Cost-effectiveness of Different Antiretroviral Treatment in Patients HIV Naive. Randomized Clinical, Not Masked, Trial Comparing DRVr3TC, ABC3TC (Kivexa) RPV, or EVG COBI FTC TDF (Stribild) for 48 Weeks
Phase: PHASE4
Conditions: Patient Compliance, Antiretroviral Therapy Intolerance
Sponsor: Juan A. Arnaiz

Protocolo Cost-effect-clinic 
Nº EudraCT: 2014-004820-24 
Protocolo versión 1.0 de 04 de octubre de 2014 
1 
 
 
Cost-effectiveness of different antiretroviral treatment 
regimens in naïve patients. Randomized, open-label clinical 
trial comparing DRV/r+3TC, AUC+3TC (Kivexa)+RPV, or 
EVG/COBI/FTC/TDF (Stribild) for 48 weeks 
 
 
 
 
CLINICAL TRIAL PROTOCOL WITH DRUGS 
 
 
 
 
Protocol Code: Cost-Effect-Clinic 
 
 
 
 
 
 
 
 
Version / Date: 1.0 / October 04, 2014 EudraCT 
number: 2014-004820-24 
 
SPONSOR: Clinic Foundation for Biomedical Research 
Principal Investigator and coordinator of the study: 
Dr. Josep Mallolas 
Infectious Diseases Service. Hospital 
Clínic de Barcelona. 
Spain. 
Phone: +34 932275400 / ext 3312 Email: 
mallolas@clinic.ub.es 

Protocolo Cost-effect-clinic 
Nº EudraCT: 2014-004820-24 
Protocolo versión 1.0 de 04 de octubre de 2014 
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1. 
 SUMMARY 
 
1.0. Type of application: 
Prospective, comparative, randomized, open-label, single-center, phase IV clinical trial. 
 
1.1. Identification of the developer: 
Clínic Foundation for Biomedical Research 
C. Roselló, 143 
08036 Barcelona 
 
1.2. Clinical Trial Title: 
 
Cost-effectiveness of different antiretroviral treatment regimens in naïve patients. 
Randomized, open-label clinical trial comparing DRV/r+3TC, AUC+3TC (Kivexa)+RPV, or 
EVG/COBI/FTC/TDF (Stribild) for 48 weeks 
Version / Date: 1.0 / October 4, 2014. 
 
 
1.3. Protocol code: Cost-Effect-Clinic. 
 
 
EudraCT number: 2014-004820-24 
1.4. Principal Investigator and Study Coordinator: Dr Josep Mallolas, 
Collaborating Investigators: Dr Maria Martínez 
 
1.5. Centres in which the trial is planned to be carried out: 
The study will be Unicentric (Hospital Clínic de Barcelona). 
 
 
1.6. Clinical Research Ethics Committees that have approved the trial: 
The trial has been submitted to the CEIC of the Hospital Clínic de Barcelona. 
 
1.7. Name and qualification of the person responsible for monitoring: 
Dr. Anna Cruceta. 
Clinical Trials Unit. 
CTU Clinic. Clinical Pharmacology Service. 
(Hospital Clínic de Barcelona). 
 
 
1.8. Information about study medications: 
 
DRV/r+3TC, 
ABC+3TC (Kivexa)+ RPV 
ECG / COBI / FTC / TDF (Stribild) 
 
1.9. Clinical Trial Phase: Phase IV 

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Nº EudraCT: 2014-004820-24 
Protocolo versión 1.0 de 04 de octubre de 2014 
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1.10. 
Objectives: 
1.10.1. Main objective: 
 
The main objective of this study is to determine the efficiency (cost-effectiveness) or cost per 
responder) at 48 weeks after initiation of antiretroviral treatment, taking as a reference the Stribild 
arm 
 
 
1.10.2. Secondary objectives: 
• 
Virologic efficacy at 48 weeks (using standard plasma viral load with a limit of detection of 50 
copies/mL) 
• 
CD4+ Cell Response 
 
• 
Change in body composition and bone mineral density (body and lumbar) measured with DEXA 
• 
Renal function markers (creatinine, estimated glomerular filtration rate (eGFR)) and renal tubular 
function 
 
• 
Mortality and clinical progression 
 
• 
Safety study, including: vitamin D levels, plasma lipids at the beginning and end of the study, as 
well as overall tolerability. 
 
 
 
1.11. Design: 
Prospective, comparative, three-parallel-group, randomized, open-label, single-center, Phase IV 
clinical trial. 
 
 
1.12. Disease under study: 
HIV infection 
 
1.13. Assessment variables: 
1.13.1. Principal 
Cost-effectiveness of antiretroviral therapy at 48 weeks from baseline, based on the Stribild arm. 
Economic evaluation of costs and efficiency (cost/effectiveness) through the construction of decision 
trees. Efficacy was defined as the probability of having a viral load <50 copies/mL at week 48 in 
intention-to-treat analysis. The cost of starting treatment with a regimen was defined as the costs of 
ART and all its consequences (adverse effects, changes in antiretroviral regimen, resistance study, 
days of work missed by the patient and number of days of hospital admission) that occur in the 
following 48 weeks. The perspective of the National Health System was used, considering only 
differential direct costs: drugs (at official price), management of adverse effects, resistance studies 
and determination of HLA B*5701. The scope is the Spanish state, with updated costs. Deterministic 
sensitivity analyses were performed constructing three scenarios for each guideline: baseline, most 
favorable and most unfavorable. 
The application to calculate the prices of antiretrovirals is located on the GSIDA website and can be 
accessed completely free of charge. 

Protocolo Cost-effect-clinic 
Nº EudraCT: 2014-004820-24 
Protocolo versión 1.0 de 04 de octubre de 2014 
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http://www.gesida-seimc. 
org/contenidos/utilidades/aplicacion-tarv-vih-gesida-2014.exe or 
https://dl.dropboxusercontent.com/u/35731022/coste-eficacia- 
2014/aplicacion-tarv-vih-gesida-2014.exe. 
 
1.13.2. Secondary 
• 
Proportion of patients with virologic response at 48 weeks (plasma viral load less than 50 
copies/mL) 
 
• 
Change in CD4+ cell count at 48 weeks 
 
• 
Change in body composition and bone mineral density (body and lumbar) measured with DEXA 
at baseline and at 48 weeks 
 
• 
Change in markers of renal function (creatinine, estimated glomerular filtration rate – eGFR-) 
and renal tubular function at 48 weeks 
 
• 
Mortality rate and clinical progression at 48 weeks 
 
• 
Safety and overall tolerability: description of adverse events (AEs) and serious AEs. 
 
 
 
1.14. Study population and total number of patients: 
Adult patients with chronic HIV infection who have not received antiretroviral treatment. 
A total of 150 patients will be included, 50 per arm, to detect differences in the cost-effectiveness 
ratio of more than €300 per year. 
 
 
1.15. Duration of treatment: 
The approximate expected duration for the inclusion of patients is 12 months; The duration of 
treatment will be 48 weeks. 
 
 
1.16. Schedule and expected completion date: 
The study is expected to begin, once permits have been obtained, in March 2015. The recruitment 
period will be one year. Patients will be followed for 48 weeks from the start of treatment. The study 
is expected to be completed after the last visit of the last patient included in March 2017. 

Protocolo Cost-effect-clinic 
Nº EudraCT: 2014-004820-24 
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1. INDEX 
 
1. SUMMARY 
2. INDEX 
 
3. OVERVIEW 
 
4. JUSTIFICATION 
5. OBJECTIVE AND PURPOSE OF THE TRIAL 
 
6. ESSAY DESIGN 
 
7. SUBJECT SELECTION AND WITHDRAWAL 
8. TREATMENT OF SUBJECTS 
9. ASSESSMENT OF EFFECTIVENESS 
10. SAFETY RATING 
11. STATISTICS 
12. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
 
13. ETHICS 
 
14. DATA MANAGEMENT AND ARCHIVING OF RECORDS 
15. FINANCING AND INSURANCE 
 
16. PRIVACY POLICY 
 
 
Annexes and documents: 
 
Annex I 
Protocol Acceptance IP Document Annex II
 
 Toxicity Grading Table (WHO) 
Annex III 
Serious Adverse Event Reporting Form. 
Annex IV 
Serious and Unexpected Adverse Event Reporting Form Annex VII
 
Declaration of Helsinki. 
Annex IX 
Civil Liability Insurance 

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3. Overview 
 
3.1 Trial identification 
Title: 
Cost-effectiveness of different antiretroviral treatment regimens in naïve patients. 
Randomized, open-label clinical trial comparing DRV/r+3TC, AUC+3TC (Kivexa)+RPV, or 
EVG/COBI/FTC/TDF (Stribild) for 48 weeks 
 
Protocol Code: Cost-Effect-Clinic 
 
Version / Date: 1.0 / October 4, 2014. EudraCT 
number: 2014-004820-24 
 
 
 
3.2 Developer Identification 
Clinic Foundation for Biomedical Research. 
C/ Rossello 143 
8036 elona 
 
 
3.3 Identification of the promoter's representative 
Manager: Ms. Rosa Vilavella Gasull Clinical 
Foundation for Biomedical Research. C/ 
Rossello 143 
8036 elona 
 
 
3.4 Identification of researchers of the sponsoring entity 
Hospital Clínic 
Principal Investigator and Study Coordinator: 
Dr. Josep Mallolas Masferrer 
Infectious Diseases Service. 
 
Collaborating researchers: 
Dr Maria Martínez from the Infectious Diseases Service 
 
 
3.5 Identification of principal investigators from participating centers 
The study is single-center. It will be held at the Hospital Clinic of Barcelona 
 
 
3.6 Identification of researchers from other services involved. 
Biostatistician: Elisa DeLazzari 
Pharmacy: Begoña Gómez, GloriaMolas 
Laboratory Technician: Pilar Callau 

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3.7 Information on the laboratories or technical departments involved 
Clinical evaluation of patients included in the study, routine blood/urine laboratory determinations 
and viral (HIV) determinations, will be performed at the Infections Day Hospital. And Retrovirology 
and Immunopathology Laboratory of the Infection Service: 
 
 
3.8 Monitoring 
CTU (Clinical Trials Unit). Clinical 
Pharmacology Service. Hospital 
Clínic de Barcelona 
Monitoring manager: Dr. Anna 
Cruceta. acruceta@clinic.ub.es 
tel 932275400 ext 4380 fax 932279877 
 
 
4.  Justification 
HIV-infected patients can live longer thanks to effective antiretroviral treatment. In addition, efforts 
are being made to diagnose people who may be infected with HIV as soon as possible, and the 
initiation of antiretroviral treatment is increasingly recommended and at earlier stages. 
 
On the other hand, antiretroviral treatment must be administered indefinitely. All these factors have 
contributed to the incessant increase in the budget for antiretroviral treatment, in such a way that its 
provision free of cost represents a major challenge for public health systems even in developed 
countries such as Spain. 
 
Stribild ® has become standard of care in patients not previously treated with antiretrovirals. It is a 
triple antiretroviral treatment option in a single pill, very effective, well tolerated and whose treatment 
cost is competitive compared to other options in naïve patients. 
Kivexa ® + RPV was tested in the Thrive study and the overall result was similar to Truvada ® 
+ RPV. However, the direct cost may be lower, the more favorable cost-effectiveness, renal tubular 
toxicity, and the reduction in bone mineral density should be lower. 
 
Finally, the efficacy of a nucleoside analogue-sparing regimen composed of LPV/r 
+3TC in patients without prior antiretroviral treatment was demonstrated in the Gardel study (even 
among those patients with a high baseline viral load). Most likely, substituting LPV/r for DRV/r would 
be associated with an even better outcome, including better tolerance. Considering that 3TC, the 
combination of ritonavir-boosted PI in treatment-naïve patients may be associated with the most 
favorable cost-effectiveness. 
Hypothesis: 
In naive patients, DRV/r + 3TC or Kivexa ® + RPV will have a similar cost-effectiveness (efficiency) 
compared to Stribild ® at 48 weeks in patients not previously treated with ARV and with a baseline 
viral load below 100,000 copies of HIV per mL. 
 
 
4.1 Identifying investigational drugs 
 
Study Guidelines: 
1. 
Darunavir 800 mg (Prezista®) 1 pack of 800 mg + Ritonavir 100 mg (Norvir®) 1 tablet of 
100mg + lamivudine (Epivir®) 1 pack of 300 mg. QD. When Darunavir 

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800 mg plus Cobicistat 150 mg is marketed as a single tablet, DRV/r will be replaced by said 
single tablet. 
1. 
Abacavir 600 mg + lamivudine 300mg (Kivexa®) 1cp + rilpivirine (Edurant®) 1 coated 
purchase of 25 mg. QD. With food. 
2. 
EVG / COBI / FTC / TDF (Stribild®) 150 mg de elvitegravir, 150 mg de cobicistat, 200 mg de 
emtricitabina y 245 mg de tenofovir disoproxil. 1 compr recubierto QD 
 
 
4.2 Investigational Drug Information 
The antiretrovirals used in the study are approved and registered in the European Union for use in 
patients with HIV infection. 
 
 
4.3 Treatment Dosage Guidelines 
1. 
Guideline 1: (Prezista®): 1 tablet + (Norvir®) 1 tablet (Epivir®) 1 tablet. In total: three 
tablets orally once daily 
2. 
Guideline 2: (Kivexa®) 1 tablet + (edurant®) 1 coated tablet. In total two tablets orally 
once a day 
3. 
Regimen 3: (Stribild®) 1 tablet. In total one tablet orally once a day. 
 
 
Description: 
 
These drugs are all indicated for the treatment of human immunodeficiency virus-1 (HIV-1) infection in 
adults 18 years of age or older. 
 
The study is an initiative of an independent promoter and does not receive any grant or financial aid 
from the pharmaceutical industry or any other institution. It is self-financed with funds from the 
infectious diseases service of the Hospital Clínic 
 
Route of administration: oral 
 
Storage: Keep in the original packaging to protect it from moisture. Keep the bottle tightly closed. 
The treatments used in the study do not require special conditions for their conservation. 
 
 
Study period and treatment: 
Randomization to three treatment groups: 
 
GROUP 1 (control): (prezista®): 1 tablet + (norvir®) 1 tablet (epivir®) 1 tablet. In total: three tablets 
orally once daily for a period of 48 weeks. 
 
GROUP 2 (control): (Kivexa®) 1 tablet + (edurant®) 1 coated tablet. In total, two tablets orally once a 
day for a period of 48 weeks. 
 
GROUP 3: (experimental)(Stribild®) 1 tablet. In total, one tablet orally once a day for a period of 48 
weeks. 
 
 
 
4.4 Compliance Statement 
 
General considerations: 

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The study will be carried out in accordance with the principles emanating from the Declaration of 
Helsinki (see annex), and in accordance with current legal regulations (Royal Decree 223/2004), and 
will not begin until the approval of the CEIC and the authorisation of the AEMPS have been 
obtained. 
 
 
4.5 Study population 
Adults with HIV-1 infection who have not received antiretroviral treatment and who attend the 
Infectious Diseases Service of the Hospital Clinic of Barcelona. 
 
 
4.6 Relevant Bibliography 
 
1. 
Blasco AJ, et al. Costs and cost-efficacy analysis of the 2014 GESIDA/Spanish National AIDS 
Plan recommended guidelines for initial antiretroviral therapy in HIV-infected adults. Enferm 
Infecc Microbiol Clin. 2014. 
2. 
A 
randomized, 
double-blind 
comparison 
of 
single-tablet 
regimen 
elvitegravir/cobicistat/emtricitabine/tenofovir 
DF 
vs 
ritonavir-boosted 
atazanavir 
plus 
emtricitabine/tenofovir DF for initial treatment of HIV-1 infection: analysis of week 144 results. 
Clumeck N, Molina JM, Henry K, Gathe J, Rockstroh JK, DeJesus E, Wei X, White K, Fordyce 
MW, Rhee MS, Szwarcberg J; GS-236-0103 Study Team. J Acquir Immune Defic Syndr. 2014 
Mar 1; 65(3):e121-4. 
3. 
A 
randomized, 
double-blind 
comparison 
of 
single-tablet 
regimen 
elvitegravir/cobicistat/emtricitabine/tenofovir 
DF 
versus 
single-tablet 
regimen 
efavirenz/emtricitabine/tenofovir DF for initial treatment of HIV-1 infection: analysis of week 
144 results. Wohl DA1, Cohen C, Gallant JE, Mills A, Sax PE, Dejesus E, Zolopa A, Liu HC, 
Plummer A, White KL, Cheng AK, Rhee MS,Szwarcberg J; GS-US-236-0102 Study Team. J 
Acquir Immune Defic Syndr. 2014 Mar 1; 65(3):e118-20. 
 
