading Table Version 2.0- November 2014 
Page 11 
Gastrointestinal 
 
 
  
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Anorexia 
Loss of appetite 
without decreased 
oral intake 
Loss of appetite 
associated with 
decreased oral intake 
without significant 
weight loss 
Loss of appetite 
associated with 
significant weight loss 
Life-threatening 
consequences OR 
Aggressive intervention 
indicated (e.g., tube 
feeding, total parenteral 
nutrition) 
Ascites 
No symptoms 
Symptoms AND 
Intervention indicated 
(e.g., diuretics, 
therapeutic 
paracentesis) 
Symptoms recur or 
persist despite 
intervention 
Life-threatening 
consequences 
Bloating or Distension 
Report only one 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Cholecystitis 
NA 
Symptoms AND 
Medical intervention 
indicated 
Radiologic, 
endoscopic, or 
operative intervention 
indicated 
Life-threatening 
consequences (e.g., 
sepsis, perforation) 
Constipation 
NA 
Persistent 
constipation requiring 
regular use of dietary 
modifications, 
laxatives, or enemas 
Obstipation with 
manual evacuation 
indicated 
Life-threatening 
consequences (e.g., 
obstruction) 
Diarrhea 
≥ 1 year of age 
Transient or 
intermittent episodes 
of unformed stools 
OR Increase of ≤ 3 
stools over baseline 
per 24-hour period 
Persistent episodes of 
unformed to watery 
stools OR Increase of 
4 to  6 stools over 
baseline per 24-hour 
period 
Increase of ≥ 7 stools 
per 24-hour period 
OR IV fluid 
replacement indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Dysphagia or 
Odynophagia 
Report only one and 
specify location 
Symptoms but able 
to eat usual diet 
Symptoms causing 
altered dietary intake 
with no intervention 
indicated 
Symptoms causing 
severely altered 
dietary intake with 
intervention indicated 
Life-threatening 
reduction in oral intake 
Gastrointestinal 
Bleeding 
Not requiring 
intervention other 
than iron 
supplement 
Endoscopic 
intervention indicated 
Transfusion indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 


DAIDS AE Grading Table Version 2.0- November 2014 
Page 12 
Gastrointestinal 
 
 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Mucositis or Stomatitis 
Report only one and 
specify location 
Mucosal erythema 
Patchy 
pseudomembranes or 
ulcerations 
Confluent 
pseudomembranes or 
ulcerations OR 
Mucosal bleeding 
with minor trauma 
Life-threatening 
consequences (e.g., 
aspiration, choking) OR 
Tissue necrosis OR 
Diffuse spontaneous 
mucosal bleeding 
Nausea 
Transient (< 24 
hours) or 
intermittent AND 
No or minimal 
interference with 
oral intake 
Persistent nausea 
resulting in decreased 
oral intake for 24 to 
48 hours 
Persistent nausea 
resulting in minimal 
oral intake for > 48 
hours OR 
Rehydration indicated 
(e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Pancreatitis 
NA 
Symptoms with 
hospitalization not 
indicated 
Symptoms 
with 
hospitalizati
i di
d
Life-threatening 
consequences (e.g., 
circulatory failure, 
hemorrhage, sepsis) 
Perforation 
(colon or rectum) 
NA 
NA 
Intervention indicated 
Life-threatening 
consequences 
Proctitis 
Rectal discomfort 
with no intervention 
indicated 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Medical 
intervention indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
perforation) 
Rectal Discharge 
Visible discharge 
Discharge requiring 
the use of pads 
NA 
NA 
Vomiting 
Transient or 
intermittent AND 
No or minimal 
interference with 
oral intake 
Frequent episodes 
with no or mild 
dehydration 
Persistent vomiting 
resulting in orthostatic 
hypotension OR 
Aggressive 
rehydration indicated 
(e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 


DAIDS AE Grading Table Version 2.0- November 2014 
Page 13 
Musculoskeletal 
 
 
 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Arthralgia 
Joint pain causing 
no or minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
inability to perform 
usual social & 
functional activities 
Disabling joint pain 
causing inability to 
perform basic self-care 
functions 
Arthritis 
Stiffness or joint 
swelling causing no 
or minimal 
interference with 
usual social & 
functional activities 
Stiffness or joint 
swelling causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Stiffness or joint 
swelling causing 
inability to perform 
usual social & 
functional activities 
Disabling joint stiffness 
or swelling causing 
inability to perform basic 
self-care functions 
Myalgia (generalized) 
Muscle pain causing 
no or minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
inability to perform 
usual social & 
functional activities 
Disabling muscle pain 
causing inability to 
perform basic self-care 
functions 
Osteonecrosis 
NA 
No symptoms but 
with radiographic 
findings AND No 
operative intervention 
indicated 
Bone pain with 
radiographic findings 
OR Operative 
intervention indicated 
Disabling bone pain with 
radiographic findings 
causing inability to 
perform basic self-care 
functions 
Osteopenia 6 
≥ 30 years of age 
BMD t-score 
-2.5 to -1 
NA 
NA 
NA 
< 30 years of age 
BMD z-score 
-2 to -1 
NA 
NA 
NA 
Osteoporosis6 
≥ 30 years of age 
NA 
BMD t-score < -2.5 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences 
< 30 years of age 
NA 
BMD z-score < -2 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences 
  
 
 
 
 
 
 
 
 
 
6 BMD t and z scores can be found in: Kanis JA on behalf of the World Health Organization Scientific Group (2007). Assessment of osteoporosis 
at the primary health-care level. Technical Report. World Health Organization Collaborating Centre for Metabolic Bone Diseases, University of 
Sheffield, UK. 2007: Printed by the University of Sheffield.


DAIDS AE Grading Table Version 2.0- November 2014 
Page 14 
Neurologic 
 
 
  
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Acute CNS Ischemia 
NA 
NA 
Transient ischemic 
attack 
Cerebral vascular 
accident (e.g., stroke 
with neurological 
deficit) 
Altered Mental Status 
(for Dementia, see 
Cognitive, Behavioral, or 
Attentional Disturbance 
below) 
Changes causing no 
or minimal 
interference with 
usual social & 
functional activities 
Mild lethargy or 
somnolence causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Confusion, memory 
impairment, lethargy, 
or  somnolence 
causing inability to 
perform usual social 
& functional activities 
Delirium OR 
Obtundation OR 
Coma 
Ataxia 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
OR No symptoms 
with ataxia detected 
on examination 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Disabling symptoms 
causing inability to 
perform basic self-care 
functions 
Cognitive, Behavioral, 
or Attentional 
Disturbance (includes 
dementia and attention 
deficit disorder) 
Specify type, if applicable 
Disability causing 
no or minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources not 
indicated 
Disability causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources on part- 
time basis indicated 
Disability causing 
inability to perform 
usual social & 
functional activities 
OR Specialized 
resources on a full- 
time basis indicated 
Disability causing 
inability to perform 
basic self-care functions 
OR Institutionalization 
indicated 
Developmental Delay 
< 18 years of age 
Specify type, if applicable 
Mild developmental 
delay, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Moderate 
developmental delay, 
either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Severe developmental 
delay, either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Developmental 
regression, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental screening 
tool appropriate for the 
setting 
Headache 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
basic self-care functions 
OR Hospitalization 
indicated  OR Headache 
with significant 
impairment of alertness 
or other neurologic 
function 


DAIDS AE Grading Table Version 2.0- November 2014 
Page 15 
Neurologic 
 
 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Neuromuscular 
Weakness (includes 
myopathy and 
neuropathy) 
Specify type, if applicable 
Minimal muscle 
weakness causing no 
or minimal 
interference with 
usual social & 
functional activities 
OR No symptoms 
with decreased 
strength on 
examination 
Muscle weakness 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Muscle weakness 
causing inability to 
perform usual social 
& functional activities 
Disabling muscle 
weakness causing 
inability to perform 
basic self-care functions 
OR  Respiratory muscle 
weakness impairing 
ventilation 
Neurosensory Alteration 
(includes paresthesia and 
painful neuropathy) 
Specify type, if applicable 
Minimal paresthesia 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
OR No symptoms 
with sensory 
alteration on 
examination 
Sensory alteration or 
paresthesia causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Sensory alteration or 
paresthesia causing 
inability to perform 
usual social & 
functional activities 
Disabling sensory 
alteration or paresthesia 
causing inability to 
perform basic self-care 
functions 
Seizures 
New Onset Seizure 
≥ 18 years of age 
NA 
NA 
1 to  3 seizures 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult 
to control (e.g., 
refractory epilepsy) 
Pre-existing Seizure 
NA 
Increased frequency 
from previous level 
of control without 
change in seizure 
character 
Change in seizure 
character either in 
duration or quality 
(e.g., severity or 
focality) 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult 
to control (e.g., 
refractory epilepsy) 
Syncope 
Near syncope 
without loss of 
consciousness (e.g., 
pre-syncope) 
Loss of consciousness 
with no intervention 
indicated 
Loss of consciousness 
AND Hospitalization 
or intervention 
required 
NA 


