Clinical trial NCT02394730
Conditions: HIV
Keywords: HIV, d-dimer, hs-CRP, activated T-lymphocytes
Sponsor: Kirby Institute
Start date: 2015-09-01; Completion date: 2018-01-01
Enrollment: 65 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
ADVICE is a randomised, international, double-blind, placebo-controlled trial. The purpose of the ADVICE study is to compare the safety and efficacy of vorapaxar in reducing d-dimer expression and markers of cellular immune activation over a period of 12 weeks among people with HIV infection who are successfully treated with combination antiretroviral therapy containing an HIV integrase inhibitor. A secondary objective of the study will be to demonstrate that following cessation of vorapaxar in patients with well controlled HIV replication there will be an increase in the levels of d-dimer over a 6 week period. 60 participants from 4 clinical sites in Australia and the USA will be recruited and followed for a minimum of 18 weeks.

Detailed description:
Consenting participants will be screened and within 14 days randomly allocated to receive either vorapaxar (2.5mg) or matched placebo once daily for 12 weeks (phase 1). Participants will be seen one week after randomisation and then at weeks 4, 8 and 12 (phase 1). At the week 12 visit, patients will not be dispensed any study treatment. In phase 2 all study treatment will stop for 6 weeks. At week 18 patients will be seen for a final study visit.

Arms: arm 1: 2.5mg of vorapaxar po qd arm 2: sugar pill po qd
Interventions: intervention 1: vorapaxar intervention 2: Placebo
Intervention descriptions: intervention 1: 2.5mg of vorapaxar taken orally once daily for 12 weeks intervention 2: Sugar pill taken orally once daily for 12 weeks

Protocol documents:
Prot_000.pdf: 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 1 of 99 
 
 
 
 
 
 
 
 
 
 
 
 
ADVICE: Attenuation of D-dimer using Vorapaxar to target Inflammatory and Coagulation Endpoints 
 
A double blind randomised comparison of vorapaxar versus placebo for the treatment of HIV associated 
inflammation and coagulopathy in patients with well controlled HIV replication 
 
 
Protocol version: 
3.0 
 
 
 
Original protocol date: Version 1, 17 February 2015; Version 2, 16 November 2015 
 
Protocol amendment date: 12 July 2016 
 
 
Sponsor: 
 
University of New South Wales 
The Kirby Institute  
University of NSW, New South Wales, Australia 2052 
Email: advice@kirby.unsw.edu.au 
Telephone: +61 2 9385 0900; Facsimile: +61 2 9385 0910 

Coordinating Principal Investigator (CPI):
Professor Sean Emery 
The Kirby Institute 
The University of New South Wales 
UNSW Medicine 
University of NSW, New South Wales, Australia 2052 
Email: semery@kirby.unsw.edu.au 
Telephone: +61 2 9385 0900; Facsimile: +61 2 9385 0910 
 
 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 2 of 99 
Table of Contents 
1.0 Protocol Synopsis ............................................................................................................................................ 6 
2.0 Study Flow Chart: Time and events schedule ............................................................................................... 12 
3.0 Background and rationale ............................................................................................................................. 13 
3.1 Clinical setting ........................................................................................................................................... 13 
3.2 Coagulation and immune activation ......................................................................................................... 13 
3.3 Vorapaxar .................................................................................................................................................. 13 
4.0 Hypotheses ................................................................................................................................................... 14 
5.0 Study objectives ............................................................................................................................................ 14 
5.1 Primary objective ...................................................................................................................................... 14 
5.2 Secondary objective .................................................................................................................................. 14 
5.3 Exploratory objectives .............................................................................................................................. 14 
5.4 Primary endpoint ...................................................................................................................................... 15 
5.5 Secondary endpoints ................................................................................................................................ 15 
5.6 Exploratory endpoints ............................................................................................................................... 16 
6.0 Study design & Statistics ............................................................................................................................... 16 
6.1 Sample size determination ....................................................................................................................... 17 
6.2 Analysis Plan .............................................................................................................................................. 17 
6.2.1 Statistical analysis .............................................................................................................................. 17 
6.2.2 Safety analysis .................................................................................................................................... 18 
6.3 Schedule of Analyses ................................................................................................................................. 18 
7.0 Participant population .................................................................................................................................. 18 
7.1 Eligibility criteria........................................................................................................................................ 18 
8.0 Treatment of participants ............................................................................................................................. 19 
8.1 Vorapaxar .................................................................................................................................................. 19 
8.2 Prior and concomitant medications .......................................................................................................... 19 
8.3 ART Regimen ............................................................................................................................................. 20 
9.0 Study procedures .......................................................................................................................................... 20 
9.1 Initial screening period ............................................................................................................................. 20 
9.1.1 Clinical assessments at screening ...................................................................................................... 21 
9.1.2 Laboratory assessments at screening ................................................................................................ 21 
9.1.3 Rescreening ........................................................................................................................................ 21 
9.2 Randomisation visit ................................................................................................................................... 21 
9.2.1 Clinical assessments at week 0 (prior to randomisation) .................................................................. 21 
9.2.2 Laboratory assessments at week 0 (prior to randomisation) ............................................................ 22 
9.2.3 Randomisation and Drug Supply ........................................................................................................ 22 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 3 of 99 
9.3 Follow Up Visits ......................................................................................................................................... 22 
9.3.1 Clinical assessments at weeks 1, 4, 8, 12, 18 ..................................................................................... 22 
9.3.2 Laboratory assessments at weeks 1, 4, 8, 12, 18 ............................................................................... 23 
9.4 Missed visits and missed assessments ...................................................................................................... 23 
9.5 Withdrawal of study participants ............................................................................................................. 23 
10.0 Clinical & Toxicity Management Guidelines ............................................................................................... 24 
10.1 Clinical and Toxicity Management Guidelines ........................................................................................ 24 
10.2 Dose modifications ................................................................................................................................. 24 
10.2.1 DAIDS Grade 1 or 2 adverse events ................................................................................................. 24 
10.2.2 DAIDS Grade 3 adverse events ........................................................................................................ 24 
10.2.3 DAIDS Grade 4 adverse events ........................................................................................................ 25 
10.2.4 Monitoring of Renal Function .......................................................................................................... 25 
10.3 Protocol-specific toxicity management guidelines ................................................................................. 25 
10.3.1 Vorapaxar Side Effect Profile ........................................................................................................... 25 
10.3.2 Bleeding ........................................................................................................................................... 26 
10.3.3 Other Adverse Reactions ................................................................................................................. 27 
10.4 Discontinuation of study treatment ....................................................................................................... 27 
11.0 Adverse Event Recording & Reporting ........................................................................................................ 28 
11.1  
Adverse Events ................................................................................................................................ 28 
11.1.1 Reporting of Adverse Events ............................................................................................................ 28 
11.2 Serious Adverse Event (SAE) ................................................................................................................... 29 
11.2.1 Reporting Serious Adverse Events ................................................................................................... 29 
11.3 Suspected Unexpected Serious Adverse Reaction (SUSAR).................................................................... 30 
11.3.1 Reporting of SUSARs ........................................................................................................................ 30 
11.4 Serious Non-AIDS events (SNAEs) and AIDS events ................................................................................ 30 
11.4.1 Reporting of SNAEs and AIDS defining illnesses .............................................................................. 31 
11.5 Reporting of pregnancy .......................................................................................................................... 32 
11.6 Definition and reporting of an overdose ................................................................................................ 32 
11.7 Unblinding ............................................................................................................................................... 32 
12.0 Packaging, labelling, storage and accountability of clinical trial supplies .................................................. 33 
12.1 Drug packaging, labelling and distribution ............................................................................................. 33 
12.2 Handling and dispensing of study drugs ................................................................................................. 33 
12.3 Study drug accountability records at investigational site(s) ................................................................... 34 
12.4 Destruction of study drug ....................................................................................................................... 34 
12.5 Post study drug supply ............................................................................................................................ 34 
13.0 Biological samples ....................................................................................................................................... 34 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 4 of 99 
13.1 Blood collection ...................................................................................................................................... 34 
13.2 Labelling of blood collection tubes ......................................................................................................... 35 
13.3 Transportation of samples ...................................................................................................................... 35 
13.4 Storage of samples .................................................................................................................................. 35 
13.5 Processing of samples ............................................................................................................................. 36 
13.6 Reporting of results ................................................................................................................................. 36 
13.7 Plasma d-dimer determination ............................................................................................................... 36 
14.0  
Data collection, source documents and record retention .................................................................. 36 
14.1 Records and reports ................................................................................................................................ 36 
14.2 Source documents .................................................................................................................................. 36 
14.3 Submission of data .................................................................................................................................. 37 
14.4 Records retention and archiving ............................................................................................................. 37 
14.5 Study monitoring .................................................................................................................................... 37 
14.6 Auditing ................................................................................................................................................... 38 
15.0  
Ethics committee/regulatory approval and informed consent .......................................................... 38 
15.1 Ethical conduct of the study ................................................................................................................... 38 
15.2 Compliance with the protocol and protocol revisions ............................................................................ 38 
15.4 Updates to the consent form .................................................................................................................. 40 
16.0  
Confidentiality of data ........................................................................................................................ 40 
16.1 Confidentiality of participant records ..................................................................................................... 40 
16.2 Confidentiality of study data ................................................................................................................... 41 
17.0  
Governance ......................................................................................................................................... 41 
17.1 Protocol Steering Committee (PSC) ........................................................................................................ 41 
17.2 Project Team ........................................................................................................................................... 41 
18.0  
Data Safety and Monitoring Board (DSMB) ........................................................................................ 41 
19.0  
Financing and insurance ..................................................................................................................... 42 
19.1 Indemnity and compensation ................................................................................................................. 42 
20.0  
Quality Control (QC) and Quality Assurance (QA) .............................................................................. 42 
21.0  
Publication Policy ................................................................................................................................ 42 
22.0 List of References ........................................................................................................................................ 44 
23.0 Abbreviations List ........................................................................................................................................ 45 
Appendix 1: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Paediatric Adverse Events 
(Version 2.0, November 2014) ............................................................................................................................ 47 
Appendix 2: Bleeding Academic Research Consortium (BARC) Definitions for Bleeding Events ....................... 75 
Appendix 3: Definitions and Criteria for HIV Disease and AIDS Events .............................................................. 76 
Appendix 4: Diagnostic Criteria for Serious Non-AIDS Events ............................................................................ 82 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 5 of 99 
Appendix 5: Participant Information Sheet and Consent Form .......................................................................... 86 
PARTICIPANT INFORMATION AND CONSENT FORM ...................................................................................... 86 
CONSENT FORM .............................................................................................................................................. 97 
REVOCATION OF CONSENT ............................................................................................................................. 98 
Appendix 6: Investigator Agreement and Signature Page .................................................................................. 99 
 
 
 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 6 of 99 
1.0 Protocol Synopsis  
Title 
A double blind randomised comparison of vorapaxar versus placebo for the 
treatment of HIV associated inflammation and coagulopathy in patients with well 
controlled HIV replication 
Protocol 
registration 
no, 
NCT02394730 
 
Background 
and 
rationale 
 
Clinical setting 
Elevated expression of d-dimer (corresponding to coagulopathy) and hs-CRP/IL-6 
(corresponding to immune activation/inflammation) are associated with increased 
risk of death and serious end-organ diseases among people with HIV infection1-3. 
While increased levels of these markers are driven by HIV replication, it is clear that 
even among people with well controlled HIV replication there is a consistent 
relationship between higher d-dimer levels and poorer clinical outcome. While 
combination antiretroviral therapy (cART) reduces levels of d-dimer, it does not 
result in normalisation4. Even among patients with suppressed HIV RNA replication, 
expression of these markers is higher among people with HIV infection than those 
observed in age matched populations without HIV infection5. Interventions to 
reduce either hypercoagulopathy and/or immune activation may permit a clearer 
understanding of the pathogenesis that underpins this presentation. Similarly, the 
interventions may also be consistent with improved prognosis that could be 
evaluated in additional studies. 
 
Coagulation and immune activation 
The relationship between coagulopathic disorder and immune activation is not clear. 
Data suggest that there is an evolutionary link between the immune system and the 
coagulation cascade. Tissue injury results in the release of tissue factor that 
promotes the coagulation cascade resulting in thrombus formation. T-cells 
differentially express receptors linked to this cascade and are activated at times 
when tissue injury has occurred.  Recently, a novel observation was made suggesting 
that CD8+ T lymphocytes from HIV infected persons over-express Protease Activated 
Receptor-1 (PAR-1). This receptor is activated by thrombin and CD8+ cells expressing 
the receptor respond in a dose dependent fashion to exogenous thrombin6. In this 
setting CD8+ cell responses included expression of chemokines and cytokines.  
 
The sources of tissue injury, immune activation and hypercoagulopathy in people 
with well controlled HIV replication are not known. It is established that there are 
increased levels of tissue factor expression in monocytes from people with HIV-1 
infection9. In the most comprehensive analysis of coagulation factors to date, 
mathematical modelling of thrombin generation indicated that the net effect of HIV 
replication was pro-coagulant. However, it was unclear from this investigation 
whether there were residual coagulation abnormalities after suppression of HIV 
replication10. As such it is plausible that tissue injury in the setting of HIV replication 
promotes thrombin formation and PAR-1 dependent signalling that in turn supports 
immune activation and inflammation. PAR-1 may mediate the intersection between 
these physiologic responses to injury and microbial threat. It is therefore a potential 
target for therapeutic manipulation in the setting of well controlled HIV infection. 
 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 7 of 99 
Vorapaxar 
Vorapaxar (Zontivity™) is an oral competitive PAR-1 antagonist that inhibits 
thrombin-induced platelet aggregation. Vorapaxar has recently been licensed as 
secondary prophylaxis for patients with a history of MI or peripheral arterial disease 
except ischemic stroke and was commercially available in the USA in July 2014 with 
other countries expected to follow. 
Study 
objectives 
To compare the safety and efficacy of vorapaxar versus placebo in reducing d-dimer 
expression and markers of cellular immune activation over a period of 12 weeks among 
people with HIV infection who are successfully treated with combination antiretroviral 
therapy that does not contain HIV protease inhibitors and/or NNRTIs (except 
rilpivirine).  A secondary objective of the study will be to demonstrate that following 
cessation of vorapaxar in patients with suppressed plasma HIV viremia there will be an 
increase in the levels of d-dimer over a 6 week period. 
 
Primary endpoint 
 
Differences between treatment groups in mean change from baseline log10 d-
dimer at week 8 and week 12 
 
Secondary endpoints 
Secondary endpoints to be measured during the two treatment phases will include, but 
not be limited to the following: 
 
Virologic measures of interest 
 
Proportion of participants in each treatment group with plasma HIV-1 RNA <50 
copies/mL at week 12 and week 18 
Immunologic measures of interest 
 
Differences between treatment groups in mean change from baseline in CD4+ cell 
counts at week 12  
 
Differences between treatment groups in mean change from baseline in CD4+ cell 
counts at week 18 
 
Differences between treatment groups in mean change from baseline in CD8+ cell 
counts at week 12  
 
Differences between treatment groups in mean change from baseline in CD8+ cell 
counts at week 18 
 
Activation/Coagulation measures of interest 
 
Percentage of patients in each treatment group with d-dimer <165ng/mL ( 
0.165mg/L) at week 8 and week 12 
 
Percentage of patients in each treatment group with d-dimer >165ng/mL (0.165 
mg/L) at week 18 
 
Differences between treatment groups in mean change from baseline log10 d-
dimer at week 18 
 
Differences between treatment groups in mean change from baseline log10 hs-CRP 
at week 8 and week 12 
 
Differences between treatment groups in mean change from baseline log10 hs-CRP 
at week 18 
 
Differences between treatment groups in mean change from baseline log10 IL-6 at 
week 8 and week 12 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 8 of 99 
 
Differences between treatment groups in mean change from baseline log10 IL-6 at 
week 18 
Safety endpoints 
 
 
Total number of participants in each treatment group with Type 1, 2, 3, 4 or 5 
bleeding episodes (using BARC16 criteria – see Appendix 2) 
 
Total number of participants in each treatment group with any Serious Adverse 
Event (SAE) and the cumulative incidence of SAEs. 
 
Total number of participants in each treatment group with any Adverse event (AE) 
and the cumulative incidence of AEs 
 
Changes from baseline in selected serum biochemical parameters, including 
changes in renal function measured by the CKD-EPI estimate of creatinine clearance 
Exploratory analysis 
During conduct of the study blood will be collected to support a range of exploratory 
laboratory analyses. If the primary endpoint of the trial is reached, the following 
measures of interest will be analysed: 
Virologic measures 
 
Cell associated HIV RNA/DNA 
 
Ultrasensitive plasma viral load 
Immunopathogenesis measures 
 
Plasma markers of monocyte activation (sCD14 and sCD163) 
 
Antibody function (ADCC)  
 
NK cell activation 
 
T cell activation markers (eg. CD38+ HLA+DR+ expression on CD4+/CD8+ cells) 
 
PAR-1 expression 
 
Participant 
population  
60 patients will be recruited from approximately 7 study centres in Australia and 
USA. Eligible patients will satisfy all of the following criteria within 14 days prior to 
randomisation: 
 
Inclusion criteria 
1. HIV-1 positive by licensed diagnostic test 
2. aged ≥40 years 
3. plasma HIV RNA <50 copies/mL for at least 24 weeks 
4. screening CD4+ cell count > 50 cells/mm3 
5. treated for at least 12 weeks with a suppressive regimen of combination 
antiretroviral therapy that does not include HIV protease inhibitors and/or 
NNRTIs (except rilpivirine)  
6. plasma d-dimer >200ng/mL (>0.2μg/mL or >0.2mg/L) fibrinogen equivalent 
units or >100ng/mL (>0.1 μg/mL or >0.1mg/L) d-dimer units in the absence 
of established cause (deep vein thrombosis/embolism)  
7. provision of written informed consent 
 
 
 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 9 of 99 
 
Exclusion criteria 
1. Absolute neutrophil count (ANC) <1000 cells/μL 
2. hemoglobin <10.0 g/dL 
3. platelet count <75,000 cells/μL 
4. AST and/or ALT >2.5 x ULN 
5. estimated glomerular filtration rate<30mL/min/1.73m2 using CKD-EPI 
(Chronic Kidney Disease Epidemiology Collaboration) equation 
6. history of myocardial infarction or unstable atherosclerotic disease  
7. history of ischemic stroke or transient ischaemic attack (TIA) 
8. active peptic/duodenal ulcer or other bleeding disorder within the previous 
12 months 
9. intent to have surgery within the 6 month period after randomisation 
10. current use of aspirin or P2Y12 antiplatelet therapy 
11. current use of anticoagulants, (eg. heparin or warfarin), fibrinolytic therapy, 
chronic use (more than 5 consecutive days) of nonsteroidal anti-
inflammatory drugs (NSAIDS), strong CYP3A4 inhibitors or inducers. See 
Manual of Operations for full list of medications to avoid. 
12. participants unlikely to be able to remain in follow-up 
13. pregnant or nursing mothers 
14. in the clinical judgement of the investigator, participation in this trial is 
deemed inappropriate as this may conflict with the well-being of the 
participant. 
 
Study design 
This is an international, multi-centre, double-blind, randomised trial measuring the 
effects of vorapaxar versus placebo on inflammation and coagulopathy markers in 
patients with well controlled HIV infection. Randomisation will be stratified by 
clinical site.  
 
Treatment 
of 
participants 
Consenting participants will be screened and within 14 days randomly allocated to 
receive either vorapaxar sulphate (2.5mg) or matched placebo once daily for 12 
weeks (phase 1).  All patients will stop the study treatment at week 12 for a period 
of 6 weeks (phase 2) and have a final visit at week 18. 
 
   
 
 
 
 
 -2 weeks                                Day 0                                                      week 12                             week 18 
 
Figure 1. Study Design 
 
 
Study 
procedures 
Participants will be seen one week after randomisation and then at weeks 4, 8 and 
12 (phase 1). At the week 12 visit, patients will not be dispensed any study 
treatment. In phase 2 all study treatment will stop for 6 weeks. At week 18 patients 
. 
 
Screening 
. 
 
Randomisation of 
eligible patients 
(N=60) 
Phase 1 
Vorapaxar sulphate 
2.5mg qd (N=30)) 
Placebo (N=30) 
Phase 2  
No study drug 
administered 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 10 of 99 
will be seen for a final study visit. 
 
Procedures include; 
1. 
Informed consent 
2. 
Medical  and HIV history 
3. 
Vital Signs (height, weight and sitting blood pressure) 
4. 
Symptom directed physical exam  
5. 
Blood sample collection for local laboratory analysis; 
 
D-dimer (screening only for eligibility purposes) 
 
Serum or urine pregnancy test  
 
Virology: HIV-1 RNA measured using assays with lower limit of detection of 
at least 50 copies/mL 
 
Haematology: full blood count  
 
Fasted lipids  
 
Biochemistry: Urea, Electrolytes, Creatinine, Liver Function Tests 
 
Immunology: CD4+, CD8+ T cell count 
6. 
Blood sample collection for storage and central laboratory analysis; 
 
Coagulation /  Immune Activation: D-dimer, IL-6, Hs-CRP 
7. 
 Blood sample collection for storage and central laboratory analysis 
(exploratory analyses); 
 
Virology: cell associated HIV RNA/DNA, ultrasensitive HIV plasma viral load  
 
Immunopathogenesis: ADCC Antibody, NK cell activation, T-cell activation 
markers, plasma markers of monocyte activation (sCD14, sCD163) and PAR-
1 expression (PAR-1 to be analysed on fresh whole blood collected from a 
subset of participants from sites with capacity to perform this assay in real 
time) 
8. 
Collection of AEs (including SAEs regardless of relationship to study drug) 
9. 
Collection of concomitant medications 
Statistics 
Statistical analysis 
Primary analyses will compare the two randomised arms in an intention to treat 
manner once all patients have completed follow up. Secondary analyses will exclude 
data in patients who cease study drug. There will be no adjustment of analyses for 
multiple comparisons. 
 