4. 
Cohen CJ, Andrade-Villanueva J,Clotet B, et al.on behalf of the THRIVE study group. 
Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse 
transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, 
randomised, non-inferiority trial. The Lancet, Volume 378, Issue 9787, Pages 229 - 237, 16 
July 2011 
5. 
Cahn P et al. Dual therapy with lopinavir/ritonavir (LPV/r) and lamivudine (3TC) is non- inferior 
to standard triple drug therapy in naive HIV-1 infected subjects: 48-week results of the 
GARDEL study.14th European AIDS Conference, Brussels, abstract LBPS7/6, 2013. 
 
 
 
5.  Objective and Purpose of the Trial 
Principal: 
The main objective of this study is to know the efficiency (cost-effectiveness) at 48 weeks after 
initiation of antiretroviral treatment of three treatment strategies 
 
 
Side: 
1. 
Proportion of patients with virologic response at 48 weeks (plasma viral load less than 50 
copies/mL) 

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• 
Change in CD4+ cell count at 48 weeks 
• 
Change in body composition and bone mineral density (body and lumbar) measured with DEXA at 
48 weeks 
 
• 
Change in markers of renal function (creatinine, estimated glomerular filtration rate – eGFR-) and 
renal tubular function at 48 weeks 
 
• 
Mortality rate and clinical progression at 48 weeks 
 
• 
Safety and overall tolerability: description of adverse events (AEs) and serious AEs. 
 
 
6.0  Trial Design 
Prospective, open-label, Phase IV, pilot, single-center prospective study. 
 
 
6.1 Primary and secondary Endpoints 
Primary Endpoint: 
The main objective of this study is to know the efficiency (cost-effectiveness) at 48 weeks after 
initiation of antiretroviral treatment. of three treatment strategies 
Methodology: The economic evaluation of costs and efficiency (cost/effectiveness) is carried out 
through the construction of decision trees. Efficacy was defined as the probability of having a viral 
load 
<37 copies/mL at week 48 in intention-to-treat analysis. The cost of starting treatment with a regimen 
was defined as the costs of ART and all its consequences (adverse effects, changes in antiretroviral 
regimen, resistance study if necessary, days of sick leave by the patient and days of hospital 
admission) that occur in the following 48 weeks. The perspective of the National Health System will 
be used, considering only differential direct costs: drugs (at official price), management of adverse 
effects, resistance studies and determination of HLA B*5701. The scope is Spain, with updated 
costs. Deterministic sensitivity analyses will be performed by constructing three scenarios for each 
guideline: baseline, most favorable and most unfavorable. 
 
The application to calculate the prices of antiretrovirals is located on the GSIDA website and can be 
accessed completely free of charge. 
http://www.gesida-seimc. 
org/contenidos/utilidades/aplicacion-tarv-vih-gesida-2014.exe or 
https://dl.dropboxusercontent.com/u/35731022/coste-eficacia- 
2014/aplicacion-tarv-vih-gesida-2014.exe. 
 
 
Secondary endpoints: 
• 
Proportion of patients with virologic response at 48 weeks (plasma viral load less than 50 
copies/mL) 
 
• 
Change in CD4+ cell count at 48 weeks 
 
• 
Change in body composition and bone mineral density (body and lumbar) measured with DEXA at 
48 weeks 
• 
Change in markers of renal function (creatinine, estimated glomerular filtration rate – eGFR-) and 
renal tubular function at 48 weeks 
 
• 
Mortality rate and clinical progression at 48 weeks 

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6.2 Design 
Although the hypothesis of the study has been based on various congruent information that allow us 
to face with sufficient guarantee the feasibility of the study and the eventual demonstration of the 
main hypothesis, we are not absolutely certain that an unacceptably high virological failure rate 
(standard viral load ≥37 copies/mL on two consecutive occasions) may occur in the experimental 
arm. We will consider a priori that the failure of at least 20% (n=6) of the patients in the experimental 
arm will represent an unacceptably high virological failure rate. In this case, its conclusion will be 
considered premature. In this extreme case, the data of the patients already included up to the time 
of the premature conclusion of the study would be analyzed. 
 
The present study is proposed as a proof of concept to be able to formulate another study with a 
sufficiently large sample size to adequately demonstrate the non-inferiority of the strategy. The 
results of the present study can help to design the non-inferiority study and to estimate its sample 
size. 
 
 
STUDY PROCEDURES 
 
 
Vital signs 
X 
Weight Determination 
X 
Height determination 
X 
Demographics 
X 
Medical history 
X 
Physical examination 
X 
Concomitant Medications 
X 
Confirmation of the use of contraceptive methods by the patient and his or her partner 
X 
 
Clinical Evaluations 
Basal 
Day 
0 
S 4 
(#) 
S 12 
(#) 
S 24 
(#) 
S 36 
(#) 
S 48 
(#) 
Meet inclusion and exclusion criteria 
X 
Signed informed consent 
X 
Vital signs 
X 
Weight 
X 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
Simplified Compliance Questionnaire 
X 
X 
X 
X 
X 
Haematology 
X 
X 
X 
Blood biochemistry with GFR and renal 
function 
X 
X 
X 
Standard plasma viral load 
X 
X 
X 
X 
X 
X 
Immunology (CD4/CD8) 
X 
X 
X 
DEXA 
X 
X 
Pregnancy test (only in women susceptible to 
pregnancy (&) 
X 
X 
X 
X 
X 
X 
Urinalysis (basic) (*) 
X 
X 
X 
Questionnaire on loss of working days/days of 
income 
X 
X 
X 
X 
X 

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All laboratory specimens should be obtained prior to administration of the first dose of study 
medication. 
 
& At baseline visit it is advised to perform a blood pregnancy test 
* 
Basic sediment, proteinuria, hematuria, protein/creatinine ratio. 
Blood biochemistry: lipids (TG, total cholesterol and HDL), creatinine and estimated glomerular filtration rate 
(CPK-EPI), 
Hematology: basic blood count 
 
 
 
6.3 Guidelines for Modifying Patient Treatment Doses 
Grade 1 and 2 AEs require close follow-up but no change in treatment. 
 
All grade 3 toxicities will be treated by the investigator of the center according to medical criteria. 
Any grade 4 toxicity that, in the opinion of the investigator of the center, is directly related to the 
treatment of the study, will be treated with the permanent suspension of the study. 
 
In all cases, the recommendations contained in each of the technical data sheets of the drugs 
used in this study will be followed (see Fact Sheets) 
 
6.4 Trial Treatments 
DRUG SUPPLY AND LABELLING 
 
This study uses drugs that have already been marketed and authorized for use in HIV-infected 
patients; The study drug will be distributed by the Pharmacy service of the Hospital Clínic. For 
clinical trials carried out in Spain, labelling in Spanish is mandatory in accordance with the 
regulations currently in force. 
 
 
6.5 Trial duration 
The approximate expected duration for the inclusion of patients is 12 months, and the duration of 
treatment and follow-up of the included patients will be extended by a maximum of 48 weeks. 
 
 
6.6 Termination and/or discontinuation criteria 
The treatment will be compulsorily terminated during the study for any of the following reasons: 
 
1. Virologic failure, defined by two consecutive standard viral load determinations >37 copies/mL 
separated by at least one week from each other. 
2. I express the patient's wish. 
3. Medical decision. 
4. Death. 

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7. Pregnancy detection during the study. 
 
Treatment may be terminated during the study for any of the following reasons: 
 
8. The medical investigator determines that a SAE is possibly or likely related to the study drug. 
9. Failure to administer, evaluate, or other study requirements. 
 
If the confirmatory result is ≥37 copies/mL, a genotypic resistance detection study would be 
scheduled and the most appropriate attitude towards modifying their antiretroviral treatment would be 
discussed with the patient. In this case, unless he or she is against it, the patient would continue in 
the study. 
 
The resistance study should be carried out only in case of virilological failure. 
 
Do not confuse virological failure with viral load "blip". In case of detection of a single viral load 
determination > to 37 colpias/mL followed by an undetectable viral load determination, it shall be 
defined as blip. 
To be considered virological failure, there must be two consecutive determinations of standard 
viral load >37 copies/mL separated by at least one week between them and a maximum of 4 weeks. 
 
 
6.7 End of rehearsal 
The end of the trial will be considered the time of the last visit of the last subject recruited. 
 
 
7.  Subject Selection 
7.1 Inclusion criteria for subjects 
A patient must meet ALL of the criteria listed below in order to participate: 
 
1. Adults (≥18 years) 
2. Negative pregnancy test in women of childbearing potential, and commitment to use 
acceptable contraceptive methods from at least 2 weeks before day 1 and until at least 6 
months after the last dose of study drug. 
 
3. Clinically stable HIV-1 infection and who have not received prior antiretroviral treatment 
 
4. Have HIV viral load < 100,000 copies/mL 
 
5. Have CD4 levels >100 mm3 
6. Glomerular filtration rate of > 70ml/min 
 
7. Have HLA B5701 negative 
 
8. Patients must have given written informed consent 
9. In the opinion of the researcher, to be able to follow the design of the protocol visits. 

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7.2 Exclusion Criteria 
Patients who meet ANY of the following criteria will be excluded from the study: 
 
1. Patients who have had previous virologic failure with any antiretroviral regimen 
 
2. Evidence of prior mutations against some of the study drugs 
 
3. 
Use of any other chronic antiretroviral therapy has been introduced within 6 months prior to the 
patient's entry into the study 
 
4. Any contraindications to study drugs 
 
5. 
Any condition that does not allow the patient to ensure correct adherence to the study at the 
discretion of the physician 
 
6. Uncontrolled pre-existing psychiatric illness 
 
7. Any current signs of alcoholism or active drug addiction 
 
 
 
7.3 Withdrawal criteria 
The initial antiretroviral treatment regimen may be changed in any of the following situations: 
 
• 
Patient with virologic failure or clinical progression 
• 
Serious adverse events possibly or probably related to the study drug. 
• 
Pregnancy during the study. 
 
• 
Express wish of the patient 
 
• 
Medical criteria 
 
• 
Patient non-adherence or non-compliance with study tests, evaluations, or other procedures. 
 
All patients who, after starting the assigned treatment, abandon the treatment under study or are 
withdrawn for any reason, will be included in an analysis "by intention to treat". 
 
Patients who do not continue to attend the visit (follow-up losses) will be considered for analysis until 
such time as the loss occurs. 
 
 
 
8. Treatment of Subjects 
8.1 Treatment Branches 
A total of 150 patients will be included. 

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Randomization to three treatment groups in an equivalent ratio between arms (1:1:1). Random 
assignment will be centralized. 
 
There will be no stratification by subgroups. 
The list of random numbers will be generated by a computer program. The investigator will not know 
the size of the randomization blocks and will not be aware of the assignment of each patient until 
the time of inclusion. 
 
The CRD data collection notebook will be electronic. 
 
 
GROUP 1 (control): (prezista®): 1 tablet + (norvir®) 1 tablet (epivir®) 1 tablet. In total: three tablets 
orally once daily for a period of 48 weeks 
 
GROUP 2 (control): (Kivexa®) 1 tablet + (edurant®) 1 coated tablet. In total, two tablets orally once 
daily for a period of 48 weeks 
 
GROUP 3: (experimental)(Stribild®) 1 tablet. In total, one tablet orally once a day for a period of 48 
weeks. 
 
 
 
8.2 Concomitant and rescue medication 
Any concomitant medication must be reflected in the CRF in an appropriate way (detailing the 
product, dosage, route, days of administration, reason for treatment, etc.). 
 
Treatments not allowed: 
 
Those specified in the technical sheets. (see technical sheets) 
 
 
8.3 Compliance monitoring 
Adherence: to ensure the control and registration of medication, an adherence questionnaire will be 
added to the data collection notebook. At each visit, the investigator will ask the patient about 
treatment adherence. 
 
Tablet count: The patient will be asked to bring any leftover medication or empty bottles with them to 
check whether or not they have taken all the capsules or tablets of the medication since the previous 
visit. 
 
 
 
9. Effectiveness Assessment 
9.1 Efficiency parameters 
 
 
Virological tests 
a) Determination of viral load 
Standard determination of viral load (limit of detection 37 copies/mL) The virologic response 
shall be defined as plasma viral load <37 copies/mL. Once undetectability has been 
achieved, if a plasma viral load ≥37 copies/mL. is subsequently determined, the plasma viral 
load determination shall be repeated during the following week for confirmation. 

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16 
 
 
 
 
 
b) Methods of Analysis and Sensitivity 
The standard HIV-1 viral load in the plasma sample will be previously performed using the 
commercial VERSANT HIV-1 RNA 1.0 Assay (kPCR) (SIEMENS HEALTHCARE 
DIAGNOSTICS) technique with a sensitivity of up to 37 copies/mL. The manufacturer's 
recommendations will be followed. 
 
 
Other Tests 
The estimated glomerular filtration rate will be calculated using the usual formula, available in 
http://www.nephron.com/MDRD_GFR.cgi . 
 
Cost/effectiveness assessment. 
The software available in the GSIDA application will be used: 
http://www.gesida-seimc.org/contenidos/utilidades/aplicacion-tarv-vih-gesida-2014.exe or 
https://dl.dropboxusercontent.com/u/35731022/coste-eficacia-2014/aplicacion-tarv-vih-gesida- 
2014.exe. 
 
 
10. Safety Rating 
10.1 
Detection and recording of Adverse Events 
It is the investigator's responsibility to detect and document any event that meets the criteria and 
definitions of adverse event (AE) or serious adverse event (SAE) as set forth in this protocol. During 
the study, the existence of adverse events, whether serious or not, will be checked in accordance 
with the definition given in this section of the protocol. 
 
a) Minimum information to be specified: 
 
Description/definition: 
 
Adverse event (AE) is any adverse health event in a patient or clinical trial subject treated 
with a medicine, even if it is not necessarily causally related to that treatment. Therefore, it can be 
any unfavorable and unintended signs (including an abnormal laboratory finding), symptom, or 
illness temporarily associated with the use of an investigational drug, whether or not related to the 
investigational drug. 
Laboratory abnormalities of clinical importance that meet one or more of the following criteria are 
also considered AEs: 
 
• 
It requires additional intervention or treatment. 
• 
Requires a modification of the dose. 
• 
It is accompanied by a clinical manifestation. 
 
Any analytical anomaly that the investigating physician considers to be of clinical importance must be 
recorded as such in the printed copy of the laboratory report, indicating the physician's initials and 
the date of revision. An AA is also considered to be any event associated or observed in conjunction 
with an accidental or intentional overdose of the product, or with abuse or withdrawal of the product. 
 
All AEs will be recorded in the subject's medical record and in the eCRDe. The start and end dates 
of each AA, the intensity and the relationship with the study drug will be recorded. 

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Criteria for subject treatment, dose discontinuation, dosage adjustment, withdrawal, or treatment 
changes will only apply to toxicities attributable to study drugs. 
 
The classification system for drug toxicity is set out in the DAIDS Table for Grading the Intensity of 
Adverse Events in Adults and Children, which can be found on the DAIDS RSC website: 
http://rsc.tech-res.com/safetyandpharmacovigilance/. 
 
In addition, for each AA, the measures taken or the outcome (e.g. hospitalization, discontinuation of 
treatment) will be recorded. 
 