DAIDS AE Grading Table Version 2.0- November 2014 
Page 16 
Pregnancy, Puerperium, and Perinatal 
 
 
 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Fetal Death or Stillbirth 
(report using mother’s 
participant ID) 
Report only one 
NA 
NA 
Fetal loss occurring at 
≥ 20 weeks gestation 
NA 
Preterm Delivery 7 
(report using mother’s 
participant ID) 
Delivery at 34 to 
< 37 weeks 
gestational age 
Delivery at 28 to 
< 34 weeks 
gestational age 
Delivery at 24 to 
< 28 weeks 
gestational age 
Delivery at < 24 weeks 
gestational age 
Spontaneous Abortion 
or Miscarriage 8 (report 
using mother’s participant 
ID) 
Report only one 
Chemical pregnancy 
Uncomplicated 
spontaneous abortion 
or miscarriage 
Complicated 
spontaneous abortion 
or miscarriage 
NA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7 Definition:  A delivery of a live-born neonate occurring at ≥ 20 to < 37 weeks gestational age. 
8 Definition:  A clinically recognized pregnancy occurring at < 20 weeks gestational age.


DAIDS AE Grading Table Version 2.0- November 2014 
Page 17 
Psychiatric 
 
 
  
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Insomnia 
Mild difficulty 
falling asleep, 
staying asleep, or 
waking up early 
Moderate difficulty 
falling asleep, staying 
asleep, or waking up 
early 
Severe difficulty 
falling asleep, staying 
asleep, or waking up 
early 
NA 
Psychiatric Disorders 
(includes anxiety, 
depression, mania, and 
psychosis) 
Specify disorder 
Symptoms with 
intervention not 
indicated OR 
Behavior causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms with 
intervention indicated 
OR Behavior causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms with 
hospitalization 
indicated OR 
Behavior causing 
inability to perform 
usual social & 
functional activities 
Threatens harm to self or 
others OR Acute 
psychosis OR Behavior 
causing inability to 
perform basic self-care 
functions 
Suicidal Ideation or 
Attempt 
Report only one 
Preoccupied with 
thoughts of death 
AND No wish to kill 
oneself 
Preoccupied with 
thoughts of death 
AND Wish to kill 
oneself with no 
specific plan or intent 
Thoughts of killing 
oneself with partial or 
complete plans but no 
attempt to do so OR 
Hospitalization 
indicated 
Suicide attempted 


DAIDS AE Grading Table Version 2.0- November 2014 
Page 18 
Respiratory 
 
 
  
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Acute Bronchospasm 
Forced expiratory 
volume in 1 second 
or peak flow 
reduced to 
≥ 70 to < 80% OR 
Mild symptoms with 
intervention not 
indicated 
Forced expiratory 
volume in 1 second or 
peak flow 50 to 
< 70% OR Symptoms 
with intervention 
indicated OR 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Forced expiratory 
volume in 1 second 
or peak flow 25 to 
< 50% OR Symptoms 
causing inability to 
perform usual social 
& functional 
activities 
Forced expiratory 
volume in 1 second or 
peak flow < 25% OR 
Life-threatening 
respiratory or 
hemodynamic 
compromise OR 
Intubation 
Dyspnea or Respiratory 
Distress 
Report only one 
Dyspnea on exertion 
with no or minimal 
interference with 
usual social & 
functional activities 
OR Wheezing OR 
Minimal increase in 
respiratory rate for 
age 
Dyspnea on exertion 
causing greater than 
minimal interference 
with usual social & 
functional activities 
OR Nasal flaring OR 
Intercostal retractions 
OR Pulse oximetry 90 
to < 95% 
Dyspnea at rest 
causing inability to 
perform usual social 
& functional 
activities OR Pulse 
oximetry < 90% 
Respiratory failure with 
ventilator support 
indicated (e.g., CPAP, 
BPAP, intubation) 


DAIDS AE Grading Table Version 2.0- November 2014 
Page 19 
Sensory 
 
 
  
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Hearing Loss 
≥ 12 years of age 
NA 
Hearing aid or 
intervention not 
indicated 
Hearing aid or 
intervention indicated 
Profound bilateral 
hearing loss (> 80 dB at 
2 kHz and above) OR 
Non-serviceable hearing 
(i.e., >50 dB audiogram 
and <50% speech 
discrimination) 
Tinnitus 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
with intervention not 
indicated 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
with intervention 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Uveitis 
No symptoms AND 
Detectable on 
examination 
Anterior uveitis with 
symptoms OR 
Medicamylasal 
intervention indicated 
Posterior or pan- 
uveitis OR Operative 
intervention indicated 
Disabling visual loss in 
affected eye(s) 
Vertigo 
Vertigo causing no 
or minimal 
interference with 
usual social & 
functional activities 
Vertigo causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Vertigo causing 
inability to perform 
usual social & 
functional activities 
Disabling vertigo 
causing inability to 
perform basic self-care 
functions 
Visual Changes 
(assessed from baseline) 
Visual changes 
causing no or 
minimal interference 
with usual social & 
functional activities 
Visual changes 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Visual changes 
causing inability to 
perform usual social 
& functional activities 
Disabling visual loss in 
affected eye(s) 


Systemic 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 
 
 
  
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Acute Allergic 
Reaction 
Localized urticaria 
(wheals) with no 
medical intervention 
indicated 
Localized urticaria 
with intervention 
indicated OR Mild 
angioedema with no 
intervention 
indicated 
Generalized urticaria 
OR Angioedema with 
intervention indicated 
OR Symptoms of mild 
bronchospasm 
Acute anaphylaxis OR 
Life-threatening 
bronchospasm OR 
Laryngeal edema 
Chills 
Symptoms causing no 
or minimal 
interference with usual 
social & functional 
activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Cytokine Release 
Syndrome9 
Mild signs and 
symptoms AND 
Therapy (i.e., antibody 
infusion) interruption 
not indicated 
Therapy (i.e., 
antibody infusion) 
interruption 
indicated AND 
Responds promptly 
to symptomatic 
treatment OR 
Prophylactic 
medications 
indicated for ≤ 24 
hours 
Prolonged severe signs 
and symptoms OR 
Recurrence of 
symptoms following 
initial improvement 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
Fatigue or Malaise 
Report only one 
Symptoms causing no 
or minimal 
interference with usual 
social & functional 
activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Incapacitating symptoms 
of fatigue or malaise 
causing inability to 
perform basic self-care 
functions 
Fever (non-axillary 
temperatures only) 
38.0 to < 38.6°C or 
100.4 to < 101.5°F 
≥ 38.6  to < 39.3°C 
or ≥ 101.5 to 
< 102.7°F 
≥ 39.3 to < 40.0°C or 
≥ 102.7 to < 104.0°F 
≥ 40.0°C or ≥ 104.0°F 
Pain10 (not associated 
with study agent 
injections and not 
specified elsewhere) 
Specify location 
Pain causing no or 
minimal interference 
with usual social & 
functional activities 
Pain causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Pain causing inability 
to perform usual social 
& functional activities 
Disabling pain causing 
inability to perform basic 
self-care functions OR 
Hospitalization indicated 
Serum Sickness 11 
Mild signs and 
symptoms 
Moderate signs and 
symptoms AND 
Intervention 
indicated (e.g., 
antihistamines) 
Severe signs and 
symptoms AND 
Higher level 
intervention indicated 
(e.g., steroids or IV 
fluids) 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
 
9 Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness of breath. 
10 For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section (page 23). 
11 Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked discomfort, and/or dyspnea.