The primary endpoint will be mean changes in log10 d-dimer levels from baseline at 
weeks 8 and 12. The proportion of patients with d-dimer<165ng/mL (0.165mg/L) will 
also be summarised. 
 
Formal analyses will compare the randomised treatment arms in terms of mean 
differences in changes in log10 d-dimer at week 8 and week 12 using repeated 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 11 of 99 
measures regression methods.  
 
A focus of safety monitoring and analyses will be bleeding events assessed according 
to the Bleeding Academic Research Consortium (BARC)16 criteria as BARC type 1, 2, 
3, 4 or 5 bleeding events. Treatment arms will be compared in terms of proportions 
of patients with bleeding events using chi-square tests or Fisher’s exact tests as 
appropriate. 
 
Sample size 
Using a repeated measures regression analysis at week 8 and 12, variability in 
change in log10 d-dimer =0.4, and correlation between these two time points as 0.5 
(STEAL trial 14), then a total sample size of 56 patients (2x28) gives 80% (90%) power 
to detect a mean difference of 0.26 (0.30) logs. A total of 60 patients gives some 
modest allowance for non-completion. 
 
 
 
 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 12 of 99 
2.0 Study Flow Chart: Time and events schedule 
 
Study Phase 
Screening 
Randomisation    
Phase 1 
 
Phase 2 
Study week numberc 
SCRNa 
0b 
1 4 8 12 
13-17 
No study 
drug  
18 
Clinical Assessments 
Informed consent 
• 
 
 
 
 
 
 
 
Medical and HIV history  
• 
 
 
 
 
 
 
 
Interim history, AEs assessment and concomitant 
medication 
 
• 
• • • 
• 
 
• 
Targeted physical examination (symptom directed) 
• 
• 
• • • 
• 
 
• 
Vital Signsd 
 
• 
• • • 
• 
 
• 
Dispense study medication 
 
• 
 
• • 
 
 
 
Real time local laboratory assessments 
Biochemistrye 
• 
• 
 
 
 
• 
 
• 
Liver functionf 
• 
• 
 
 
 
• 
 
• 
Haematologyg 
• 
• 
• • • 
• 
 
• 
Fasted lipidsh 
 
• 
 
 
 
 
 
 
CD4+ and CD8+ T cell (absolute and %)i 
• 
• 
• • • 
• 
 
• 
Virology: plasma HIV-1 RNA j 
• 
• 
• • • 
• 
 
• 
d-dimer  
• 
 
 
 
 
 
 
 
Pregnancy testk 
• 
• 
 
• • 
• 
 
• 
Storage samples for central laboratory analysis  
D-dimer 
 
• 
• • • 
• 
 
• 
Hs-CRP  
 
• 
• • • 
• 
 
• 
IL-6 
 
• 
• • • 
• 
 
• 
Storage samples for central laboratory analysis (exploratory analysis) 
Ultrasensitive plasma viral load 
 
• 
 
 
 
• 
 
• 
T cell activation marker 
 
• 
• • • 
• 
 
• 
ADCC Antibody/ NK cell function 
 
• 
• • • 
• 
 
• 
PAR-1 expressionl 
 
• 
• • 
 
• 
 
• 
Plasma markers of inflammation (sCD14, sCD163) 
 
• 
 
 
 
• 
 
• 
a All screening assessments are to be completed within 14 days prior to randomisation;  
b All randomisation (week 0) assessments should be completed before the participant commences study drugs. Study drug should commence within 1 
day of randomisation; 
c Study Week Number:  All efforts should be made to schedule visits in keeping with the proposed week numbers. Phase 1: week 1 to be conducted 
within 13 days of randomisation, weeks 4, 8 and 12 to be done +/- 2 weeks of scheduled visit date. Phase 2: week 18 to be conducted within + 2 weeks 
of scheduled visit date.  
d Vital Signs: Sitting blood pressure (all visits), height (week 0 only) and weight (week 0 and week 18 only); 
e Biochemistry: electrolytes (sodium, potassium, calcium, bicarbonate, chloride, phosphate), creatinine, urea; 
f Liver Function test: ALT and AST;  
g Haematology: haemoglobin, white blood cells, neutrophils, lymphocytes, platelets to be done (day 0 and week 12 to be done as standard of care). 
Haemoglobin to be tested at the time of any clinically significant bleeding event (clinical judgement to be used);  
h Fasting lipid parameters includes: total cholesterol, HDL cholesterol, calculated LDL cholesterol and triglycerides;  
i CD4+ and CD8+ cell counts: Day 0 and week 12 to be done as standard of care; 
j HIV-1 RNA assays will be conducted at local laboratories with a lower limit of detection of at least 50 copies/mL plasma (day 0 and week 12 to be done 
as standard of care);  
k Urine or serum pregnancy test if female and of child bearing potential; 
l PAR-1 expression to be analysed on a subset of participants from selected sites with capacity to perform this assay in real time. 
 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 13 of 99 
3.0 Background and rationale 
 
3.1 Clinical setting 
 
Elevated expression of d-dimer (corresponding to coagulopathy) and hs-CRP/IL-6 (corresponding to immune 
activation/inflammation) are associated with increased risk of death and serious end-organ diseases among 
people with HIV infection1-3. While increased levels of these markers are driven by HIV replication, it is clear 
that even among people with well controlled HIV replication there is a consistent relationship between 
higher d-dimer levels and poorer clinical outcome. While combination antiretroviral therapy (cART) reduces 
levels of d-dimer, it does not result in normalisation4. Even among patients with suppressed HIV RNA 
replication, expression of these markers is higher among people with HIV infection than those observed in 
age matched populations without HIV infection5. Interventions to reduce either hypercoagulopathy and/or 
immune activation may permit a clearer understanding of the pathogenesis that underpins this presentation. 
Similarly, the interventions may also be consistent with improved prognosis that could be evaluated in 
additional studies. 
3.2 Coagulation and immune activation 
 
The relationship between coagulopathic disorder and immune activation is not clear. Data suggest that there 
is an evolutionary link between the immune system and the coagulation cascade. Tissue injury results in the 
release of tissue factor that promotes the coagulation cascade resulting in thrombus formation. T-cells 
differentially express receptors linked to this cascade and are activated at times when tissue injury has 
occurred.  Recently, a novel observation was made suggesting that CD8+ T lymphocytes from HIV infected 
persons over-express the Protease Activated Receptor-1 (PAR-1). This receptor is activated by thrombin and 
CD8+ cells expressing the receptor respond in a dose dependent fashion to exogenous thrombin6. In this 
setting CD8+ cell responses included expression of chemokines and cytokines. Furthermore, it is also known 
that natural polymorphisms in the PAR-1 gene that reduce PAR-1 expression are protective for thrombo-
embolism in men7, 8.  
 
The sources of tissue injury, immune activation and hypercoagulopathy in people with well controlled HIV 
replication are not known. It is established that there are increased levels of tissue factor expression in 
monocytes from people with HIV-1 infection9. In the most comprehensive analysis of coagulation factors to 
date, mathematical modelling of thrombin generation indicated that the net effect of HIV replication was 
pro-coagulant. However, it was unclear from this investigation whether there were residual coagulation 
abnormalities after suppression of HIV replication10. As such it is plausible that tissue injury in the setting of 
HIV replication promotes thrombin formation and PAR-1 dependent signalling that in turn supports immune 
activation and inflammation. PAR-1 may mediate the intersection between these physiologic responses to 
injury and microbial threat. It is therefore a potential target for therapeutic manipulation in the setting of 
well controlled HIV infection. 
3.3 Vorapaxar 
 
Vorapaxar sulphate (Zontivity™) is a first in class, tricyclic himbacine-derived selective inhibitor of platelet 
aggregation mediated by PAR-1.  
 
Vorapaxar has been developed in a number of primary and secondary care settings for cardiovascular 
diseases. In the setting of acute coronary syndromes vorapaxar did not affect a composite primary endpoint 
that included death, MI, stroke, recurrent ischemia or coronary revascularisation but did significantly 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 14 of 99 
increase the risk of major bleeding including intracranial haemorrhage11. In a further study that followed 
26,449 patients with a history of MI, cerebral stroke or peripheral arterial disease, vorapaxar significantly 
reduced the risk of cardiovascular disease mortality and ischemic events among patients with stable 
atherosclerosis while also increasing the risk of moderate to severe bleeding including intracranial  
haemorrhage12. This study identified the risk of severe bleeding among patients with a history of stroke – 
which would now be regarded as contraindicated for treatment with vorapaxar and therefore participation in 
this study. Importantly, the findings arose among a patient group who were also receiving standard 
secondary prophylaxis for CVD (88% receiving aspirin and 78% receiving thienopyridine) and so the effects 
reflect adjunctive use to already potent anti-thrombotic therapy. The hazard ratio (95% CI) for vorapaxar 
recipients relative to placebo recipients for the primary endpoint (fatal CV event, MI or stroke) was 0.87 
(0.80-0.94; p<0.001). A total of 2204 patients experienced a primary event over three years, 1028 (9.3%) 
vorapaxar recipients and 1176 (10.5%) of placebo recipients. Moderate or severe bleeding occurred in 4.2% 
of patients who received vorapaxar and 2.5% of patients who received placebo (HR, 1.66; 95% CI 1.43–1.93: 
p<0.001).  
 
Vorapaxar has now been licensed in the USA as secondary prophylaxis for patients with a history of MI or 
peripheral arterial disease except ischemic stroke. 
 
4.0 Hypotheses 
 
In patients with well controlled HIV disease treated with a suppressive cART regimen that does not contain 
HIV protease inhibitors and/or NNRTIs (except rilpivirine) who have relatively high levels of d-dimer, the use 
of vorapaxar will reduce d-dimer levels. 
 
5.0 Study objectives 
 
To compare the safety and efficacy of anti-platelet therapy with the PAR-1 antagonist vorapaxar versus 
placebo  in reducing d-dimer expression and markers of cellular immune activation among people with HIV 
infection who are successfully treated with combination antiretroviral therapy that does not contain HIV 
protease inhibitors and/or NNRTIs (except rilpivirine).  
 
5.1 Primary objective 
 
To determine whether vorapaxar reduces d-dimer levels compared to placebo over a 12 week period. 
5.2 Secondary objective 
 
To demonstrate that following cessation of vorapaxar in patients with well controlled HIV replication there 
will be an increase in the levels of d-dimer over a 6 week period. 
5.3 Exploratory objectives 
 
To analyse the effect of vorapaxar on a range of virological, immunological and coagulation measures 
including cell associated HIV RNA/DNA, ultra-sensitive plasma HIV levels, T cell and NK cell function, 
monocyte activation, antibody function and PAR-1 expression. 
 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 15 of 99 
5.4 Primary endpoint 
 
Differences between treatment groups in mean change from baseline log10 d-dimer at weeks 8 and week 12 
 
5.5 Secondary endpoints 
 
Secondary endpoints to be measured during the two treatment phases will include, but not be limited to the 
following: 
 
 
Virologic measures of interest 
 
 Proportion of participants in each treatment group with plasma HIV-1 RNA <50 copies/mL at week 12 and 
week 18 
 
Immunologic measures of interest 
 Differences between treatment groups in mean change from baseline in CD4+ cell counts at week 12  
 Differences between treatment groups in mean change from baseline in CD4+ cell counts at week 18 
 Differences between treatment groups in mean change from baseline in CD8+ cell counts at week 12  
 Differences between treatment groups in mean change from baseline in CD8+ cell counts at week 18 
 
Activation/Coagulation measures of interest 
 
 Percentage of patients in each treatment group with d-dimer <165ng/mL (0.165mg/L) at week 8 and week 
12 
 Percentage of patients in each treatment group with d-dimer >165ng/mL  (0.165mg/L) at week 18 
 Differences between treatment groups in mean change from baseline log10 d-dimer at week 18 
 Differences between treatment groups in mean change from baseline log10 hs-CRP at week 8 and week 12 
 Differences between treatment groups in mean change from baseline log10 hs-CRP at week 18 
 Differences between treatment groups in mean change from baseline log10 IL-6 at week 8 and week 12 
 Differences between treatment groups in mean change from baseline log10 IL-6 at week 18 
 
Safety endpoints 
 
 Total number of participants in each treatment group with Type 1, 2, 3, 4 or 5 bleeding episodes (using 
BARC16 criteria – see Appendix 2) 
 Total number of participants in each treatment group with any Serious Adverse Event (SAE) and the 
cumulative incidence of SAEs. 
 Total number of participants in each treatment group with any Adverse event (AE) and the cumulative 
incidence of AEs 
 Changes from baseline in selected serum biochemical parameters, including changes in renal function 
measured by the CKD-EPI estimate of creatinine clearance 
 
 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 16 of 99 
5.6 Exploratory endpoints 
During conduct of the study blood will be collected to support a range of exploratory laboratory analyses. If 
the primary endpoint of the trial is reached, the following measures of interest will be analysed: 
 
Virological measures 
 
 Cell associated HIV RNA/DNA 
 Ultrasensitive plasma viral load 
 
Immunopathogenesis measures 
 Plasma markers of monocyte activation (sCD14 and sCD163) 
 Antibody function (ADCC)  
 NK cell activation 
 T cell activation markers (e.g. CD38+ HLA+DR+ expression on CD4+/CD8+ cells) 
 PAR-1 expression (to be analysed on fresh whole blood collected from a subset of participants at 
participating sites with the capacity to perform this assay in real time) 
 
6.0 Study design & Statistics 
 
This is an international, multi-centre, double-blind, placebo controlled trial. Randomisation will be stratified 
by clinical site.  
 
Consenting participants will be screened and within 14 days randomly allocated to receive either vorapaxar 
sulphate (2.5mg qd) or matched placebo once daily for 12 weeks (phase 1).  At the week 12 visit, all study 
treatment will stop for 6 weeks (phase 2). Patients will be seen for a final visit at week 18.  
 
The study designed is summarised in Figure 1.  
 
   
 
 
 
 
 
                              -2 weeks                   Day 0                                                week 12                       week 18 
 
Figure 1.  Study Design 
 
60 participants will be randomised from approximately 7 selected centres in Australia and the USA and 
followed for a total of 18 weeks. It is anticipated that approximately 120 patients will need to be screened to 
randomise 60 participants. It is expected that the majority of ineligible participants through screening will be 
those with low d-dimer levels.  
 
 
. 
 
Screening 
. 
 
Randomisation of 
eligible patients 
(N=60) 
Phase 1 
Vorapaxar sulphate 
2.5mg qd (N=30)) 
Placebo (N=30) 
Phase 2  
 
 
No study drug 
administered 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 17 of 99 
6.1 Sample size determination 
 
Assumptions are based on data from the STEAL trial14. Excluding patients with d-dimer<200ng/mL, the 
standard deviation in change in log10 d-dimer is 0.356 at week 12 and 0.414 at week 24. The correlation of 
these two endpoints is 0.5726.  
 
Using a repeated measures regression analysis at week 8 and 12, variability in change in log10 d-dimer =0.4, 
and correlation between these two time points as 0.5 (STEAL trial 14), then a total sample size of 56 patients 
(2x28) gives 80% (90%) power to detect a mean difference of 0.26 (0.30) logs. A total of 60 patients gives 
some modest allowance for non-completion. 
 
Mean baseline d-dimer in STEAL15 (excluding patients with d-dimer<200 ng/mL at baseline) was 430ng/mL. 
Mean log10 decrease in STEAL was 0.07logs, which corresponds to about a 15% decrease – i.e. in the control 
arm we might expect a decrease from 430 to about 370ng/mL. We are powered to detect log differences of 
the order of 0.26, so in total in the vorapaxar arm we expect a 0.33log decrease – i.e. a decrease from 430 to 
about 200 ng/mL. In absolute terms we have 80% power to detect a difference in d-dimer changes of around 
170 ng/mL. 
 
These are quite large effect sizes, both compared with the expected variability (0.75 standard deviations), 
and in absolute terms (differences in d-dimer changes of around 170 ng/mL from expected baseline mean of 
430 ng/mL. However, we believe that such large effects would be clinically significant, and will be required to 
justify expanded studies of vorapaxar treatment in HIV-positive individuals.  
 
6.2 Analysis Plan 
6.2.1 Statistical analysis 
 
Baseline characteristics will be summarised by randomised group. Patients failing to complete study drug will 
be listed, with accompanying reasons. The primary endpoint will be mean changes in log10 d-dimer levels 
from baseline at weeks 8 and 12. The proportion of patients with d-dimer<165ng/mL will also be 
summarised. 
 
Mean or median changes, or percentages, as appropriate, in primary and secondary endpoints will be plotted 
by study week. 
 
Formal analyses will compare the randomised treatment arms in terms of mean differences in changes in 
log10 d-dimer at week 8 and week 12 using repeated measures regression methods. Models will be fitted 
using maximum likelihood methods using robust standard errors. Simple unadjusted models will initially be 
used to estimate the difference between randomised treatment arms in mean changes in log10 d-dimer. 
Models adjusted for key baseline covariates will also be fitted. If there is overall evidence of a difference 
between randomised treatment arms at 2p<0.05, then further sensitivity analyses will also be performed 
using simple two-sample (t-test or rank-sum test) applied to the mean change in log10d-dimer at weeks 8 
and 12. 
 
Similar longitudinal methods will also be used to analyse mean changes from baseline in, or proportions of, 
secondary endpoints at weeks 8 and 12.  
 
Differences between randomised treatment arms in mean changes in, or proportions of, all endpoints at 
week 18 will be investigated using linear regression or logistic regression methods. 


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6.2.2 Safety analysis 
 
The proportion of participants with all DAIDS (Division of AIDS) grade adverse events and DAIDS grade 3/4 
adverse events (see Appendix 1) will be summarised by randomised treatment group, by severity and by 
relation to study drug for all subjects treated with study drug.  Serious adverse events will be summarised for 
all enrolled subjects.  The analysis of safety variables will be done according to a per protocol approach.  
 
A particular focus of safety analyses will be bleeding events. These will be solicited adverse events, and 
classified according to Bleeding Academic Research Consortium (BARC) criteria16 (see Appendix 2) as BARC 
Type 1, 2, 3, 4 or 5 bleeding events. Bleeding events reported as unsolicited adverse events or serious 
adverse events will also be summarised. The proportions of patients with bleeding events will be compared 
between treatment arms using chi-square tests. If numbers of events are small, some bleeding events may 
be aggregated. 
 
6.3 Schedule of Analyses 
 
Primary analyses will compare the two randomised arms in an intention to treat manner once all patients 
have completed follow up (week 18). Secondary analyses will exclude data in patients who cease study drug. 
There will be no adjustment of analyses for multiple comparisons. 
 
7.0 Participant population 
Eligible participants will satisfy all the following inclusion and exclusion criteria within 14 days prior to 
randomisation.  No waivers will be issued.  
 
7.1 Eligibility criteria 
 
Inclusion criteria 
1. HIV-1 positive by licensed diagnostic test 
2. aged ≥40 years 
3. plasma HIV RNA <50 copies/mL for at least 24 weeks 
4. screening CD4+ cell count >50 cells/mm3 
5. treated for at least 12 weeks with a suppressive regimen of combination antiretroviral therapy that 
does not include HIV protease inhibitors and/or NNRTIs (except rilpivirine)  
6. plasma d-dimer >200ng/mL mL (>0.2μg/mL or >0.2mg/L) fibrinogen equivalent units or >100ng/mL 
(>0.1 μg/mL or >0.1mg/L) d-dimer units in the absence of established cause (deep vein 
thrombosis/embolism)  
7. provision of written informed consent 
 
Exclusion criteria 
 
1. Absolute neutrophil count (ANC) <1000 cells/μL 
2. haemoglobin <10.0 g/dL 
3. platelet count <75,000 cells/μL 
4. AST and/or ALT >2.5 x ULN 
5. estimated glomerular filtration rate<30mL/min/1.73m2 ) using CKD-EPI (Chronic Kidney Disease 
Epidemiology Collaboration) equation 
6. history of myocardial infarction or unstable atherosclerotic disease  
7. history of ischemic stroke or transient ischaemic attack (TIA) 
8. active peptic/duodenal ulcer or other bleeding disorder within the previous 12 months 


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9. intent to have surgery within the 6 month period after randomisation 
10. current use of aspirin or  P2Y12 antiplatelet therapy 
11. current use of anticoagulants, (e.g. heparin or warfarin), fibrinolytic therapy, chronic (more than 5 
consecutive days) nonsteroidal anti-inflammatory drugs (NSAIDS), strong CYP3A4 inhibitors or 
inducers. See Manual of Operations for full list of medications to avoid. 
12. participants unlikely to be able to remain in follow-up 
13. pregnant or nursing mothers 
14. in the clinical judgement of the investigator, participation in this trial is deemed inappropriate as this 
may conflict with the well-being of the participant 
 
 
8.0 Treatment of participants 
 
Eligible participants will be randomised  in equal proportions to receive either:  
I. 
vorapaxar sulphate (2.5mg qd) for 12 weeks 
II. 
matched placebo for 12 weeks  
All participants will stop study treatment at the week 12 visit and then be seen for a final visit at week 18. All 
participants will stop taking the study medication at the week 12 visit, even if having undergone a period of 
study drug interruption. The treatment period will not be extended to account for the missing days. 
Randomisation will be conducted via the electronic case report form.  Specific details regarding 
randomisation will be provided in the study Manual of Operations (MOOP). Randomisation will be stratified 
by centre on a 1:1 basis.   
 