 
Adverse reaction (AR) is any harmful, unintended reaction to an investigational drug, 
regardless of the dose administered. In this case, there is a suspicion of a causal relationship 
between the investigational drug and the adverse event. 
Serious adverse event (SAE) is any adverse event that, at any dose, results in death, 
threatens the life of the subject, makes hospitalization necessary or prolonged hospitalization, results 
in permanent or significant disability or disability, or results in a congenital anomaly or malformation. 
For the purposes of notification, suspected adverse events that are considered medically significant, 
even if they do not meet the above criteria, will also be treated as serious, including major medical 
events that require intervention to prevent one of the consequences described above from occurring. 
Likewise, all suspected transmission of an infectious agent through a drug will be reported as 
serious. Examples of these events include allergic bronchospasm requiring intensive treatment in an 
emergency department or at the individual's home, blood dyscrasia or seizures that do not require 
hospitalization, or the development of drug dependence or abuse. 
 
Medical and scientific judgement should be used to decide whether other situations that have not 
resulted in the outcomes listed in the above definitions should be reported as SAGs. 
 
A life-threatening term is defined as a situation where, in the opinion of the physician, the patient at 
the time of the adverse event or adverse reaction is at real risk of death. 
 
Hospitalization or prolongation of a hospitalization is a criterion for considering an AA to be serious. 
Only admission in which the patient spends the night in the hospital should be considered as 
hospitalization. The following situations will not meet the AAG criteria: 
- 
if hospitalization or prolongation of hospitalization is necessary to perform a procedure 
required by the protocol (for example, if day or night visits will be made for biopsies or 
surgeries required by the protocol). 
 
- 
if hospitalization or prolongation of hospitalization is part of the facility's routine procedure 
(e.g., removal of a stent after surgery) 
- 
in case of scheduled hospitalization for a pre-existing process that has not worsened (e.g. 
scheduled hospitalization for the implantation of a knee prosthesis for a previous osteoarthritis 
process) 
 
 
Grade IV laboratory alterations will be considered AAG. 
 
DO NOT confuse the concept of "serious" with "severe" which refers to the intensity of the adverse 
event or adverse reaction. 

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Unexpected serious adverse reaction (RAGI) is a serious adverse reaction whose nature 
or severity does not correspond to the information regarding the product (for example, the 
investigator's manual in the case of an investigational medicinal product not authorised for marketing 
or the product label in the case of an authorised medicinal product). 
 
 
b) Imputability criteria. 
The causal relationship between the investigational product and the occurrence of AA/AAG shall be 
established on the basis of clinical judgment. To this end, other causes will be considered and 
studied, such as the natural history of the underlying diseases, concomitant treatment, other risk 
factors and the temporal relationship of the event with the investigational product. In addition, the 
technical data sheet of the products will be consulted. 
 
In order to analyse the possible cause-effect relationship, the temporal relationship between the 
administration of the drug and the AA, possible alternative causes, the evolution (complete 
remission, partial recovery, death, sequelae, persistence), persistence or not after the suspension of 
administration, reappearance with the readministration of the product or the prior knowledge of said 
event coinciding with the known or expected response pattern of the drug under study will be 
considered. 
The causal relationship of an AA with the medication under study will be established according to the 
following definitions: 
 
Unlikely relationship: The adverse event does not occur after a plausible chronological 
sequence related to the administration of the product under study and/or is reasonably explainable 
by other factors, such as the patient's clinical status or other concomitant therapeutic, toxic, or 
environmental interventions. In addition, it does not match the known or expected response pattern 
of the drug. 
 
Possible relationship: the adverse event occurs after a plausible chronological sequence 
related to the administration of the product under study, but can also be explained by the patient's 
clinical status or other concomitant therapeutic, toxic, or environmental interventions. It also matches 
the known or expected response pattern of the drug. 
 
Probable relationship: the event Adverse drug occurs after a plausible chronological 
sequence related to the administration of the product under study, cannot be reasonably explained 
by the patient's clinical status or other concomitant therapeutic, toxic, or environmental interventions, 
and after withdrawal or reduction of the dose of the suspect drug the event follows a logical clinical 
sequence. It also matches the known or expected response pattern of the drug. 
Very likely relationship: the adverse event occurs after a plausible chronological sequence 
related to the administration of the product under study, cannot be reasonably explained by the 
clinical status of the patient or other concomitant therapeutic, toxic or environmental interventions, 
after withdrawal or reduction of the dose of the suspect drug the event follows a logical clinical 
sequence and it is necessary that after the readministration of the suspicious drug the adverse event 
reappears. It also matches the known or expected response pattern of the drug. 
 
Unrelated: Adverse event clearly due to causes unrelated to the medication under study and 
the criteria for another causal relationship are not met. 
 
Non-assessable relationship: any notification that suggests an adverse effect, which 
cannot be judged because the information is insufficient or contradictory and which cannot be 
supplemented or verified. 

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19 
 
 
 
 
10.2. Notification 
The investigator or designee must notify all AAGs, regardless of whether or not they are 
considered drug-related or planned, to the head of the CTU. Dr. Anna Cruceta 
(acruceta@clinic.ub.es) tel 2275400 ext 4380 and fax 932279877 in order to notify local and national 
health authorities within one working day of becoming aware of the event., so that the contact of 
the designated promoter can prepare the corresponding written report. AAGs occurring will be 
reported at any time from the subject's inclusion in the study and up to 30 days after the study has 
been completed or discontinued. In the specific case of selection failure, the AAGs will be recorded 
from the moment the consent is signed until the subject is considered a selection failure. 
 
Regardless of the classification of adverse effects, the Investigator must collect all the AEs in the 
corresponding section of the study data collection notebook (CRD) and fill in all the information 
pertaining to them. 
The sponsor must notify in an EXPEDITIOUS manner all relevant SAFETY INFORMATION, i.e. that 
could modify the risk/benefit ratio of the investigational medicine, or determine changes in its 
administration schedule or in the conduct of the trial, for example: 
- 
a qualitative change or an increase in the percentage of occurrence of expected RAGs, which 
is considered clinically important. 
- 
RAGIs that occur after the completion of a clinical trial and that are notified by the investigator 
to the sponsor. 
- 
New developments related to the conduct of the trial or development of the investigational 
medicinal product that are likely to affect the safety of subjects, such as: 
• 
Serious adverse events that may be associated with the trial procedures and may modify 
the conduct of the trial 
• 
A significant risk to subjects such as the lack of efficacy of an investigational drug used 
for the treatment of a life-threatening disease. 
• 
Important new safety findings from new animal studies (such as cardiogenicity). 
• 
Any premature termination or temporary halt of a clinical trial with the same 
investigational medicinal product for safety reasons, carried out in another country 
and by the same sponsor. 
• 
GRAs related only to an MNI that are considered relevant as they are not subject to 
RAGI's general rules of expedited reporting of individual cases. 
- 
Any recommendations from the data monitoring committee, which are relevant to the safety of 
the subjects. 
 
This information must be notified as soon as possible and no later than 15 days after the promoter 
has become aware of it. In addition, if additional information that is relevant is obtained, it must be 
notified as quickly as possible. 
 
 
10.3 Evaluation of toxicity parameters 
The classification system for drug toxicity is set out in the DAIDS Table for the Gradation of Intensity 
of Adverse Events in Adults and Children, which can be found in the annexes section of this protocol 
and also on the DAIDS CSR website: 
http://rsc.tech-res.com/safetyandpharmacovigilance/. 

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Treatment of adverse effects 
In some cases, doses may be reduced. It is important to always follow the express indications for each drug and 
each specific case. 
 
(see Technical Data Sheets) 
 
 
 
10.4 COMMUNICATION TO RESEARCHERS 
The sponsor shall communicate to investigators any information that may affect the safety of the trial 
subjects as soon as possible. 
 
It is advisable when deemed appropriate that information on serious and unexpected adverse 
reactions (RAGI) be presented in a list together with a brief analysis of the data provided. 
Researchers must also be informed of the safety aspects that impact the conduct of the clinical trial 
or the development of the product. Including disruption of the development program or security-
related protocol modifications. 
 
Follow-up of subjects after adverse events will be performed by clinical and complementary 
examinations necessary for the duration of treatment and then on a monthly basis during follow-up 
and up to 30 days after the end of treatment. In the event of a possible pregnancy, the health status 
of both the mother and the newborn will be monitored during the trial, whether the person who has 
become pregnant is the one who is taking the investigational drug or if it has been taken by her 
partner. 
No interim analyses are planned for the present study. 
 
 
11.  Statistics 
The coefficient 
 
11.1 
Sample size 
 
 
A difference in cost-effectiveness ratio> = 300 euros for 48-week therapy will be detected, if any, with 
a sample size of 45 patients per arm using a two-tailed test, a power of 90% and a p-value of 0.05. 
Assuming a proportion of 10% of patients lost to follow-up, we would consider including 50 patients 
per treatment group.11.3 Analysis 
 
The comparison of proportions will be performed using Fisher's exact test and the 95% confidence 
interval will be calculated for the difference in proportions. 
 
Quantitative data at baseline and at 48 weeks, as well as absolute and relative changes at 48 
weeks, will be compared using the Wilcoxon rank sum test. The point estimate and 95% confidence 
interval of the difference in medians will be estimated using the Hodges-Lehman methodology using 
the Moses free distribution. 
Correlations between continuous variables will be evaluated using Spearman's rank correlation 
coefficient. 
The study of baseline predictors of response will be carried out by means of a multivariate analysis 
of multiple logistic regression. 
 
Limitations of the study: 

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Although the hypothesis of the study has been based on various congruent information that allow us 
to face with sufficient guarantee the feasibility of the study and the eventual demonstration of the 
virological and immunological efficacy of the treatment strategy, we are not absolutely certain that a 
virological failure rate (standard viral load ≥37 copies/mL on two consecutive occasions at least one 
week apart) can be produced in the experimental branch. We will consider a priori that the failure of 
at least 20% (n=6) of the patients in the experimental arm will represent an unacceptably high 
virological failure rate. In this case, its conclusion will be considered premature. In this extreme case, 
the data of the patients already included would be analyzed. 
This study, even with the most favorable virologic and immunological results, would not constitute 
definitive proof of the safety and efficacy of ATRIPLA'® s dose reduction strategy. The present study 
is only a proof of concept and another study with a sufficiently large sample size would be needed to 
adequately demonstrate the non-inferiority of the strategy. The results of the present study can help 
to design the non-inferiority study and to estimate its sample size. 
 
 
11.2 
Completion Criteria 
 
The study will be considered to have been completed on the date of the last visit of the last subject 
recruited into the study. 
 
11.3 Processing of lost data 
Missing data imputation techniques will not be used. Only the available data will be analyzed. 
 
11.4 Deviations from the statistical plan 
Any deviation from the planned statistical analyses will be justified and detailed in the reports derived 
from the processing of the data. 
 
11.5 Populations under analysis 
The safety population will consist of all patients included in the study who have received at least one 
dose of the treatment. 
The intention-to-treat population will consist of all randomized patients 
 
The protocol population will consist of all patients included in the study as detailed in the protocol 
and without major deviations from the protocol. 
 
 
 
12.  Direct Access to Source Data/Documents 
The sponsor shall ensure that it is specified in the protocol or other written agreement that the 
investigator or institution shall allow direct access to the source data or documents for monitoring, 
auditing and review by the IRB as well as inspection of the trial by the competent health authorities. 
 
 
13. 
 Ethics 
General considerations: The test will be carried out in accordance with the principles emanating from 
the Declaration of Helsinki (See Annex VIII) and according to the legal regulations in force (Royal 
Decree 223/2004) and will not be started until the approval of the reference IRB has been obtained, 
the 

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22 
 
 
 
 
approval of the Management of all participating centres, and authorisation from the Spanish Agency 
for Medicines and Health Products. 
 
Information to the subjects: Patients will be informed orally and in writing and all relevant 
information adapted to their level of understanding will be communicated to the participants. 
(See Attachment III: Patient Information Sheet/Written Consent Sheet) 
 
 
14. Data Management and Records Archiving 
The patient will be informed that their participation in the trial will be treated with the same 
confidentiality as their clinical documentation. 
 
In the data collection notebook, the patient will be identified only by their inclusion code in the study. 
 
The patient's name will not appear in any publication or communication of the results of the study. 
The patient's participation in the trial will be reflected in their medical history. 
 
The investigator will complete a list that will include the names of the patients participating in the trial, 
their inclusion number in the trial and their medical history. 
 
Only researchers and data quality assurance and data analysis personnel will have access to the 
participant's clinical documentation. Eventually, persons duly authorised by the Sponsor and the 
Health Authorities and the Clinical Research Ethics Committee may audit or inspect the trial. 
Personal information will not be available to the public, in compliance with the provisions of Organic 
Law 15/1999, of 13 December, on the Protection of Personal Data. 
The data will be collected through an online electronic CRD. 
 
 
15.  Financing & Insurance 
The promoter has taken out civil liability insurance in accordance with current regulations. 
 
 
16. 
 Publication Policy 
The Promoter undertakes to publish the results, both positive and negative, of this study as stated in 
art. 39 of RD 223/2004. 

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23 
 
 
 
 
 
17. Table of Examinations and treatment during follow-up 
 
 
Selection Evaluations 
Clinical Evaluations 
Selection 
Informed consent 
X 
Inclusion and exclusion criteria 
X 
Assignment of the selection code 
X 
Vital signs 
X 
Weight Determination 
X 
Height determination 
X 
Demographics 
X 
Medical history 
X 
Physical examination 
X 
Concomitant Medications 
X 
Confirmation of the use of contraceptive methods by the patient and his or her partner 
X 
 
Clinical Evaluations 
Basal 
Day 
0 
S 4 
(#) 
S 12 
(#) 
S 24 
(#) 
S 36 
(#) 
S 48 
(#) 
Meet 
Inclusion and 
Exclusion 
 Criteria 
X 
Signed 
Informed 
Consent 
X 
Vital signs 
X 
Weight 
X 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
Simplified Compliance 
Questionnaire 
X 
X 
X 
X 
X 
Haematology 
X 
X 
X 
Blood Biochemistry with GFR 
and Renal Function 
X 
X 
X 
Standard plasma  viral  load 
X 
X 
X 
X 
X 
X 
Immunology (CD4/CD8) 
X 
X 
X 
DEXA 
X 
X 
Pregnancy test (women only) 
Y(&) 
X 
X 
X 
X 
X 
X 
All laboratory specimens should be obtained prior to administration of the first dose of study 
medication. 
(#) These visits will be made only to patients who are in the experimental treatment arm (3-day-per-week 
treatment) 
& At baseline visit it is advised to perform a blood pregnancy test 

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Blood biochemistry: lipids (TG, total cholesterol and HDL), creatinine and estimated glomerular 
filtration rate (CPK-EPI), levels of 25OH vitamin D. 
 
Hematology: Blood count 

Protocolo 
COST-EFFECT-CLINIC 
Nº EudraCT: 2014-004820-24 
Protocolo versión 1.0, de 4 de Octubre de 2014 
Anexo I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ANEXO I. DOCUMENTO DEL IP DE ACEPTACIÓN DEL PROTOCOLO 

 
 
 
 
 
 
Anexo B. Documento de firma del protocolo por el investigador principal 
 
 
 
Don Josep Mallolas 
Servicio: Enfermedades Infecciosas 
Centro: Hospital Clínic 
 
Hace constar: 
 
Que ha evaluado el protocolo del ensayo clínico titulado "Coste-efectividad de distintas pautas de 
tratamiento antirretrovira/ en pacientes naive. Ensayo clínico aleatorizado, no enmascarado, 
comparando DRV/r+3TC, ABC+3TC (kivexa)+RPV, o EVG/COBI/FTC/TDF {Stribild} durante 48 
semanas". 
 
Código del promotor: COST-EFFECT-CLINIC 
Versión: 1.0 
EudraCT:2014-004820-24 
Fecha: 4 de octubre de 2014 
Cuyo promotor es Fundacló Clínic pera la Recerca Biomedica. 
 