DAIDS AE Grading Table Version 2.0- November 2014 
Page 21 
 
 
  
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Underweight12 
> 5 to 19 years of 
age 
NA 
WHO BMI z-score 
< -2 to ≤ -3 
WHO BMI z-score 
< -3 
WHO BMI z-score 
< -3 with life-threatening 
consequences 
Weight Loss (excludes 
postpartum weight 
loss) 
NA 
5 to < 9% loss in 
body weight from 
baseline 
≥ 9 to < 20% loss in 
body weight from 
baseline 
≥ 20% loss in body weight 
from baseline OR 
Aggressive intervention 
indicated (e.g., tube 
feeding, total parenteral 
nutrition) 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12 WHO reference tables may be accesed by clicking the desired age range or by accessing the following URLs: 
http://www.who.int/growthref/who2007_bmi_for_age/en/ for participants > 5 to 19 years of age and 
http://www.who.int/childgrowth/standards/chart_catalogue/en/ for those ≤ 5 years of age.


Urinary 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 
 
 
22 
  
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Urinary Tract 
Obstruction 
NA 
Signs or symptoms of 
urinary tract 
obstruction without 
hydronephrosis or 
renal dysfunction 
Signs or symptoms of 
urinary tract 
obstruction with 
hydronephrosis or 
renal dysfunction 
Obstruction causing life- 
threatening 
consequences 


 
 
 
Site Reactions to Injections and Infusions 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Injection Site Pain or 
Tenderness 
Report only one 
Pain or tenderness 
causing no or 
minimal limitation 
of use of limb 
Pain or tenderness 
causing greater than 
minimal limitation of 
use of limb 
Pain or tenderness 
causing inability to 
perform usual social 
& functional activities 
Pain or tenderness 
causing inability to 
perform basic self-care 
function OR 
Hospitalization indicated 
Injection Site Erythema 
or Redness 13 
Report only one 
> 15 years of age 
2.5 to < 5 cm in 
diameter OR 6.25 to 
< 25 cm2 surface 
area AND 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
≥ 5 to < 10 cm in 
diameter OR ≥ 25 to 
< 100 cm2 surface 
area OR  Symptoms 
causing greater than 
minimal interference 
with usual social & 
functional activities 
≥ 10 cm in diameter 
OR ≥ 100 cm2 surface 
area OR Ulceration 
OR Secondary 
infection OR Phlebitis 
OR Sterile abscess 
OR Drainage OR 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Potentially life- 
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
Injection Site 
Induration or Swelling 
Report only one 
> 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, > 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, > 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, > 15 years of 
age 
Injection Site Pruritus 
Itching localized to 
the injection site that 
is relieved 
spontaneously or in 
< 48 hours of 
treatment 
Itching beyond the 
injection site that is 
not generalized OR 
Itching localized to 
the injection site 
requiring ≥ 48 hours 
treatment 
Generalized itching 
causing inability to 
perform usual social 
& functional activities 
NA 
 
 
 
13 Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or measured surface area.


Laboratory Values
Chemistries 
14 Direct bilirubin > 1.5 mg/dL in a participant < 28 days of age should be graded as grade 2, if < 10% of the total 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 
 
 
  
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Acidosis 
NA 
pH ≥ 7.3 to < LLN 
pH < 7.3 without life- 
threatening 
consequences 
pH < 7.3 with life- 
threatening 
consequences 
Albumin, Low 
(g/dL; g/L) 
3.0 to < LLN 
30  to < LLN 
≥ 2.0 to < 3.0 
≥ 20  to < 30 
< 2.0 
< 20 
NA 
Alkaline Phosphatase, 
High 
1.25  to < 2.5 
x ULN 
2.5  to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
Alkalosis 
NA 
pH > ULN to ≤ 7.5 
pH > 7.5 without life- 
threatening 
consequences 
pH > 7.5 with life- 
threatening 
consequences 
ALT or SGPT, High 
Report only one 
1.25  to < 2.5 
x ULN 
2.5 to < 5.0 x ULN 
5.0  to < 10.0 x ULN 
≥ 10.0 x ULN 
Amylase (Pancreatic) or 
Amylase (Total), High 
Report only one 
1.1  to < 1.5 x ULN 
1.5  to < 3.0 x ULN 
3.0  to < 5.0 x ULN 
≥ 5.0 x ULN 
AST or SGOT, High 
Report only one 
1.25  to < 2.5 
x ULN 
2.5  to < 5.0 x ULN 
5.0  to < 10.0 x ULN 
≥ 10.0 x ULN 
Bicarbonate, Low 
(mEq/L; mmol/L) 
16.0 to <  LLN 
16.0 to <  LLN 
11.0  to < 16.0 
11.0  to < 16.0 
8.0  to < 11.0 
8.0  to < 11.0 
< 8.0 
< 8.0 
Bilirubin 
Direct Bilirubin14, 
High 
> 28 days of age 
NA 
NA 
> ULN 
> ULN with life- 
threatening 
consequences (e.g., signs 
and symptoms of liver 
failure) 
≤ 28 days of age 
ULN to ≤ 1 mg/dL 
> 1 to ≤ 1.5 mg/dL 
> 1.5 to ≤ 2 mg/dL 
> 2 mg/dL 
Total Bilirubin, High 
> 28 days of age 
1.1 to < 1.6 x ULN 
1.6 to < 2.6 x ULN 
2.6 to < 5.0 x ULN 
≥  5.0 x ULN 
≤ 28 days of age 
See Appendix A. 
Total Bilirubin for 
Term and Preterm 
Neonates 
See Appendix A. 
Total Bilirubin for 
Term and Preterm 
Neonates 
See Appendix A. 
Total Bilirubin for 
Term and Preterm 
Neonates 
See Appendix A. Total 
Bilirubin for Term and 
Preterm Neonates 
Calcium, High 
(mg/dL; mmol/L) 
≥ 7 days of age 
10.6   to < 11.5 
2.65  to < 2.88 
11.5  to < 12.5 
2.88  to < 3.13 
12.5   to < 13.5 
3.13  to < 3.38 
≥  13.5 
≥  3.38 
< 7 days of age 
11.5  to < 12.4 
2.88  to < 3.10 
12.4  to < 12.9 
3.10  to < 3.23 
12.9  to < 13.5 
3.23  to < 3.38 
≥  13.5 
≥  3.38 


Chemistries 
15 Use the applicable formula (i.e., Cockroft-Gault in mL/min or Schwatrz in 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 25 
 
 
  