8.1 Vorapaxar 
 
Vorapaxar sulphate is an oral competitive PAR-1 antagonist that inhibits thrombin-induced platelet 
aggregation. Vorapaxar is eliminated primarily by metabolism with contributions from CYP3A4 and CYP2J2. 
The primary route of elimination is through the faeces and to a lesser degree in urine. It has an effective half-
life of 3-4 days and an apparent terminal elimination half-life of 8 days (range 5-13 days). 
 
One vorapaxar sulphate encapsulated tablet (2.5mg) or matching placebo should be taken orally, once daily 
with or without food.  A one month supply of vorapaxar or matching placebo will be provided at each 
dispensing visit (weeks 0, 4 and 8). Study drug will be dispensed from local pharmacies in a bottle containing 
a desiccant packet to protect the drug from moisture. The bottles must be stored at 20-25°C (68-77°F). 
Temperature monitoring logs will be kept at each pharmacy and checked during monitoring visits. All details 
regarding supply and dispensing of study treatment will be outlined in the MOOP.  
 
8.2 Prior and concomitant medications 
 
Given the involvement of CYP3A4 and CYP2J2 in the metabolism of vorapaxar, participants with HIV infection 
whose ART therapy includes ritonavir or cobicistat boosted PIs or NNRTIs (apart from rilpivirine) will not be 
enrolled into the study.  Vorapaxar can increase the risk of bleeding in proportion to a participant’s 
underlying bleeding risk. To this end, participants who have a history of bleeding disorders, active bleeding or 
are planning to undergo an elective surgical procedure within the 6 month period following randomisation 
will be excluded from the study. Certain concomitant medications are also known to increase the risk of 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 20 of 99 
bleeding. As such, participants taking anticoagulants, (e.g. heparin or warfarin), fibrinolytic therapy or chronic 
(more than 5 consecutive days) nonsteroidal anti-inflammatory drugs (NSAIDS) will also be excluded from the 
study. A list of medications to avoid will be listed in the MOOP. 
 
If during the course of the study, a participant needs treatment with a potent CYP3A4 inhibitor or inducer or 
other medication listed above, study treatment must be discontinued immediately. In the case of a potent 
CYP3A4 inhibitor or inducer, where possible, an alternative treatment should be given to avoid participants 
coming off study medication unnecessarily. Study treatment should recommence as soon as clinically 
possible with the safety and well-being of the participant paramount. It is important that the treating 
physician is informed that vorapaxar results in residual platelet aggregation activity 4 weeks after stopping 
and appropriate clinical decisions are made.  Whilst there is no known antedote for vorapaxar, monkey data 
suggest that platelet transfusions of sufficient quantity (a full pheresis pack or two) have the potential to 
transiently (a few hours) reverse the antiplatelet activity of vorapaxar. It is the investigator’s responsibility to 
inform the treating physician of this.   
 
In this protocol all concomitant medications including over the counter medicines and natural supplements 
will be recorded.  
 
8.3 ART Regimen 
Participants will continue to have their ART regimen managed as directed by their treating physician in 
accordance with national and international guidelines. Modifications to the ART regimen can be made if 
required. However, ritonavir boosted PIs, elvitegravir+cobicistat (Stribild™ Genvoya™) or NNRTIs (apart from 
rilpivirine), should not be prescribed as they are potent inhibitors or inducers of CYP3A4.  Rilpivirine is 
permitted as it is not a potent CYP3A4 inducer. At the recommended dose of 25mg daily, rilpivirine is not 
expected to have a clinically significant effect on vorapaxar exposure. Similarly, maraviroc is not expected to 
have a clinically significant effect on vorapaxar exposure as it does not inhibit any of the major CYP isoforms. 
Conversely vorapaxar is not expected to have a clinically significant effect on rilpivirine or maraviroc.  
Warnings and precautions regarding medications to avoid whilst taking vorapaxar can be found in the FDA 
approved product information and Investigator Brochure. For ART medications Investigators can refer to the 
respective product information or www.HIV‐druginteractions.org.  
Participants will receive their ART medication in the usual manner and this will not be provided by the study.  
 
9.0 Study procedures 
 
9.1 Initial screening period 
Potentially eligible individuals can be screened within 14 days before the randomisation visit and all results 
from screening must be available for randomisation.  All subjects should be given adequate information 
about the trial including the Participant Information Sheet and be given an opportunity to ask questions 
about the trial.  Written consent for the trial should be obtained at the screening visit before any protocol 
specified assessments are performed.  The following evaluations will be performed within 14 days prior to 
randomisation: 
 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 21 of 99 
9.1.1 Clinical assessments at screening 
 
 Informed consent 
 Complete medical history to include; non-HIV related diagnosis including liver disease, renal  disease, 
cardiovascular disease, bleeding disorders, race and gender at birth, surgical history and concomitant 
medications 
 Full HIV history to include: mode of transmission, duration of HIV infection, ART history and current ART 
regimen, current stage of HIV disease (CDC classification – refer Appendix 3)  
 Symptom directed physical examination  
 
9.1.2 Laboratory assessments at screening 
 
 If the patient is female and is of child bearing potential, she must have a urine or blood sample pregnancy 
test 
 Serum chemistries and liver function tests: electrolytes (sodium, potassium, bicarbonate, chloride, 
phosphate), urea, creatinine and LFTs (ALT and AST only) 
 Assessment of renal function will be undertaken with derivation of creatinine clearance using the CKD-EPI 
(Chronic Kidney Disease Epidemiology Collaboration) equation: 
Estimated GFR = 141 x min(SCR/κ,1)α x max(SCR/κ,1)-1.209 x 0.993Age x (1.018 if female x (1.159 if black) 
 Haematology: full blood count (haemoglobin, white cells, neutrophils, lymphocytes, platelets) 
 Plasma HIV-RNA analysis  
 Immunology: CD4 and CD8 (% and absolute) 
 Plasma d-dimer  
 
9.1.3 Rescreening 
Rescreening is not permitted, including those participants with abnormal laboratory results. All screen 
failures must be documented on the site screening and randomisation log.  
 
9.2 Randomisation visit  
 
To proceed to the randomisation visit, all participants must have fulfilled the eligibility criteria by the results 
of evaluations at screening.  All randomisation evaluations must be completed prior to the commencement 
of study drug 
 
9.2.1 Clinical assessments at week 0 (prior to randomisation) 
 
 Targeted physical examination (symptom directed). Symptoms reported by the subject will be reviewed 
by the clinician at each visit and recorded on the CRFs as adverse events 
 Vital Signs: height, weight and sitting blood pressure 
 Information required for Framingham risk17 equation (smoking and diabetes) 
 Concomitant medication information  
 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 22 of 99 
9.2.2 Laboratory assessments at week 0 (prior to randomisation) 
 
 If the patient is female and is of child bearing potential, she must have a urine or blood sample pregnancy 
test 
 Serum chemistries and liver function tests: electrolytes (sodium, potassium, bicarbonate, chloride, 
phosphate), urea, creatinine and LFTs (ALT and AST only) 
 Haematology: full blood count (haemoglobin, white cells, neutrophils, lymphocytes, platelets) 
 Fasted lipids  
 Plasma HIV-RNA levels  
 Immunology: CD4 and CD8 (% and absolute) 
 PAR-1 (to be analysed in a subset of participants from selected sites with capacity to perform this assay in 
real time) 
 Plasma storage for central laboratory testing of d-dimer, Hs-CRP, IL-6 
 Plasma, PBMC and serum storage for possible exploratory analysis of ultra-sensitive plasma viral load, T 
cell activation, NK cell function, ADCC antibody and markers of inflammation (sCD14, sCD163) 
 
9.2.3 Randomisation and Drug Supply 
 
After completion of all randomisation study visit assessments the participant will be randomised online via 
the web based CRF.  Eligibility must be confirmed and the participant will then be automatically randomised 
to commence either vorapaxar sulphate (2.5mg) or matching placebo once daily. A Participant Identification 
(PID) number will be provided.  
 
The treatment assignment will be stratified according to clinical site. 
 
The investigator should complete a prescription and the participant should fill the prescription that same day 
or the next.  Therefore, the study drug should be commenced within 1 day of randomisation. 
 
9.3 Follow Up Visits 
 
The scheduled date of study visits will be calculated from the date of randomisation (day 0, week 0).  A 
schedule of the dates for study visits will be provided for each participant, once randomisation has been 
completed.  Guidance for site staff will also be detailed in the MOOP.  
 
The window period for each study visit is continuous so that all data collected may be used. The window 
period for: week 1 is between day 1 and day 13 from randomisation (inclusive); week 4, 8 and 12 visits in 
each treatment phase should be conducted 2 weeks before or after the scheduled visit date.  Week 18 to be 
conducted no later than 2 weeks after the scheduled visit date. 
9.3.1 Clinical assessments at weeks 1, 4, 8, 12, 18 
 
 Targeted physical examination (symptom directed) [weeks 1, 4, 8, 12, 18] 
 Symptoms reported by the subject or symptoms identified after examination will be reviewed by the 
clinician at each visit and recorded on the CRFs as adverse events [weeks 1, 4, 8, 12, 18] 
 Updated medical history including changes or additions to diagnoses, diseases, or any change in 
antiretroviral drugs, prescribed concomitant medications [weeks 1, 4, 8, 12, 18] 
 Sitting blood pressure [weeks 1, 4, 8, 12, 18] 
 Weight [week 18 only] 
 Dispense study medication [weeks 4 and 8 only] 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 23 of 99 
9.3.2 Laboratory assessments at weeks 1, 4, 8, 12, 18 
 
 If the participant is female and is of child bearing potential, she must have a urine or blood sample 
pregnancy test [weeks 4, 8, 12, 18] 
 Haematology: full blood count (haemoglobin, white cells, neutrophils, lymphocytes, platelets) [weeks 1, 4, 
8, 12, 18] 
 Blood sample for haemoglobin measurement to be taken if the participant experiences a clinically 
significant bleeding event (clinical judgement to be used) 
 Plasma HIV-RNA levels [weeks 1, 4, 8, 12, 18] 
 Immunology: CD4 and CD8 (% and absolute) [weeks 1, 4, 8, 12, 18] 
 Serum chemistries and liver function tests: electrolytes (sodium, potassium, bicarbonate, chloride, 
phosphate), urea, creatinine and LFTs (ALT and AST only) [weeks 12 and 18 only] 
 PAR-1 (to be analysed in a subset of participants from selected sites with capacity to perform this assay in 
real time) [weeks 1, 4, 12, 18] 
 Plasma storage for central laboratory testing of d-dimer, Hs-CRP, IL-6 [weeks 1, 4, 8, 12, 18] 
 Plasma, PBMC and serum storage for possible exploratory analysis of T cell activation, NK cell function and 
ADCC antibody [weeks 1, 4, 8, 12, 18] 
 Plasma storage for possible exploratory analysis of markers of inflammation (sCD14, sCD163) and ultra-
sensitive plasma viral load [weeks 12 and 18 only] 
 
9.4 Missed visits and missed assessments 
 
All efforts should be made to schedule visits in keeping with the proposed week numbers and to carry out all 
required assessments at these visits.  Any missed study visits or missed assessments should be indicated as 
such on the eCRF. If a scheduled visit is conducted after the window period has ceased for that specific visit, 
it will be counted as the next visit, and the previous visit should be documented as “missed”.  DO NOT 
conduct a second routine visit in the same window period. 
 
9.5 Withdrawal of study participants 
 
In general terms, all randomised study participants should remain in follow-up for the duration of the study, 
regardless of whether or not they continue to take randomly assigned therapy.  All study participants should 
continue to attend all study visits and complete all study-mandated assessments as per protocol. No 
participants will be replaced if there is a withdrawal.  
 
The reasons for premature study discontinuation and withdrawal of participants from the study include the 
following criteria: 
 
Termination of the study by the Protocol Steering Committee 
 
Withdrawal of consent - participants may revoke consent for follow-up without jeopardising their 
relationship with either their doctor or the Sponsor.  If a participant revokes consent then, if possible, 
all assessments scheduled for the final visit should be completed. The date of the withdrawal of 
consent must be documented in the participant’s medical notes.  See MOOP for more details. 
 
 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 24 of 99 
10.0 Clinical & Toxicity Management Guidelines 
 
10.1 Clinical and Toxicity Management Guidelines 
 
Investigators and study sites are encouraged to keep participants enrolled within the protocol regardless of 
whether they continue on their original randomised study treatment. For the purposes of uniform 
assessment of adverse events (including toxicities) this protocol employs the current DAIDS Common Toxicity 
Grading Scale (see Appendix 1). In this protocol bleeding events will be graded according to the Bleeding 
Academic Research Consortium (BARC) definitions for bleeding (see Appendix 2). Any neurological event 
should be investigated to rule out bleeding as an underlying cause. Any event with neurological symptoms 
and signs that is linked to bleeding of the central nervous system will be graded according to the BARC scale 
and managed as outlined in section 10.3.2. Neurological events without bleeding should be graded using the 
DAIDS scale and managed as clinically indicated.  
 
This systematic approach is intended to also provide a framework for clinical management of emergent 
adverse events after randomisation as described in 10.2 below. These recommendations are guidelines that 
do not override sound and qualified clinical judgement.  
 
10.2 Dose modifications 
 
No vorapaxar dose modifications should be made in response to observed toxicities. If vorapaxar is suspected 
in the etiology of a significant adverse event then dosing should cease immediately. This could apply if an 
event unrelated to vorapaxar could be worsened as a consequence of continued exposure to the study drug. 
Rechallenge can occur if or when clinically appropriate.  
 
10.2.1 DAIDS Grade 1 or 2 adverse events 
Participants who develop a Grade 1 or 2 adverse event or toxicity may continue the study drug without 
modification. Participants experiencing Grade 1 or 2 adverse events who choose to discontinue the study 
drug should remain on study and continue to undergo protocol-mandated evaluations and assessments. 
 
10.2.2 DAIDS Grade 3 adverse events 
If the investigator has compelling evidence that the adverse event has NOT been caused by the study drug, 
dosing may continue. Participants who develop a Grade 3 adverse event or toxicity considered to be possibly, 
probably or definitely related to the study drug (including raised AST/ALT levels in the presence of clinical 
symptoms) should have study drug withheld, at the investigator’s discretion. The participant should be re-
evaluated regularly until the adverse event returns to Grade <2, at which time the study drug may be 
reintroduced at the discretion of the investigator or according to standard practice.  
If the same Grade 3 adverse event recurs within four weeks, study drug must be permanently discontinued if 
the investigator considers the adverse event related to study drug.  However, if the same Grade 3 adverse 
event recurs after four weeks, the management scheme outlined above may be repeated. 
Participants experiencing Grade 3 adverse events requiring permanent discontinuation of study drug therapy 
should be followed regularly (weekly is suggested) until resolution of the adverse event. Participants should 
remain in follow-up and continue to attend for protocol-mandated assessments and evaluations.   


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 25 of 99 
10.2.3 DAIDS Grade 4 adverse events 
Participants who develop a Grade 4 adverse event or toxicity considered to be possibly, probably or definitely 
related to the study drug will have the study drug temporarily discontinued. The AE should be resolved 
before any decision is made to rechallenge the subject with the study drug. Participants experiencing Grade 4 
AEs requiring permanent discontinuation of study drug therapy should be followed regularly (weekly is 
suggested) until resolution of the adverse event.  The patient should remain on study and continue to 
undergo protocol-specified evaluations and assessments. 
Participants with Grade 4 asymptomatic or non-significant laboratory abnormalities may continue study drug 
therapy if the investigator has compelling evidence that the toxicity is NOT related to the study drug(s). 
However, if a participant develops a Grade 4 AST/ALT adverse event, without clinical symptoms, must have 
their study drug permanently discontinued. The participant should remain in follow-up and continue to 
attend for protocol-mandated assessments and evaluations.   
 
10.2.4 Monitoring of Renal Function 
 
There is no dose adjustment required in patients with renal impairment. However, routine assessment of 
renal function will be undertaken with derivation of creatinine clearance using the CKD-EPI (Chronic Kidney 
Disease Epidemiology Collaboration) equation13: 
 
Estimated GFR = 141 x min(SCR/κ,1)α x max(SCR/κ,1)-1.209 x 0.993Age x (1.018 if female x (1.159 if black) 
ĸ = 0.7 if female 
ĸ = 0.9 if male 
 
α = -0.329 if female 
α = -0.411 if male 
 
min = the minimum of Scr/ĸ or 1 
max = the maximum of Scr/ĸ or 1 
 
Scr = serum creatinine (mg/dL) 
 
Dosing of all medications in a patient’s regimen should be critically reviewed if the eGFR falls below 
60ml/min/1.73m2. It is recommended that Investigators follow the current local guidelines for the 
management of renal impairment in HIV-1-infected patients and/or reference the current EACS guidelines at: 
(Europeanaidsclinicalsociety.org/guidelinespdf/2_Non_Infectious_Co_Morbidities_in_HIV.pdf. 
Accessed 
01Dec2010) 
10.3 Protocol-specific toxicity management guidelines  
10.3.1 Vorapaxar Side Effect Profile 
 
The most common AEs associated with the use of vorapaxar sulphate (2.5mg) given once daily in patients 
with a history of cardiovascular disease are bleeding (including intracerebral bleeding), anaemia, depression 
and rash, retinal disorder and diplopia/oculomotor disturbance. The most clinically relevant are summarised 
below. 
 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 26 of 99 
10.3.2 Bleeding 
 
In the phase 3 TRA 2°P TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic 
Ischemic Events) study12 (Morrow et al), vorapaxar sulphate (2.5mg) given once daily in patients with a 
history of myocardial infarction or peripheral vascular disease with no history of ischaemic stroke or transient 
ischaemic attack saw an increase in GUSTO moderate or severe bleeding by 55% compared to the placebo 
arm. (GUSTO: Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries). 
These bleeding events were assessed as being non-CABG related bleeds. GUSTO moderate to severe bleeding 
was defined as bleeding requiring transfusion of whole blood or packed red blood cells with or without 
haemodynamic compromise, intracranial haemorrhage or fatal bleeding.  
 
To minimise the occurrence of bleeding events, participants with a high risk of bleeding will be excluded from 
this study. See section 7.1 for details. 
Adverse events involving bleeding will be assessed according to the BARC definitions (see Appendix 2) for 
bleeding. If participants are suspected of having a clinically significant bleeding event, then a blood sample 
should be taken to monitor haemoglobin levels in order to classify the event according to the BARC criteria. 
Participants will be managed as outlined below. 
 
10.3.2.1 BARC Type 1 Bleeding 
Participants who develop a BARC type 1 adverse bleeding event should continue with the study drug. 
Participants experience a BARC type 1 adverse bleeding event who choose to discontinue the study drug 
should remain on study and continue to undergo protocol-mandated evaluations and assessments. 
10.3.2.2 BARC Type 2 Bleeding 
Participants who develop a BARC type 2 adverse bleeding event that requires nonsurgical, medical 
intervention by a healthcare professional or leads to hospitalisation or increased level of care, should 
discontinue study drug but remain on study and continue to undergo protocol mandated evaluations and 
assessments. The participant should be monitored as frequently as clinically required for the particular 
bleeding event. At least weekly is recommended. The appropriateness of whether to re-challenge the 
participant with the study drug will be left to the investigator’s clinical judgement but the long half-life of 
vorapaxar must be taken into account.  
 
10.3.2.3 BARC Type 3 Bleeding 
Participants who develop a BARC type 3a, 3b or 3c (intracranial or intraocular) bleeding event will have the 
study drug permanently discontinued.  Participants experiencing BARC type 3a or 3b AEs must be followed 
regularly (at least 4-5 times per week is suggested) until resolution of the adverse event.  Participants 
experiencing a BARC Type 3c event (intracranial or intraocular bleed) must be followed on a daily basis until 
the resolution of the event. The patient should remain on study and continue to undergo protocol-specified 
evaluations and assessments. A BARC type 3 event would trigger an ‘out of session’ meeting of the Data 
Safety Monitoring Board to review the event in an unblinded manner. 
 
10.3.2.4 BARC Type 4 Bleeding 
Any participant who is planning to undergo any planned surgical procedure 6 months after the planned 
randomisation should not be enrolled into the study. If there is a need for a participant to undergo an 
emergency CABG or any other surgical procedure during the course of the study, the study drug should be 
immediately and permanently discontinued. If deemed necessary, unblinding procedures could be initiated 
but attention to how best do this will be given to avoid site staff becoming aware of the treatment allocation. 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 27 of 99 
It is important that the treating physician is informed that vorapaxar results in residual platelet aggregation 
activity 4 weeks after stopping and appropriate clinical decisions are made. There is no known antedote for 
vorapaxar. It is the investigator’s responsibility to inform the treating physician of this. 
 
10.3.2.5 BARC Type 5 Bleeding 
If any participant suffers a fatal bleed the blind for that participant will be broken. If the participant was 
taking vorapaxar at the time of the event, the trial will be temporarily stopped whilst the Data Safety 
Monitoring Board (DSMB) reviews the event in light of other clinical safety information for the study. Please 
see section 18.0 for details on DSMB. 
10.3.3 Other Adverse Reactions  
 
Pooling the adverse event data from the TRA 2°P TIMI 50 study12 (13,186 patients) and TRA●CER (Thrombin 
Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) study11 (6,446 patients), the 
incidence of the adverse events was as shown in Table 1.   
 
Table 1. Percentage of patients reporting non-haemorrhagic adverse events   
 
 
Vorapaxar 
N= 19,632 
Placebo 
N= 19,607 
Anemia 
5% 
4% 
Depression 
2.4% 
2.1% 
Rashes, Eruptions and 
Exanthemas 
2.2% 
2.0% 
 
Less common adverse reactions (occurred at a rate of less than 2% in those patients taking vorapaxar but at 
least 40% greater rate than placebo) were iron deficiency, retinopathy or retinal disorder and diplopia / 
oculomotor disturbance. 
 