 
Que el ensayo clínico respeta las normas éticas aplicables a este tipo de estudios. 
Que acepta participar como investigador principal en este ensayo clínico. 
Que cuenta con los recursos materiales y humanos necesarios para llevar a cabo el ensayo clínico, 
sin que ello interfiera en la realización de otro tipo de estudios ni en otras tareas que tienen 
habitualmente encomendadas. 
 
Que se compromete a que cada sujeto sea tratado y controlado siguiendo lo establecido en el 
protocolo con dictamen favorable por el Comité Ético de Investigación Clínica y autorizado por la 
Agencia Española de Medicamentos y Productos Sanitarios. 
 
Que respetará las normas éticas y legales aplicables a este tipo de estudios y seguirá las normas de 
buena práctica clínica en su realización. 
 
Que los colaboradores que necesita para realizar el ensayo clínico propuesto son idóneos. 
En Barcelona, a Z?Je)../( Hc,(µ'etA.,೦ 
/4 ZO14ε 
 
 
 
 
 
Dr. Josep Mallolas 
Investigador principal 
 
 
 
Protocolo: COST-EFFECT-CUNIC_Anexo B. Documento defirma del protocolo 

 
Protocolo 
COST-EFFECT-CLINIC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ANEXO II. TABLA GRADACIÓN DE TOXICIDAD (OMS) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nº EudraCT: 2014-004820-24 
Protocolo versión 1.0, de 4 de Octubre de 2014 
Anexo II 

DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS 
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009 
28-Dec-04/Clarification Aug 09 
Page 1 of 21 
Version 1.0/Clarification 1 
 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (“DAIDS AE 
Grading Table”) is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A 
grading (severity) scale is provided for each AE term. 
 
This clarification of the DAIDS Table for Grading the Severity of Adult and Pediatric AE’s provides 
additional explanation of the DAIDS AE Grading Table and clarifies some of the parameters. 
 
I. 
Instructions and Clarifications 
Grading Adult and Pediatric AEs 
The DAIDS AE Grading Table includes parameters for grading both Adult and Pediatric AEs. When a 
single set of parameters is not appropriate for grading specific types of AEs for both Adult and Pediatric 
populations, separate sets of parameters for Adult and/or Pediatric populations (with specified respective 
age ranges) are given in the Table. If there is no distinction in the Table between Adult and Pediatric 
values for a type of AE, then the single set of parameters listed is to be used for grading the severity of 
both Adult and Pediatric events of that type. 
Note: In the classification of adverse events, 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. 
 
Addenda 1-3 Grading Tables for Microbicide Studies 
For protocols involving topical application of products to the female genital tract, male genital area or 
rectum, strong consideration should be given to using Appendices I-III as the primary grading scales for 
these areas. The protocol would need to specifically state that one or more of the Appendices would be 
primary (and thus take precedence over the main Grading Table) for items that are listed in both the 
Appendix and the main Grading Table. 
• 
Addendum 1 - Female Genital Grading Table for Use in Microbicide Studies - PDF 
• 
Addendum 2 - Male Genital Grading Table for Use in Microbicide Studies - PDF 
• 
Addendum 3 - Rectal Grading Table for Use in Microbicide Studies - PDF 
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 
In order to grade a clinical AE that is not identified in the DAIDS AE grading table, use the category 
“Estimating Severity Grade” located on Page 3. 
 
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. 

DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS 
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009 
28-Dec-04/Clarification Aug 09 
Page 2 of 21 
Version 1.0/Clarification 1 
 
 
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: Phosphate, Serum, Low, Adult and Pediatric > 14 years (Page 20) Grade 1 range is 2.50 
mg/dL - < LLN. A particular laboratory’s normal range for Phosphate is 2.1 – 3.8 mg/dL. A participant’s 
actual lab value is 2.5. In this case, the value of 2.5 exceeds the LLN for the local lab, but will be graded 
as Grade 1 per DAIDS AE Grading Table. 
. 
II. Definitions of terms used in the Table: 
 
Basic Self-care Functions 
Adult 
Activities such as bathing, dressing, toileting, transfer/movement, 
continence, and feeding. 
Young Children 
Activities that are age and culturally appropriate (e.g., feeding self with 
culturally appropriate eating implement). 
LLN 
Lower limit of normal 
Medical Intervention 
Use of pharmacologic or biologic agent(s) for treatment of an AE. 
NA 
Not Applicable 
Operative Intervention 
Surgical OR other invasive mechanical procedures. 
ULN 
Upper limit of normal 
Usual Social & Functional 
Activities 
Adult 
Adaptive tasks and desirable activities, such as going to work, 
shopping, cooking, use of transportation, pursuing a hobby, etc. 
Young Children 
Activities that are age and culturally appropriate (e.g., social 
interactions, play activities, learning tasks, etc.). 

DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS 
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
Page 3 of 21 
28 Dec 04/Clarification Aug 09 
Version 1.0/Clarification 1 
 
 
 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
ESTIMATING SEVERITY GRADE 
Clinical adverse event 
Symptoms causing no 
Symptoms causing 
Symptoms causing 
Symptoms causing 
NOT identified 
or minimal 
greater than minimal 
inability to perform usual 
inability to perform basic 
elsewhere in this 
interference with 
interference with usual 
social & functional 
self-care functions OR 
DAIDS AE Grading 
usual social & 
social & functional 
activities 
Medical or operative 
Table 
functional activities 
activities 
intervention indicated to 
prevent permanent 
impairment, persistent 
disability, or death 
SYSTEMIC 
Acute systemic 
Localized urticaria 
Localized urticaria with 
Generalized urticaria 
Acute anaphylaxis OR 
allergic reaction 
(wheals) with no 
medical intervention 
OR Angioedema with 
Life-threatening 
medical intervention 
indicated OR Mild 
medical intervention 
bronchospasm OR 
indicated 
angioedema with no 
indicated OR 
laryngeal edema 
medical intervention 
Symptomatic mild 
indicated 
bronchospasm 
Chills 
Symptoms causing no 
Symptoms causing 
Symptoms causing 
NA 
or minimal 
greater than minimal 
inability to perform usual 
interference with 
interference with usual 
social & functional 
usual social & 
social & functional 
activities 
functional activities 
activities 
Fatigue 
Symptoms causing no 
Symptoms causing 
Symptoms causing 
Incapacitating fatigue/ 
Malaise 
or minimal 
interference with 
usual social & 
functional activities 
greater than minimal 
interference with usual 
social & functional 
activities 
inability to perform usual 
social & functional 
activities 
malaise symptoms 
causing inability to 
perform basic self-care 
functions 
Fever (nonaxillary) 
37.7 – 38.6C 
38.7 – 39.3C 
39.4 – 40.5C 
> 40.5C 
Pain (indicate body 
site) 
DO NOT use for pain 
due to injection (See 
Injection Site 
Reactions: Injection 
site pain) 
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 (other 
than emergency room 
visit) indicated 
See also Headache, 
Arthralgia, and 
Myalgia 

DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS 
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
Page 4 of 21 
28 Dec 04/Clarification Aug 09 
Version 1.0/Clarification 1 
 
 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Unintentional weight 
NA 
5 – 9% loss in body 
10 – 19% loss in body 
 20% loss in body 
loss 
weight from baseline 
weight from baseline 
weight from baseline OR 
Aggressive intervention 
indicated [e.g., tube 
feeding or total 
parenteral nutrition 
(TPN)] 
INFECTION 
Infection (any other 
Localized, no 
Systemic antimicrobial 
Systemic antimicrobial 
Life-threatening 
than HIV infection) 
systemic antimicrobial 
treatment indicated 
treatment indicated 
consequences (e.g., 
treatment indicated 
OR Symptoms 
AND Symptoms causing 
septic shock) 
AND Symptoms 
causing greater than 
inability to perform usual 
causing no or minimal 
minimal interference 
social & functional 
interference with 
with usual social & 
activities OR Operative 
usual social & 
functional activities 
intervention (other than 
functional activities 
simple incision and 
drainage) indicated 
INJECTION SITE REACTIONS 
Injection site pain 
Pain/tenderness 
Pain/tenderness 
Pain/tenderness 
Pain/tenderness causing 
(pain without touching) 
causing no or minimal 
limiting use of limb OR 
causing inability to 
inability to perform basic 
Or 
limitation of use of 
Pain/tenderness 
perform usual social & 
self-care function OR 
limb 
causing greater than 
minimal interference 
with usual social & 
functional activities 
functional activities 
Hospitalization (other 
than emergency room 
visit) indicated for 
management of 
pain/tenderness 
Tenderness (pain 
when area is touched) 
Injection site reaction (localized) 
Adult > 15 years 
Erythema OR 
Induration 
of 5x5 cm – 9x9 cm 
(or 25 cm2 – 81cm2) 
Erythema OR 
Induration OR Edema 
> 9 cm any diameter 
(or > 81 cm2) 
Ulceration OR 
Secondary infection OR 
Phlebitis OR Sterile 
abscess OR Drainage 
Necrosis (involving 
dermis and deeper 
tissue) 
Pediatric  15 
Erythema OR 
Erythema OR 
Erythema OR Induration 
Necrosis (involving 
years 
Induration OR Edema 
Induration OR Edema 
OR Edema involving 
dermis and deeper 
present but  2.5 cm 
> 2.5 cm diameter but 
 50% surface area of 
tissue) 
diameter 
< 50% surface area of 
the extremity segment 
the extremity segment 
(e.g., upper arm/thigh) 
(e.g., upper arm/thigh) 
OR Ulceration OR 
Secondary infection OR 
Phlebitis OR Sterile 
abscess OR Drainage 

DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS 
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
Page 5 of 21 
28 Dec 04/Clarification Aug 09 
Version 1.0/Clarification 1 
 
 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Pruritis associated 
with injection 
See also Skin: Pruritis 
(itching - no skin 
lesions) 
Itching localized to 
injection site AND 
Relieved 
spontaneously or with 
< 48 hours treatment 
Itching beyond the 
injection site but not 
generalized OR Itching 
localized to injection 
site requiring  48 
hours treatment 
Generalized itching 
causing inability to 
perform usual social & 
functional activities 
NA 
SKIN – DERMATOLOGICAL 
Alopecia 
Thinning detectable 
by study participant 
(or by caregiver for 
young children and 
disabled adults) 
Thinning or patchy hair 
loss detectable by 
health care provider 
Complete hair loss 
NA 
Cutaneous reaction – 
rash 
Localized macular 
rash 
Diffuse macular, 
maculopapular, or 
morbilliform rash OR 
Target lesions 
Diffuse macular, 
maculopapular, or 
morbilliform rash with 
vesicles or limited 
number of bullae OR 
Superficial ulcerations 
of mucous membrane 
limited to one site 
Extensive or generalized 
bullous lesions OR 
Stevens-Johnson 
syndrome OR Ulceration 
of mucous membrane 
involving two or more 
distinct mucosal sites 
OR Toxic epidermal 
necrolysis (TEN) 
Hyperpigmentation 
Slight or localized 
Marked or generalized 
NA 
NA 
Hypopigmentation 
Slight or localized 
Marked or generalized 
NA 
NA 
Pruritis (itching – no 
skin lesions) 
(See also Injection 
Site Reactions: 
Pruritis associated 
with injection) 
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 
CARDIOVASCULAR 
Cardiac arrhythmia 
(general) 
(By ECG or physical 
exam) 
Asymptomatic AND 
No intervention 
indicated 
Asymptomatic AND 
Non-urgent medical 
intervention indicated 
Symptomatic, non-life- 
threatening AND Non- 
urgent medical 
intervention indicated 
Life-threatening 
arrhythmia OR Urgent 
intervention indicated 
Cardiac- 
ischemia/infarction 
NA 
NA 
Symptomatic ischemia 
(stable angina) OR 
Testing consistent with 
ischemia 
Unstable angina OR 
Acute myocardial 
infarction 

DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS 
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
Page 6 of 21 
28 Dec 04/Clarification Aug 09 
Version 1.0/Clarification 1 
 
 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Hemorrhage 
(significant acute 
blood loss) 
NA 
Symptomatic AND No 
transfusion indicated 
Symptomatic AND 
Transfusion of  2 units 
packed RBCs (for 
children  10 cc/kg) 
indicated 
Life-threatening 
hypotension OR 
Transfusion of > 2 units 
packed RBCs (for 
children > 10 cc/kg) 
indicated 
Hypertension 
Adult > 17 years 
(with repeat testing 
at same visit) 
140 – 159 mmHg 
systolic 
OR 
90 – 99 mmHg 
diastolic 
160 – 179 mmHg 
systolic 
OR 
100 – 109 mmHg 
diastolic 
≥ 180 mmHg systolic 
OR 
≥ 110 mmHg diastolic 
Life-threatening 
consequences (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated (other than 
emergency room visit) 
Correction: in Grade 2 to 160 - 179 from > 160-179 (systolic) and to  100 -109 from > 100-109 (diastolic) and 
in Grade 3 to  180 from > 180 (systolic) and to  110 from > 110 (diastolic). 
Pediatric  17 
years 
(with repeat 
testing at same 
visit) 
NA 
91st – 94th percentile 
adjusted for age, 
height, and gender 
(systolic and/or 
diastolic) 
≥ 95th percentile 
adjusted for age, height, 
and gender (systolic 
and/or diastolic) 
Life-threatening 
consequences (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated (other than 
emergency room visit) 
Hypotension 
NA 
Symptomatic, 
corrected with oral 
fluid replacement 
Symptomatic, IV fluids 
indicated 
Shock requiring use of 
vasopressors or 
mechanical assistance 
to maintain blood 
pressure 
Pericardial effusion 
Asymptomatic, small 
effusion requiring no 
intervention 
Asymptomatic, 
moderate or larger 
effusion requiring no 
intervention 
Effusion with non-life 
threatening physiologic 
consequences OR 
Effusion with non-urgent 
intervention indicated 
Life-threatening 
consequences (e.g., 
tamponade) OR Urgent 
intervention indicated 
Prolonged PR interval 
Adult > 16 years 
PR interval 
0.21 – 0.25 sec 
PR interval 
> 0.25 sec 
Type II 2nd degree AV 
block OR Ventricular 
pause > 3.0 sec 
Complete AV block 
Pediatric ≤ 16 
years 
1st degree AV block 
(PR > normal for age 
and rate) 
Type I 2nd degree AV 
block 
Type II 2nd degree AV 
block 
Complete AV block 

DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS 
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
Page 7 of 21 
28 Dec 04/Clarification Aug 09 
Version 1.0/Clarification 1 
 
 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Prolonged QTc 
Adult > 16 years 
Asymptomatic, QTc 
interval 0.45 – 0.47 
sec OR Increase 
interval < 0.03 sec 
above baseline 
Asymptomatic, QTc 
interval 0.48 – 0.49 
sec OR Increase in 
interval 0.03 – 0.05 
sec above baseline 
Asymptomatic, QTc 
interval  0.50 sec OR 
Increase in interval 
 0.06 sec above 
baseline 
Life-threatening 
consequences, e.g. 
Torsade de pointes or 
other associated serious 
ventricular dysrhythmia 
Pediatric ≤ 16 
years 
Asymptomatic, QTc 
interval 0.450 – 
0.464 sec 
Asymptomatic, QTc 
interval 0.465 – 
0.479 sec 
Asymptomatic, QTc 
interval  0.480 sec 
Life-threatening 
consequences, e.g. 
Torsade de pointes or 
other associated serious 
ventricular dysrhythmia 
Thrombosis/embolism 
NA 
Deep vein thrombosis 
AND No intervention 
indicated (e.g., 
anticoagulation, lysis 
filter, invasive 
procedure) 
Deep vein thrombosis 
AND Intervention 
indicated (e.g., 
anticoagulation, lysis 
filter, invasive 
procedure) 
Embolic event (e.g., 
pulmonary embolism, 
life-threatening 
thrombus) 
Vasovagal episode 
(associated with a 
procedure of any kind) 
Present without loss 
of consciousness 
Present with transient 
loss of consciousness 
NA 
NA 
Ventricular 
dysfunction 
(congestive heart 
failure) 
NA 
Asymptomatic 
diagnostic finding AND 
intervention indicated 
New onset with 
symptoms OR 
Worsening symptomatic 
congestive heart failure 
Life-threatening 
congestive heart failure 
GASTROINTESTINAL 
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 or total 
parenteral nutrition 
(TPN)] 
Comment: Please note that, while the grading scale provided for Unintentional Weight Loss may be used as a guideline when 
grading anorexia, this is not a requirement and should not be used as a substitute for clinical judgment. 
Ascites 
Asymptomatic 
Symptomatic AND 
Intervention indicated 
(e.g., diuretics or 
therapeutic 
paracentesis) 
Symptomatic despite 
intervention 
Life-threatening 
consequences 

DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS 
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
Page 8 of 21 
28 Dec 04/Clarification Aug 09 
Version 1.0/Clarification 1 
 
 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Cholecystitis 
NA 
Symptomatic AND 
Medical intervention 
indicated 
Radiologic, endoscopic, 
or operative intervention 
indicated 
Life-threatening 
consequences (e.g., 
sepsis or 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 
Adult and 
Pediatric  1 year 
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 – 6 stools over 
baseline per 24-hour 
period 
Bloody diarrhea OR 
Increase of ≥ 7 stools 
per 24-hour period OR 
IV fluid replacement 
indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Pediatric < 1 year 
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 
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR 
Hypotensive shock 
Dysphagia- 
Odynophagia 
Symptomatic but able 
to eat usual diet 
Symptoms causing 
altered dietary intake 
without medical 
intervention indicated 
Symptoms causing 
severely altered dietary 
intake with medical 
intervention indicated 
Life-threatening 
reduction in oral intake 
Mucositis/stomatitis 
(clinical exam) 
Indicate site (e.g., 
larynx, oral) 
See Genitourinary for 
Vulvovaginitis 
Erythema of the 
mucosa 
Patchy 
pseudomembranes or 
ulcerations 
Confluent 
pseudomembranes or 
ulcerations OR Mucosal 
bleeding with minor 
trauma 
Tissue necrosis OR 
Diffuse spontaneous 
mucosal bleeding OR 
Life-threatening 
consequences (e.g., 
aspiration, choking) 
See also Dysphagia- 
Odynophagia and 
Proctitis 
Nausea 
Transient (< 24 hours) 
or intermittent nausea 
with no or minimal 
interference with oral 
intake 
Persistent nausea 
resulting in decreased 
oral intake for 24 – 48 
hours 
Persistent nausea 
resulting in minimal oral 
intake for > 48 hours 
OR Aggressive 
rehydration indicated 
(e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 

DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS 
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
Page 9 of 21 
28 Dec 04/Clarification Aug 09 
Version 1.0/Clarification 1 
 
 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Pancreatitis 
NA 
Symptomatic AND 
Hospitalization not 
indicated (other than 
emergency room visit) 
Symptomatic AND 
Hospitalization indicated 
(other than emergency 
room visit) 
Life-threatening 
consequences (e.g., 
circulatory failure, 
hemorrhage, sepsis) 
Proctitis (functional- 
Rectal discomfort 
Symptoms causing 
Symptoms causing 
Life-threatening 
symptomatic) 
AND No intervention 
greater than minimal 
inability to perform usual 
consequences (e.g., 
Also see 
indicated 
interference with usual 
social & functional 
perforation) 
social & functional 
activities OR Operative 
Mucositis/stomatitis 
activities OR Medical 
intervention indicated 
intervention indicated 
for clinical exam 
Vomiting 
Transient or 
intermittent vomiting 
with no or minimal 
interference with oral 
intake 
Frequent episodes of 
vomiting 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) 
NEUROLOGIC 
Alteration in 
Alteration causing no 
Alteration causing 
Alteration causing 
Behavior potentially 
personality-behavior 
or minimal 
greater than minimal 
inability to perform usual 
harmful to self or others 
or in mood (e.g., 
interference with 
interference with usual 
social & functional 
(e.g., suicidal and 
agitation, anxiety, 
usual social & 
social & functional 
activities 
homicidal ideation or 
depression, mania, 
functional activities 
activities 
attempt, acute 
psychosis) 
psychosis) OR Causing 
inability to perform basic 
self-care functions 
Altered Mental Status 
For Dementia, see 
Cognitive and 
behavioral/attentional 
disturbance (including 
dementia and 
attention deficit 
disorder) 
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 
Asymptomatic ataxia 
detectable on exam 
OR Minimal ataxia 
causing no or minimal 
interference with 
usual social & 
functional activities 
Symptomatic ataxia 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Symptomatic ataxia 
causing inability to 
perform usual social & 
functional activities 
Disabling ataxia causing 
inability to perform basic 
self-care functions 

DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS 
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
Page 10 of 21 
28 Dec 04/Clarification Aug 09 
Version 1.0/Clarification 1 
 
 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Cognitive and 
behavioral/attentional 
disturbance (including 
dementia and 
attention deficit 
disorder) 
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 
CNS ischemia 
(acute) 
NA 
NA 
Transient ischemic 
attack 
Cerebral vascular 
accident (CVA, stroke) 
with neurological deficit 
Developmental delay 
– Pediatric  16 
years 
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 
(other than emergency 
room visit) OR 
Headache with 
significant impairment of 
alertness or other 
neurologic function 
Insomnia 
NA 
Difficulty sleeping 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Difficulty sleeping 
causing inability to 
perform usual social & 
functional activities 
Disabling insomnia 
causing inability to 
perform basic self-care 
functions 
Neuromuscular 
weakness 
(including myopathy & 
neuropathy) 
Asymptomatic with 
decreased strength 
on exam OR Minimal 
muscle weakness 
causing no or minimal 
interference with 
usual social & 
functional activities 
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 

DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS 
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
Page 11 of 21 
28 Dec 04/Clarification Aug 09 
Version 1.0/Clarification 1 
 
 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Neurosensory 
Asymptomatic with 
Sensory alteration or 
Sensory alteration or 
Disabling sensory 
alteration (including 
sensory alteration on 
paresthesia causing 
paresthesia causing 
alteration or paresthesia 
paresthesia and 
exam or minimal 
greater than minimal 
inability to perform usual 
causing inability to 
painful neuropathy) 
paresthesia causing 
no or minimal 
interference with 
usual social & 
functional activities 
interference with usual 
social & functional 
activities 
social & functional 
activities 
perform basic self-care 
functions 
Seizure: (new onset) 
NA 
1 seizure 
2 – 4 seizures 
Seizures of any kind 
– Adult ≥ 18 years 
which are prolonged, 
See also Seizure: 
repetitive (e.g., status 
epilepticus), or difficult 
(known pre-existing 
to control (e.g., 
refractory epilepsy) 
seizure disorder) 
Seizure: (known pre- 
existing seizure 
disorder) 
– Adult ≥ 18 years 
For worsening of 
existing epilepsy the 
grades should be 
based on an increase 
from previous level of 
control to any of these 
levels. 
NA 
Increased frequency of 
pre-existing seizures 
(non-repetitive) without 
change in seizure 
character OR 
Infrequent break- 
through seizures while 
on stable medication 
in a previously 
controlled seizure 
disorder 
Change in seizure 
character from baseline 
either in duration or 
quality (e.g., severity or 
focality) 
Seizures of any kind 
which are prolonged, 
repetitive (e.g., status 
epilepticus), or difficult 
to control (e.g., 
refractory epilepsy) 
Seizure 
Seizure, generalized 
Seizure, generalized 
Seizure, generalized 
Seizure, generalized 
– Pediatric < 18 
onset with or without 
onset with or without 
onset with or without 
onset with or without 
years 
secondary 
generalization, lasting 
< 5 minutes with < 24 
hours post ictal state 
secondary 
generalization, lasting 
5 – 20 minutes with 
< 24 hours post ictal 
state 
secondary 
generalization, lasting 
> 20 minutes 
secondary 
generalization, requiring 
intubation and sedation 
Syncope (not 
associated with a 
procedure) 
NA 
Present 
NA 
NA 
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 

DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS 
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
Page 12 of 21 
28 Dec 04/Clarification Aug 09 
Version 1.0/Clarification 1 
 
 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
RESPIRATORY 
Bronchospasm (acute) 
FEV1 or peak flow 
reduced to 
70 – 80% 
FEV1 or peak flow 
50 – 69% 
FEV1 or peak flow 
25 – 49% 
Cyanosis OR FEV1 or 
peak flow < 25% OR 
Intubation 
Dyspnea or respiratory distress 
Adult ≥ 14 years 
Dyspnea on exertion 
with no or minimal 
interference with 
usual social & 
functional activities 
Dyspnea on exertion 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Dyspnea at rest causing 
inability to perform usual 
social & functional 
activities 
Respiratory failure with 
ventilatory support 
indicated 
Pediatric < 14 
years 
Wheezing OR 
minimal increase in 
respiratory rate for 
age 
Nasal flaring OR 
Intercostal retractions 
OR Pulse oximetry 90 
– 95% 
Dyspnea at rest causing 
inability to perform usual 
social & functional 
activities OR Pulse 
oximetry < 90% 
Respiratory failure with 
ventilatory support 
indicated 
MUSCULOSKELETAL 
Arthralgia 
See also Arthritis 
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 
See also Arthralgia 
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 
Bone Mineral Loss 
Adult ≥ 21 years 
BMD t-score 
-2.5 to -1.0 
BMD t-score < -2.5 
Pathological fracture 
(including loss of 
vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences 
Pediatric < 21 
years 
BMD z-score 
-2.5 to -1.0 
BMD z-score < -2.5 
Pathological fracture 
(including loss of 
vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences 
Myalgia 
(non-injection site) 
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 

DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS 
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
Page 13 of 21 
28 Dec 04/Clarification Aug 09 
Version 1.0/Clarification 1 
 
 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Osteonecrosis 
NA 
Asymptomatic with 
radiographic findings 
AND No operative 
intervention indicated 
Symptomatic bone pain 
with radiographic 
findings OR Operative 
intervention indicated 
Disabling bone pain with 
radiographic findings 
causing inability to 
perform basic self-care 
functions 
GENITOURINARY 
Cervicitis 
Symptoms causing no 
Symptoms causing 
Symptoms causing 
Symptoms causing 
(symptoms) 
or minimal 
greater than minimal 
inability to perform usual 
inability to perform basic 
(For use in studies 
interference with 
interference with usual 
social & functional 
self-care functions 
usual social & 
social & functional 
activities 
evaluating topical 
functional activities 
activities 
study agents) 
For other cervicitis see 
Infection: Infection 
(any other than HIV 
infection) 
Cervicitis 
Minimal cervical 
Moderate cervical 
Severe cervical 
Epithelial disruption 
(clinical exam) 
abnormalities on 
abnormalities on 
abnormalities on 
> 75% total surface 
(For use in studies 
examination 
examination 
examination (erythema, 
(erythema, 
(erythema, 
mucopurulent 
evaluating topical 
mucopurulent 
mucopurulent 
discharge, or friability) 
study agents) 
discharge, or friability) 
OR Epithelial 
disruption 
< 25% of total surface 
discharge, or friability) 
OR Epithelial 
disruption of 25 – 49% 
total surface 
OR Epithelial disruption 
50 – 75% total surface 
For other cervicitis see 
Infection: Infection 
(any other than HIV 
infection) 
Inter-menstrual 
Spotting observed by 
Inter-menstrual 
Inter-menstrual bleeding 
Hemorrhage with life- 
bleeding (IMB) 
participant OR 
bleeding not greater in 
greater in duration or 
threatening hypotension 
Minimal blood 
duration or amount 
amount than usual 
OR Operative 
observed during 
than usual menstrual 
menstrual cycle 
intervention indicated 
clinical or colposcopic 
cycle 
examination 
Urinary tract 
NA 
Signs or symptoms of 
Signs or symptoms of 
Obstruction causing life- 
obstruction (e.g., 
urinary tract 
urinary tract obstruction 
threatening 
stone) 
obstruction without 
hydronephrosis or 
renal dysfunction 
with hydronephrosis or 
renal dysfunction 
consequences 

DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS 
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
Page 14 of 21 
28 Dec 04/Clarification Aug 09 
Version 1.0/Clarification 1 
 
 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Vulvovaginitis 
(symptoms) 
(Use in studies 
evaluating topical 
study agents) 
For other 
vulvovaginitis see 
Infection: Infection 
(any other than HIV 
infection) 
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 
Vulvovaginitis 
(clinical exam) 
(Use in studies 
evaluating topical 
study agents) 
For other 
vulvovaginitis see 
Infection: Infection 
(any other than HIV 
infection) 
Minimal vaginal 
abnormalities on 
examination OR 
Epithelial disruption 
< 25% of total surface 
Moderate vaginal 
abnormalities on 
examination OR 
Epithelial disruption of 
25 - 49% total surface 
Severe vaginal 
abnormalities on 
examination OR 
Epithelial disruption 
50 - 75% total surface 
Vaginal perforation OR 
Epithelial disruption 
> 75% total surface 
OCULAR/VISUAL 
Uveitis 
Asymptomatic but 
detectable on exam 
Symptomatic anterior 
uveitis OR Medical 
intervention indicated 
Posterior or pan-uveitis 
OR Operative 
intervention indicated 
Disabling visual loss in 
affected eye(s) 
Visual changes (from 
Visual changes 
Visual changes 
Visual changes causing 
Disabling visual loss in 
baseline) 
causing no or minimal 
interference with 
usual social & 
functional activities 
causing greater than 
minimal interference 
with usual social & 
functional activities 
inability to perform usual 
social & functional 
activities 
affected eye(s) 
ENDOCRINE/METABOLIC 
Abnormal fat 
Detectable by study 
Detectable on physical 
Disfiguring OR Obvious 
NA 
accumulation 
participant (or by 
exam by health care 
changes on casual 
(e.g., back of neck, 
caregiver for young 
provider 
visual inspection 
breasts, abdomen) 
children and disabled 
adults) 
Diabetes mellitus 
NA 
New onset without 
need to initiate 
medication OR 
Modification of current 
medications to regain 
glucose control 
New onset with initiation 
of medication indicated 
OR Diabetes 
uncontrolled despite 
treatment modification 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non- 
ketotic coma) 

DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS 
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
Page 15 of 21 
28 Dec 04/Clarification Aug 09 
Version 1.0/Clarification 1 
 
 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Gynecomastia 
Detectable by study 
participant or 
caregiver (for young 
children and disabled 
adults) 
Detectable on physical 
exam by health care 
provider 
Disfiguring OR Obvious 
on casual visual 
inspection 
NA 
Hyperthyroidism 
Asymptomatic 
Symptomatic 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 
Asymptomatic 
Symptomatic causing 
greater than minimal 
interference with usual 
social & functional 
activities OR Thyroid 
replacement therapy 
indicated 
Symptoms causing 
inability to perform usual 
social & functional 
activities OR 
Uncontrolled despite 
treatment modification 
Life-threatening 
consequences (e.g., 
myxedema coma) 
Lipoatrophy 
(e.g., fat loss from the 
face, extremities, 
buttocks) 
Detectable by study 
participant (or by 
caregiver for young 
children and disabled 
adults) 
Detectable on physical 
exam by health care 
provider 
Disfiguring OR Obvious 
on casual visual 
inspection 
NA 

DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS 
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009 
 Values are for term infants. Preterm infants should be assessed using local normal ranges. 
† Use age and sex appropriate values (e.g., bilirubin). 
Page 16 of 21 
28 Dec-04/Clarification Aug 09 
Version 1.0/Clarification 1 
 
 
 