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Calcium (Ionized), High 
(mg/dL; mmol/L) 
> ULN to < 6.0 
> ULN  to < 1.5 
6.0 to < 6.4 
1.5 to < 1.6 
6.4 to < 7.2 
1.6 to < 1.8 
≥ 7.2 
≥ 1.8 
Calcium, Low 
(mg/dL; mmol/L) 
≥ 7 days of age 
7.8  to < 8.4 
1.95  to < 2.10 
7.0   to < 7.8 
1.75  to < 1.95 
6.1  to < 7.0 
1.53  to < 1.75 
< 6.1 
< 1.53 
< 7 days of age 
6.5  to < 7.5 
1.63  to < 1.88 
6.0 to < 6.5 
1.50  to < 1.63 
5.50  to < 6.0 
1.38  to < 1.50 
< 5.50 
< 1.38 
Calcium (Ionized),  Low 
(mg/dL; mmol/L) 
< LLN  to 4.0 
< LLN to 1.0 
3.6 to < 4.0 
0.9 to < 1.0 
3.2 to < 3.6 
0.8 to < 0.9 
< 3.2 
< 0.8 
Cardiac Troponin I, 
High 
NA 
NA 
NA 
Levels consistent with 
myocardial infarction or 
unstable angina as 
defined by the local 
laboratory 
Creatine Kinase, High 
3 to < 6 x ULN 
6 to < 10 x ULN 
10 to < 20 x ULN 
≥ 20 x ULN 
Creatinine, High 
1.1 to 1.3 x ULN 
> 1.3 to 1.8 x ULN 
OR Increase of 
> 0.3 mg/dL above 
baseline 
> 1.8  to < 3.5 
x ULN OR Increase 
of 1.5 to < 2.0 x 
above baseline 
≥ 3.5 x ULN OR 
Increase of ≥ 2.0 x 
above baseline 
Creatinine Clearance 15 
or eGFR, Low 
Report only one 
NA 
< 90 to 60 ml/min or 
ml/min/1.73 m2 
OR 
10 to < 30% decrease 
from baseline 
< 60 to 30 ml/min or 
ml/min/1.73 m2 
OR 
≥ 30 to < 50% 
decrease from 
baseline 
< 30 ml/min or 
ml/min/1.73 m2 
OR 
≥ 50% decrease from 
baseline or dialysis 
needed 
Glucose 
(mg/dL; mmol/L) 
Fasting, High 
110 to 125 
6.11 to < 6.95 
> 125 to 250 
6.95 to < 13.89 
> 250 to 500 
13.89 to < 27.75 
> 500 
≥ 27.75 
Nonfasting, High 
116 to 160 
6.44 to < 8.89 
> 160 to 250 
8.89 to < 13.89 
> 250 to 500 
13.89  to < 27.75 
> 500 
≥ 27.75 
Glucose, Low 
(mg/dL; mmol/L) 
≥ 1 month of age 
55  to 64 
3.05  to 3.55 
40  to < 55 
2.22  to < 3.05 
30  to < 40 
1.67 to < 2.22 
< 30 
< 1.67 
< 1 month of age 
50 to 54 
2.78  to 3.00 
40 to < 50 
2.22 to < 2.78 
30 to < 40 
1.67 to < 2.22 
< 30 
< 1.67 
Lactate, High 
ULN to  < 2.0 
x ULN without 
acidosis 
≥ 2.0 x ULN without 
acidosis 
Increased lactate with 
pH < 7.3 without life- 
threatening 
consequences 
Increased lactate with 
pH < 7.3 with life- 
threatening 
consequences 


DAIDS AE Grading Table Version 2.0- November 2014 
Page 26 
 
 
  
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Lipase, High 
1.1  to < 1.5 x ULN 
1.5  to < 3.0 x ULN 
3.0  to < 5.0 x ULN 
≥ 5.0 x ULN 
Lipid Disorders 
(mg/dL; mmol/L) 
Cholesterol, Fasting, 
High 
≥ 18 years of age 
200  to < 240 
5.18  to < 6.19 
240  to < 300 
6.19  to < 7.77 
≥  300 
≥  7.77 
NA 
< 18 years of age 
170  to < 200 
4.40  to < 5.15 
200  to < 300 
5.15  to < 7.77 
≥  300 
≥  7.77 
NA 
LDL, Fasting, High 
≥ 18 years of age 
130  to < 160 
3.37  to < 4.12 
160 to < 190 
4.12  to < 4.90 
≥ 190 
≥ 4.90 
NA 
> 2 to < 18 years of 
age 
110  to < 130 
2.85  to < 3.34 
130 to < 190 
3.34  to < 4.90 
≥ 190 
≥ 4.90 
NA 
Triglycerides, Fasting, 
High 
150 to 300 
1.71 to 3.42 
>300  to 500 
>3.42 to 5.7 
>500 to < 1,000 
>5.7 to 11.4 
> 1,000 
> 11.4 
Magnesium16, Low 
(mEq/L; mmol/L) 
1.2   to < 1.4 
0.60  to < 0.70 
0.9  to < 1.2 
0.45  to < 0.60 
0.6  to < 0.9 
0.30  to < 0.45 
< 0.6 
< 0.30 
Phosphate, Low 
(mg/dL; mmol/L) 
> 14 years of age 
2.0 to < LLN 
0.81 to < LLN 
1.4 to < 2.0 
0.65 to < 0.81 
1.0 to < 1.4 
0.32 to < 0.65 
< 1.0 
< 0.32 
1 to 14 years of age 
3.0  to < 3.5 
0.97  to < 1.13 
2.5  to < 3.0 
0.81  to < 0.97 
1.5  to < 2.5 
0.48  to < 0.81 
< 1.5 
< 0.48 
< 1 year of age 
3.5  to < 4.5 
1.13  to < 1.45 
2.5  to < 3.5 
0.81  to < 1.13 
1.5  to < 2.5 
0.48  to < 0.81 
< 1.5 
< 0.48 
Potassium, High 
(mEq/L; mmol/L) 
5.6  to < 6.0 
5.6  to < 6.0 
6.0  to < 6.5 
6.0  to < 6.5 
6.5  to < 7.0 
6.5  to < 7.0 
≥ 7.0 
≥ 7.0 
Potassium, Low 
(mEq/L; mmol/L) 
3.0  to < 3.4 
3.0  to < 3.4 
2.5  to < 3.0 
2.5  to < 3.0 
2.0  to < 2.5 
2.0  to < 2.5 
< 2.0 
< 2.0 
Sodium, High 
(mEq/L; mmol/L) 
146  to < 150 
146  to < 150 
150  to < 154 
150  to < 154 
154  to < 160 
154  to < 160 
≥ 160 
≥ 160 
Sodium, Low 
(mEq/L; mmol/L) 
130  to < 135 
130  to < 135 
125  to < 130 
125  to < 135 
121  to < 125 
121  to < 125 
≤ 120 
≤ 120 
Uric Acid, High 
(mg/dL; mmol/L) 
7.5  to < 10.0 
0.45  to < 0.59 
10.0  to < 12.0 
0.59  to < 0.71 
12.0  to < 15.0 
0.71  to < 0.89 
≥ 15.0 
≥ 0.89 
  
 
 
 
 
16 To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114.


Hematology 
 
 
  
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Absolute CD4+ Count, 
Low 
(cell/mm3; cells/L) 
> 5 years of age 
(not HIV infected) 
300 to < 400 
300 to < 400 
200 to <  300 
200 to < 300 
100 to < 200 
100  to < 200 
< 100 
< 100 
Absolute Lymphocyte 
Count, Low 
(cell/mm3; cells/L) 
> 5 years of age 
(not HIV infected) 
600  to < 650 
9 
0.600 x 10   to 
< 0.650 x 109 
500  to < 600 
9 
0.500 x 10   to 
< 0.600 x 109 
350 to < 500 
9 
0.350 x 10   to 
< 0.500 x 109 
< 350           
9 
< 0.350 x 10 
Absolute Neutrophil 
Count (ANC), Low 
(cells/mm3; cells/L) 
> 7 days of age 
800 to 1,000 
0.800 x 109 to 1.000 
x 109 
600 to 799 
0.600 x 109 to 0.799 x 
109 
400 to 599 
0.400 x 109 to 0.599 x 
109 
< 400 
< 0.400 x 109 
2 to 7 days of age 
1,250 to 1,500 
1.250 x 109 to 1.500 
x 109 
1,000 to 1,249 
1.000 x 109 to 1.249 x 
109 
750 to 999 
0.750 x 109 to 0.999 x 
109 
< 750 
< 0.750 x 109 
≤ 1 day of age 
4,000 to 5,000 
4.000 x 109 to 
5.000 x 109 
3,000 to 3,999 
3.000 x 109 to 3.999 x 
109 
1,500 to 2,999 
1.500 x 109 to 2.999 x 
109 
< 1,500 
< 1.500 x 109 
Fibrinogen, Decreased 
(mg/dL; g/L) 
100  to < 200 
1.00 to < 2.00 
OR 
0.75 to < 1.00 
x LLN 
75  to < 100 
0.75  to < 1.00 
OR 
≥ 0.50 to < 0.75 
x LLN 
50  to < 75 
0.50  to < 0.75 
OR 
0.25 to < 0.50 
x LLN 
< 50 
< 0.50 
OR 
< 0.25 x LLN 
OR Associated with 
gross bleeding 
Hemoglobin17, Low 
(g/dL; mmol/L)18 
≥ 13 years of age 
(male only) 
10.0 to 10.9 
6.19 to 6.76 
9.0 to < 10.0 
5.57 to < 6.19 
7.0 to < 9.0 
4.34 to < 5.57 
< 7.0 
< 4.34 
≥ 13 years of age 
(female only) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
 
 
 
 
17 Male and female sex are defined as sex at birth. 
18 The conversion factor used to convert g/dL to mmol/L is 0.6206 and is the most commonly used conversion factor.  For grading hemoglobin 
results obtained by an analytic method with a conversion factor other than 0.6206, the result must be converted to g/dL using the appropriate 
conversion factor for the particular laboratory.