10.4 Discontinuation of study treatment 
 
In general terms, all randomised study participants should aim to take the study treatment as per protocol. 
However, reasons for either temporarily or permanently ceasing study treatment include: 
 
Disease progression requiring medical intervention 
 
Surgical intervention 
 
Administration of prohibited therapy 
 
Investigator or participant wish to stop therapy 
 
Occurrence of unacceptable adverse drug reactions 
Participants MUST be discontinued from study treatment if there is any clinical adverse event, laboratory 
abnormality or intercurrent illness that in the opinion of the investigator indicates that continued treatment 
with study therapy is not in the best interest of the participant.  
 
 


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11.0 Adverse Event Recording & Reporting  
11.1  Adverse Events 
 
The definition of an adverse event is any untoward medical occurrence in a participant administered with a 
pharmaceutical product which does not necessarily have a causal relationship with the product.  Where 
adverse events are related to the drug, they may be referred to as Adverse Drug Reactions. 
 
Adverse events and adverse drug reactions may occur in the course of this study and within the specified 
follow-up period.  These events may also occur in screened participants during the screening period prior to  
 
randomisation as a result of protocol-specified interventions. All such events will be recorded at each study 
visit on the adverse event case report form.   
In this study we will be collecting all grade (grade 1-4) clinical adverse events.  As a general rule, isolated 
laboratory abnormalities in the absence of clinical symptoms and/or signs should not be captured as adverse 
events. If the laboratory event becomes clinically significant, then the resulting clinical event should be 
reported as an adverse event (e.g. low haemoglobin should be reported as anaemia). 
Pre-existing conditions or diseases that occur during the study (e.g. seasonal allergies, asthma or recurrent 
headaches) should not be considered as adverse events unless they change in frequency or severity. In this 
study we will be collecting all grade (grade 1-4) clinical adverse events.  If known, the diagnosis of the 
underlying illness or disorder should be recorded, rather than its individual symptoms.  
 
11.1.1 Reporting of Adverse Events 
Timely and complete reporting of all AEs assists in identifying any untoward medical occurrence, thereby 
allowing:  (1) protection of safety of study subjects; (2) a greater understanding of the overall safety profile of 
the study drugs; (3) recognition of dose-related study drug toxicity; (4) appropriate modification of study 
protocols; (5) improvements in study design or procedures; and (6) adherence to worldwide regulatory 
requirements. 
 
The collection of non-serious AE information should begin at initiation of study drugs. AEs may be either 
spontaneously reported or elicited during questioning and examination of a participant. All identified AEs 
must be recorded in the participant’s medical notes immediately and entered on the AE page of the eCRF 
within 1 week of the study visit at which they were reported. If known, the diagnosis of the underlying illness 
or disorder should be recorded, rather than its individual signs or symptoms. 
 
Participants experiencing AEs that cause interruption or discontinuation of study drugs, or those experiencing 
AEs that are present at the end of their participation in the study should receive follow-up as appropriate. If 
possible, report the outcome of any AE that caused permanent discontinuation or that was present at the 
end of the study particularly if the AE was considered by the investigator to be certainly, probably, or possibly 
related to the study drugs. 
 
Non-serious AEs should be followed to resolution or stabilisation at or until the end of the study, and 
reported as SAEs should they become serious. 
 
 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 29 of 99 
11.2 Serious Adverse Event (SAE) 
 
The definition of a SAE is any untoward medical occurrence that at any dose:  
 
results in death, 
 
is life-threatening, 
(Note: the term “life-threatening” in the definition of “serious” refers to an event/reaction in 
which the participant was at risk of death at the time of event/reaction; it does not refer to an 
event/reaction which hypothetically might have caused death if it were more severe) 
 
requires in-patient hospitalisation (≥ 24 hours) or prolongation of existing hospitalisation, 
 
results in persistent or significant disability/incapacity,  
 
is a congenital anomaly/birth defect 
or 
 
is a medically important event or reaction 
 
Medical and scientific judgment should be exercised in deciding whether other situations should be 
considered serious e.g. important medical events that may not be immediately life-threatening or result in 
death or hospitalisation but may jeopardise the participant or may require intervention to prevent one of the 
outcomes listed in the definition above.  Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsion that does not result in 
hospitalisation, or development of drug dependency or drug abuse. 
 
Where SAEs are related to the drug, they may be referred to as Serious Adverse Drug Reactions. 
 
11.2.1 Reporting Serious Adverse Events 
 
SAEs should be collected following the participant’s written consent to participate in the study. All serious 
adverse events (SAEs) must be reported within 24 working hours after the SAE occurs or from the time when 
the study investigator first becomes aware of the SAE whether or not there is a suspected causal relationship 
to the study drug.  
 
SAEs must be reported to the Kirby Institute by telephone, email or fax. The appropriate Serious Event form 
should be used.  The Project team in conjunction with the Medical Officer will review all SAEs for completion 
and accuracy. Immediate reports should be followed promptly by detailed, written follow-up reports when all 
information is not included in the initial report. The immediate and follow up reports should identify 
participants by unique code numbers assigned to study participants rather than personal identification.  Such 
reports must be supported by copies of de-identified relevant laboratory and diagnostic tests and further 
information as it becomes available. Copies of all x-rays and other imaging related to the event must be sent 
to the Sponsor, as well as all discharge summaries should the participant have been hospitalised. For deaths, 
the Principal Investigator will supply the sponsor and the IRB/IEC with any additional requested information 
(e.g. death certificate, autopsy reports and medical reports). 
 
Line listings of SAEs occurring during the study will be distributed to all sites by the Kirby Institute on a 
quarterly basis. Study treatment group will not be provided.  
 
The investigator must also comply with all applicable ethical and regulatory requirement/s relating to the 
reporting of serious adverse events.  
 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 30 of 99 
Any serious adverse event that is ongoing at the post-study follow-up visit must be followed until resolution 
or until the event stabilises (for those events that will not resolve). 
 
11.3 Suspected Unexpected Serious Adverse Reaction (SUSAR)  
 
A SUSAR is a serious adverse event which is both suspected as being related to the drug (i.e. has a reasonable 
suspected causal relationship and is unexpected) and where the nature and severity is not consistent with 
known information (e.g. the Investigator’s Brochure for an unapproved investigational product or Product 
Information for an approved product) about the drug in question.   
11.3.1 Reporting of SUSARs 
 
The Project Team in collaboration with the Medical Officer will review and identify all serious events which fit 
the criteria of a SUSAR and require expedited reporting to relevant parties. The event will be designated as 
unexpected if it is not reported in the Investigator Brochure or Product Information or if the event is of 
greater frequency, specificity or severity. 
 
The Sponsor must expedite the reporting of all suspected unexpected and certainly, probably, possibly, or of 
undetermined relationship to the study drug to all concerned investigators/institutions, IRB/IEC/s, and 
regulatory authorities within 7 days if it is life-threatening or fatal or within 15 days if not. Reports must 
comply with the applicable regulatory requirements and ICH Guideline for Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting. 
 
Researchers must inform the IRB/IEC and regulatory authorities of all serious or unexpected AEs that occur 
during the study which may affect the conduct of the study or the safety of the participants and/or their 
willingness to continue participation in the study.  
11.4 Serious Non-AIDS events (SNAEs) and AIDS events 
 
SNAEs are defined as fatal and non-fatal diagnoses in the following categories (see Appendix 4 for details): 
  Acute myocardial infarction 
 Coronary artery disease requiring drug treatment  
 Stroke  
 Coronary revascularisation 
 Congestive heart failure 
 Deep vein thrombosis 
 Peripheral arterial disease 
 Pulmonary embolism 
 End stage renal disease 
 Decompensated liver disease 
 Non-AIDS defining malignancy (except non-invasive basal cell carcinoma or squamous cell carcinoma) 
 Diabetes mellitus 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 31 of 99 
 AIDS events (CDC Category C 1993 Definition – see Appendix 3):  
o Candidiasis of bronchi, trachea, or lungs 
o Candidiasis, oesophageal 
o Cervical cancer, invasive 
o Coccidioidomycosis, disseminated or extrapulmonary 
o Cryptococcosis, extrapulmonary 
o Cryptosporidiosis, chronic intestinal (> 1 month’s duration) 
o CMV disease (other than liver, spleen, or nodes) 
o CMV retinitis (with loss of vision) 
o Encephalopathy, HIV-related (including AIDS Dementia Complex) 
o Herpes simplex, chronic ulcers (> 1 month’s duration); or bronchitis, pneumonitis, or 
esophagitis 
o Histoplasmosis, disseminated or extrapulmonary 
o Isosporiasis, chronic intestinal (> 1 month’s duration) 
o Kaposi’s sarcoma (mucocutaneous or visceral) 
o Lymphoma , Burkitt’s (or equivalent term) 
o Lymphoma, primary, of brain 
o Mycobacterium avium complex or M. kansasii, disseminated or extrapulmonary 
o M. tuberculosis, any site (pulmonary or extrapulmonary) 
o Mycobacterium, other species or unidentified species, disseminated or extrapulmonary 
o Pneumocystis carinii (jiroveci) pneumonia 
o Pneumonia, recurrent bacterial (2 documented episodes within 1 year of each other 
following randomisation) 
o Progressive multifocal leukoencephalopathy 
o Salmonella septicaemia, recurrent (2 documented episodes within 1 year of each other 
following randomisation) 
o Toxoplasmosis of brain 
o Wasting syndrome due to HIV 
o Aspergillosis, invasive 
o Bartonellosis 
o Chagas disease (American trypanosomiasis) of the CNS 
o Herpes zoster, multi-dermatomal (≥10 lesions in a non-contiguous site) 
o Leishmaniasis, visceral (kala-azar) 
o Lymphoma, Hodgkin’s 
o Lymphoma, non-Hodgkin's, all cell types 
o Microsporidiosis (> 1 month’s duration) 
o Nocardiosis 
o Penicillium marneffii, disseminated 
o Pneumocystis carinii (jiroveci), extrapulmonary 
o Rhodococcus equi disease 
 
11.4.1 Reporting of SNAEs and AIDS defining illnesses 
 
All SNAEs and AIDS defining illnesses must be reported to the Kirby Institute as per SAE reporting outlined in 
section 11.2.1. Details of how to report these will be outlined in the MOOP. 
 
 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 32 of 99 
11.5 Reporting of pregnancy  
 
There are no clinical studies in the use of vorapaxar in pregnant women. Studies in rats and rabbits showed 
no embryo/foetal toxicities, malformations or maternal toxicities when exposed to high doses of vorapaxar 
during gestation.  
 
As there is a paucity of data on voraxapar in pregnancy, sexually active women of childbearing potential must 
use an effective method of birth control during the course of the study, in a manner such that risk of 
pregnancy is minimised. Women will undergo a urine dipstick or serum pregnancy test at each visit (except 
week 1) and if found to be pregnant during follow-up should be managed in keeping with prevailing national 
or international guidelines. At a minimum, women must immediately cease study medication. 
 
All pregnancies on study are subject to expedited reporting and therefore the serious event form will need to 
be completed and submitted to The Kirby Institute within 24 hours (one working day) of becoming aware of 
the pregnancy. In addition, it is requested that information from any pregnancy on study be recorded on the 
appropriate page of the eCRF.  It is the responsibility of investigators or their designees to report any 
pregnancy in a subject/patient (spontaneously reported to them) which occurs during the study (from 
screening until the week 18 visit). All subjects/participants who become pregnant must be followed to the 
completion/termination of the pregnancy. If the pregnancy continues to term, the outcome (health of infant) 
must also be reported to The Kirby Institute. 
 
It is requested that information from any pregnancy on study be recorded on the appropriate page of the 
electronic CRF. Anonymised data from these forms will then be transmitted by the Kirby Institute to the 
Antiretroviral Pregnancy Register, an international register making a systematic attempt to collect data on 
pregnancy, ART and outcomes. Submission of data to the registry is encouraged, but not mandated by the 
study and a participant may choose not to have their data submitted. The scientific conduct and analysis of 
the Registry are overseen by an Advisory Committee consisting of members from the Centers for Disease 
Control and Prevention (CDC), Food and Drug Administration (FDA), the National Institutes of Health (NIH) as 
well as the private sector (http://www.apregistry.com/). 
 
11.6 Definition and reporting of an overdose 
In previous studies, vorapaxar has been given in single doses up to 120mg and daily doses of 5mg for up to 4 
weeks without identification of a specific risk or dose related adverse events. However, for the purposes of 
this study, an overdose of vorapaxar is defined as 3 doses (7.5mg) or more within 24 hours.  Any overdose, 
whether or not associated with an adverse reaction, must be reported within 24 hours on the paper SAE form 
to the Kirby Institute and the participant monitored closely for signs and symptoms of adverse reactions and 
appropriate clinical care given 
There is no known treatment to reverse the antiplatelet effect of vorapaxar. Dialysis or platelet infusion is not 
expected to be beneficial if bleeding occurs after an overdose. Monkey data suggest that platelet 
transfusions of sufficient quantity (a full pheresis pack or two) have the potential to transiently (a few hours) 
reverse the antiplatelet activity of vorapaxar. There is no standard test available to assess the risk of bleeding 
in case of an overdose. 
 
11.7 Unblinding 
 
The necessity to unblind the participant’s randomisation prior to reporting Serious Events will be considered 
on a case-by-case basis by the Medical Officer, site Principal Investigator and the expertise of members of the 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 33 of 99 
Protocol Steering Committee. Where unblinding is authorised by the Project Leader, it will be undertaken by 
a statistician.  If the Project Leader does not authorise unblinding, the Serious Event reporting form should 
indicate that the study is blinded and that the participant may be on placebo or vorapaxar. 
 
In case of emergency, the Principal Investigator should contact the Kirby Institute to request unblinding 
where it is essential to know what treatment the participant is on to decide on the medical interventions 
required.  Access to the code break procedures must be available on a 24-hour basis. 
 
At the conclusion of the study, after the clinical database is locked, treatment allocation information will be 
given to participating centres.  
 
12.0 Packaging, labelling, storage and accountability of clinical trial supplies 
 
12.1 Drug packaging, labelling and distribution  
 
Study drug will be sent to nominated pharmacies at study sites in accordance with the random allocation, 
following receipt of orders from recognised study staff. A designated person at the pharmacy must receive 
investigational drug supplies. The designated person must check that the supplies are in good condition and 
are complete as per the shipping records. Investigational drugs must be stored in a secure location with 
limited access and according to the drug requirements and local regulations. 
 
Further detailed information on the packaging, labelling and distribution of the study drug will be outlined in 
the MOOP and dealt with in detail during the site initiation process. Distribution and receipt of the study 
drugs will be at no cost to study sites.  
 
12.2 Handling and dispensing of study drugs 
 
Study drugs must only be dispensed according to the protocol and MOOP. It is the responsibility of the 
Investigator to ensure that study drug is only dispensed to study participants and only dispensed by suitably 
trained, authorised personnel according to local regulations at recognised hospital and clinic pharmacies.  
 
Study drugs should only be dispensed on receipt of a prescription written by the Principal Investigator or 
designee at the site. This prescription must contain the unique participant identification number. 
The participant must be instructed to take the study drug tablets whole and to store all medication safely out 
of sight and reach of children.  
 
Once the participant has been randomised, a one month blinded supply of vorapaxar or placebo will be 
dispensed to the participant from clinical supplies stored at the study site.  At each subsequent visit, 
participants will be required to return empty, partially used and unused study drug containers that will be 
retained at the site for later destruction at the approval of the Sponsor. Records must be kept of unreturned 
study drug and/or containers. No drugs will be returned to the Sponsor. 
 
At each dispensing, participants should be counselled on adherence issues. All participants should be 
counselled regularly on the need for maintaining strict adherence with the allocated study regimens. The 
objective should be 100% adherence at all times during follow-up. The site Principal Investigator is 
responsible for assessing adherence with all aspects of the study including use of study drugs and attendance 
at protocol-mandated clinical visits and assessments. 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 34 of 99 
The Investigator must be satisfied that the participant has returned or accounted for all unused study drug 
before additional medication is dispensed. If the number of encapsulated tablets recorded as used is 
substantially different from the number prescribed, the participant must be counselled on how study drugs 
should be taken. If such deviations persist, the Investigator may consider discontinuing the regimen for non-
adherence. If this occurs, the participant must remain in follow-up and undergo the protocol-specified 
assessments and evaluations. 
 
12.3 Study drug accountability records at investigational site(s) 
 
It is the responsibility of the Principal Investigator to ensure that a current record of study drug disposition is 
maintained at each study site where they are inventoried and disposed. Records and/or logs must comply 
with applicable regulations and guidelines, and should include: 
 
Amount received from the sponsor and placed in storage area (temperature logs to be kept to 
document appropriate storage conditions) 
 
Label ID number or batch number 
 
Amount dispensed to and returned by each participant, including unique participant identifiers 
 
Non-study disposition (e.g. lost, wasted, broken) 
 
Amount destroyed at study site (with Sponsor authorisation), as applicable.  
 
Dates and initials of person responsible for each investigational product inventory entry/movement 
The Kirby Institute will provide forms to facilitate inventory control. Please refer to the MOOP for further 
details. 
 
12.4 Destruction of study drug 
 
Study drugs will not be returned to the Kirby Institute for destruction. Instead, it will be destroyed at site 
after reconciliation has been conducted by the study monitor. For further details of destruction of study 
medications, please refer to the MOOP.  
 
12.5 Post study drug supply 
 
The Sponsor will not provide vorapaxar to study participants beyond the duration of the study.  
 
13.0 Biological samples 
13.1 Blood collection 
It is important that the handling of blood samples is undertaken according to local guidelines and regulations 
for handling infectious substances.  The blood tubes required to be used for each test should be as per local 
laboratory guidelines.  Storage samples will be collected for d-dimer, IL-6 and Hs-CRP analysis at a central 
laboratory as well as other exploratory analyses.  This includes plasma, serum and PBMC. The blood tubes 
required for storage samples will be outlined in the MOOP. These samples will be processed locally and then 
shipped to central laboratories for storage and analysis.  
Any unused plasma, serum or PBMC samples (unused back up samples or if exploratory analyses are not 
conducted due to failure to reach the primary endpoint) will be kept for possible future HIV related research. 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 35 of 99 
Ethics approval would need to be granted for any future HIV research on these samples prior to these 
samples being released.  
 
The following details can be found in the laboratory MOOP:  
 
Types and quantities of specimens  
 
Collection schedule  
 
Methods for processing laboratory samples prior to analysis 
 
Shipping and storage 
Only the laboratory supplies as described in the clinical trial agreement with sites are to be provided by the 
Sponsor. It is strongly recommended that the blood is collected on the date of the actual study visit. 
However, if this cannot occur for some particular reason, a blood sample taken within 2-3 days of the actual 
visit date is acceptable. However, all blood samples for eligibility purposes must be taken at the screening 
visit.  
 
13.2 Labelling of blood collection tubes 
 
Blood collection tubes should be labelled accurately and legibly as outlined in the MOOP.  The Sponsor can 
provide the site with specimen labels if needed.  These labels are only to be used on the blood tubes to be 
sent to the local laboratory, not to be placed on the aliquot tubes for frozen storage. Aliquot tubes for 
storage must only be labelled with the participant’s identification number.   
 
 
13.3 Transportation of samples  
 
It is important that during the transportation of blood samples precaution is taken according to local 
guidelines and regulations for handling infectious substances. 
Sites will be required to set up the procedures for transporting the blood tubes to the local laboratory.  It is 
important that the samples arrive at the laboratory within 3 hours of blood collection (this time frame is 
determined by need to process the plasma sample for d-dimer within 4 hours of collection).   
It is the responsibility of the Principal Investigator at each site to ensure that all site staff handling, packaging, 
and/or shipping biological samples understand and comply with International Air Transport Association 
(IATA) regulations relating to the handling and shipping of hazardous goods and/or diagnostic specimens. 
Methods for packaging and shipping biological samples are detailed in the laboratory MOOP. 
 
13.4 Storage of samples 
Plasma, serum and PBMC samples will be collected and processed at the local laboratory.  The samples will 
be stored in the interim at local laboratories and then sent for central storage at St Vincent’s Centre for 
Applied Medical Research laboratory (AMR) in Sydney at regular intervals throughout the study. Transport to 
AMR in Sydney will be organised by The Kirby Institute.  The cost of processing and storage of bloods will be 
provided to the sites as per the clinical trial agreement.  For more detailed information on the types of tubes 
and processing requirements please refer to the Manual of Operations. 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 36 of 99 
13.5 Processing of samples 
All blood samples for routine clinical care and safety monitoring will be analysed at the local laboratory. 
Analysis of d-dimer, IL-6 and Hs-CRP will be performed centrally at LEIDOS Biomedical Research Inc. in the 
USA on frozen plasma samples from each participant. 
It is important that the handling of blood samples is undertaken according to local guidelines and regulations 
for handling infectious substances.  The investigator may be contacted should the technical condition of the 
sample, absence of information or inconsistencies on the request form be such that the samples cannot be 
processed.  Demographic errors (i.e. incomplete or inconsistent participant information) will be called 
through to the site and a faxed confirmation of correct information requested.  Where such errors are noted 
after a report has been sent to the site, then a second corrected report will be reissued by the local 
laboratory. 
 
13.6 Reporting of results 
The blood results from routine clinical care and safety monitoring will be reported to the site as per local 
standard procedure.  It is important that once these results are received they are entered into the eCRF and a 
hardcopy of the results are kept in the medical notes.  If results are received electronically, the electronic 
format is adequate for source data verification.  
 