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
HEMATOLOGY 
Standard International Units are listed in italics 
Absolute CD4+ count 
300 – 400/mm3 
200 – 299/mm3 
100 – 199/mm3 
< 100/mm3 
– Adult and Pediatric 
300 – 400/µL 
200 – 299/µL 
100 – 199/µL 
< 100/µL 
> 13 years 
(HIV NEGATIVE ONLY) 
Absolute lymphocyte 
600 – 650/mm3 
500 – 599/mm3 
350 – 499/mm3 
< 350/mm3 
count 
0.600 x 109 – 
0.500 x 109 – 
0.350 x 109 – 
< 0.350 x 109/L 
– Adult and Pediatric 
0.650 x 109/L 
0.599 x 109/L 
0.499 x 109/L 
> 13 years 
(HIV NEGATIVE ONLY) 
Comment: Values in children ≤ 13 years are not given for the two parameters above because the absolute counts are variable. 
Absolute neutrophil count (ANC) 
Adult and Pediatric, 
1,000 – 1,300/mm3 
750 – 999/mm3 
500 – 749/mm3 
< 500/mm3 
> 7 days 
1.000 x 109 – 
0.750 x 109 – 
0.500 x 109 – 
< 0.500 x 109/L 
1.300 x 109/L 
0.999 x 109/L 
0.749 x 109/L 
Infant†, 2 –  7 days 
1,250 – 1,500/mm3 
1.250 x 109 – 
1,000 – 1,249/mm3 
1.000 x 109 – 
750 – 999/mm3 
0.750 x 109 – 
< 750/mm3 
< 0.750 x 109/L 
1.500 x 109/L 
1.249 x 109/L 
0.999 x 109/L 
Infant†, ≤1 day 
4,000 – 5,000/mm3 
4.000 x 109 – 
3,000 – 3,999/mm3 
3.000 x 109 – 
1,500 – 2,999/mm3 
1.500 x 109 – 
< 1,500/mm3 
< 1.500 x 109/L 
5.000 x 109/L 
3.999 x109/L 
2.999 x 109/L 
Comment: Parameter changed from “Infant, < 1 day” to “Infant, ≤1 day” 
Fibrinogen, decreased 
100 – 200 mg/dL 
75 – 99 mg/dL 
50 – 74 mg/dL 
< 50 mg/dL 
1.00 – 2.00 g/L 
0.75 – 0.99 g/L 
0.50 – 0.74 g/L 
< 0.50 g/L 
OR 
OR 
OR 
OR 
0.75 – 0.99 x LLN 
0.50 – 0.74 x LLN 
0.25 – 0.49 x LLN 
< 0.25 x LLN 
OR 
Associated with gross 
bleeding 

DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS 
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009 
 Values are for term infants. Preterm infants should be assessed using local normal ranges. 
† Use age and sex appropriate values (e.g., bilirubin). 
Page 17 of 21 
28 Dec-04/Clarification Aug 09 
Version 1.0/Clarification 1 
 
 
 
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Hemoglobin (Hgb) 
Comment: The Hgb values in mmol/L have changed because the conversion factor used to convert g/dL to mmol/L has been 
changed from 0.155 to 0.6206 (the most commonly used conversion factor). For grading Hgb 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 that lab. 
Adult and Pediatric 
 57 days 
(HIV POSITIVE ONLY) 
8.5 – 10.0 g/dL 
5.24 – 6.23 mmol/L 
7.5 – 8.4 g/dL 
4.62–5.23 mmol/L 
6.50 – 7.4 g/dL 
4.03–4.61 mmol/L 
< 6.5 g/dL 
< 4.03 mmol/L 
Adult and Pediatric 
 57 days 
(HIV NEGATIVE 
ONLY) 
10.0 – 10.9 g/dL 
6.18 – 6.79 mmol/L 
OR 
Any decrease 
2.5 – 3.4 g/dL 
1.58 – 2.13 mmol/L 
9.0 – 9.9 g/dL 
5.55 - 6.17 mmol/L 
OR 
Any decrease 
3.5 – 4.4 g/dL 
2.14 – 2.78 mmol/L 
7.0 – 8.9 g/dL 
4.34 - 5.54 mmol/L 
OR 
Any decrease 
 4.5 g/dL 
> 2.79 mmol/L 
< 7.0 g/dL 
< 4.34 mmol/L 
Comment: The decrease is a decrease from baseline 
Infant†, 36 – 56 days 
(HIV POSITIVE OR 
NEGATIVE) 
8.5 – 9.4 g/dL 
5.24 – 5.86 mmol/L 
7.0 – 8.4 g/dL 
4.31 – 5.23 mmol/L 
6.0 – 6.9 g/dL 
3.72 – 4.30 mmol/L 
< 6.00 g/dL 
< 3.72 mmol/L 
Infant†, 22 – 35 days 
(HIV POSITIVE OR 
NEGATIVE) 
9.5 – 10.5 g/dL 
5.87 - 6.54 mmol/L 
8.0 – 9.4 g/dL 
4.93 – 5.86 mmol/L 
7.0 – 7.9 g/dL 
4.34 – 4.92 mmol/L 
< 7.00 g/dL 
< 4.34 mmol/L 
Infant†, ≤ 21 days 
(HIV POSITIVE OR 
NEGATIVE) 
12.0 – 13.0 g/dL 
7.42 – 8.09 mmol/L 
10.0 – 11.9 g/dL 
6.18 – 7.41 mmol/L 
9.0 – 9.9 g/dL 
5.59- 6.17 mmol/L 
< 9.0 g/dL 
< 5.59 mmol/L 
Correction: Parameter changed from “Infant < 21 days” to “Infant ≤ 21 days” 
International Normalized 
Ratio of prothrombin time 
(INR) 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 3.0 x ULN 
> 3.0 x ULN 
Methemoglobin 
5.0 – 10.0% 
10.1 – 15.0% 
15.1 – 20.0% 
> 20.0% 
Prothrombin Time (PT) 
1.1 – 1.25 x ULN 
1.26 – 1.50 x ULN 
1.51 – 3.00 x ULN 
> 3.00 x ULN 
Partial Thromboplastin 
Time (PTT) 
1.1 – 1.66 x ULN 
1.67 – 2.33 x ULN 
2.34 – 3.00 x ULN 
> 3.00 x ULN 
Platelets, decreased 
100,000 – 
124,999/mm3 
100.000 x 109 – 
124.999 x 109/L 
50,000 – 
99,999/mm3 
50.000 x 109 – 
99.999 x 109/L 
25,000 – 
49,999/mm3 
25.000 x 109 – 
49.999 x 109/L 
< 25,000/mm3 
< 25.000 x 109/L 
WBC, decreased 
2,000 – 2,500/mm3 
2.000 x 109 – 
2.500 x 109/L 
1,500 – 1,999/mm3 
1.500 x 109 – 
1.999 x 109/L 
1,000 – 1,499/mm3 
1.000 x 109 – 
1.499 x 109/L 
< 1,000/mm3 
< 1.000 x 109/L 

DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS 
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009 
 Values are for term infants. Preterm infants should be assessed using local normal ranges. 
† Use age and sex appropriate values (e.g., bilirubin). 
Page 18 of 21 
28 Dec-04/Clarification Aug 09 
Version 1.0/Clarification 1 
 
 
 
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
CHEMISTRIES 
Standard International Units are listed in italics 
Acidosis 
NA 
pH < normal, but  7.3 
pH < 7.3 without life- 
threatening 
consequences 
pH < 7.3 with life- 
threatening 
consequences 
Albumin, serum, low 
3.0 g/dL – < LLN 
30 g/L – < LLN 
2.0 – 2.9 g/dL 
20 – 29 g/L 
< 2.0 g/dL 
< 20 g/L 
NA 
Alkaline Phosphatase 
1.25 – 2.5 x ULN† 
2.6 – 5.0 x ULN† 
5.1 – 10.0 x ULN† 
> 10.0 x ULN† 
Alkalosis 
NA 
pH > normal, but  7.5 
pH > 7.5 without life- 
threatening 
consequences 
pH > 7.5 with life- 
threatening 
consequences 
ALT (SGPT) 
1.25 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10.0 x ULN 
> 10.0 x ULN 
AST (SGOT) 
1.25 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10.0 x ULN 
> 10.0 x ULN 
Bicarbonate, serum, low 
16.0 mEq/L – < LLN 
16.0 mmol/L – < LLN 
11.0 – 15.9 mEq/L 
11.0 – 15.9 mmol/L 
8.0 – 10.9 mEq/L 
8.0 – 10.9 mmol/L 
< 8.0 mEq/L 
< 8.0 mmol/L 
Comment: Some laboratories will report this value as Bicarbonate (HCO3) and others as Total Carbon Dioxide (CO2). These 
are the same tests; values should be graded according to the ranges for Bicarbonate as listed above. 
Bilirubin (Total) 
Adult and Pediatric > 
14 days 
1.1 – 1.5 x ULN 
1.6 – 2.5 x ULN 
2.6 – 5.0 x ULN 
> 5.0 x ULN 
Infant†, ≤ 14 days 
(non-hemolytic) 
NA 
20.0 – 25.0 mg/dL 
342 – 428 µmol/L 
25.1 – 30.0 mg/dL 
429 – 513 µmol/L 
> 30.0 mg/dL 
> 513.0 µmol/L 
Infant†, ≤ 14 days 
(hemolytic) 
NA 
NA 
20.0 – 25.0 mg/dL 
342 – 428 µmol/L 
> 25.0 mg/dL 
> 428 µmol/L 
Calcium, serum, high 
Adult and Pediatric 
≥ 7 days 
10.6 – 11.5 mg/dL 
2.65 – 2.88 mmol/L 
11.6 – 12.5 mg/dL 
2.89 – 3.13 mmol/L 
12.6 – 13.5 mg/dL 
3.14 – 3.38 mmol/L 
> 13.5 mg/dL 
> 3.38 mmol/L 
Infant†, < 7 days 
11.5 – 12.4 mg/dL 
2.88 – 3.10 mmol/L 
12.5 – 12.9 mg/dL 
3.11 – 3.23 mmol/L 
13.0 – 13.5 mg/dL 
3.245 – 3.38 mmol/L 
> 13.5 mg/dL 
> 3.38 mmol/L 
Calcium, serum, low 
Adult and Pediatric 
≥ 7 days 
7.8 – 8.4 mg/dL 
1.95 – 2.10 mmol/L 
7.0 – 7.7 mg/dL 
1.75 – 1.94 mmol/L 
6.1 – 6.9 mg/dL 
1.53 – 1.74 mmol/L 
< 6.1 mg/dL 
< 1.53 mmol/L 
Infant†, < 7 days 
6.5 – 7.5 mg/dL 
1.63 – 1.88 mmol/L 
6.0 – 6.4 mg/dL 
1.50 – 1.62 mmol/L 
5.50 – 5.90 mg/dL 
1.38 – 1.51 mmol/L 
< 5.50 mg/dL 
< 1.38 mmol/L 
Comment: Do not adjust Calcium, serum, low or Calcium, serum, high for albumin 

DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS 
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009 
 Values are for term infants. Preterm infants should be assessed using local normal ranges. 
† Use age and sex appropriate values (e.g., bilirubin). 
Page 19 of 21 
28 Dec-04/Clarification Aug 09 
Version 1.0/Clarification 1 
 
 
 
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Cardiac troponin I (cTnI) 
NA 
NA 
NA 
Levels consistent with 
myocardial infarction 
or unstable angina as 
defined by the 
manufacturer 
Cardiac troponin T (cTnT) 
NA 
NA 
NA 
 0.20 ng/mL 
OR 
Levels consistent with 
myocardial infarction 
or unstable angina as 
defined by the 
manufacturer 
Cholesterol (fasting) 
Adult ≥ 18 years 
200 – 239 mg/dL 
5.18 – 6.19 mmol/L 
240 – 300 mg/dL 
6.20 – 7.77 mmol/L 
> 300 mg/dL 
> 7.77 mmol/L 
NA 
Pediatric < 18 years 
170 – 199 mg/dL 
4.40 – 5.15 mmol/L 
200 – 300 mg/dL 
5.16 – 7.77 mmol/L 
> 300 mg/dL 
> 7.77 mmol/L 
NA 
Creatine Kinase 
3.0 – 5.9 x ULN† 
6.0 – 9.9 x ULN† 
10.0 – 19.9 x ULN† 
 20.0 x ULN† 
Creatinine 
1.1 – 1.3 x ULN† 
1.4 – 1.8 x ULN† 
1.9 – 3.4 x ULN† 
 3.5 x ULN† 
 
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Glucose, serum, high 
Nonfasting 
116 – 160 mg/dL 
6.44 – 8.88 mmol/L 
161 – 250 mg/dL 
8.89 – 13.88 mmol/L 
251 – 500 mg/dL 
13.89 – 27.75 mmol/L 
> 500 mg/dL 
> 27.75 mmol/L 
Fasting 
110 – 125 mg/dL 
6.11 – 6.94 mmol/L 
126 – 250 mg/dL 
6.95 – 13.88 mmol/L 
251 – 500 mg/dL 
13.89 – 27.75 mmol/L 
> 500 mg/dL 
> 27.75 mmol/L 
Glucose, serum, low 
Adult and Pediatric 
≥ 1 month 
55 – 64 mg/dL 
3.05 – 3.55 mmol/L 
40 – 54 mg/dL 
2.22 – 3.06 mmol/L 
30 – 39 mg/dL 
1.67 – 2.23 mmol/L 
< 30 mg/dL 
< 1.67 mmol/L 
Infant†, < 1 month 
50 – 54 mg/dL 
2.78 – 3.00 mmol/L 
40 – 49 mg/dL 
2.22 – 2.77 mmol/L 
30 – 39 mg/dL 
1.67 – 2.21 mmol/L 
< 30 mg/dL 
< 1.67 mmol/L 
Lactate 
ULN - < 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 

DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS 
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009 
 Values are for term infants. Preterm infants should be assessed using local normal ranges. 
† Use age and sex appropriate values (e.g., bilirubin). 
Page 20 of 21 
28 Dec-04/Clarification Aug 09 
Version 1.0/Clarification 1 
 
 
 
Comment: Added ULN to Grade 1 parameter 
LDL cholesterol (fasting) 
Adult ≥ 18 years 
130 – 159 mg/dL 
3.37 – 4.12 mmol/L 
160 – 190 mg/dL 
4.13 – 4.90 mmol/L 
 190 mg/dL 
 4.91 mmol/L 
NA 
Pediatric > 2 - < 18 
years 
110 – 129 mg/dL 
2.85 – 3.34 mmol/L 
130 – 189 mg/dL 
3.35 – 4.90 mmol/L 
≥ 190 mg/dL 
≥ 4.91 mmol/L 
NA 
Lipase 
1.1 – 1.5 x ULN 
1.6 – 3.0 x ULN 
3.1 – 5.0 x ULN 
> 5.0 x ULN 
Magnesium, serum, low 
1.2 – 1.4 mEq/L 
0.60 – 0.70 mmol/L 
0.9 – 1.1 mEq/L 
0.45 – 0.59 mmol/L 
0.6 – 0.8 mEq/L 
0.30 – 0.44 mmol/L 
< 0.60 mEq/L 
< 0.30 mmol/L 
Pancreatic amylase 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 5.0 x ULN 
> 5.0 x ULN 
Phosphate, serum, low 
Adult and Pediatric 
> 14 years 
2.5 mg/dL – < LLN 
0.81 mmol/L – < LLN 
2.0 – 2.4 mg/dL 
0.65 – 0.80 mmol/L 
1.0 – 1.9 mg/dL 
0.32 – 0.64 mmol/L 
< 1.00 mg/dL 
< 0.32 mmol/L 
Pediatric 1 year – 14 
years 
3.0 – 3.5 mg/dL 
0.97 – 1.13 mmol/L 
2.5 – 2.9 mg/dL 
0.81 – 0.96 mmol/L 
1.5 – 2.4 mg/dL 
0.48 – 0.80 mmol/L 
< 1.50 mg/dL 
< 0.48 mmol/L 
Pediatric < 1 year 
3.5 – 4.5 mg/dL 
1.13 – 1.45 mmol/L 
2.5 – 3.4 mg/dL 
0.81 – 1.12 mmol/L 
1.5 – 2.4 mg/dL 
0.48 – 0.80 mmol/L 
< 1.50 mg/dL 
< 0.48 mmol/L 
Potassium, serum, high 
5.6 – 6.0 mEq/L 
5.6 – 6.0 mmol/L 
6.1 – 6.5 mEq/L 
6.1 – 6.5 mmol/L 
6.6 – 7.0 mEq/L 
6.6 – 7.0 mmol/L 
> 7.0 mEq/L 
> 7.0 mmol/L 
Potassium, serum, low 
3.0 – 3.4 mEq/L 
3.0 – 3.4 mmol/L 
2.5 – 2.9 mEq/L 
2.5 – 2.9 mmol/L 
2.0 – 2.4 mEq/L 
2.0 – 2.4 mmol/L 
< 2.0 mEq/L 
< 2.0 mmol/L 
Sodium, serum, high 
146 – 150 mEq/L 
146 – 150 mmol/L 
151 – 154 mEq/L 
151 – 154 mmol/L 
155 – 159 mEq/L 
155 – 159 mmol/L 
 160 mEq/L 
 160 mmol/L 
Sodium, serum, low 
130 – 135 mEq/L 
130 – 135 mmol/L 
125 – 129 mEq/L 
125 – 129 mmol/L 
121 – 124 mEq/L 
121 – 124 mmol/L 
 120 mEq/L 
 120 mmol/L 
Triglycerides (fasting) 
NA 
500 – 750 mg/dL 
5.65 – 8.48 mmol/L 
751 – 1,200 mg/dL 
8.49 – 13.56 mmol/L 
> 1,200 mg/dL 
> 13.56 mmol/L 

DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS 
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009 
 Values are for term infants. Preterm infants should be assessed using local normal ranges. 
† Use age and sex appropriate values (e.g., bilirubin). 
Page 21 of 21 
28 Dec-04/Clarification Aug 09 
Version 1.0/Clarification 1 
 
 
 
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Uric acid 
7.5 – 10.0 mg/dL 
0.45 – 0.59 mmol/L 
10.1 – 12.0 mg/dL 
0.60 – 0.71 mmol/L 
12.1 – 15.0 mg/dL 
0.72 – 0.89 mmol/L 
> 15.0 mg/dL 
> 0.89 mmol/L 
URINALYSIS 
Standard International Units are listed in italics 
Hematuria (microscopic) 
6 – 10 RBC/HPF 
> 10 RBC/HPF 
Gross, with or without 
clots OR with RBC 
casts 
Transfusion indicated 
Proteinuria, random 
collection 
1 + 
2 – 3 + 
4 + 
NA 
Proteinuria, 24 hour collection 
Adult and Pediatric 
 10 years 
200 – 999 mg/24 h 
0.200 – 0.999 g/d 
1,000 – 1,999 mg/24 h 
1.000 – 1.999 g/d 
2,000 – 3,500 mg/24 h 
2.000 – 3.500 g/d 
> 3,500 mg/24 h 
> 3.500 g/d 
Pediatric > 3 mo - 
< 10 years 
201 – 499 mg/m2/24 h 
0.201 – 0.499 g/d 
500 – 799 mg/m2/24 h 
0.500 – 0.799 g/d 
800 – 1,000 
mg/m2/24 h 
0.800 – 1.000 g/d 
> 1,000 mg/ m2/24 h 
> 1.000 g/d 

 
Protocolo 
COST-EFFECT-CLINIC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ANNEX III. SERIOUS ADVERSE EVENT REPORTING FORM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nº EudraCT: 2014-004820-24 
Protocolo versión 1.0, de 4 de Octubre de 2014 
Anexo III 

 
 
 
NOTIFICACIÓN DE ACONTECIMIENTOS ADVERSOS 
GRAVES – I 
Código Protocolo: 
Estudio COST-EFFECT- 
CLINIC 
Nº EudraCT: 
2014-004820-24 
 
1. Tipo informe 
Inicial 
Seguimiento 
2. País: España 
3. Código paciente: | 
| 
| 
| 
| 
I. DATOS PERSONALES DEL PACIENTE 
4. Fecha nacimiento: | 
| 
| 
| 
DD 
MM  AA 
5.Sexo 
 Hombre 
Mujer 
6. Iniciales: |  | 
| 
N  A 
7. Peso: | 
| 
| 
| . | 
| 
Kg. 
8. Talla: | 
| 
| 
| 
cm. 
9. Edad: | 
| 
| 
Años 
II. ACONTECIMIENTO ADVERSO GRAVE 
10. Descripción del acontecimiento: 
11. Fecha de inicio: | 
| 
| 
| 
12. Gravedad del acontecimiento: 
resultado de muerte 
amenaza de vida 
hospitalización 
prolongación de la hospitalización 
invalidez / incapacidad 
anomalía / malformación congénita 
médicamente relevante 
13. Acción tomada 
ninguna 
interrupción temporal 
discontinuación permanente 
tratamiento concomitante de los síntomas 
hospitalización 
prolongación de la hospitalización 
Otros: (especificar) 
14. Resultado / Desenlace 
desconocido 
recuperación total → Fecha: | 
|  
|  
| 
recuperación parcial → Fecha: | 
 | 
 | 
 | 
persiste 
empeoramiento 
muerte → Fecha: | 
| 
| 
| 
Causa de muerte: 
III. MEDICACIÓN EN ESTUDIO (registrar cada uno de los medicamentos en estudio) 
15. Medicamentos 
16. Dosis 
diaria 
17. Vía 
18. Fecha 
inicio 
19. Fecha final 
20. Relación causal 
(indicar nº según 20a) 
continúa 
continúa 
20a. Relación causal: 1 clara 2 probable 3 posible 4 improbable 5 no relacionado 6 no valorable 
21. ¿Remitió la reacción al suspender la medicación? 
Sí 
No 
No procede 
22. ¿Remitió la reacción al reducir la dosis? 
Sí 
No 
No procede 
23. ¿Reapareció la reacción al administrar de nuevo la medicación? 
Sí 
No 
No procede 
IV. MEDICACIÓN CONCOMITANTE 
 No hay 
24. Medicamentos 
25. Dosis 
diaria 
26. Fecha 
inicio 
27. Fecha final 
28. Relación 
causal 
(según 20a) 
29. Indicación 
continúa 
continúa 
continúa 
continúa 
continúa 

 
 
 
NOTIFICACIÓN DE ACONTECIMIENTOS ADVERSOS 
GRAVES – II 
Código Protocolo: 
Estudio: COST-EFFECT- 
CLINIC 
Nº EudraCT: 
2014-004820-24 
 
V. DATOS RELEVANTES DE LABORATORIO 
 No hay 
30. Variable de laboratorio 
31. Resultado 
(indicar unidades) 
32. Rango de normalidad 
33. Fecha extracción 
VI. DATOS RELEVANTES DE LA HISTORIA CLÍNICA 
 No hay 
34. Enfermedad / Intervención 
35. Fecha inicio 
36. Fecha final 
37. Sigue 
Sí 
No 
Sí 
No 
Sí 
No 
Sí 
No 
38. Información complementaria: 
No hay 
39. ¿Se adjunta informe complementario?: 
Sí 
No 
(nº páginas:  
) 
VII. DATOS DEL INVESTIGADOR 
40. Nombre del investigador que informa: 
41. Dirección del investigador: 
42. Fecha notificación: | 
| 
| 
| 
43. Firma investigador: 
VIII. DATOS A RELLENAR POR EL PROMOTOR 
44. Nombre del receptor de la 
notificación: 
45. Fecha recepción: | 
| 
| 
| 
46. Firma del receptor: 
47. Clasificación del acontecimiento descrito: 
Acontecimiento Adverso Grave 
Reacción Adversa Grave 
Reacción Adversa Grave e Inesperada→ NOTIFICACIÓN A AUTORIDADES SANITARIAS OBLIGATORIA 
48.Notificación expeditiva realizada: 
Sí → Fecha | 
| 
| 
| 
No 
No procede 
49. Comunicado a Eudravigilance: 
Sí → Fecha | 
| 
| 
| 
No Procede 
 
 
FAX TO THE STUDY COORDINATING CENTRE FAX NUMBER: 
93 227 98 77 

Protocolo 
COST-EFFECT-CLINIC 
Nº EudraCT: 2014-004820-24 
Protocolo versión 1.0, de 4 de octubre de 2014 
Anexo IV 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ANNEX IV. SERIOUS AND UNEXPECTED ADVERSE 
REACTION REPORTING FORM 

Protocolo 
COST-EFFECT-CLINIC 
Nº EudraCT: 2014-004820-24 
Protocolo versión 1.0, de 4 de octubre de 2014 
Anexo IV 
 
 
 
 
Anexo D Formulario de notificación de reacción adversa grave e inesperada ocurrida 
en España 
 
NOTIFICACION DE SOSPECHA DE 
REACCION ADVERSA PARA 
MEDICAMENTOS EN INVESTIGACIÓN 
CODIGO DE PROTOCOLO 
(promotor)………………. 
Nº EUDRACT/ Nº Protocolo 
AEMPS……………….. 
Nº NOTIFICACION 
(Promotor) 
Notificación realizada a Eudravigilance  SI 
 NO 
PACIENTE Nº 
Nº NOTIFICACION 
INFORMACION SOBRE LA REACCIÓN ADVERSA 
 
1a. PAÍS 
2. FECHA DE NACIMIENTO 
2a. EDAD 
3. SEXO 
3a. PESO 
3b. TALLA 
4-6. FECHA DE INICIO DE LA 
REACCIÓN 
DÍA 
MES 
AÑO 
 HOMBRE 
 MUJER 
DÍA 
MES 
AÑO 
7. DESCRIPCIÓN DE LA REACCIÓN ADVERSA (Incluyendo resultados relevantes de exploración o de laboratorio, y la fecha de finalización, si 
procede). 
8-13b. CRITERIOS DE 
GRAVEDAD/ DESENLACE 
 FALLECIMIENTO 
 LA VIDA DEL PACIENTE HA 
ESTADO EN PELIGRO 
 HOSPITALIZACIÓN 
 PROLONGACIÓN 
HOSPITALIZACIÓN 
 INCAPACIDAD PERMANENTE 
O SIGNIFICATIVA 
 RA CLINICAMENTE 
RELEVANTE 
Desenlace 
 PERSISTENCIA DE LA RA 
 RECUPERACIÓN SIN 
SECUELAS 
 RECUPERACIÓN CON 
SECUELAS 
 DESCONOCIDO 
 
II. INFORMACION DEL MEDICAMENTO EN INVESTIGACIÓN 
 
14. MEDICAMENTO SOSPECHOSO 
15. DOSIS 
DIARIA 
16. VÍA 
17. ENFERMEDAD EN ESTUDIO 
18. FECHAS DE 
INICIO 
FINAL 
19. DURACIÓN DEL 
TRATAMIENTO 
20. ¿REMITIÓ LA REACCIÓN AL SUSPENDER LA 
MEDICACIÓN? 
 SI   NO   NO PROCEDE 
20a. ¿REMITIÓ LA REACCIÓN AL REDUCIR LA 
DOSIS? 
 SI 
 NO 
 NO PROCEDE 
21. ¿REAPARECIÓ LA REACCIÓN AL 
ADMINISTRAR DE NUEVO LA MEDICACIÓN? 
 SI   NO  NO PROCEDE 
III. MEDICAMENTOS CONCOMITANTES E HISTORIA CLÍNICA 
 
22. MEDICAMENTOS CONCOMITANTES (Márquese con un 
asterisco el o los medicamentos sospechosos) 
22a. DOSIS 
DIARIA 
22b. VÍA 
22c. FECHAS DE 
INICIO 
FINAL 
22d. MOTIVO DE LA PRESCRIPCIÓN 
23. DATOS IMPORTANTES DE LA HISTORIA CLÍNICA (ej. diagnósticos, alergias, embarazos, etc.) 
IV. INFORMACION SOBRE PROMOTOR E INVESTIGADOR 
 
24a. NOMBRE Y DIRECCION DEL PROMOTOR 
24b. NOMBRE Y DIRECCION DEL INVESTIGADOR 
24c. CODIGO DE LABORATORIO 
25a. TIPO DE INFORME 
24c. TECNICO DEL PROMOTOR QUE INFORMA 
(Nº AEMPS) 
□ INICIAL 
NOMBRE: 
□ SEGUIMIENTO 
TELEFONO: 
FIRMA: 
24e. FECHA DEL INFORME 
24f. FECHA DE ENTRADA AEM 
25b. SE ADJUNTA INFORME COMPLEMENTARIO 

Protocolo 
COST-EFFECT-CLINIC 
Nº EudraCT: 2014-004820-24 
Protocolo versión 1.0, de 4 de octubre de 2014 
Anexo IV 
 
 
 
 
GENERAL INSTRUCTIONS 
1. 
This form will be used only to report suspected serious and unexpected adverse reactions (ARs) 
that occur with investigational medicines. 
 
2. 
Suspicions of fatal or life-threatening AR (those that would have resulted in the death of the patient 
if there had not been an immediate therapeutic intervention) will be reported within a maximum period of 
7 calendar days; If not all information is available, it can be completed within an additional 8 days. Other 
suspected serious and unexpected AR will be reported within a maximum period of 15 days. 
 
3. 
When the available space is insufficient, an additional information sheet will be added, correctly 
identified with the name of the promoter and the number assigned to the notification. This information 
may include the assessment of causality carried out by the reporting technician. 
 
SPECIFIC INSTRUCTIONS 
1. 
The protocol code is the one assigned by the sponsor to identify the trial. The promoter's 
notification number is the one used by the promoter for its filing. In the case of tracking information, the 
same number shall be used or, if amended, the number of the initial notification shall be indicated. The 
"Notification number" space that appears in the shade will be left unfilled. 
 
2. 
The age will be set in years, months, weeks or days as appropriate, but always indicating it. If the 
age is not precisely known, at least the age group to which the child belongs (e.g., infant, child, 
adolescent, adult, elderly) should be referred. 
7. The RA shall be described in full, indicating the date of completion of the RA and including the 
results of the complementary examinations or laboratory tests that are considered of interest. This 
notification may be accompanied by as many reports as deemed appropriate for the proper 
interpretation of the clinical picture suspected of being an adverse reaction. 
 
8-13. Categories are not mutually exclusive. Assistance in an Emergency Department of a Hospital 
of less than 24 hours will not be considered hospitalisation. 
14. Investigational medicinal products shall be identified if possible by their generic name (DOE or 
INN), indicating where the trade name is available, or failing that, by the proposed name or 
laboratory code for the product. 
 
15. In the event that the administration is not daily, an attempt will be made to describe it with one of 
the following possibilities: cyclical, weekly, monthly, annual or number of times it has been used (in 
this case putting the dose of each dose, not the total). 
 
17. The pathological process of the patient for whom the investigational product is intended shall be 
recorded, or "healthy volunteer" in the case of such. 
19. The duration of treatment until the onset of the adverse reaction shall be recorded. 
 
22. It shall be explicitly indicated whether no concomitant drugs have been taken. If one or more of 
the concomitant drugs are considered suspicious, they should be marked with an asterisk (e.g., * 
AMOXICILLIN). Medicinal products used to treat the adverse reaction shall be excluded. 

Protocolo 
COST-EFFECT-CLINIC 
Nº EudraCT: 2014-004820-24 
Protocolo versión 1.0, de 4 de Octubre de 2014 
Anexo V 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ANEXO V. DECLARACIÓN DE HELSINKI 

Clinical Review & Education 
Downloaded From: http://jama.jamanetwork.com/ by a Universidad de Barcelona User on 10/21/2013 
 
 
Special Communication 
World Medical Association Declaration of Helsinki 
Ethical Principles for Medical Research 
Involving Human Subjects 
World Medical Association 
 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington, DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
Preamble 
1. The World Medical Association (WMA) has developed the Dec- 
laration of Helsinki as a statement of ethical principles for medi- 
cal research involving human subjects, including research on 
identifiable human material and data. 
 