Hematology 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 28 
 
 
  
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
57 days of age to < 13 
years of age 
(male and female) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
36 to 56 days of age 
(male and female) 
8.5 to 9.6 
5.26 to 5.99 
7.0 to < 8.5 
4.32 to < 5.26 
6.0 to < 7.0 
3.72 to < 4.32 
< 6.0 
< 3.72 
22 to 35 days of age 
(male and female) 
9.5 to 11.0 
5.88 to 6.86 
8.0 to < 9.5 
4.94 to < 5.88 
6.7 to < 8.0 
4.15 to < 4.94 
< 6.7 
< 4.15 
8 to ≤ 21 days of age 
(male and female) 
11.0 to 13.0 
6.81 to 8.10 
9.0 to < 11.0 
5.57 to < 6.81 
8.0 to < 9.0 
4.96 to < 5.57 
< 8.0 
< 4.96 
≤ 7 days of age 
(male and female) 
13.0 to 14.0 
8.05 to 8.72 
10.0 to < 13.0 
6.19 to < 8.05 
9.0 to < 10.0 
5.59 to < 6.19 
< 9.0 
< 5.59 
INR, High 
(not on anticoagulation 
therapy) 
1.1  to < 1.5 x ULN 
1.5  to < 2.0 x ULN 
2.0  to < 3.0 x ULN 
≥  3.0 x ULN 
Methemoglobin 
(% hemoglobin) 
5.0  to < 10.0% 
10.0  to < 15.0% 
15.0  to < 20.0% 
≥  20.0% 
PTT, High 
(not on anticoagulation 
therapy) 
1.1  to < 1.66 
x ULN 
1.66 to < 2.33 
x ULN 
2.33 to < 3.00 
x ULN 
≥  3.00 x ULN 
Platelets, Decreased 
(cells/mm3; cells/L) 
100,000  to 
< 124,999 
100.000 x 109  to 
< 124.999 x 109 
50,000  to 
< 100,000 
50.000 x 109  to 
< 100.000 x 109 
25,000  to 
< 50,000 
25.000 x 109  to 
< 50.000 x 109 
< 25,000 
< 25.000 x 109 
PT, High 
(not on anticoagulation 
therapy 
1.1  to < 1.25 
x ULN 
1.25  to < 1.50 
x ULN 
1.50  to < 3.00 
x ULN 
≥  3.00 x ULN 
WBC, Decreased 
(cells/mm3; cells/L) 
> 7 days of age 
2,000 to 2,499 
2.000 x 109 to 2.499 
x 109 
1,500 to 1,999 
1.500 x 109 to 1.999 x 
109 
1,000 to 1,499 
1.000 x 109 to 1.499 x 
109 
< 1,000 
< 1.000 x 109 
≤ 7 days of age 
5,500 to 6,999 
5.500 x 109 to 6.999 
x 109 
4,000 to 5,499 
4.000 x 109 to 5.499 x 
109 
2,500 to 3,999 
2.500 x 109 to 3.999 x 
109 
< 2,500 
< 2.500 x 109 
 
 
 
 
 
 
 
 
 


 
 
 
 
Protocol Version 1.0 
 
 
 
 
 
 
  
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENIN
G
Glycosuria (random 
collection tested by 
dipstick) 
Trace to 1+ or 
≤ 250 mg 
2+ or ˃ 250 to 
≤ 500 mg 
> 2+ or > 500 mg 
NA 
Hematuria (not to be 
reported based on dipstick 
findings or on blood 
believed to be of 
menstrual origin) 
6  to < 10 RBCs per 
high power field 
≥ 10 RBCs per high 
power field 
Gross, with or 
without clots OR 
With RBC casts OR 
Intervention indicated 
Life-
threatening 
consequences 
Proteinuria (random 
collection tested by 
dipstick) 
1+ 
2+ 
3+  or higher 
NA 
 


 
 
 
 
Protocol Version 1.0 
 
 
 
 
 
 
                                 
 
APPENDIX F: ADVERSE EVENT REPORTING FORM (FOR DSI) 
 
 


Daiichi Sankyo, Inc. 
Form Version 3.0, 08 Oct 2013 
 
 
1 
SERIOUS ADVERSE EVENT REPORT (SAVER) FORM 
 
Protocol 
#: 
      
Site #: 
      
Subject 
Initials: 
      
 
 
 
 
 
 
 
 
 
When completed, send to <<CRO>>. 
Supplemental pages used (Mark all that apply): 
 SAE 
 Lab Results 
 Concomitant Medications 
Report Type: 
 Initial 
 Follow-up #       
1. Source 
Investigator 
Name: 
      
Country
: 
      
 
Address
: 
      
 
Phone 
#: 
      
Fax #: 
      
 
 
 
 
 
 
2. Subject and Study Information 
Screening #/Subject 
#: 
      
Randomization 
#: 
      
Subject 
Initials: 
      
 
Birth Date: (dd Mmm 
yyyy) 
      
 
Gender: 
 Male 
 Female 
Weight: 
 
kg 
 
lb 
      
 
Height
: 
 cm 
 in 
      
 
Ethnicity
: 
 Hispanic or 
Latino 
 Not Hispanic or Latino 
Race: 
 Asian 
 Black 
 Caucasian 
 American Indian/Alaskan Native 
 
 Native Hawaiian/Pacific 
Islander 
 Other  
      
 
Phase of Study at time of 
SAE: 
 Screening 
 Washout 
 Placebo/Run-in 
 
 Randomized 
 Post Study 
 Open-label 
Date of Informed Consent: (dd Mmm 
yyyy) 
      
 
 
 
 
3. Primary Serious Adverse Event 
(Use appropriate medical terminology, symptoms should be grouped together as syndromes and diagnosis.) 
If additional events are reported, use supplemental page.  If supplemental SAE pages were used, mark here: 
 
SAE 
(Event/Diagnosis): 
      
 
Date Event Became Serious: (dd Mmm 
yyyy) 
      
 
Date Event Stopped  or : (dd Mmm 
yyyy) 
      
 
 
 
 
 
 
 
Continuing 
Severity 
Outcome 
Seriousness Criteria 
(see protocol for SAE definitions) 
 Yes 
 No 
 Mild 
 Moderate 
 Severe 
 Recovered/Resolved 
 Recovered/Resolved with sequelae 
 Not Recovered/Not Resolved 
 Fatal 
 Unknown 
 Death 
 Life-threatening 
 Hospitalization-initial or prolonged 
 Disability or Permanent Damage 
 Congenital anomaly/Birth Defect 
 Important Medical Event 
 
Not 
Applicable 
Related 
Not 
Related 
Study Procedure (eg, Biopsy, CT scan, MRI scan, other protocol specified procedures; 
Separate from study drug administration) 
 
 
 


Daiichi Sankyo, Inc. 
Form Version 3.0, 08 Oct 2013 
 
 
2 
SERIOUS ADVERSE EVENT REPORT (SAVER) FORM 
 
Protocol 
#: 
      
Site #: 
      
Subject 
Initials: 
      
 
 
 
 
 
 
 
 
 
Is the event related to a study procedure? 
Study Drug Causality (Complete one line for each study drug) 
Drug Name 
Related 
Not 
Related 
      
 
 
      
 
 
      
 
 
      
 
 
4. In Case of Death 
Date: (dd Mmm 
yyyy) 
      
 
Autopsy: 
 Yes 
 No 
 
 
 
Certificate
: 
 Yes 
 No 
Cause: 
      
 
 
 
 
 
 
 
 
 
 
5. Study Drug Dosing 
Record only dose given to subject at time of SAE.  Complete all previous dosing regimes including placebo 
run-in Section 6. 
Study Drug Dosing 
Study Drug Action 
Taken 
Study Drug 
Unit 
Dose 
Frequency 
Route 
Start Date 
(dd Mmm yyyy) 
Stop Date 
(dd Mmm yyyy) 
None 
Discontinued 
Reduced 
Interrupted 
Increased 
      
      
      
      
      
      
 
 
 
 
 
      
      
      
      
      
      
 
 
 
 
 
      
      
      
      
      
      
 