13.7 Plasma d-dimer determination 
Plasma d-dimer will be measured at the local laboratory for assessment of eligibility.   Plasma samples at 
weeks 0, 1, 4, 8, 12 and 18 will be stored and sent to a central laboratory (LEIDOS Biomedical Research Inc. in 
the USA) for central assessment of d-dimer, IL-6 and Hs-CRP at the end of the study.  These central results 
will be used for the analysis of the study. Results cannot be provided in real time to individual patients. 
Results will be provided at completion of the project. 
 
14.0  Data collection, source documents and record retention 
14.1 Records and reports 
 
The Principal Investigator or designee is responsible for  preparing and maintaining adequate and accurate 
case histories designed to record all observations and other data pertinent to the investigation on each 
individual treated with the investigational product. Data reported on the CRF that are derived from source 
documents must be consistent with the source documents or the discrepancies must be explained. 
14.2 Source documents  
 
Source documents include all recordings of observations or notations of clinical activities and all reports and 
records necessary for the evaluation and reconstruction of the study.  Source documents include, but are not 
limited to, participant medical records, laboratory reports, ECG tracings, X-rays, radiologist reports, biopsy 
reports, ultrasound photographs, participant progress notes, pharmacy records and any other similar reports 
or records of procedures performed in accordance with the protocol. It is not acceptable for the CRF to be 
the only record of the participant’s study participation and progress as these must also be recorded in the 
participant medical record.  This is to ensure that anyone accessing the participant’s medical record has 
adequate knowledge of their participation in a clinical study. 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 37 of 99 
Any document that acts as a source document (the point of the initial recording of a piece of data) should be 
signed and dated by the person recording or reviewing the data for issues of medical significance (for 
example the review of laboratory reports).  Persons signing the source documents must be listed, on the 
appropriate study documentation (site delegation log), as a site staff member. 
 
14.3 Submission of data 
 
Data will be collected for this study using an Electronic Data Capture system using a web-enabled password 
protected platform. Following each participant visit the designated site staff will complete the visit specific 
eCRF. The Principal Investigator is responsible for ensuring the data collected are complete, accurate and 
recorded in a timely manner.  The confidentiality of records that could identify participants must be 
protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory 
requirement(s). 
 
Once all of the information is received the eCRF will be completed.  Sponsor staff will then monitor the data 
for completeness and accuracy.  Any discrepancies either manual or automatic will be notified to the site 
staff for clarification. Corrections to eCRFs will only be possible by study personnel with sufficient 
authorisation to make changes. All changes will record time, date, computer ID and the name of the 
authorised person’s access code. 
 
14.4 Records retention and archiving  
 
The Investigator must retain investigational product disposition records, copies of CRFs (or electronic files) 
and source documents for the maximum period required by applicable regulations and guidelines, or 
Institution procedures, or for 15 years, whichever is longer. The Investigator must contact the Sponsor prior 
to destroying any records associated with the study. 
 
If a Principal Investigator withdraws from the study (e.g. relocation, retirement), the records will be 
transferred to a mutually agreed-upon designee or site (i.e. another Investigator or IRB). Notice of such 
transfer will be given in writing to the Sponsor. 
 
14.5 Study monitoring  
 
Representatives of the Kirby Institute or NIAID must be allowed to visit all study site locations periodically to 
assess the data, quality and study integrity. On site, Kirby Institute or NIAID representatives will review study 
records to directly compare them with source documents, discuss the conduct of the study with the Principal 
Investigator or their designee and verify that the facilities remain acceptable.  
 
Monitoring visits will be scheduled in advance and with sufficient warning to allow arrangements of diaries 
and personnel as appropriate.  The number of visits shall depend upon recruitment rate; however, the 
monitor shall conduct a minimum of two source data verification visits at each site during the study.  These 
shall occur shortly after the study entry of the first participant(s) and at the end of the study once all study 
visits have been completed. 
 
The Principal Investigator is responsible for retaining all essential documents listed in ICH Good Clinical 
Practice (GCP) guidelines.  These must be organised in a comprehensive filing system that is accessible to 
study monitors and other relevant personnel. 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 38 of 99 
14.6 Auditing 
 
The study may be subject to audit by the Kirby Institute, NIAID, Merck, the ethics committee, relevant 
regulatory agencies or the relevant government authorities. Under such circumstances, the investigator must 
agree to allow access to study documents and relevant hospital/clinic records. Audit reports will be kept 
confidential between the site and the Sponsor. 
 
The Principal Investigator must notify the Sponsor promptly of any inspections scheduled by regulatory 
authorities and forward copies of inspection reports to the Sponsor. 
 
15.0  Ethics committee/regulatory approval and informed consent 
15.1 Ethical conduct of the study  
 
This study shall be conducted in accordance with the ethical principles laid out in the National Statement on 
Ethical Conduct in Research Involving Humans, the Declaration of Helsinki (most current version issued, 
available at www.wma.net) and will be consistent with GCP, and applicable regulatory requirements. 
 
The rights, safety and wellbeing of the study participants are the most important considerations and should 
prevail over interests of science and society. All personnel involved in conducting this study will be qualified 
by education, training, and experience to perform their respective task(s). 
The Sponsor is responsible for obtaining regulatory approval for the study. Before study initiation, the 
Investigator must have written and dated approval/favourable opinion from the IRB/IEC and local regulatory 
authorities for the protocol, consent form, participant recruitment materials/process (e.g. advertisements) 
and any other written information to be provided to participants. The approval must clearly identify all 
documents approved by the IRB/EC and regulatory authorities including version number and dates of the 
protocol and participant information/informed consent form. A copy of the approval must be sent to the 
study Sponsor. 
 
The Principal Investigator must comply with all IRB/EC, and where relevant regulatory authorities, reporting 
requirements for all serious or unexpected AEs, annual updates and end of study reports and must agree to 
abide by any IRB/EC conditions of approval. Researchers must inform the IRB/IEC, and where relevant 
regulatory authorities, as soon as possible of any new information from other published or unpublished 
studies which may have an impact on the continued ethical acceptability of the study or which may indicate 
the need for amendments to the study protocol. In addition, the Principal Investigator should provide any 
updates or other information required by relevant parties in accordance with any local regulatory 
requirements or institution procedures. 
 
This study will not use the services of study personnel where sanctions have been invoked or where there has 
been scientific misconduct or fraud (e.g. loss of medical licensure, debarment). 
Monitoring systems with procedures to maximise the quality of every aspect of the study will be 
implemented. 
 
15.2 Compliance with the protocol and protocol revisions 
 
The study shall be conducted as described in this approved protocol. The protocol and any amendments and 
the participant information and consent will receive IRB/IEC approval prior to initiation of the study. This 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 39 of 99 
study will be reviewed by the relevant local ethics committees and regulatory authorities, in accordance with 
current local guidelines. The Sponsor will assist in the process of approval as required by each individual site. 
 
The Principal Investigator should not implement any deviation or change to the protocol without prior review 
and documented approval/favourable opinion from the IRB/IEC of an Amendment, except where necessary 
to eliminate an immediate hazard(s) to study participants. Any significant deviation must be documented and 
notified to the Sponsor. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to obtaining 
IRB/IEC approval/favourable opinion, as soon as possible the deviation or change will be submitted to: 
 
IRB/IEC for review and approval/favourable opinion; 
 
The Sponsor; 
 
Regulatory Authority(ies), if required by local regulations. 
 
Documentation of approval signed by the chairperson or designee of the IRB/IEC must be sent to the Sponsor 
along with other required documentation. 
 
If the revision is an Administrative Letter, the Principal Investigator must inform their IRB/IEC. 
If an Amendment substantially alters the study design or increases the potential risk to the participant: (1) 
the consent form must be revised and submitted to the IRB/IEC for review and approval/favourable opinion; 
(2) the revised approved form must be used to obtain consent from participants currently enrolled in the 
study if they are affected by the Amendment; and (3) the new approved form must be used to obtain 
consent from new participants prior to enrolment. 
 
Preparation of the consent form is the responsibility of the Principal Investigator and must include all 
elements required by ICH-GCP and applicable regulatory requirements, and must adhere to GCP and to the 
ethical principles that have their origin in the Declaration of Helsinki.  The consent form must also include a 
statement that the sponsor, Merck, the ethics committee, and regulatory authorities will have direct access 
to participant study records (See Appendix 5 for participant information and consent form template).  
 
Prior to beginning the study, the Principal Investigator must have the IRB/IEC’s written approval/favourable 
opinion of the written informed consent form and any other information to be provided to the participants. 
 
The Principal Investigator should endeavour to provide the participant or legally authorised representative 
with a copy of the consent form and written information about the study in the language in which the 
participant is most proficient.  The language must be non-technical and easily understood.  The Principal 
Investigator should allow time necessary for participant or participant's legally authorised representative to 
inquire about the details of the study.  The Principal Investigator must ensure that participants or their legally 
authorised representative are clearly and fully informed about the purpose, potential risks and other critical 
issues regarding clinical trials in which they volunteer to participate.  
 
Freely given written informed consent must be obtained from every participant or his or her legally 
authorised representative prior to any protocol-specific procedures being conducted on that participant.  
Consent must be documented by the participant’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.  
 
If the participant is illiterate, an impartial witness should be present during the entire consent discussion. 
Once the discussion is complete, the participant must sign and date the informed consent form, if capable.  


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 40 of 99 
The impartial witness must also sign and date the informed consent form along with the person who 
conducted the consent discussion. 
 
Should an ethics committee-approved informed consent form not be available in a participant’s most 
proficient language, then a translator should be sought. This translator should act as a witness to the 
informed consent process and be asked to sign the informed consent form accordingly. 
If the participant is legally incompetent (i.e. mentally incapacitated) the written consent of a parent, guardian 
or legally authorised representative must be obtained. 
Imprisonment or the compulsory detention for treatment of either a psychiatric or physical (e.g. infectious 
disease) illness precludes enrolment in clinical trials. 
When a participant may be in a dependent relationship with the investigator, a well-informed physician who 
is not engaged in the study and is completely independent of the relationship between the participant and 
investigator should obtain the participant’s informed consent. This issue will be addressed within the site 
training process. 
 
The participant or legally authorised representative should receive a copy of the signed and dated informed 
consent and any other written information provided prior to the participant's participation in the study.  
 
15.4 Updates to the consent form 
 
The informed consent and any other information provided to participants or the participant's legally 
authorised representative, should be revised whenever important new information becomes available that is 
relevant to the participant's consent.  This information should receive IRB/IEC approval/favourable opinion 
prior to use, except if the safety of the participant is compromised.  The Principal Investigator, or a person 
designated by the Principal Investigator, should fully inform the participant or the participant's legally 
authorised representative of all pertinent aspects of the study and of any new information relevant to the 
participant's willingness to continue participation in the study. This communication should be documented.  
During participation in the study, any updates to the consent form and/or the written information will be 
provided to the participant. 
 
16.0  Confidentiality of data 
16.1 Confidentiality of participant records 
 
By signing the Clinical Trial Agreement, the site Principal Investigator agrees that the sponsor, IRB/EC or 
regulatory authorities may consult and/or copy study documents to verify information in the case report 
form. By signing the consent form the participant agrees to these processes.   
 
Participant confidentiality will be maintained at all times and no documents containing the participant’s 
name or other identifying information will be collected by the sponsor.  It may be necessary for the sponsor’s 
representatives, the IRB/EC and regulatory authority representatives to have direct access to the 
participant’s medical records. If study documents need to be photocopied during the process of verifying 
case report form data, the participant will be identified by a unique code only; full names and other 
identifying information will be masked.  
 
 
 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 41 of 99 
16.2 Confidentiality of study data 
 
By signing the Clinical Trial Agreement, the site Principal Investigator affirms to the sponsor that information 
provided to them by the sponsor will be maintained in confidence and divulged only as necessary to the 
ethics committee and institution employees directly involved in the study.  Both ethics committee members 
and employees must also understand the confidentiality requirements for any information divulged to them.  
The data generated by this study will be considered confidential, except where it is included in a publication 
as agreed in the publication policy of this protocol. 
 
17.0  Governance 
 
This international research protocol is funded by The National Health Medical & Research Council, Australia. 
The study intervention/clinical trial supplies will be provided by Merck.  The study is sponsored by the 
University of New South Wales (UNSW) and coordinated through the Kirby Institute for infection and 
immunity in society.  The Kirby Institute has established governance and implementation structures which use 
resources efficiently to deliver program objectives on schedule. 
 
17.1 Protocol Steering Committee (PSC) 
 
There will be a single PSC chaired by Professor Sean Emery. This group will comprise a representative from 
each participating site, representatives from UNSW and NIAID project teams and the project biostatistician.  
A representative from Merck will also be invited to join the PSC. The PSC will seek the expertise of other key 
opinion leaders as necessary. The PSC will be the primary management entity for the collaborative study 
group. This group will meet by teleconference, arranged as required and at least twice per year during the 
study follow up period. Decisions in this group will be reached by consensus among the designated 
membership. Routinely the views of other stakeholders will be sought at meetings of the PSC and this will 
allow others to attend meetings. The PSC, comprised of members from a range of internal and external 
stakeholders will guide the design, implementation and conduct of the study.  
 
17.2 Project Team 
 
Day-to-day management of the protocol will be undertaken by a dedicated project team based at The Kirby 
Institute at UNSW and NIAID and supported as required by contract service organisations. The Project Team 
is accountable to the PSC. 
 
For contact details on the clinical trial sites, laboratories and pharmacies please refer to the MOOP. 
 
18.0  Data Safety and Monitoring Board (DSMB) 
 
The DSMB will be accountable to the PSC and will undertake independent review of protocol-specified and ad 
hoc interim analyses if required. The DSMB will be composed of individuals neither directly associated with 
the study nor employees of any of the organisations responsible for the conduct of the research. The study 
biostatistician will be an ex officio member of the DSMB. The primary focus of the reviews undertaken by the 
DSMB will be safety. The first scheduled review will take place after 20 patients have completed 6 weeks of 
treatment with further reviews scheduled every 8 weeks thereafter. For ad hoc reviews an interim analysis 
would be prompted when four (4) BARC type 2 events or one (1) BARC type 3 event are reported. During the 
ad hoc review and until the PSC has received and acted upon a DSMB recommendation, patient recruitment 
will be paused but randomised patients will continue study treatment. The terms of reference and operating 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 42 of 99 
guidelines of the DSMB will be drafted by the study biostatistician (as documents separate to the Protocol) 
and finalised in collaboration with the DSMB prior to the commencement of the study. 
 
19.0  Financing and insurance 
 
The Principal Investigator should provide details of the study budget to the IRB/IEC, as required by the 
individual committee. In addition, any participant payments or reimbursement of expenses for participation 
in the study must be clearly stated in the participant information and consent form and must be approved by 
the IRB/IEC.  
 
19.1 Indemnity and compensation 
 
Indemnification for site personnel, investigators and institutions will be provided as required in keeping with 
the provisions as determined by the Medicines Australia guidelines through the UNSW for Australian sites. 
Details of this provision will be documented in separate agreements. 
 
No-fault-compensation is available to study participants who experience injury as a result of their 
participation in this study. Details of the method of compensation will be provided in separate agreements 
between institutions. 
 
20.0  Quality Control (QC) and Quality Assurance (QA) 
 
By signing this protocol (Appendix 6), the sponsor agrees to be responsible for implementing and maintaining 
quality control and quality assurance systems with written standard operating procedures to ensure the 
study is conducted and data are generated, documented and reported in compliance with the protocol, Good 
Clinical Practice standards and all applicable local laws and regulations relating to the conduct of a clinical 
study.  
 
21.0  Publication Policy 
 
There will be one final written manuscript arising from the ADVICE protocol to describe the primary results as 
defined in the protocol. In the interests of collegiality and recognising that completion of this study will have 
resulted from the contribution of many people around the world the masthead authorship for this 
manuscript will be “The ADVICE Study Group”. The PSC will compose a writing committee for this primary 
manuscript who will be identified as such in an appendix. In addition, one person from each investigational 
site will be listed in a separate appendix as being part of the ADVICE Study Group. The PSC will determine if 
there is a need for additional appendices in which to identify others who have contributed in a significant 
way to the design AND conduct AND reporting of resultant study data. If the journal will not accept group 
authorship the writing committee will be listed as authors and be completed with the phrase ‘on behalf of 
the ADVICE Study Group’. 
 
Additional manuscripts that are expected to report on the findings of any subsequent substudies should have 
named investigators and be completed with the phrase ‘on behalf of the ADVICE Study Group’. In these 
circumstances an appendix should contain the names of the PSC. 
 
All proposed manuscripts should be submitted to the PSC 45 days before they are to be submitted to a 
journal for peer review. 
 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 43 of 99 
Conference presentations should identify an authorship group consistent with those who have contributed to 
the data to be reported. All proposed conference presentations should be submitted to the PSC at least 20 
days before submission of an abstract. 
 
 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 44 of 99 
22.0 List of References 
 
1. 
Kuller LH, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV-infection. 
PLoS Med 2008; 5: e203. 
2. 
Duprez D, et al. Inflammation, coagulation and cardiovascular disease in HIV-infected patients. PLoS 
ONE 2012; 7: e44454. 
3. 
Borges ÁH, et al. Predicting risk of cancer during HIV infection: the role of inflammatory and 
coagulation biomarkers. AIDS 2013; 27: 1433-1441. 
4. 
Baker JV, et al. Changes in inflammatory and coagulation biomarkers: a randomised comparison of 
immediate versus deferred antiretroviral therapy in patients with HIV infection. J Acquir Immune Defic 
Syndr 2011; 56: 1509-17. 
5. 
Neuhaus J, et al. Markers of inflammation, coagulation and renal function are elevated in adults with 
HIV infection. J Infect Dis 2010; 201: 1788-1795. 
6. 
Hurley A, et al. Enhanced effector function of CD*+ T cells from healthy controls and HIV infected 
patients occurs through thrombin activation of protease-activated receptor-1. J Infec Dis 2013; 207: 
638-50. 
7. 
Arnaud E, et al. Protective effect of a thrombin receptor (protease-activated receptor-1) gene 
polymorphism toward venous thromboembolism. Arterioscler Thromb Vasc Biol 2000; 20: 585-92. 
8. 
Dupont A, et al. An intronic polymorphism in the PAR-1 gene is associated with platelet receptor 
density and response to SFLLRN. Blood 2003; 101: 1833-40. 
9. 
Funderberg NT, et al. Increased tissue factor expression on circulating monocytes in chronic HIV 
infection: relationship to in vivo coagulation and immune activation. Blood 2010; 115: 161-67. 
10. 
Baker JV, et al. HIV replication alters the composition of extrinsic pathway coagulation factors and 
increases thrombin generation. J Am Heart Assoc 2013; 2: e000264 
11. 
Tricoci P, et al. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med 
2012; 366: 20-33. 
12. 
Morrow DA, et al. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med 
2012; 366: 1404-13. 
13. 
Levey AS, Stevens LA, et al. A New Equation to Estimate Glomerular Filtration Rate. Ann Intern Med. 
2009; 150:604-612. 
14. 
Martin A, Bloch M, Amin J Baker D, Cooper DA, Emery S, and Carr A for the STEAL Study Group. 
Simplification of antiretroviral therapy with tenofovir-emtricitabine or abacavir-lamivudine: a 
randomised, 96-week trial. Clin Infect Dis 2009; 49: 1509-1601.  
15. 
Martin A, Amin J, Cooper DA, Carr A, Kelleher AD, Bloch M, Baker D, Woolley I, Emery S for the STEAL 
study group. Abacavir does not affect circulating levels of inflammatory or coagulopathic biomarkers in 
suppressed HIV: a randomised clinical trial. AIDS 2010; 24: 2657-63. 
16. 
Mehran R, et al. Standardized Bleeding Definitions for Cardiovascular Clinical Trials: A Consensus 
Report from the Bleeding Academic Research Consortium. J Am Heart Assoc 2011; 123:2736-2747. 
17. 
Wilson, D'Agostino, Levy et al. Prediction of Coronary Heart Disease using Risk Factor Categories. 
Circulation 1998.  
18. 
Cai TQ et al. Platelet transfusion reverses bleeding evoked by triple anti-platelet therapy including 
vorapaxar, a novel platelet thrombin receptor antagonist. Eur J Pharmacol 2015; July 5; 758:107-14. 
 