The Declaration is intended to be read as a whole and each of 
its constituent paragraphs should be applied with consider- 
ation of all other relevant paragraphs. 
 
2. Consistent with the mandate of the WMA, the Declaration is ad- 
dressed primarily to physicians. The WMA encourages others 
who are involved in medical research involving human subjects 
to adopt these principles. 
 
General Principles 
3. The Declaration of Geneva of the WMA binds the physician with 
the words, “The health of my patient will be my first consider- 
ation,” and the International Code of Medical Ethics declares that, 
“A physician shall act in the patient's best interest when provid- 
ing medical care.” 
 
4. It is the duty of the physician to promote and safeguard the 
health, well-being and rights of patients, including those who are 
involved in medical research. Thephysician's knowledge and con- 
science are dedicated to the fulfilment of this duty. 
 
5. Medical progress is based on research that ultimately must in- 
clude studies involving human subjects. 
 
6. The primary purpose of medical research involving human sub- 
jects is to understand the causes, development and effects of 
diseases and improve preventive, diagnostic and therapeutic in- 
terventions (methods, procedures and treatments). Even the 
best proven interventions must beevaluated continually through 
research for their safety, effectiveness, efficiency, accessibility 
and quality. 
 
7. Medical research is subject toethical standards that promote and 
ensure respect for all human subjects and protect their health 
and rights. 
 
8. While the primary purpose of medical research is to generate new 
knowledge, this goal can never take precedence over the rights 
and interests of individual research subjects. 
 
9. It is the duty of physicians who are involved in medical research 
to protect the life, health, dignity, integrity, right to self- 
determination, privacy, and confidentiality of personal informa- 
tion of research subjects. The responsibility for the protection 
of research subjects must always rest with the physician or other 
health care professionals and never with the research subjects, 
even though they have given consent. 
 
10. Physicians must consider the ethical, legal and regulatory norms 
and standards for research involving human subjects in their own 
countries as well as applicable international norms and stan- 
dards. No national or international ethical, legal or regulatory re- 
quirement should reduce or eliminate any of the protections for 
research subjects set forth in this Declaration. 
 
11. Medical research should be conducted in a manner that mini- 
mises possible harm to the environment. 
 
12. Medical research involving human subjects must be conducted 
only by individuals with the appropriate ethics and scientific edu- 
cation, training and qualifications. Research on patients or 
healthy volunteers requires the supervision of a competent and 
appropriately qualified physician or other health care profes- 
sional. 
 
jama.com 
JAMA Published online October 19, 2013 
E1 

Clinical Review & Education Special Communication 
World Medical Association Declaration of Helsinki 
Downloaded From: http://jama.jamanetwork.com/ by a Universidad de Barcelona User on 10/21/2013 
 
 
13. Groups that are underrepresented in medical research should 
be provided appropriate access to participation in research. 
 
14. Physicians who combine medical research with medical care 
should involve their patients in research only to the extent that 
this is justified by its potential preventive, diagnostic or thera- 
peutic value and if the physician has good reason to believe that 
participation in the research study will not adversely affect the 
health of the patients who serve as research subjects. 
 
15. Appropriate compensation and treatment for subjects who are 
harmed as a result of participating in research must be en- 
sured. 
 
Risks, Burdens and Benefits 
16. In medical practice and in medical research, most interventions 
involve risks and burdens. 
 
Medical research involving human subjects may only be con- 
ducted if the importance of the objective outweighs the risks and 
burdens to the research subjects. 
 
17. All medical research involving human subjects must be pre- 
ceded by careful assessment of predictable risks and burdens 
to the individuals and groups involved in the research in com- 
parison with foreseeable benefits to them and to other individu- 
als or groups affected by the condition under investigation. 
 
Measures to minimise the risks must be implemented. The risks 
must be continuously monitored, assessed and documented by 
the researcher. 
 
18. Physicians may not be involved in a research study involving hu- 
man subjects unless they are confident that the risks have been 
adequately assessed and can be satisfactorily managed. 
 
When the risks are found to outweigh the potential benefits or 
when there is conclusive proof of definitive outcomes, physi- 
cians must assess whether to continue, modify or immediately 
stop the study. 
 
Vulnerable Groups and Individuals 
19. Some groups and individuals are particularly vulnerable and may 
have an increased likelihood of being wronged or of incurring ad- 
ditional harm. 
 
All vulnerable groups and individuals should receive specifi- 
cally considered protection. 
 
20. Medical research with a vulnerable group is only justified if the 
research is responsive to the health needs or priorities of this 
group and the research cannot be carried out in a non- 
vulnerable group. In addition, this group should stand to ben- 
efit from the knowledge, practices or interventions that result 
from the research. 
Scientific Requirements and Research Protocols 
21. Medical research involving human subjects must conform to gen- 
erally accepted scientific principles, be based on a thorough 
knowledge of the scientific literature, other relevant sources of 
information, and adequate laboratory and, as appropriate, ani- 
mal experimentation. The welfare of animals used for research 
must be respected. 
 
22. The design and performance of each research study involving 
human subjects must be clearly described and justified in a re- 
search protocol. 
 
The protocol should contain a statement of the ethical consid- 
erations involved and should indicate how the principles in this 
Declaration have been addressed. The protocol should include 
information regarding funding, sponsors, institutional affilia- 
tions, potential conflicts of interest, incentives for subjects and 
information regarding provisions for treating and/or compen- 
sating subjects who are harmed as a consequence of participa- 
tion in the research study. 
 
In clinical trials, the protocol must also describe appropriate ar- 
rangements for post-trial provisions. 
 
Research Ethics Committees 
23. The research protocol must be submitted for consideration, com- 
ment, guidance and approval to the concerned research ethics 
committee before the study begins. This committee must be 
transparent in its functioning, must be independent of the re- 
searcher, the sponsor and any other undue influence and must 
be duly qualified. It must take into consideration the laws and 
regulations of the country or countries in which the research is 
to be performed as well as applicable international norms and 
standards but these must not be allowed to reduce or eliminate 
any of the protections for research subjects set forth in this Dec- 
laration. 
 
The committee must have the right to monitor ongoing stud- 
ies. The researcher must provide monitoring information to the 
committee, especially information about any serious adverse 
events. No amendment to the protocol may be made without 
consideration and approval by the committee. After the end of 
the study, the researchers must submit a final report to the com- 
mittee containing a summary of the study’s findings and con- 
clusions. 
 
Privacy and Confidentiality 
24. Every precaution must be taken to protect the privacy of re- 
search subjects and the confidentiality of their personal infor- 
mation. 
 
Informed Consent 
25. Participation by individuals capable of giving informed consent 
as subjects in medical research must be voluntary. Although it 
 
 
 
 
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may be appropriate to consult family members or community 
leaders, no individual capable of giving informed consent may 
be enrolled in a research study unless he or she freely agrees. 
 
26. In medical research involving human subjects capable of giving 
informed consent, each potential subject must be adequately 
informed of the aims, methods, sources of funding, any pos- 
sible conflicts of interest, institutional affiliations of the re- 
searcher, the anticipated benefits and potential risks of the study 
and the discomfort it may entail, post-study provisions and any 
other relevant aspects of the study. The potential subject must 
be informed of the right to refuse to participate in the study or 
to withdraw consent to participate at any time without repri- 
sal. Special attention should be given to the specific informa- 
tion needs of individual potential subjects as well as to the meth- 
ods used to deliver the information. 
 
After ensuring that the potential subject has understood the in- 
formation, the physician or another appropriately qualified in- 
dividual must then seek the potential subject’s freely-given in- 
formed consent, preferably in writing. If the consent cannot be 
expressed in writing, the non-written consent must be formally 
documented and witnessed. 
 
All medical research subjects should be given the option of being 
informed about the general outcome and results of the study. 
 
27. When seeking informed consent for participation in a research 
study the physician must be particularly cautious if the poten- 
tial subject is in a dependent relationship with the physician or 
may consent under duress. In such situations the informed con- 
sent must be sought by an appropriately qualified individual who 
is completely independent of this relationship. 
 
28. For a potential research subject who is incapable of giving in- 
formed consent, the physician must seek informed consent from 
the legally authorised representative. These individuals must not 
be included in a research study that has no likelihood of benefit 
for them unless it is intended to promote the health of the group 
represented by the potential subject, the research cannot in- 
stead be performed with persons capable of providing in- 
formed consent, and the research entails only minimal risk and 
minimal burden. 
 
29. When a potential research subject who is deemed incapable of 
giving informed consent is able to give assent to decisions about 
participation in research, the physician must seek that assent in 
addition to the consent of the legally authorised representa- 
tive. The potential subject’s dissent should be respected. 
 
30. Research involving subjects who are physically or mentally in- 
capable of giving consent, for example, unconscious patients, 
may be done only if the physical or mental condition that pre- 
vents giving informed consent is anecessary characteristic of the 
research group. In such circumstances the physician must seek 
informed consent from the legally authorised representative. If 
no such representative is available and if the research cannot be 
delayed, the study may proceed without informed consent pro- 
vided that the specific reasons for involving subjects with a con- 
dition that renders them unable to give informed consent have 
been stated in the research protocol and the study has been ap- 
proved by a research ethics committee. Consent to remain in the 
research must be obtained as soon as possible from the subject 
or a legally authorised representative. 
 
31. The physician must fully inform the patient which aspects of their 
care are related to the research. The refusal of a patient to par- 
ticipate in a study or the patient’s decision to withdraw from the 
study must never adversely affect the patient-physician rela- 
tionship. 
 
32. For medical research using identifiable human material or data, 
such as research on material or data contained in biobanks or 
similar repositories, physicians must seek informed consent for 
its collection, storage and/or reuse. There may be exceptional 
situations where consent would be impossible or impracti- 
cable to obtain for such research. In such situations the re- 
search may be done only after consideration and approval of a 
research ethics committee. 
 
Use of Placebo 
33. The benefits, risks, burdens and effectiveness of a new inter- 
vention must be tested against those of the best proven inter- 
vention(s), except in the following circumstances: 
 
Where no proven intervention exists, the use of placebo, or no 
intervention, is acceptable; or 
 
Where for compelling and scientifically sound methodological 
reasons the use of any intervention less effective than the best 
proven one, the use of placebo, or no intervention is necessary 
to determine the efficacy or safety of an intervention 
 
and the patients who receive any intervention less effective than 
the best proven one, placebo, or no intervention will not be sub- 
ject to additional risks of serious or irreversible harm as a result 
of not receiving the best proven intervention. 
 
Extreme care must be taken to avoid abuse of this option. 
 
Post-Trial Provisions 
34. Inadvance of a clinical trial, sponsors, researchers and host coun- 
try governments should make provisions for post-trial access for 
all participants who still need an intervention identified as ben- 
eficial in the trial. This information must also be disclosed to par- 
ticipants during the informed consent process. 
 
Research Registration and Publication and Dissemination 
of Results 
35. Every research study involving human subjects must be regis- 
tered in a publicly accessible database before recruitment of the 
first subject. 
 
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36. Researchers, authors, sponsors, editors and publishers all have 
ethical obligations with regard to the publication and dissemi- 
nation of the results of research. Researchers have a duty to make 
publicly available the results of their research on human sub- 
jects and are accountable for the completeness and accuracy of 
their reports. All parties should adhere to accepted guidelines 
for ethical reporting. Negative and inconclusive as well as posi- 
tive results must be published or otherwise made publicly avail- 
able. Sources of funding, institutional affiliations and conflicts 
of interest must be declared in the publication. Reports of re- 
search not in accordance with the principles of this Declaration 
should not be accepted for publication. 
Unproven Interventions in Clinical Practice 
37. In the treatment of an individual patient, where proven inter- 
ventions do not exist or other known interventions have been 
ineffective, the physician, after seeking expert advice, with in- 
formed consent from the patient or a legally authorised repre- 
sentative, may use an unproven intervention if in the physi- 
cian's judgement it offers hope of saving life, re-establishing 
health or alleviating suffering. This intervention should subse- 
quently be made the object of research, designed to evaluate 
its safety and efficacy. In all cases, new information must be re- 
corded and, where appropriate, made publicly available. 
 
 
 
ARTICLE INFORMATION 
Corresponding Author: World Medical 
Association, 13, ch. du Levant, CIB - Bâtiment A, 
01210 Ferney-Voltaire, France; wma@wma.net. 
Published Online: October 19, 2013. 
doi:10.1001/jama.2013.281053. 
Disclaimer: ©2013 World Medical Association, Inc. 
All Rights Reserved. All intellectual property rights 
in the Declaration of Helsinki are vested in the 
World Medical Association. The WMA has granted 
JAMA exclusive rights to publish the 
English-language version of the Declaration through 
December 31, 2013. 
Online-Only Content: Audio podcast is available at 
www.jama.com. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocolo 
COST-EFFECT-CLINIC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ANEXO VI. SEGURO DE RESPONSABILIDAD CIVIL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nº EudraCT: 2014-004820-24 
Protocolo versión 1.0, de 4 de Octubre de 2014 
Anexo VI 

 
 
Certificado de seguro 
 
 
 
Zurich Insurance PLC Sucursal en España. 
 
C E R T I F I C A: 
 
1. Que la FUNDACIÓ PRIVADA CLÍNIC PER A LA RECECA BIOMÈDICA domiciliada en 
c/Rosselló 149, 08036 Barcelona, tiene contratada la póliza de seguros num 
(riesgo aceptado en proceso de emisión por la Compañía) con el fin de cubrir la 
Responsabilidad Civil derivada de la realización de Ensayos Clínicos. Esta cobertura 
es válida para el producto y estudio siguiente: 
Ensayo: “Coste-efectividad de distintas pautas de tratamiento antirretroviral en 
pacientes naive. Ensayo clínico aleatorizado, no enmascarado, comparando 
DRV/r+3TC, ABC+3TC (Kivexa)+RPV, o EVG / COBI / FTC / TDF (Stribild) durante 48 
semanas”. Versión / Fecha: 1.0 / 4 de octubre de 2014. 
Código del protocolo: cost-effect-clinic, NºEudraCT: 2014-004820-24 
 
Tomador: FUNDACIÓ PRIVADA CLÍNIC PER A LA RECECA BIOMÈDICA 
Fecha inicio: 01.01.2015 
Fecha final: 01.01.2017 
Nº Pacientes: 150 
Fase: IV 
Investigador principal: Dr Josep Mallolas 
Promotor del ensayo: FUNDACIÓ PRIVADA CLÍNIC PER A LA RECECA BIOMÈDICA 
Que va a realizarse en el siguiente hospital: 
Hospital Clínic de Barcelona 
 
2. La póliza mencionada cubre, en los límites y condiciones pactados y de acuerdo 
con el Real Decreto Ley de 6 de Febrero de 2004 nº 223/2004 al promotor, 
investigador y colaboradores, así como al centro hospitalario donde se realice el 
ensayo. 
3. Que los límites de garantía establecidos son: 
EUROS 600.000,00 (seiscientos mil) por paciente sometido a ensayo, límite de 
EUROS 6.000.000,00 (seis millones) por ensayo y año. 
 
4. 
Que el período de validez de este seguro vence el día 01.01.2017 . 
 
 
 
Zurich Insurance PLC Sucursal en 
España 
Global Corporate 
 
Diagonal, 431 bis 
08036 Barcelona 
 
Fax 93 400 44 22 
 
www.zurichspain.com 
5. 
Coste del seguro: 
Prima Neta: 5.878,47euros. 
Prima Total: 6.240,00euros. 
 
1. Y para que conste en donde convenga se expide el presente certificado en Barcelona, a 
02 de Diciembre de 2014. 
 
 
 
 
Zurich Insurance PLC Sucursal en España. Inscrita en el Registro Mercantil de Barcelona, tomo 41342, folio 164, hoja B390869, inscripción 1ª con 
dirección y domicilio social en Vía Augusta 200, 08021 Barcelona, NIF W0072130H. 
61 14