 
 
 
 
Was the subject withdrawn due to 
SAE? 
 Yes 
 No 
Was Study Drug Code broken due to 
SAE? 
 Yes 
 No 
If Yes, Date: (dd Mmm 
yyyy) 
      
 
Who: 
      
Drug: 
      
Dosing
: 
      
 
 
 
 
 
 
 
 
6. Previous Study Drug Dosing Regimens per Protocol, including placebo run-in. 
Study drug dosing at the time of SAEs is captured in Section 5.  Do NOT complete with “See Attached”. 
If not applicable mark here: 
 
Drug Name 
Unit Dose 
Frequency 
Route 
Start Date 
(dd Mmm yyyy) 
Stop Date 
(dd Mmm yyyy) 
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      


Daiichi Sankyo, Inc. 
Form Version 3.0, 08 Oct 2013 
 
 
3 
SERIOUS ADVERSE EVENT REPORT (SAVER) FORM 
 
Protocol 
#: 
      
Site #: 
      
Subject 
Initials: 
      
 
 
 
 
 
 
 
 
 
7. Relevant Concomitant Medications 
(Include those taken before the onset of the event, not taken as a treatment for the event.)  Do NOT complete with 
“See Attached”.  If Supplemental Concomitant Medication page is used, mark here: 
 
Generic/Brand 
Name 
Dose 
Frequency 
Route 
Start Date 
(dd Mmm 
yyyy) 
Stop Date 
(dd Mmm yyyy) 
Indication 
Continuing
? 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
8. Relevant Lab Results 
Do NOT complete with “See Attached.”  If supplemental Lab Results pages were used, mark here: 
 
Lab Test 
Date 
(dd Mmm yyyy) 
Results 
Reference Normal 
Range (Units) 
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
9. Relevant Medical History Including Allergies 
Do NOT complete with “See Attached.” 
Date of Onset 
(dd Mmm yyyy) 
Current 
Past 
Description 
(Mark one only) 
      
 
 
      
      
 
 
      
      
 
 
      
      
 
 
      
      
 
 
      
      
 
 
      
      
 
 
      
      
 
 
      
      
 
 
      
      
 
 
      
10. Narrative 
Record a detailed description of the event including the course of the event, evaluation, assessment and 
treatment. 
 
 
 
 


Daiichi Sankyo, Inc. 
Form Version 3.0, 08 Oct 2013 
 
 
4 
SERIOUS ADVERSE EVENT REPORT (SAVER) FORM 
 
Protocol 
#: 
      
Site #: 
      
Subject 
Initials: 
      
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11. Person Completing This Form 
 
      
 
 
 
 
 
 
Name 
 
Signature 
 
Date 
 
 
      
 
      
 
 
 
 
Title 
 
Phone Number 
 
 
 
 
      
 
 
 
 
 
 
Investigator Name 
 
Signature 
 
Date 
 


Daiichi Sankyo, Inc. 
Form Version 3.0, 08 Oct 2013 
 
Page 1 of 2 
SERIOUS ADVERSE EVENT REPORT (SAVER) FORM 
(Supplemental SAE) 
 
Protocol #: 
      
Site #: 
      
Subject Initials: 
      
 
 
 
 
 
 
 
 
 
SAE (Event/Diagnosis) #: 2 
      
 
Date Event Became Serious: (dd Mmm yyyy) 
      
 
Date Event Stopped  or : (dd Mmm yyyy) 
      
 
 
 
 
 
 
 
Continuing 
Severity 
Outcome 
Seriousness Criteria 
(see protocol for SAE definitions) 
 Yes 
 No 
 Mild 
 Moderate 
 Severe 
 Recovered/Resolved 
 Recovered/Resolved with sequelae 
 Not Recovered/Not Resolved 
 Fatal 
 Unknown 
 Death 
 Life-threatening 
 Hospitalization-initial or prolonged 
 Disability or Permanent Damage 
 Congenital anomaly/Birth Defect 
 Important Medical Event 
 
Not 
Applicable 
Related 
Not Related 
Study Procedure (eg, Biopsy, CT scan, MRI scan, other protocol specified procedures; Separate 
from study drug administration) 
Is the event related to a study procedure? 
 
 
 
Study Drug Causality (Complete one line for each study drug) 
Drug Name 
Related 
Not Related 
      
 
 
      
 
 
      
 
 
      
 
 
SAE (Event/Diagnosis) #: 3 
      
 
Date Event Became Serious: (dd Mmm yyyy) 
      
 
Date Event Stopped  or : (dd Mmm yyyy) 
      
 
 
 
 
 
 
 
Continuing 
Severity 
Outcome 
Seriousness Criteria 
(see protocol for SAE definitions) 
 Yes 
 No 
 Mild 
 Moderate 
 Severe 
 Recovered/Resolved 
 Recovered/Resolved with sequelae 
 Not Recovered/Not Resolved 
 Fatal 
 Unknown 
 Death 
 Life-threatening 
 Hospitalization-initial or prolonged 
 Disability or Permanent Damage 
 Congenital anomaly/Birth Defect 
 Important Medical Event 
 
Not 
Applicable 
Related 
Not Related 
Study Procedure (eg, Biopsy, CT scan, MRI scan, other protocol specified procedures; Separate 
from study drug administration) 
Is the event related to a study procedure? 
 
 
 
Study Drug Causality (Complete one line for each study drug) 
Drug Name 
Related 
Not Related 
      
 
 
      
 
 
      
 
 
      
 
 
SAE (Event/Diagnosis) #: 4 
      
 
Date Event Became Serious: (dd Mmm yyyy) 
      
 
Date Event Stopped  or : (dd Mmm yyyy) 
      
 
 
 
 
 
 
 
Continuing 
Severity 
Outcome 
Seriousness Criteria 
(see protocol for SAE definitions) 
 Yes 
 No 
 Mild 
 Moderate 
 Severe 
 Recovered/Resolved 
 Recovered/Resolved with sequelae 
 Not Recovered/Not Resolved 
 Death 
 Life-threatening 
 Hospitalization-initial or prolonged 


Daiichi Sankyo, Inc. 
Form Version 3.0, 08 Oct 2013 
 
Page 2 of 2 
SERIOUS ADVERSE EVENT REPORT (SAVER) FORM 
(Supplemental SAE) 
 
Protocol #: 
      
Site #: 
      
Subject Initials: 
      
 
 
 
 
 
 
 
 
 
 Fatal 
 Unknown 
 Disability or Permanent Damage 
 Congenital anomaly/Birth Defect 
 Important Medical Event 
 
Not 
Applicable 
Related 
Not Related 
Study Procedure (eg, Biopsy, CT scan, MRI scan, other protocol specified procedures; Separate 
from study drug administration) 
Is the event related to a study procedure? 
 
 
 
Study Drug Causality (Complete one line for each study drug) 
Drug Name 
Related 
Not Related 
      
 
 
      
 
 
      
 
 
      
 
 


Daiichi Sankyo, Inc. 
Form Version 3.0, 08 Oct 2013 
 
1 of 1 
SERIOUS ADVERSE EVENT REPORT (SAVER) FORM 
(Supplemental Concomitant Medications) 
 
Protocol #: 
      
Site #: 
      
Subject Initials: 
      
 
 
 
 
 
 
 
 
 
7. Relevant Concomitant Medications (Continued) 
(Include those taken before the onset of the event, not taken as a treatment for the event.)  Do NOT complete with “See 
Attached”. 
Generic/Brand Name 
Dose 
Frequency 
Route 
Start Date 
(dd Mmm yyyy) 
Stop Date 
(dd Mmm yyyy) 
Indication 
Continuing? 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 
      
      
      
      
      
      
      
 


Daiichi Sankyo, Inc. 
Form Version 3.0, 08 Oct 2013 
 
1 of 1 
SERIOUS ADVERSE EVENT REPORT (SAVER) FORM 
(Supplemental Lab Results) 
 
Protocol 
#: 
      
Site #: 
      
Subject 
Initials: 
      
 
 
 
 
 
 
 
 
 
8. Relevant Lab Results (Continued) 
Do NOT complete with “See Attached.” 
Lab Test 
Date 
(dd Mmm yyyy) 
Results 
Reference Normal 
Range (Units) 
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      