 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 45 of 99 
23.0 Abbreviations List 
 
ADVICE 
Attenuation of d-dimer using vorapaxar 
to target inflammatory and coagulation 
endpoints 
LFT 
Liver function test 
AE 
Adverse event 
MI 
Myocardial infarction 
AIDS 
Acquired immune deficiency syndrome 
MOOP 
Manual of operations 
ALP 
Alkaline phosphatase 
NIAID 
National Institute of Allergy and 
Infectious Diseases 
ALT 
Alanine amino transferase 
NHI 
National Institutes of Health 
ANC 
Absolute neutrophil count 
NNRTI 
Non-nucleoside reverse 
transcriptase inhibitor 
ART 
Antiretroviral therapy 
NRTI 
Nucleoside reverse transcriptase 
inhibitor 
AST 
Aspartate amino transferase 
NSAID 
Non-steroidal anti-inflammatory 
drug 
BARC 
Bleeding Academic Research Consortium 
PAR-1 
Protease Activated Receptor-1 
BID 
Twice daily 
PBMC 
Peripheral blood mononuclear cell 
CABG 
Coronary artery bypass graft 
PI 
Protease inhibitor 
CART 
Combined antiretroviral therapy 
PID 
Patient Identification 
CDC 
Centres for disease control 
QA 
Quality assurance 
CI 
Confidence interval 
QC 
Quality control 
CKD-EPI 
Chronic Kidney Disease Epidemiology 
Collaboration 
Qd 
Once daily 
CRF/eCRF 
Case report form/electronic case report 
form 
PI/r 
Ritonavir-boosted protease 
inhibitor 
CVD 
Cardiovascular disease 
PSC 
Protocol Steering Committee 
DAIDS 
Division of AIDS 
RNA 
Ribonucleic acid 
DNA 
Deoxyribonucleic acid 
SAE 
Serious adverse event 
DSMB 
Data safety monitoring board 
SD 
Standard deviation  
EACS 
European AIDS Clinical Society 
SNAE 
Serious non-AIDS defining event 
ECG 
Electrocardiograph 
STEAL 
Simplification of antiretroviral 
therapy with tenofovir-
emtricitabine or abacavir-
lamivudine 
FDA 
Food and Drug Administration 
SUSAR 
Suspected unexpected serious 
adverse reaction 
GCP 
Good Clinical Practice 
TIA 
Transient ischaemic attack 
GFR 
Glomerular Filtration Rate 
 
 
GUSTO 
Global utilization of streptokinase and 
tissue plasminogen activator for occluded 
arteries 
TRACER 
Thrombin receptor antagonist for 
clinical event reduction in acute 
coronary syndrome 
HIV 
Human Immunodeficiency Virus 
TRA 2°P 
TIMI 
Thrombin receptor antagonist in 
secondary prevention of 
atherothrombotic ischemic events 
study 
Hs-CRP 
High sensitivity c reative protein 
ULN 
Upper limit of normal 
IATA 
International Air Transport Association 
UNSW 
University of New South Wales  


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 46 of 99 
ICH 
International Conference on 
Harmonisation 
USA 
United States of America 
ID 
Identification 
 
 
IEC 
Institutional ethics committee 
 
 
IRB 
Institutional review board 
 
 
 
 
 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 47 of 99 
Appendix 1: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and 
Paediatric Adverse Events (Version 2.0, November 2014) 
 
General Instructions  
The DAIDS Table provides descriptive terminology which can be utilized for Adverse Event (AE) reporting. A 
grading (severity) scale is provided for each AE term. 
 
In the classification of AEs, the term “severe” is not the same as “serious”. Severity is an indication of the 
intensity of a specific event (as in mild, moderate, or severe chest pain). The term “serious” relates to a 
participant/event outcome or action criteria, usually associated with events that pose a threat to a 
participant’s life or functioning. 
 
Grade 5: 
For any AE where the outcome is death, the severity of the AE is classified as Grade 5. 
 
Estimating Severity Grade for Parameters Not Identified in the 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 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 48 of 99 
Determining Severity Grade for Parameters “Between Grades”: 
If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE could be 
either Grade 2 or Grade 3), select the higher of the two grades for the AE. If a laboratory value that is graded 
as a multiple of the ULN or LLN falls between two grades, select the higher of the two grades for the AE. For 
example, Grade 1 is 2.5 x ULN and Grade 2 is 2.6 x ULN for a parameter. If the lab value is 2.53 x ULN (which 
is between the two grades), the severity of this AE would be Grade 2, the higher of the two grades. 
 
Values Below Grade 1: 
Any laboratory value that is between either the LLN or ULN and Grade 1 should not be graded.  
 
Determining Severity Grade when Local Laboratory Normal Values Overlap with Grade 1 Ranges: 
In these situations, the severity grading is based on the ranges in the DAIDS AE Grading Table, even when 
there is a reference to the local lab LLN. 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. 
 
Definitions of terms used in the Table: 
 
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. 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 49 of 99 
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 
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 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 50 of 99 
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: 
 
Adults 
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 
 
 
 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 51 of 99 
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 
Abnormalities1 
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. 


 
 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 52 of 99 
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 
Interval2 
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 
 
 


 
 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 53 of 99 
Dermatologic 
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 
Pruritus3 
(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 
 


 
 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 54 of 99 
Endocrine and Metabolic 
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) 
Lipoatrophy4 
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 
Lipohypertrophy5 
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. 
 


 
 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 55 of 99 
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) 
< 1 year of age 
Liquid stools (more 
unformed than 
usual) but usual 
number of stools 
Liquid stools with 
increased number of 
stools OR Mild 
dehydration 
Liquid stools with 
moderate dehydration 
Life-threatening 
consequences (e.g., 
liquid stools resulting in 
severe dehydration, 
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) 3
For pruritus associated with injections or infusions, see the Site Reactions to Injections and 
Infusions section (page 23). 


 
 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 56 of 99 
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 
hospitalization 
indicated 
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) 


 
 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 57 of 99 
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 
Osteopenia6 
≥ 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. 


 
 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 58 of 99 
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 


 
 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 59 of 99 
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) 
< 18 years of age 
(includes new or pre- 
existing febrile 
seizures) 
Seizure lasting < 5 
minutes with < 24 
hours postictal state 
Seizure lasting 5 to < 
20 minutes with 
< 24 hours postictal 
state 
Seizure lasting ≥ 20 
minutes OR > 24 
hours postictal state 
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 


 
 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 60 of 99 
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 Delivery7 
(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 Miscarriage8 (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. 
 


 
 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 61 of 99 
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 


 
 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 62 of 99 
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) 


 
 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 63 of 99 
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) 
< 12 years of age 
(based on a 1, 2, 3, 4, 6 
and 8 kHz audiogram) 
> 20 dB hearing loss 
at  ≤ 4 kHz 
> 20 dB hearing loss 
at > 4 kHz 
> 20 dB hearing loss 
at  ≥ 3 kHz in one ear 
with additional speech 
language related 
services indicated 
(where available) OR 
Hearing loss 
sufficient to indicate 
therapeutic 
intervention, 
including hearing aids 
Audiologic indication for 
cochlear implant and 
additional speech- 
language related services 
indicated (where 
available) 
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) 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 64 of 99 
Systemic 
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 Sickness11 
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. 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 65 of 99 
Systemic 
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 
2 to 5 years of age 
NA 
WHO Weight-for- 
height z-score 
< -2 to ≤ -3 
WHO Weight-for- 
height z-score < -3 
WHO Weight-for-height 
z-score < -3 with life- 
threatening consequences 
< 2 years of age 
NA 
WHO Weight-for- 
length z-score 
< -2 to ≤ -3 
WHO Weight-for- 
length z-score < -3 
WHO Weight-for-length 
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. 
 


 
 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 66 of 99 
Urinary 
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 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 67 of 99 
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 Redness13 
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) 
≤ 15 years of age 
2.5 cm in diameter 
> 2.5 cm in diameter 
with < 50% surface 
area of the extremity 
segment involved 
(e.g., upper arm or 
thigh) 
50% surface area of 
the extremity segment 
involved (e.g., upper 
arm or thigh) OR 
Ulceration OR 
Secondary infection 
OR Phlebitis OR 
Sterile abscess OR 
Drainage 
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 
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. 


ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 68 of 99 
Laboratory Values 
Chemistries 
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 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 69 of 99 
Chemistries 
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 Clearance15 
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 15
Use the applicable formula (i.e., Cockroft-Gault in mL/min or Schwatrz in mL/min/1.73m2 ). 
 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 70 of 99 
Chemistries 
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. 
 


 
 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 71 of 99 
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 
0.600 x 109  to 
< 0.650 x 109 
500 to < 600 
0.500 x 109  to 
< 0.600 x 109 
350 to < 500 
0.350 x 109  to 
< 0.500 x 109 
< 350 
< 0.350 x 109 
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. 


 
 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 72 of 99 
Hematology 
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 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 73 of 99 
Urinalysis 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
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 
 
 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 74 of 99 
Total Bilirubin Table for Term and Preterm Neonates 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Total Bilirubin19, High 
(mg/dL; µmol/L)20 
Term Neonate21 
< 24 hours of age 
4 to < 7 
68.4 to < 119.7 
7 to < 10 
119.7 to < 171 
10 to < 17 
171 to < 290.7 
≥ 17 
≥ 290.7 
24 to < 48 hours of 
age 
5 to < 8 
85.5 to < 136.8 
8 to < 12 
136.8 to < 205.2 
12 to < 19 
205.2 to < 324.9 
≥ 19 
≥ 324.9 
48 to < 72 hours of 
age 
8.5 to < 13 
145.35 to < 222.3 
13 to < 15 
222.3 to < 256.5 
15 to < 22 
256.5 to < 376.2 
≥ 22 
≥ 376.2 
72 hours to < 7 days 
of age 
11 to < 16 
188.1 to < 273.6 
16 to < 18 
273.6 to < 307.8 
18 to < 24 
307.8 to < 410.4 
≥ 24 
≥ 410.4 
7 to 28 days of age 
(breast feeding) 
5 to < 10 
85.5 to < 171 
10 to < 20 
171 to < 342 
20 to < 25 
342 to < 427.5 
≥ 25 
≥ 427.5 
7 to 28 days of age 
(not breast feeding) 
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 
Preterm Neonate20 
35 to < 37 weeks 
gestational age 
Same as for Total 
Bilirubin, High, Term 
Neonate (based on 
days of age). 
Same as for Total 
Bilirubin, High, Term 
Neonate (based on 
days of age). 
Same as for Total 
Bilirubin, High, 
Term Neonate (based 
on days of age). 
Same as for Total 
Bilirubin, High, Term 
Neonate (based on 
days of age). 
32 to < 35 weeks 
gestational age and 
< 7 days of age 
NA 
NA 
10 to < 14 
171 to < 239.4 
≥ 14 
≥ 239.4 
28 to < 32 weeks 
gestational age and 
< 7 days of age 
NA 
NA 
6 to < 10 
102.6 to < 171 
≥ 10 
≥ 171 
< 28 weeks 
gestational age and 
< 7 days of age 
NA 
NA 
5 to < 8 
85.5 to < 136.8 
≥ 8 
≥ 136.8 
7 to 28 days of age 
(breast feeding) 
5 to < 10 
85.5 to < 171 
10 to < 20 
171 to < 342 
20 to < 25 
342 to < 427.5 
≥ 25 
≥ 427.5 
7 to 28 days of age 
(not breast feeding) 
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 
 
 
 
 
 19
Severity grading for total bilirubin in neonates is complex because of rapidly changing total 
bilirubin normal ranges in the first week of life followed by the benign phenomenon of breast 
milk jaundice after the first week of life.  Severity grading in this appendix corresponds 
approximately to cut-offs for indications for phototherapy at grade 3 and for exchange 
transfusion at grade 4. 20
A laboratory value of 1 mg/dL is equivalent to 17.1 µmol/L. 21
Definitions: Term is defined as ≥ 37 weeks gestational age; near-term, as ≥ 35 weeks  
gestational age; preterm, as < 35 weeks gestational age; and neonate, as 0 to 28 days of age. 
 
 
 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 75 of 99 
 
Appendix 2: Bleeding Academic Research Consortium (BARC) Definitions for 
Bleeding Events 
 
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 haemorrhage (eg, 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 to <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  
 
Perioperative intracranial bleeding within 48 hrs 
 
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-hr period† 
 
Chest tube output ≥2L within a 24hr period 
CABG indicates coronary artery bypass graft. Platelet transfusions should be recorded and 
reported but are not included in these definitions until further information is obtained 
about the relationship to outcomes. If a CABG-related bleed is not adjudicated as at least a 
type 3 severity event, it will be classified as not a bleeding event. If a bleeding event occurs 
with a clear temporal relationship to CABG (ie, within a 48-h time frame) but does not meet 
type 4 severity criteria, it will be classified as not a bleeding event.  
* Corrected for transfusion (1 U packed red blood cells or 1 U whole blood=1 g/dL 
hemoglobin).  
† Cell saver products are not counted. 
Type 5 
Fatal bleeding  
Type 5a  
 
Probable fatal bleeding; no autopsy or imaging confirmation but clinically 
suspicious 
Type 5b  
 
Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation 
 
 
 
 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 76 of 99 
Appendix 3: Definitions and Criteria for HIV Disease and AIDS Events 
 
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 month’s duration); 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 documented episodes within 1 year of each other 
following randomization) 
• Progressive multifocal leukoencephalopathy 
• Salmonella septicemia, recurrent (2 documented episodes within 1 year of each other 
following 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 
 
 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 77 of 99 
 
CONFIRMED  
PROBABLE  
CONSTITUTIONAL DISEASE 
 
 
HIV wasting syndrome 
None 
A plus B plus C: (A) unexplained, 
involuntary weight loss >10% from 
baseline, (B) persistent diarrhoea with  
>2 liquid stools/d for >1 month or 
weakness for >1 month or fever for >1 
month, (C) tests for alternate causes of 
weight loss, such as cancer, TB, MAC, 
cryptosporidiosis or other specific 
causes of weight loss, if obtained, should 
be negative 
INFECTIONS 
 
 
Aspergillosis, invasive pulmonary 
A plus B plus C: (A) CXR abnormality 
compatible with aspergillosis, (B) 
invasive mycelia consistent with 
Aspergillus on lung biopsy, (C) positive 
culture from lung biopsy or sputum 
collected by any method 
A plus B: (A) CXR abnormality 
compatible with aspergillosis, (B) 
invasive mycelia consistent with 
Aspergillus on lung biopsy or positive 
culture of lung tissue or positive culture 
of sputum collected by any method 
Aspergillosis, other invasive 
A plus B plus C: (A) compatible clinical 
course, (B) invasive mycelia consistent 
with Aspergillus on tissue biopsy or 
clinical evidence of infection, (C) 
positive culture from the affected 
tissue 
A plus B: (A) clinical evidence of invasive 
infection, (B) invasive mycelia consistent 
with Aspergillus on tissue biopsy or 
positive culture at a normally sterile site 
(e.g., blood) apart from the involved 
tissue 
Bartonellosis 
A plus B: (A) Clinical or histologic 
evidence of bacillary angiomatosis or 
bacillary peliosis, (B) a positive culture 
or PCR for B. quintana or B. henselae 
A plus B: (A) Clinical evidence of bacillary 
angiomatosis or bacillary peliosis, (B) 
positive silver stain for bacilli from a skin 
lesion or an affected organ 
Candidiasis of bronchi, trachea or 
lungs 
Macroscopic appearance at 
bronchoscopy or autopsy plus 
microscopic evidence of yeasts or 
pseudo hyphae 
None 
Candidiasis, esophageal 
A plus B: (A) Macroscopic appearance 
at esophagoscopy or autopsy, (B) 
microscopic evidence of yeasts or 
pseudo hyphae 
A plus B plus C: (A) Recent onset of 
retrosternal pain or difficulty on 
swallowing, (B) a clinical diagnosis of 
oral candidiasis plus microscopic 
evidence of yeasts or pseudo hyphae 
from oropharyngeal mucosa, (C) clinical 
response to treatment 
Chagas disease (American 
trypanosomiasis) of the CNS 
Histologic evidence obtained by brain 
tissue biopsy or autopsy 
A plus B plus C plus D: (A) Focal, typically 
hemispheral neurological dysfunction 
with onset over several days or weeks; 
(B) enhancing focal lesion(s) with mass 
effect, and surrounding edema and 
contrast enhancement, typically located 
in grey matter; (C) serum antibodies to 
T. cruzi, (D) response to standard 
therapy with documented clinical or 
radiographic improvement (if 
radiography was done, it must be 
improved), or peripheral blood smear or 
CSF smear positive for T. cruzi 
Coccidioidomycosis, disseminated or 
extrapulmonary 
From tissue other than lung or hilum, 
A or B or C: (A) Microscopic 
demonstration of spherules, (B) 
positive culture, (C) antigen detection   
None 
 
 
 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 78 of 99 
 
CONFIRMED 
PROBABLE 
INFECTIONS 
(CONTINUED) 
 
 
Cryptococcosis, meningitis or 
extrapulmonary 
From tissue other than lung or hilum, 
A or B or C or D: (A) microscopic 
demonstration of narrow based 
budding yeast, (B) for meningitis, if 
done, a positive CSF India ink test, (C) 
positive culture, (D) antigen detention  
None 
Cryptosporidiosis 
Diarrhea for >1 month and positive 
microscopy  
None 
CMV retinitis 
Autopsy demonstration 
Typical appearance on fundoscopy of 
discrete patches of retinal whitening, 
spreading along blood vessels, associated 
with vasculitis, hemorrhage and necrosis, 
confirmed by ophthalmologist  
CMV radiculomyelitis 
Autopsy demonstration 
A plus B plus C plus D plus E plus F: (A) 
Loss of sensation, leg weakness, or 
decreased reflexes, (B) presentation over 
3 days to 3 weeks, (C) CT, MRI or 
myelogram must be done and all imaging 
studies must not show a mass lesion, (D) 
CSF shows >10 WBC with >50% 
polymorphs, (E) CSF shows no other 
pathogen, (F) persistence of symptoms in 
the absence of CMV treatment, or 
elevated quantitative CMV in the CSF by 
PCR  
CMV meningoencephalitis 
Autopsy or brain biopsy demonstration 
A plus B: (A) Rapid <4 weeks syndrome 
with progressive delirium, cognitive 
impairment and fever, (B) CT/MRI 
demonstration of periventricular 
abnormalities or elevated quantitative 
CMV DNA in the CSF by PCR 
CMV, other disease 
A plus B plus C plus D: (A) compatible 
illness, (B) histologic demonstration of 
inclusion bodies from affected tissue, 
(C) if done, detectible CMV antibodies, 
(D) if done, detectible CMV DNA or 
CMV antigen in blood  
A plus B plus C plus D: (A) Compatible 
illness, (B) moderate to markedly high 
CMV antigen or CMV DNA in blood, (C) 
response to therapy, (D) if done, 
detectible CMV antibodies  
HSV mucocutaneous ulceration 
A plus B: (A) Ulceration for >1 month, 
(B) histology or culture or detection of 
antigen from affected tissue 
A plus B: (A) Typical HSV ulceration for >1 
month, (B) response to an antiviral active 
against HZV unless resistance is 
demonstrated 
HSV, bronchitis, pneumonitis, 
esophagitis or other visceral disease 
A plus B: (A) Compatible symptoms, (B) 
histology or culture or detection of 
antigen from affected tissue 
None 
HZV, disseminated 
A plus B: (A) multiple ulcerated lesions 
affecting at least 2 non-contiguous 
dermatomes, or with genralised 
cutaneous dissemination: or HZV 
involvement of the lung, liver, brain, or 
other internal organs (B) positive 
culture, PCR, or antigen asssay from 
from affected tissue 
A plus B: (A) multiple typical ulcerated 
lesions affecting at least 2 non-contiguous 
dermatomes, or with generalised 
cutaneous dissemination (B) response to 
an antiviral active against HZV unless 
resistance is demonstrated 
Histoplasmosis, disseminated or 
extrapulmonary 
A plus B: (A) Compatible symptoms, (B) 
histology or culture or elevated blood 
or urine antigen levels 
None 
 
 
 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 79 of 99 
 
 
CONFIRMED 
PROBABLE 
INFECTIONS 
(CONTINUED) 
 
 
Isosporiasis 
Diarrhea for >1 month, plus 
microscopic identification of Isospora 
belli  
None 
Leishmaniasis, visceral 
Compatible symptoms, plus 
microscopic identification of 
Leishmania 
None 
Microsporidiosis 
Diarrhea for >1 month plus 
Microscopic identification of 
Microsporidia 
None 
MAC and other mycobacterial 
disseminated disease  
A plus B: (A) Fever, fatigue, anemia or 
diarrhea, (B) positive culture from 
blood, body fluids or tissue other than 
pulmonary, hilar or stool 
A plus B plus C: (A) Fever, fatigue, anemia 
or diarrhea, (B) AFB or positive direct MAC 
PCR in blood, body fluids or tissue other 
than pulmonary, hilar or stool (C) no 
concurrent non-pulmonary TB 
M. tuberculosis disease, pulmonary 
A plus B: (A) Compatible symptoms of 
fever, dyspnea, cough, weight loss or 
fatigue, (B) culture or PCR from 
sputum or bronchial lavage or lung 
tissue  
A plus B plus C plus D: (A) Symptoms of 
fever, dyspnea, cough, weight loss or 
fatigue, (B) abnormal chest X-ray, (C) AFBs 
seen in sputum or lavage or lung tissue 
but not grown in culture, (D) responds to 
treatment  
M. tuberculosis disease, 
extrapulmonary 
A plus B: (A) Compatible symptoms, (B) 
culture or PCR from blood or affected 
tissue  
A plus B plus C: (A) Compatible symptoms, 
(B) AFBs seen from affected tissue or 
blood (C) concurrent diagnosis of 
pulmonary TB or responds to treatment  
Nocardiosis 
Clinical evidence of invasive infection 
plus a positive culture from the 
affected tissue or blood  
Clinical evidence of invasive infection plus 
microscopic evidence of bronchial weakly 
acid fast organisms from the affected 
tissue 
Penicillium marneffei, disseminated 
Culture from a non-pulmonary site  
Known presence in a P. marneffei endemic 
area plus characteristic skin lesions plus 
response to antifungal therapy for 
penicillosis  
PCP 
A plus B: (A) compatible clinical 
syndrome, (B) microscopic or 
histoloical demonstration of P. carinii 
cysts in a pulmonary specimen 
A plus B plus C plus D plus E: (A) dyspnea 
or cough, or fever progressive over >1 
week, (B) diffuse chest x-ray abnormality 
or, if on inhalational pentamidine, diffuse 
upper lung field abnormality, (C) evidence 
of hypoxia, (D) not suggestive of bacterial 
pneumonia (i.e., not purulent sputum or 
hemoptysis, no bacterial pathogen 
identified in blood or bronchial wash), (E) 
response to PCP treatment 
Pneumocystis jirovecii, 
extrapulmonary 
Compatible symptoms, plus 
microscopy  
None 
 