Protocol version 2.0 
 
 
1 
 
APPENDIX G: SAMPLE INFORMED CONSENT FORM (ICF) 
 
 
 
 
 
SUBJECT INFORMATION AND INFORMED CONSENT FORM (ICF)  
 
Protocol: 
Targeted AntiCoagulation Therapy to Reduce Inflammation and 
Cellular Activation in Long-Term HIV Disease 
 
Short Title: 
TACTICAL-HIV 
 
Funding: 
National Heart Lung and Blood Institute /National Institutes of  
Health 
Daiichi-Sankyo (study drug) 
 
Site: 
Hennepin County Medical Center (HCMC) 
 
Investigator:   Jason Baker, MD, MS 
 
 
 
CONSENT FOR PARTICIPATING IN AN NHLBI/NIH-FUNDED RESEARCH TRIAL 
 
 
INTRODUCTION AND PURPOSE: WHY IS THIS STUDY BEING DONE? 
You are invited to be in a research study that looks at the use of a medication that may 
improve the health of HIV positive people who are already on HIV medicines. The 
medication (edoxaban) is approved by the Food and Drug Administration (FDA), but not 
for treatment of HIV infection; it is commonly used to treat or prevent blood clots.  
However, this medication may help address some of the damage that HIV causes in the 
body.  Forty HIV positive patients will be enrolled in this study at HCMC in Minneapolis.  
 
Damage caused by HIV infection results in problems with the immune system and other 
organs in the body. One of these problems involves the coagulation system, which is how 
our bodies form blood clots to prevent bleeding.  HIV ‘activates’ or turns on the 
coagulation system.  Over time this increases risk for having blood clots and also results 
in ‘inflammation’ that can damage the body. Inflammation occurs when the body’s 
immune system is responding to injury or infection.  Inflammation can be helpful in the 
short term, but when it is persistent it can also cause more damage to the body over time. 
These problems impair normal health over many years and cannot be fully corrected, 
even with effective HIV treatment using antiretroviral medications.   
 
Problems with clotting and ongoing inflammation with damage to the body contribute to 
risk for diseases like heart disease among HIV positive persons.  This study will determine 
if a low dose of edoxaban, which reduces blood clotting, will reduce inflammation.  If 


Protocol version 2.0 
 
 
2 
successful, edoxaban may then be studied as an approach to achieve normal health 
outcomes for persons with HIV infection.   
 
YOUR PARTICIPATION IS VOLUNTARY  
This consent form gives you information about the clinical research study that will be 
discussed with you.  Once you understand the study, and if you agree to take part, you 
will be asked to sign this consent form. You will be given a copy to keep.  
 
Before you learn about the study, it is important that you know the following: 
Your participation is entirely voluntary.  
 
You may decide not to take part or to withdraw from the study at any time without losing 
the benefits of your routine medical care. 
 
Eligibility:  Who is being asked to be part of this research study? 
You may be eligible for this study if you have HIV infection, you are taking your 
antiretroviral medications, you have evidence of increased coagulation (‘risk for clotting’) 
based on a blood test, and you do not have contraindications to study procedures.  Your 
HIV ‘viral load’ must be undetectable.  If your doctor or the study investigators feel that it 
would not be safe to take the study medication then you will not be eligible to participate. 
Some factors that could make you ineligible for this study include using other anti-clotting 
medications (‘blood thinners’) or having other inflammatory, liver or kidney disease. 
 
HOW LONG WILL YOU BE IN THE STUDY? 
The study will last approximately 12 months and consists of 12 visits.  After the screening 
visit, if you qualify, you will come in for a ‘baseline’ study visit, and then follow-up visits at 
1, 2, 3, 4, 7, 8, 9, 10, 11 and 12 months. 
 
HOW WILL THE STUDY WORK? 
If you agree to participate in this study, you will be asked to take 30mg of edoxaban and 
a matching placebo pill once daily, but you would only be taking one medication at any 
given time during the study (i.e., you would not be taking edoxaban and placebo at the 
same time).  At the beginning of the study you will be randomly assigned to start one 
study medication, which will either be edoxaban or a matching placebo.  At month 4 you 
will stop taking study medications.  At month 8 you will be asked to start the second study 
medication.  The second medication will be placebo if your first medication was edoxaban, 
and will be edoxaban if your first medication was placebo. Neither you, nor the study 
investigators, will know which study medication you take first or second.  A picture of this 
process is then shown below. 
 


Protocol version 2.0 
 
 
3 
 
 
 
PROCEDURES:  WHAT DO YOU HAVE TO DO IF YOU ARE IN THIS STUDY? 
 
Screening visit: 
You will be asked to come in for a screening visit, where your study investigators will 
review the study procedures and this consent form.  If you agree to participate, you will 
have your blood drawn (approximately 2 tablespoons) and medical history reviewed 
(similar to a routine clinic visit) to determine if you are eligible to participate.  If you meet 
study criteria, you will then return within 1 month to begin the study. 
 
Baseline and follow-up (month 1, 2, 3, 4, 7, 8, 9, 10, 11, 12) clinic study visits: 
The baseline and follow-up clinical visit will last approximately 1-2 hours, and will consist 
of: 
 
Medical History: You will be interviewed to review your medical history and assess your 
risk for developing heart disease.  We will also access your medical chart to obtain the 
results of recent lab tests and medications you are taking.  
 
Blood Draw:  We will obtain a blood sample (up to 8 tablespoons) from a vein in your arm.  
The total blood draw volumes per visit will be less than 100 mL.  You must be fasting for 
at least 6 hours prior to having your blood drawn at study visits. Blood samples will be 
used to measure markers in the blood related to inflammation, coagulation (‘clotting’) and 
other markers that may contribute to heart disease and other complications of HIV 
infection.  These samples may be stored for up to 20 years. 
 
At the baseline visit, you will start taking edoxaban (or placebo). You will take 1 tablet (30 
mg) every day in the morning. The nurses will give you the study medicine during your 
clinic visits. At follow-up visits you will be asked to bring in all of your study medication, 
and adherence and tolerability to the treatment will be assessed. 
 
STORED SAMPLES 
During your participation in this study, blood will be collected by standard blood drawing 
techniques.  
 


Protocol version 2.0 
 
 
4 
Samples will be used to evaluate the potential benefits of edoxaban. Additional samples 
will be stored up to 20 years for future research.  These samples can help us learn more 
about HIV, AIDS, immune function, inflammation, coagulation (blood ‘clotting’), or other 
related diseases that affect patients with HIV infection.  In general, the research tests we 
perform are not like routine medical tests and may not relate directly to your medical care.  
For this reason, we may not put future research test results in your medical record or 
share these test results with your medical provider.  We will communicate any clinical labs 
obtained during the study to your primary medical provider. 
 
Genetic Testing 
Future research on stored samples might involve genetic testing.  Genetic testing may 
tell researchers something about how health or illness is passed on to you by your parents 
or from you to your children. Some genetic information, such as the ability to make certain 
proteins in the body, has been associated with an increased risk of certain diseases like 
arthritis.  
 
Any genetic information collected or discovered about you or your family will be 
confidential. Genetic information about you will not be revealed to others, including your 
relatives, without your permission. We will not release any information about you or your 
family to any insurance company or employer unless you sign a document allowing 
release of information.  
 
HOW WILL YOU GET MEDICINES FOR THE STUDY? 
Study medications will be provided to you by the study and will be distributed by study 
nurses during study visits.   You will be provided with sufficient supply to last the duration 
of the study.  You will be asked to return any unused study medication, including empty 
containers. 
 
WHAT ARE THE RISKS AND/OR DISCOMFORTS OF THIS STUDY? 
 
You will be monitored for side effects at each visit, and your lab tests will include an 
evaluation for signs of medication toxicity. 
 
Risks of Study Procedures 
You will have your blood drawn at each study visit. This is identical to having your blood 
drawn at a medical clinic, and can involve discomfort, light-headedness and/or minor 
bruising. Discussion of past medical history or risk factors for HIV infection may be 
stressful and cause anxiety. You may decline to answer any questions that you do not 
feel comfortable answering. 
 
Study Medication: Edoxaban 
This medication is approved by the FDA. Edoxaban is used to prevent and treat blood 
clots. The most significant possible side effects of edoxaban is bleeding.  This may be 
mild, like a bloody nose, or more significant and require medical evaluation.  Examples 
of serious or major bleeding from edoxaban include bleeding in the stomach or 
intestines, or bleeding in the brain.  Major bleeding events were rare, occurring between 
1-2% of the time, in prior clinical studies of edoxaban.  We will ask you about signs or 
symptoms of bleeding during each of your visits, such as abdominal pain, black stools, 
dizziness, lightheadedness, fatigue, or headache.  We will also monitor your blood 


Protocol version 2.0 
 
 
5 
results for signs of bleeding at each visit.  We do not expect that edoxaban will interact 
with any of your HIV medicines.   
 
This medication should not be used during pregnancy. If a developing fetus is exposed 
to edoxaban, injury or even death may result. For this reason, if you are a woman of 
childbearing potential, you will be asked what type of birth control you use. You must be 
willing to use a reliable form of birth control for the duration of the study period, such as 
a barrier method or spermicide. Condoms cannot be the only form of birth control you 
use. If you become pregnant during the study or think you may be pregnant, you should 
inform either the site investigator or a study nurse immediately. We will ask that you return 
any study medication. We will ask permission to contact you at the end of the pregnancy 
to check on the health of you and the baby. 
 
WHAT ABOUT PREGNANCY AND BREASTFEEDING? 
If you are pregnant, breastfeeding or planning to become pregnant, you will not be eligible 
for this study.  If you become pregnant during the study, you will be asked to stop study 
medications and withdraw.  Therefore, if it is possible that you could become pregnant, 
we ask that you use a reliable form of birth control for the duration of the study (listed 
above in ‘Study Medication’). 
 
WHAT ARE THE BENEFITS OF THIS STUDY? 
If you take part in this study, there are no anticipated benefits directly to your health.  The 
research has the potential to benefit people with HIV infection, after the study is completed 
and the findings have been analyzed.   
  
COMPENSATION 
You will be paid $25 for each study visit you attend after the screening visit.  You may 
receive a total of $275 for participating in the study.  Study investigators may ask for your 
social security number as part of the monitoring process for this compensation. 
 
WHAT IF THERE ARE NEW FINDINGS? 
We will not be analyzing data during the study.  However, if during the course of this 
research study, there are significant new findings discovered which might influence your 
willingness to continue, the researchers will inform you of those developments.  You may 
request your own results after the study by contacting the research investigators.  
 
WHAT IF YOU DON’T WANT TO BE IN THE STUDY ANY LONGER?  
If you enroll in this study, you may decide to stop participating at any time.  Withdrawing 
from this study will not affect the benefits of your regular medical care.   
 
CAN YOUR STUDY PARTICIPATION BE STOPPED WITHOUT YOUR CONSENT?  
You may be taken off of study medicines before the end of the study if investigators or 
your doctor recommend this.  You may be taken off the entire study without your consent 
if: 
 Your study doctor decides that continuing in the study would harm you; 
 Your lab results indicate that you are experiencing toxicity from study medications; 
 
WHAT OTHER CHOICES DO YOU HAVE BESIDES THIS STUDY?  
You may discuss other strategies for improving your health with your doctor.  


Protocol version 2.0 
 
 
6 
 
WHAT ARE THE COSTS TO YOU? 
The medications that are part of this study will be provided free-of-cost to you, and will be 
distributed during study visits.   During the study, you, your insurance company, or some 
other third-party payer must pay for all other medicines, including HIV medicines not paid 
by the study and medicines needed to prevent or treat other illnesses.  We will provide all 
clinical and professional services, lab work, and other tests that are part of this study and 
not part of your regular care at no cost to you. 
 
HOW IS YOUR PRIVACY PROTECTED?  
Any information that could be used to identify you will be treated in strict confidence to 
the extent allowed by law.  Nevertheless, some uses and disclosures of your information 
are necessary to conduct the study.  If you agree to be part of this study, you will also be 
allowing the uses and disclosures of your private health information as needed for the 
purposes of this study as described in this consent.  
 
“Private health information” means information that identifies you and is collected: 
 during this study; 
 from your past and current medical records maintained by your regular health care 
providers, to the extent the information is relevant to this study or to your eligibility for 
this study; or 
 from any payment records relating to items or services furnished to you during this 
study. 
 
By signing this consent, you are agreeing that your private health information may be 
disclosed to and used by: 
 the doctors and other health care providers involved in this study; 
 their staff;  
 the research center; 
 members of this institution’s Human Subjects Research Committee/Institutional 
Review Board; 
 Daiichi-Sankyo; 
 the sponsor of this study and its agents; and 
 monitors from the United States Government and/or Food and Drug Administration 
(FDA). 
 
The findings of this study may be used for scientific meetings, written reports, and 
publications, but no information that could be used to identify you will be disclosed for 
these purposes. 
 
Once your private health information has been disclosed to a third party, federal privacy 
laws may no longer protect it from re-disclosure.  However, anyone obtaining access to 
your private health information under this consent must agree to protect your information 
as required by this consent.   
 
This consent to use your private health information as described above does not expire. 
However, if you later change your mind, you can revoke this consent by writing to Dr. 
Jason Baker [701 Park Avenue; Mail Code G5; Minneapolis, MN 55415; phone 612-873-


Protocol version 2.0 
 
 
7 
2705] saying that you no longer wish to allow your private health information to be used 
for this study.  If you revoke your consent, you may no longer be able to participate in the 
study.  Moreover, we cannot undo uses or disclosures of your private health information 
that have already taken place in reliance on your prior consent. 
 
PLEASE NOTE: 
A) In the event of a positive result for Hepatitis B or C, we may be required to 
report these results to the local state Department of Health. 
 
B) Lab results from this study that are also part of clinical care may be entered into 
the electronic medical record (EPIC) at Hennepin County Medical Center.  These 
lab results may then be viewed by your medical provider(s) and other allied health 
professionals. 
 
WHAT IF YOU ARE INJURED?  
 
If you are injured as a result of being in this study, you will be given immediate treatment.  
The cost for treatment will be charged to you or your insurance company.  There is no 
program through this institution to compensate participants who have research related 
injuries. You will not be giving up any of your legal rights by signing this consent. 
 
WHAT IF YOU HAVE PROBLEMS OR QUESTIONS?  
If you ever have questions or in the case of research-related injuries, you should contact:  
 
Hennepin County Medical Center 
Minneapolis, Minnesota, United States 55417 
Principal Investigator: Jason Baker, MD, MS    
Phone: 612-873-2700  Email: baker@umn.edu 
 
Contact: Andrea Dolan, BS 
Phone: 612-873-7678  Email:andrea.nolan@hcmed.org 
 
If you have questions about research subject’s rights you can contact: 
 
Human Subjects Research Committee 
Hennepin County Medical Center 
Contact: Karen Heim-Duthoy 
Phone: 612-873-6882  Email: heimd001@umn.edu 
 
RESEARCH STUDY REGISTRY 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This Website will not include information that can identify you.  At 
most, the Website will include a summary of the results.  You can search this Website at 
anytime. 


Protocol version 2.0 
 
 
8 
SIGNATURE PAGE FOR CONSENT TO PARTICIPATE IN THE TACTICAL-HIV 
STUDY  
 
As part of our ongoing research studies to better understand disease and improve health 
we often contact patients about clinical studies for which they may be eligible to 
participant.  By signing this consent, you would also authorize us to contact you about 
future studies.  If you would prefer we not contact you directly about future studies, please 
indicate this by placing a check after 'do not contact me' and then initialing.  
 
Do not contact me for future studies: _________   Initial: __________ 
 
 
I have read this consent form, had the opportunity to ask questions and have received 
answers to any questions I have asked.  I willingly give my consent to participate in this 
study, and authorize the use and disclosure of my health information as described in this 
form.  By signing this consent form I do not give up any of my legal rights.  Upon signing 
this form I will be given a signed copy of the form for my records. 
 
If you have read the consent (or if you have had it explained to you) and understand the 
information, and you voluntarily agree to join this study, please sign your name below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________ 
______________________ 
___________ 
Participant’s name  
 
Participant’s signature 
 
 
Date 
(typed or printed) 
 
 
 
_________________________________ 
 
 
_______________ 
 
 
Person obtaining consent  
 
 
 
 
Date