 
 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 80 of 99 
 
CONFIRMED  
PROBABLE  
INFECTIONS 
(CONTINUED) 
 
 
Pneumonia, recurrent bacterial 
excludes, (a) post-obstructive 
pneumonias, including in those with 
intrapulmonary/bronchial lesions, 
(b) aspiration pneumonia, including 
in those with decreased 
consciousness levels, (c) nosocomial 
ventilator-associated pneumonias 
Both pneumonia episodes must occur 
after enrolment and satisfy criteria (A) 
plus (B) plus (C).  The recurrent 
pneumonia must also satisfy criteria 
(D) plus (E): (A) Signs and symptoms 
suggestive of bacterial pneumonia, (B) 
focal CXR abnormality compatible with 
bacterial pneumonia, (C) identification 
of a bacterial pathogen by positive 
blood culture, positive bronchoscopic 
sputum culture, detection of 
Legionella or pneumococcal antigen in 
urine or blood or diagnostic serologic 
findings, (D) the second pneumonia 
had onset of symptoms <365 days 
after the first episode, (E) there is 
strong evidence that the first episode 
was cured such as an intervening clear 
CXR or absence of symptoms after >1 
month off antibacterials effective 
against pathogens commonly 
producing pneumonia 
Both pneumonia episodes must occur 
after enrollment and satisfy criteria (A) 
plus (B) plus (C).  The recurrent 
pneumonia must also satisfy criteria (D) 
plus (E): (A) Signs and symptoms 
suggestive of bacterial pneumonia, (B) 
focal CXR abnormality compatible with 
bacterial pneumonia, (C) diagnosed by a 
doctor, physicians’ assistant or nurse 
practitioner, (D) the second pneumonia 
had onset of symptoms <365 days after 
the first episode, (E) there is strong 
evidence that the first episode was cured 
such as an intervening clear CXR or 
absence of symptoms after >1 month off 
antibacterials effective against pathogens 
commonly producing pneumonia 
PML (progressive multifocal 
leukoencephalopathy) 
A or B: (A) positive histology, (B) 
compatible clinical and radiologic 
course and positive CSF PCR for JK 
virus 
A plus B plus C: (A) Consistent symptoms, 
(B) brain image consistent with PML, (C) 
no response to toxo treatment or 
toxoplasma seronegative 
Rhodococcus equi disease 
Clinical evidence of invasive infection 
plus microbiologic identification of the 
organism in the affected tissue or 
blood  
None 
Salmonella septicemia, recurrent 
Both episodes must occur after 
enrollment and met criterion (A).  The 
second episode must meet criteria (B) 
and C: (A) Positive blood or tissue 
culture, (B) the second septicemia had 
onset of symptoms <365 days after the 
first episode, (C) the second 
septicemia must be due to a different 
Salmonella serotype or there must be 
strong evidence that the first episode 
was cured such as a negative blood 
culture off effective antibacterials for 
>1 week or absence of symptoms off 
antibacterials for >1 month 
None 
Toxoplasmosis of brain 
Microscopy 
A plus B plus C: (A) Symptoms of focal 
intracranial abnormality or decreased 
consciousness, (B) brain image consistent 
with lesion(s) enhanced by contrast, (C) 
positive toxoplasma serology or responds 
to treatment clinically or by scan  
 
 
 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 81 of 99 
 
CONFIRMED  
PROBABLE  
INFECTIONS 
(CONTINUED) 
 
 
NEOPLASMS 
 
 
Cervical carcinoma, invasive 
Histology (NOT carcinoma-in-situ) 
None 
Kaposi sarcoma, (mucocutaneous or 
visceral) 
Histology 
Highly typical appearance and persistence 
for >1 month 
Lymphoma, primary, of brain 
Histology 
Symptoms consistent with lymphoma plus 
at least one CNS lesion with mass effect 
plus lack of clinical and radiographic 
response to at least 2 weeks of treatment 
for toxoplasmosis  
Lymphoma, Hodgkin's 
Histology 
None 
Lymphoma, non-Hodgkin's, all cell 
types 
Histology 
None 
NEUROLOGICAL 
 
 
HIV encephalopathy (including AIDS 
Dementia Complex) 
None 
Cognitive or motor dysfunction interfering 
with usual activity, progressive over weeks 
or months plus no other condition to 
explain the findings plus brain image 
obtained and suggests no other causes 
plus grade 2 or worse impairment in at 
least 2 domains by NARS (see below) 
excluding abnormal domains at trial entry.  
(For persons with abnormal domains at 
entry worsening by at least two grades 
meets criteria.) 
 
 
 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 82 of 99 
Appendix 4: Diagnostic Criteria for Serious Non-AIDS Events 
 
ACUTE MYOCARDIAL INFARCTION  
A. Rise and/or fall of cardiac biomarkers (preferably troponin), with at least one value above 99th percentile 
of upper reference limit (URL)  
B. Occurrence of a compatible clinical syndrome, including symptoms (such as chest pain) consistent with 
myocardial ischemia  
C. ECG changes indicative of new ischemia (new ST-changes or new left bundle branch block [LBBB]), or 
development of pathological Q waves on the ECG  
D. Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality  
E. Sudden unexpected cardiac death involving cardiac arrest before biomarkers are obtained or before a time 
when biomarkers appear, along with (1) new ST-changes or new LBB, or (2) evidence of fresh thrombus 
on coronary angiography or at autopsy  
F. In participants with percutaneous coronary interventions and normal baseline troponin, increases in 
troponin of three times the 99th percentile of URL  
G. In participants with coronary artery bypass grafting and normal baseline troponin, increases in troponin of 
five times the 99th percentile of URL PLUS at least one of the following: (1) new pathological Q-waves or 
new LBBB, (2) angiographically documented new graft or native artery occlusion, or (3) imaging evidence 
of new loss of viable myocardium  
H. Pathologic findings of acute myocardial infarction (including acute MI demonstrated as the cause of death 
on autopsy)  
I. Development of 1) evolving new Q waves, or 2) evolving ST elevation, preferably based on at least 2 ECGs 
taken during the same hospital admission  
J. In participants with coronary artery bypass grafting and normal baseline troponin, increases in troponin of 
five times the 99th percentile of URL  
Confirmed: One of the following 5 criteria (adapted from 2007 Universal Definition of Myocardial Infarction):  
1. A + (B or C or D)  
2. E  
3. F  
4. G  
5. H  
Probable: B+I or J  
 
CONGESTIVE HEART FAILURE  
A. Clinical signs and symptoms compatible with left or right sided heart failure (e.g., paroxysmal nocturnal 
dyspnea, rales or S3 on auscultation, jugular venous distention) without an alternative explanation  
B. Hemodynamic measurements, radionucleotide ventriculography, echocardiogram, cardiac catheterization, 
or multiple gated acquisition scan showing a decreased ejection fraction of < 45%  
C. Echocardiogram, cardiac catheterization or other studies showing evidence of increased left atrial pressure 
or right heart failure  
D. Elevated levels of Brain Natriuretic Peptide (BNP) or pro-BNP  
E. Chest x-ray or other imaging study showing evidence of congestive heart failure, including cardiac 
enlargement  
F. Documentation of treatment for congestive heart failure  
 
Confirmed: (A+B) or (A+C) or (A+D)  
Probable: A+E+F  
 
 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 83 of 99 
 
CORONARY ARTERY DISEASE REQUIRING REQUIRING DRUG TREATMENT  
Confirmed: A written report in the medical record documenting: (A) myocardial ischemia and/or coronary 
artery disease, AND (B) use of medications given to treat or prevent angina (e.g., nitrates, beta blockers, 
calcium channel blockers)  
Probable: Not applicable  
 
CORONARY REVASCULARISATION  
Confirmed: A written report in the medical record or hospital discharge summary from the hospitalization 
during which the procedure was performed for treatment of coronary artery disease, including: coronary 
artery bypass graft, coronary artery stent implant, coronary artherectomy, and percutaneous transluminal 
angioplasty  
Probable: Not applicable  
 
DECOMPENSATED LIVER DISEASE  
A. Histologic, radiographic, or ultrasound evidence of cirrhosis, as documented by one of the following:  
 
1. Histologic evidence of cirrhosis obtained by liver biopsy or autopsy  
 
2. MRI or CT consistent with cirrhosis  
 
3. A positive result on transient elastography (FibroScan) or other ultrasound imaging consistent with 
cirrhosis  
B. Clinical evidence of decompensation, as documented by one of the following, and without an alternative 
explanation:  
 
1. Ascites  
 
2. Hepatic encephalopathy  
 
3. Bleeding from gastric or esophageal varices  
4. Spontaneous bacterial peritonitis  
 
Confirmed: A+B  
Probable: B  
 
DEEP VEIN THROMBOSIS  
A. Diagnosis of deep vein thrombosis (DVT) by contrast venography, helical computed tomography, MRI, or 
ultrasonography other comparable imaging techniques  
B. An elevated D-dimer test OR abnormal plethysmography  
C. A score on the Wells Clinical Prediction Rule for DVT of >=3 points  
D. Absence of alternative diagnosis as likely or greater than that of deep venous thrombosis  
Wells Clinical Prediction Rule for DVT  
One point for each of the following:  
• Active cancer (treatment ongoing or within previous 6 months, or palliative)  
• Paralysis, paresis, or plaster immobilization of lower extremities  
• Recently bedridden for more than 3 days, or major surgery, within 4 weeks  
• Localized tenderness along distribution of the deep venous system  
• Entire leg swollen  
• Calf swelling by more than 3 cm when compared with the asymptomatic leg (measured     10 cm below 
tibial tuberosity)  
• Pitting edema (greater in the symptomatic leg)  
• Collateral superficial veins (non-varicose)  
(Adapted from: Wells PS et al. Lancet 1997;350:1796)  
Confirmed: A  
Probable: B+C+D  
 
 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 84 of 99 
 
DIABETES MELLITUS  
A. Symptoms of diabetes plus casual plasma glucose concentration >= 200 mg/dL (11.1 mmol/L). (Casual is 
defined as anytime of day without regard to time since last meal. The classic symptoms of diabetes include 
polyuria and polydipsia).  
B. Fasting plasma glucose >= 126 mg/dL (7.0 mmol/L). (Fasting is defined as no caloric intake for at least 8 
hours).  
C. 2-hour post-load glucose >= 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test. (The test 
should be performed as described by WHO, using glucose load containing the equivalent of 75 g 
anhydrous glucose dissolved in water).  
 
Confirmed: A or B or C  
Probable: none  
 
END-STAGE RENAL DISEASE  
A. Hemodialysis or peritoneal dialysis for a period of at least one month, documented in a clinical note  
B. A kidney transplant, documented in a clinical note. 
 
Confirmed: A or B  
Probable: Not applicable   
 
NON-AIDS-DEFINING CANCER  
A. Diagnosis of cancer other than lymphoma, Kaposi's sarcoma (KS), or invasive cervical cancer in an autopsy 
report  
B. Diagnosis of cancer other than lymphoma, KS, or invasive cervical cancer in a pathology report that 
established the diagnosis  
C. Diagnosis of cancer other than lymphoma, KS, or invasive cervical cancer in a hospital discharge summary 
or consultation note from the hospitalization or clinic visit during which the diagnosis was stablished  
 
Confirmed: A or B  
Probable: C  
 
PERIPHERAL ARTERIAL DISEASE  
A. Compatible clinical signs and symptoms (e.g., intermittent claudication, femoral bruit, decreased 
peripheral pulses, change in color or temperature of limb suggesting peripheral arterial disease)  
B. Positive results on diagnostic imaging studies (e.g., Doppler ultrasound, contrast arteriography, MRI 
arteriography)  
C. Ankle Brachial Pressure Index < 0.90 in non-diabetics  
D. A procedure report, hospital discharge summary, or other medical record from the hospitalization during 
which the procedure was performed documenting an invasive procedure for treatment of peripheral arterial 
disease (e.g. percutaneous transluminal angioplasty, endovascular procedures, or vascular surgery), or a 
consultation note documenting the occurrence of the procedure. 
 
Confirmed: (A+B) or (A+C) or D  
Probable: A  


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 85 of 99 
 
PULMONARY EMBOLISM  
A. Symptoms compatible with pulmonary embolism, such as shortness of breath, chest pain, or hemoptysis  
B. Results consistent with a diagnosis of pulmonary embolism on pulmonary angiography, helical CT, 
ventilation-perfusion scan or other comparable imaging studies  
C. A diagnosis of pulmonary embolism on autopsy  
D. Results consistent with a diagnosis of deep venous thrombosis on venography, ultrasound, or other 
comparable imaging studies  
E. A chest x-ray which, if performed, does not suggest an alternative etiology for the symptoms described in 
criteria A 
 
Confirmed: (A+B) or C  
Probable: A+D+E  
 
STROKE  
A. Acute onset with a clinically compatible course, including unequivocal objective findings of a localizing 
neurologic deficit  
B. CT or MRI compatible with diagnosis of stroke and current neurologic signs and symptoms  
C. Stroke diagnosed as cause of death at autopsy  
D. Positive lumbar puncture compatible with subarachnoid hemorrhage  
E. Death certificate or death note from medical record listing stroke as cause of death  
 
Confirmed: (A+B) or C  
Probable: (A+D) or (A+E) 
 
 
 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 86 of 99 
 
Appendix 5: Participant Information Sheet and Consent Form 
 
[Insert institutional logo] 
[name of local institution/s where research is being conducted] 
 
 
PARTICIPANT INFORMATION AND CONSENT FORM 
 
 
 
 
A double blind randomised comparison of vorapaxar versus placebo for the treatment of HIV associated 
inflammation and coagulopathy in patients with well controlled HIV replication 
 
 
 
ADVICE Study: Attenuation of D-dimer using Vorapaxar to target Inflammatory and Coagulation Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator(s):  [insert] 
 
Site Address: 
 
  [insert] 
 
 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 87 of 99 
Invitation 
You are invited to participate in the ADVICE research study to investigate the use of a new anti-clotting 
drug (vorapaxar sulphate) because you are currently being treated for Human Immunodeficiency Virus 
(HIV) infection with a combination of antiretroviral treatments that does not include HIV Protease 
Inhibitors and/or Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) and you have a relatively high 
level of d-dimer in your blood. This is explained in more detail in section 1 below. 
 
The study is being conducted by [insert local institution name].  The study is part of an international 
collaborative study sponsored by the Kirby Institute at the University of New South Wales in Australia and 
The National Institute of Allergy and Infectious Diseases (NIAID) in the USA. 
 
Before you decide whether or not to take part in this research study, it is important that you understand 
why the study is being done, and what it will involve.  Please read this information carefully and discuss 
with others if you wish. 
 
1. What is the purpose of the study? 
The main purpose of this study is to compare the safety and efficacy of vorapaxar versus placebo in 
reducing levels of chemical markers of clotting (d-dimer), immune activation and immune inflammation in 
people with well controlled HIV infection.  
 
Some people with HIV infection (even very well controlled HIV infection) are at increased risk of death 
(from any cause), and both fatal and non-fatal episodes of cardiovascular, renal and hepatic disease and 
cancer. Higher than normal levels of chemicals in the body associated with blood clotting, immune 
activation and inflammation appear to be closely associated with these unwelcome outcomes. One of the 
chemicals the body produces after it has broken down a blood clot is called d-dimer. It is normally present 
in small quantities in the blood. When there are increased levels of d-dimer it suggests increased clotting 
activity in the body.  
 
While combination antiretroviral therapy (cART) helps to reduce the level of chemicals associated with 
blood clotting, immune activation and inflammation, people with HIV infection still have higher levels of 
these chemicals than people without HIV infection. Vorapaxar may help to lower the level of these 
chemicals in the body. 
 
Vorapaxar is an anti-clotting medication made by Merck & Co, Inc. It is approved by the U.S. Food and 
Drug Administration (FDA) for use with other medications to reduce the risk of heart attack in some 
people with existing cardiovascular disease. We want to see if vorapaxar will lower d-dimer levels in 
people with well-controlled HIV infection who are taking cART. We will also study the safety of vorapaxar 
treatment in this same group of people. 
 
2. Why have I been invited to participate in this study? 
You are being invited to participate in this study because you: 
 
are aged 40 years or older 
 
have well controlled HIV infection (plasma HIV RNA less than 50 copies/mL for at least 24 weeks 
and a CD4 T cell count >50 cells/mm3) 
 
are being treated with combination antiretroviral treatments that does not include HIV Protease 
Inhibitors and/or Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)   
 
have elevated d-dimer levels in your blood (greater than 200 ng/mL) 
 
3. What if I don’t want to take part in this study or if I want to withdraw later? 
Participation in this study is voluntary. It is completely up to you whether or not you participate. If you 
decide not to participate, it will not affect the treatment you receive now or in the future. Whatever your 
decision, it will not affect your relationship with the staff caring for you. 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 88 of 99 
 
If you wish to withdraw from the study once it has started, you can do so at any time without having to 
give a reason and without affecting your medical care. However, data collected during your time on the 
study will still be used.  
 
If you wish, any blood samples that can still be identified as yours will be destroyed.  
 
If at any time your study doctor considers that it is in your best interest to be withdrawn from the study, 
he or she will explain the reasons and arrange for your care to continue. 
 
4. What does this study involve? 
If after reading this information and discussing the study with your doctor, you decide to take part you 
will be asked to sign a form confirming that you agree to participate. An ethics committee has reviewed 
and approved this study prior to any participant being allowed to enroll in the study. 
 
New information about the treatment being studied may become available during the course of the 
study. You will be kept informed of any significant new findings that may affect your willingness to 
continue in the study. 
 
A total of approximately 60 participants will participate from various approved sites in Australia and the 
USA. The study runs for 18 weeks. You will be required to attend the clinic 7 times over this period.  
 
If you are eligible to enter the study, you will be randomised to receive either vorapaxar (one 2.5mg 
capsule) or one placebo capsule daily.  A placebo is a medication with no active ingredients. It looks like 
the real thing but is not. You will be required to take the one capsule orally, once a day, with or without 
food. You will be required to stop taking the study treatment at the week 12 visit (for 6 weeks) and then 
be seen for a final visit at week 18.  
 
‘Randomised trial’: Sometimes we don’t know the best way of treating patients with a particular condition 
so comparisons need to be made between different treatments. To do this, study participants are put into 
groups and given different treatments, and the results are compared to see whether one treatment is 
better. To ensure the groups are similar to start with, a computer allocates each study participant into a 
group randomly, like the flip of a coin. You will have a 50% chance of receiving vorapaxar and 50% chance 
of receiving placebo. Neither the doctor nor the study participant can decide which treatment the 
participant receives. 
 
This research project has been designed to make sure the researchers interpret the results in a fair and 
appropriate way and avoids study doctors or participants jumping to conclusions. You will be participating 
in a double-blind study. Neither you nor the study staff will know which treatment you are receiving.  
However, in case of emergency, this information can be made available to your study doctor.  At the end 
of the study you will be told in which treatment you received. 
 
By signing this informed consent form, you give permission for the researchers, authorised personnel 
from the UNSW, the ethics committee and government authorities to access your medical records to 
obtain information about you that is relevant to the study. 
 
You need to attend the clinic for the specified study visits within the specified time periods and provide 
complete and accurate information about your health, including any changes to medications, as the study 
progresses. These requirements are in place to protect your safety and should be adhered to. 
 
 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 89 of 99 
It is desirable that your local doctor be advised of your decision to participate in this research project. If 
you have a local doctor, we strongly recommend that you inform them of your participation in this 
research project. If you consent to participate in this study, we will also write to your local doctor to let 
them know you are participating in this study and provide them with information on medications that 
should not be prescribed during this time. 
 
If you agree to participate in this study, you will then be asked to undergo the following procedures (see 
Table 1): 
 
Initial Screening Visit (to determine whether you are eligible to enter the study) 
 
 
Discussion and completion of informed consent; 
 
Review of your medical history, full HIV history as well as previous and current medications; 
 
A physical examination based on any symptoms you are experiencing; 
 
Blood or urine pregnancy test if you are a women of child-bearing potential; 
 
Blood tests: 
 
Biochemistry tests to measure the level of salts in your blood, kidney and liver function tests, 
 
Haematology tests to measure the number of red blood cells, white blood cells and  platelets 
(these help your blood to clot), 
 
HIV viral load (the amount of HIV in your blood), 
 
Immune monitoring tests to measure the number of CD4 and CD8 T cells, 
 
Chemistry tests to measure your d-dimer levels. 
 
The total amount of blood drawn at this visit will be approximately 26 mLs (approximately  
1.7 tablespoons where 1 tablespoon equals 15 mLs). 
 
Day 0/Randomisation Visit (commence study drugs) 
 
If you are found to not be eligible you will be informed of this by the site staff. You will not need to 
return to the clinic for this study. If you are found to be eligible you will be asked to come back to the 
clinic (up to 14 days after your initial screening visit) to complete baseline assessments and be 
randomised to a treatment arm. 
 
You will need to be fasted (you can drink plain water but must not have anything else to eat or drink 
for at least 8 hours) for this visit.  
 
At this visit, the following assessments will take place: 
 
Medical history, including review of current medications and any side effects; 
 
Physical examination (height, weight and blood pressure) and examination based on any 
symptoms you are experiencing; 
 
Blood or urine pregnancy test if you are a woman of child-bearing potential; 
 
Blood tests: 
 
The same biochemistry, liver and kidney function, haematology and HIV viral load tests as 
at screening will be repeated, 
 
Immune monitoring tests to measure the numbers of CD4 and CD8 T-cells, 
 
Metabolic tests to measure your blood fats (different types of cholesterol, triglycerides),  
 
Test a protein (PAR-1) that is part of the clotting system, 
 
Storage bloods, these are bloods that are taken and stored for measuring chemical markers 
of clotting and immune function as well as HIV research later on. There is more information 
provided below on how these samples will be used later on to increase our understanding 
of the HIV virus, the immune system and the complications of HIV infection.  
 
The total amount of blood drawn at this visit will be approximately 86 mLs (5.7 tablespoons where 1 
tablespoon equals 15 mLs). 
 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 90 of 99 
You will be supplied with a one month supply of study treatment. You should commence taking your 
randomised study treatment within 1 day of your randomisation visit (that is, the same day or the next 
day). 
 
Follow up visits at week 1, 4, 8, 12 & 18 
 
You will need to return to the clinic 1, 4, 8, 12 and 18 weeks after you have been randomised. You do 
not need to be fasting for these follow up visits. The following assessments will take place during 
these visits: 
 
 
Your blood pressure will be measured and a physical examination based on any symptoms you 
are experiencing (all follow up visits). Your weight will be checked again at week 18 
 
Review of any medical issues you report and a review of all your medications and any side 
effects (all follow up visits) 
 
Blood or urine pregnancy test if you are a woman of child-bearing potential (all follow up visits 
but not at week 1) 
 
Blood tests: 
 
The same haematology, HIV viral load and CD4 and CD8 T-cell tests (all follow up visits), 
 
The same biochemistry, liver and kidney function tests (at weeks 12 and 18 only), 
 
The same PAR-1 test (all follow up visits but not at week 8), 
 
Storage bloods, these are the bloods that are taken and stored for measurement of clotting 
and immune function as well as other HIV research later on (all follow up visits).  
 
At the week 1, week 4 and week 8 follow up visits the total amount of blood drawn at these visits will be 
approximately 67 mLs (4.5 tablespoons where 1 tablespoon equals 15mLs). At the week 12 and week 18 
visit, the total amount of blood drawn at these visits will be approximately 86mLs (5.7 tablespoons 
where 1 tablespoon equals 15mLs).  
 
Additional blood draw if you have a bleeding event 
 
If you have a significant bleed during the study, you will have another blood test to check your 
haemoglobin levels, where approximately 4 mLs of blood will be collected (0.3 tablespoons where 1 
tablespoon equals 15mLs). Your doctor will decide if you require this test. 
 
 
 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 91 of 99 
Table 1. Patient visit schedule 
 
Study week number 
Screening 
Wk 0 
Wk 1 
Wk 4 
Wk 8 
Wk 12 
No 
study 
drug 
Wk 18 
Clinical assessments 
Informed consent 
• 
 
 
 
 
 
 
 
Doctor/Nurse reviews 
medical and HIV history 
• 
 
 
 
 
 
 
 
Doctor/Nurse reviews 
medications and any  
side-effects 
• 
• 
• 
• 
• 
• 
 
• 
Physical examination 
based on symptoms you 
may be experiencing 
• 
• 
• 
• 
• 
• 
 
• 
Physical examination: 
blood pressure  
 
• 
• 
• 
• 
• 
 
• 
Physical examination: 
weight  
 
• 
 
 
 
 
 
• 
Height 
 
• 
 
 
 
 
 
 
Blood/urine tests 
Fasting blood tests 
 
• 
 
 
 
 
 
 
Biochemistry 
• 
• 
 
 
 
• 
 
• 
Liver Function  
• 
• 
 
 
 
• 
 
• 
Haematology 
• 
• 
• 
• 
• 
• 
 
• 
Viral load 
• 
• 
• 
• 
• 
• 
 
• 
Immune monitoring 
tests 
 
• 
• 
• 
• 
• 
 
• 
d-dimer levels tested 
• 
• 
• 
• 
• 
• 
 
• 
Storage bloods 
 
• 
• 
• 
• 
• 
 
• 
Urine pregnancy test 
(if you are a woman of 
child-bearing age) 
• 
• 
 
• 
• 
• 
 
• 
Provided with study 
medication  
 
• 
 
• 
• 
 
 
 
 
Blood storage 
 
Bloods will be stored at each visit from Week 0 to the last study visit at Week 18. The total amount of 
blood stored over the 18 week period will be approximately 316 mL (about 21 tablespoons).  
 
Approximately 62 mL (4.1 tablespoons) of blood will be stored at weeks 0, 12 and 18. 48 mL  
(3.2 tablespoons) will be stored at weeks 1, 4 and 8. These blood samples will be stored for tests to be 
conducted at a later stage for this research project as well as future medical research that relates to the 
treatment of HIV, blood clotting, the immune system and the complications of HIV. No tests of your genes 
(human genetic tests) will be performed on these samples. 
 
Some of the results from the tests done on your stored blood can be given to your doctor at the end of 
the study (tests for blood clotting and aspects of immune function). Other results cannot be given to you 
as the tests may not be conducted until years after the end of the study. None of the results from the 
tests undertaken are part of routine care. Therefore your health is not affected as a consequence of not 
knowing the results. 
 
This is explained further in section 10 below.  
 
 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 92 of 99 
5. How is this study being paid for? 
Financial support to cover the costs of carrying out this study is being provided by The National Health 
and Medical Research Council of Australia. 
 
All of the money being paid by the Sponsor to run the trial will be deposited into an account managed by 
[insert hospital/Area Health Service]. No money is paid directly to individual researchers. 
6. Are there risks to me in taking part in this study? 
All medical procedures involve some risk of injury. In addition, there may be risks associated with this 
study that are presently unknown or unforeseeable. In spite of all reasonable precautions, you might 
develop medical complications from participating in this study. The known risks of this study are: 
 
Risk of bleeding 
 
Vorapaxar, like other anti-clotting drugs increases the risk of bleeding. General risk factors for bleeding 
include older age, low body weight, reduced kidney or liver function, and a history of bleeding disorders. 
Taking vorapaxar with certain other medications, such as other anti-clotting drugs (eg. warfarin, 
enoxaparin or thienopyridine), opiates (cocaine, heroin and morphine) or aspirin, can also increase the 
risk of bleeding. The study doctor will carefully review the medications you are currently taking before 
you join this study; you will not be able to participate in this study if you are taking these types of 
medications. 
The most common side-effects experienced by 20,108 people receiving vorapaxar in a previous study are 
outlined in the tables below. It is important to remember that these people had a history of heart attack 
or reduced blood flow in their legs and were taking other anti-clotting medications such as aspirin and 
clopidogrel. 
 
 
placebo 
vorapaxar 
Bleeding that needs medical 
treatment or bleeding that 
results in a significant drop in 
haemoglobin levels 
9.5% (9.5 people out of every 100 
people) 
13.4% (13.4 people out of every 
100 people) 
 
In a total of 39,239 patients who have taken vorapaxar or placebo, other less common side effects have 
occurred at these rates: 
 
 
placebo 
vorapaxar 
Anemia 
4 % (4 people out of every 100 
people) 
5% (5 people out of every 100 
people) 
Depression 
2.1% 
2.4% 
Rashes or skin eruptions 
2% 
2.2% 
Double vision /eye problems 
0.06% 
0.2% 
 
Call your study doctor right away if you have any of these signs or symptoms of bleeding while taking 
vorapaxar: 
 
bleeding that is severe or that you cannot control 
 
pink, red, or brown urine 
 
vomiting blood or your vomit looks like "coffee grounds" 
 
red or black stools (looks like tar) 
 
coughing up blood or blood clots. 
 
While you take vorapaxar and for about 4 weeks after your treatment with vorapaxar is stopped: 
 
you may bruise and bleed more easily (nose bleeds may be more common) 
 
it will take longer than usual for any bleeding to stop. 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 93 of 99 
 
You should talk with your study doctor about any precautions you should take whilst participating in this 
study to reduce your risk of bleeding. eg. avoid contact sports.  
 
There are no risks associated with taking placebo pills. 
 
Interaction with other medications 
 
There can be a risk of serious and/or life threatening side effects when non-study medications are taken 
with the study drug.  For your safety, you must tell the study doctor or nurse about all medications you 
are taking before you start the study.  You must tell any doctor you see during the study about all of the 
medications you are taking, especially before starting any new medications.  This includes any other 
prescribed medicines, over-the-counter medicines, herbal medicines or supplements and illicit 
substances.  In addition, you must tell the study doctor or nurse before enrolling in any other clinical trials 
while participating in this study. 
 
It is recommended that if you experience headaches or any other pain during the trial that you use 
paracetamol instead of ibuprofen (Neurofen™). It is also important that you do not take any other non-
steroidal anti-inflammatory medicines (NSAIDs) for longer than 5 consecutive days. This includes 
medicines such as celecoxib (celebrex™) and diclofenac (voltaren™). Ask your doctor if you are unsure 
about using any medications before you commence their use. 
 
Despite all reasonable precautions there may be some risks that are unforeseeable. Participation in a 
study may impact on your employment or health insurance. You should be aware of any potential impact 
before agreeing to participate. 
 
New information about the treatment being studied may become available during the course of the 
study. You will be kept informed of any significant new findings that may affect your willingness to 
continue in the study. 
Risks of blood drawing  
 
As part of this study, you will have your blood drawn 7 times over 18 weeks. This procedure can be 
uncomfortable but rarely results in any significant problems. Side effects that have been noted with 
drawing blood include feeling light-headed or faint, fainting, formation of a blood clot, bruising and/or 
infection at the site of the needle stick. 
 
Pregnancy and breast feeding 
 
 
Women 
 
It is important that women participating in this study are not pregnant and do not become pregnant 
during the course of the study.  If you are a woman of child-bearing potential and there is any possibility 
that you are pregnant, the researchers will perform a pregnancy (urine) test before you start in the study.  
With limited data on vorapaxar in pregnancy, women must avoid becoming pregnant during the course of 
this study.  
 
[Insert for SVH patients only] 
You should speak to the study doctor about the need to avoid pregnancy during this study. 
 
[Insert for Non Catholic sites delete for Catholic sites] 
If necessary, you should use reliable contraception (such as oral or implanted contraception, an IUD or 
have had a tubal ligation) during the course of the study. 
 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 94 of 99 
If you do become pregnant during the study, you should tell your study doctor immediately. It is advised 
that pregnant women discontinue the use of vorapaxar until the conclusion of the pregnancy. Your study 
doctor will discuss the options with you at that time and will follow your progress until the baby is born. 
 
If you are found to be pregnant, information on any prenatal tests and the outcome of the pregnancy will 
be collected. If you agree, this pregnancy data will be submitted to the Antiretroviral Pregnancy Registry, 
an international register that collects data on antiretroviral treatment and pregnancy outcomes in order 
to monitor the safety of antiretroviral drugs. 
Please make your obstetrician aware of your study participation. Your study doctor will ask that you, or 
your obstetrician, provide updates on the progress of your pregnancy and its outcome. The study doctor 
will make this information available to the study sponsor for safety monitoring follow-up. 
 
Men 
 
If your spouse or partner thinks she is pregnant during the study, tell your study doctor immediately. If 
your partner becomes pregnant, she will be asked to sign a release of information form to allow your 
study doctor to contact her obstetrician to collect updates on the progress of the pregnancy and its 
outcome. The study doctor will make this information available to the study sponsor for safety monitoring 
follow-up.  
 
You need to attend the clinic for the specified study visits within the specified time periods and provide 
complete and accurate information about your health, including any changes to medications, as the study 
progresses. These requirements are in place to protect your safety. 
 
7. What happens if I suffer injury or complications as a result of the study? 
 
[St Vincent’s Hospital wording] 
 
If you suffer any injuries or complications as a result of this study, you should contact the study doctor as 
soon as possible, who will assist you in arranging appropriate medical treatment. If you are eligible for 
Medicare, you can receive any medical treatment required to treat the injury or complication, free of 
charge, as a public patient in any Australian public hospital. 
 
You may have a right to take legal action to obtain compensation for any injuries or complications 
resulting from the study. Compensation may be available if your injury or complication is caused by the 
drugs or procedures, or by the negligence of any of the parties involved in the study. If you receive 
compensation that includes an amount for medical expenses, you will be required to pay for your medical 
treatment from those compensation monies.  
 
If you are not eligible for compensation for your injury or complication under the law, but are eligible for 
Medicare, then you can receive any medical treatment required for your injury or complication free of 
charge as a public patient in any Australian public hospital. 
 
The parties to this study agree to follow the Medicines Australia Guidelines for Compensation for Injury 
Resulting from Participation in an Industry-Sponsored Clinical Trial. These Guidelines allow for some 
claims for compensation to be settled without the need for legal action to be taken. The fact that the 
parties have agreed to abide by these guidelines in respect of the clinical trial does not affect your rights 
to pursue a legal remedy in respect of any injury you may suffer as a result of participation. You can 
obtain a copy of these Guidelines from the Secretary of the Human Research Ethics Committee. 
 
[MSHC wording] 
 
If you suffer any injuries or complications as a result of this study, you should contact the study doctor as 
soon as possible, who will assist you in arranging appropriate medical treatment. If you are eligible for 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 95 of 99 
Medicare, you can receive any medical treatment required to treat the injury or complication, free of 
charge, as a public patient in any Australian public hospital. 
 
You may have a right to take legal action to obtain compensation for any injuries or complications 
resulting from the study. 
 
8. Will I benefit from the study? 
The information we obtain in this study will help us learn more about the use of vorapaxar treatment in 
people with HIV infection; however it may not directly benefit you. 
 
9. Will taking part in this study cost me anything, and will I be paid? 
Participation in this study will not cost you anything.  Your reasonable travel expenses up to $50 for each 
clinic visit will be provided. You will not be paid or reimbursed for participating in this study. 
 
10. What will happen to my blood sample after it has been taken? 
You will be asked whether you agree to have some of your blood stored. These specimens will be stored 
temporarily at your local laboratory and then sent to the central laboratory, St Vincent’s Centre for 
Applied Medical Research (AMR) in Sydney. Some of your stored samples will be then sent to a laboratory 
at the National Institute for Infection and Disease (NIAID) in Maryland (USA) for testing for this research 
project. The rest will remain at AMR in Sydney for long-term storage for testing for this research project 
and future HIV research. 
 
If you agree to your blood samples being stored, they will be used for this study and future medical 
research that relates to the treatment of HIV. Not all potentially beneficial future research can be known 
at any one time, as the need for future research is determined by ongoing developments in the field 
indefinitely for future research. The Human Research Ethics Committee will determine whether, or not, 
your consent should be obtained at that time for a particular research project.  
 
Your stored sample will not be used by private or for-profit entities, or for research leading to the 
development of commercial products. 
 
11. How will my confidentiality be protected? 
 
Of the people treating you, only the study doctor and study coordinator will know whether you are 
participating in this study. Any identifiable information that is collected about you in connection with this 
study will remain confidential and will be disclosed only with your permission, or except as required by 
law. Your health records and any information obtained during the research project are subject to 
inspection (for the purpose of verifying the procedures and data) by the relevant authorities and 
authorised representatives of the Sponsor (University of New South Wales), the institution relevant to this 
Participant Information Sheet [insert name of MSHC or St Vincent’s Hospital] or as required by law. By 
signing the Consent Form, you authorise release of, or access to, this confidential information to the 
relevant study personnel and regulatory authorities as noted above.  Your study results will be held 
securely at [insert name of MSHC or St Vincent’s Hospital].   
 
Only non-identifiable information will be sent off site. Your name will not appear on any of the 
information sent to the sponsor; instead your information will be coded using a unique study number and 
your initials. Your blood samples that are kept in storage will only be labelled with a unique study number.  
 
12. What happens with the results? 
If you give us your permission by signing the consent document, we may discuss/publish the results e.g. in 
peer-reviewed medical and scientific journals, presentations at conferences or other professional forums. 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 96 of 99 
In any publication, information will be provided in such a way that you cannot be identified. The study 
results will be provided to you, if you wish. 
 
In any publication, information will be provided in such a way that you cannot be identified.  
 
13. What happens to my treatment when the study is finished? 
Vorapaxar will not be available after the study finishes.  After the end of the study, you will continue to be 
cared for in the usual way. 
 
14. What should I do if I want to discuss this study further before I decide? 
When you have read this information, the researcher [insert name here] will discuss it with you and any 
queries you may have. If you would like to know more at any stage, please do not hesitate to contact 
him/her on [insert number here] 
 
15. Who should I contact if I have concerns about the conduct of this study? 
This study has been approved by St Vincent’s Hospital HREC. Any person with concerns or complaints 
about the conduct of this study should contact the Research Office who is nominated to receive 
complaints from research participants. You should contact them on 
tel:  02 8382 2075 and quote /14/SVH/413. 
 
The conduct of this study at [insert site name] has been authorised by the St Vincent’s Hospital/Alfred 
Hospital Governance office. Any person with concerns or complaints about the conduct of this study may 
also contact the Research Governance Officer on tel: 02 8382 2075 and quote reference number: 
/14/SVH/413. 
 
 
--- 
 
Thank you for taking the time to consider this study. 
If you wish to take part in it, please sign the attached consent form. 
This information is for you to keep or dispose of as you see fit. 
 
--- 
 
 
 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 97 of 99 
[Insert institutional logo] 
[name of local institution/s where research is being conducted] 
CONSENT FORM 
To be used in conjunction with Participant Information 
ADVICE Study: Attenuation of D-dimer using Vorapaxar to target Inflammatory and Coagulation 
Endpoints 
 
1.  I agree to participate as a participant in the study described in the Participant Information attached 
to this form. 
 
2. 
I acknowledge that I have read the Participant Information, which explains why I have been selected, 
the aims of the study and the nature and the possible risks of the investigation, and the information 
has been explained to me to my satisfaction. 
 
3. 
Before signing this consent form, I have been given the opportunity to ask any questions relating to 
any possible harm I might suffer as a result of my participation and I have received satisfactory 
answers. 
 
4. 
I understand that I can withdraw from the study at any time without prejudice to my relationship with 
my doctor or to the University of New South Wales [or insert name of local institution]. 
 
5. 
I agree that research data gathered from the results of the study may be published, provided that I 
cannot be identified. 
 
6. 
I understand that if I have any questions relating to my participation in this research, I may contact 
[insert name] on telephone [insert phone number], who will be happy to answer them. 
 
7. 
I agree to have my blood samples stored for this study as well as future research studies related to 
HIV infection and immunity. 
 
8. 
I understand that some of the exact studies for which my stored samples shall be processed are not 
yet known. 
 
9. 
I understand that my local doctor (if applicable) will be informed by the study team in writing of my 
participation in this research study. 
 
10. I acknowledge receipt of a copy of this Consent Form and the Participant Information. 
 
11. For women of child bearing potential only:  In the event of pregnancy,  
□I agree to have pregnancy data submitted to the Antiretroviral Pregnancy Registry ___(Patient’s 
initial);  
□I do not agree to have pregnancy data submitted to the Antiretroviral Pregnancy Registry ____ 
(Patient’s initial). 
 
Complaints may be directed to [insert local details] 
 
 
Signature of participant 
 
 
Please PRINT name  
 
 
Date 
 
 
Signature of witness*                 
 
Please PRINT name 
 
               Date 
 
 
Signature of investigator  
 
              Please PRINT name 
 
 
Date 
 
*“By signing the consent form, the witness attests that the information in the consent form and any other written information was accurately 
explained to, and apparently understood by, the subject or the subject’s legally acceptable representative, and that informed consent was freely 
given by the subject or the subject’s legally acceptable representative” (ref: ICH GCP 4.8.9) 
 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 98 of 99 
 
[Insert institutional logo] 
[name of local institution/s where research is being conducted] 
 
 
ADVICE Study: Attenuation of D-dimer using Vorapaxar to target Inflammatory and Coagulation 
Endpoints 
 
 
REVOCATION OF CONSENT 
 
 
I hereby wish to WITHDRAW my consent to participate in the study described above and understand that 
such withdrawal WILL NOT jeopardise any treatment or my relationship with the Insert Site Name or my 
medical attendants. 
 
 
 
 
_________________________  
______________________________ 
____________________ 
 
Signature of participant 
 
Please PRINT name  
 
 
Date 
 
 
The section for Revocation of Consent should be forwarded to [insert details] 
 
 
 


 
ADVICE Final Protocol Version 3, 12 July 2016                                                                              Page 99 of 99 
Appendix 6: Investigator Agreement and Signature Page 
between the UNSW/Sponsor (if applicable) and the study investigator(s) 
 
 
Site Name:       
 
Principal Investigator:         
 
Co-investigators (please list, if applicable):         
 
 
Study Title:   ADVICE: Attenuation of D-dimer using Vorapaxar to target Inflammatory and Coagulation 
Endpoints: A double blind randomised comparison of vorapaxar versus placebo for the treatment of 
HIV associated inflammation and coagulopathy in patients with well controlled HIV replication 
 
Protocol Version Number:   3 
 
Protocol Version Date:   12 July 2016 
 
 
I/We agree to follow the procedures outlined in this protocol.  I/We accept responsibility for the conduct of the 
research detailed in the proposal including all protocol-specific assessments, and I/We agree to abide by all 
decisions made by our Ethics Committee and Regulatory Agency. I/We agree to ensure the informed consent 
process is conducted with each participant in compliance with ICH GCP guidelines. 
 
 
PRINCIPAL/RESPONSIBLE INVESTIGATOR 
 CO-INVESTIGATOR(S) 
(signature and date) 
 
 
 
 
(signature/s and date/s) 
 
_____________________________________ 
 
___________________________________ 
 
SPONSOR’S REPRESENTATIVE 
 
 
               ___________________________________ 
(signature and date) 
 
_____________________________________ 
 
___________________________________ 
 
SPONOR’S MONITOR(S)/COORDINATOR(S)  
                ______________________________________ 
(signature/s and date/s) 
 
_____________________________________ 
 
 
 

SAP_001.pdf: