Clinical trial NCT01778413
Conditions: HIV
Sponsor: Anna Cruceta
Start date: 2013-06-03; Completion date: 2015-07-21
Enrollment: 61 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main objective is to determine the feasibility of maintaining virologic suppression on standard plasma viral load by dose reduction of ATRIPLA ®.

Detailed description:
The main objective of this study is to determine the feasibility of maintaining virologic suppression on standard plasma viral load (limit of detection 37 copies / mL) of a dose reduction strategy of ATRIPLA ® once a day to three tablets per week in patients infected with HIV-1 with sustained suppression of plasma viral load standard for more than two years.

Arms: arm 1: Atripla (600 mg/200 mg/245 mg) three times a week. arm 2: Atripla (600 mg/200 mg/245 mg) one time a day.
Interventions: intervention 1: ATRIPLA
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
A-TRI-WEEK Trial 
EudraCT number: 2012-004970-24 
Protocol version 1.0 of 30 October 2012 
1 
 
 
Virologic and immunological safety of a dose reduction 
strategy with the efavirenz/tenofovir/emtricitabine 
antiretroviral regimen 
 
CLINICAL TRIAL PROTOCOL WITH DRUGS 
 
 
 
 
Protocol Code: A-TRI-WEEK 
 
 
 
 
 
 
 
Version / Date: 1.0 Date: October 30, 2012 
EudraCT number: 2012-004970-24 
NCT Number: NCT01778413 
 
SPONSOR: Fundació Clínic per a la Recerca Biomèdica 
Principal Investigator and coordinator of the study: 
Dr. Esteban Martínez Chamorro. 
Infectious Diseases Service. Hospital 
Clínic de Barcelona. 
Spain. 
Phone: +34 932275400 / ext 3310. Email: 
estebanm@clinic.ub.es 
 
 
 
 
 
 
 
CONFIDENTIAL 


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Protocol version 1.0 of 30 October 2012 
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1.  SUMMARY 
 
1.0. Type of application: 
Open-label, phase IV, randomized, pilot, prospective, single-center study. 
 
1.1. Identification of the developer: 
Fundació Clínic per a la Recerca Biomèdica 
Manager: Ms. Pastora Martínez Samper 
C. Roselló, 143 
08036 Barcelona 
 
1.2. Clinical Trial Title: 
Virologic and immunological safety of a dose reduction strategy with the 
efavirenz/tenofovir/emtricitabine antiretroviral regimen 
Version / Date: 1.0, dated October 30, 2012. 
 
 
1.3. Protocol Code: A-TRI-WEEK 
EudraCT number: 2012-004970-24 
1.4. Principal Investigator and Study Coordinator: Dr. Esteban Martínez Chamorro 
Collaborating researchers: Dr. Polyana Monteiro, Dr. Montserrat Loncá, Dr. Ana González. 
 
 
1.5. Centres in which the trial is planned to be carried out: 
The study will be a national Unicenter (Hospital Clínic de Barcelona). 
1.6. Clinical Research Ethics Committees that have approved the trial: 
 
The trial has been submitted to the corresponding CEIC of the Hospital Clínic de Barcelona as a 
reference CEIC. 
 
 
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). 
Head of the CTU: Dr Joan Albert Arnaiz 
 
 
1.8. Study Drug Information: 
ATRIPLA® Atripla 600 mg/200 mg/245 mg film-coated tablets The drug has final approval from the 
Ministry of Health. As stated in its technical sheet (see annexes). 
 
1.9. Clinical Trial Phase: Phase IV 


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1.10. Objectives: 
1.10.1. Main objective: 
The primary objective of this study is to determine the feasibility of maintaining virologic suppression 
on standard plasma viral load (limit of detection 37 copies/mL) of a once-daily dose reduction 
strategy of ATRIPLA® to three tablets per week in HIV-1-infected patients with sustained standard 
plasma viral load suppression for more than 2 years. 
 
 
1.10.2. Secondary objectives: 
 
● 
Virological study including: ultrasensitive viral load in plasma (limit of detection 1 copy/mL), and 
HIV-1 reservoir in peripheral blood mononucellar cells, 
 
● 
Immunological study including: production of TRECs, immune profile of activation (CD38 and 
HLA-DR) and senescence (CD57 and CD28) in CD4 and CD8 lineages, apoptosis (annexin V 
staining), and ratios of naïve T cells and effectors and memory cells (CCR7 and CD45RA). 
 
● 
Pharmacokinetic study, including baseline plasma levels of efavirenz at the beginning and end of 
the study. 
 
● 
Safety study, which includes: test on sleep quality, vitamin D levels, estimated glomerular 
filtration rate and plasma lipids at the beginning and end of the study, as well as general 
tolerability. 
 
 
 
1.11. Design: 
Open-label, randomized, Phase IV, prospective, pilot, single-center study. 
 
 
1.12. Disease under study: 
HIV infection (acquired immunodeficiency virus) 
 
 
1.13. Assessment variables: 
 
1.13.1. Main 
The primary endpoint of the study will be the proportion of patients who continue to have a viral load 
<37 copies/mL at 24 weeks using an intention-to-treat analysis. 
 
1.13.2. Secondary 
• 
Percentage of patients with virologic response viral load <1 copy/mL after 24 weeks. 
 
• 
Change from baseline to 24 weeks in the viral reservoir of peripheral blood mononuclear 
cells 
 
• 
Changes from baseline to 24 weeks in REBT production 
 
• 
Changes in the immune profile of activation (CD38 and HLA-DR) and senescence (CD57 
and CD28) in the CD4 and CD8 lineages, and in the proportions of naïve and effector and 
memory T cells (CCR7 and CD45RA). 


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• 
Changes in apoptosis levels in vitro by annexin V staining. 
 
• 
Changes in plasma levels of efavirenz. 
 
• 
Changes in sleep quality (Pittsburgh Sleep Quality Index), plasma levels of vitamin 25OH-D 
and lipids, and estimated glomerular filtration rate (CPK-EPI). 
 
• 
Overall safety (reporting side effects, serious side effects, and discontinuation of treatment 
due to side effects) 
 
 
 
1.14. Study population and total number of patients: 
Adult patients with well-controlled chronic HIV infection and on treatment with ATRIPLA.® A total of 
60 patients will be included. 
 
1.15. Duration of treatment: 
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 24 weeks. 
 
 
1.16. Schedule and expected completion date: 
The study is expected to begin, once the permits have been obtained, in March 2013. The 
recruitment period will be 48 weeks. The follow-up of the patients will last 24 weeks to start the 
study. The study is expected to be completed in October 2014. 


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2.  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 
Technical data sheets 
Annex II 
Protocol Acceptance IP Document 
Annex III 
 Patient Information Sheet and Study Informed Consent Annex IV 
Toxicity grading table (WHO) 
Annex V 
Serious Adverse Event Reporting Form.  
Annex VI 
Data collection notebook. List of CRD variables  
Annex VII 
Economic Report 
Annex VIII 
Declaration of Helsinki. 
Annex IX 
Liability Insurance 


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3.  Overview 
3.1 Trial identification 
Title: 
Virologic and immunological safety of a dose reduction strategy with the 
efavirenz/tenofovir/emtricitabine antiretroviral regimen 
Open-label study, Phase IV, randomized, prospective, pilot, single-center. 
 
 
1.3. Protocol Code: A-TRI-WEEK 
 
Version / Date: 1.0, dated October 30, 2012. EudraCT 
number: 2012-004970-24 
. 
 
 
 
3.2 Developer Identification 
 
Fundació Clinic per a la Recerca Biomèdica. 
C/ Rossello 143 
08036 Barcelona 
 
 
3.3 Identification of the promoter's representative 
Manager: Dr. Pastora Martínez Samper 
Fundació Clinic per a la Recerca biomedica. 
C/ Rossello 143 
08036 Barcelona 
e-mail: PMARTIN2@clinic.ub.es 
 
 
3.4 Identification of researchers of the sponsoring entity 
Hospital Clínic 
Principal Investigator and Study Coordinator: 
Dr. Esteban Martinez Chamorro 
Infectious Diseases Service. 
estebanm@clinic.ub.es 
 
Collaborating researchers: 
Dr Polyana Monteiro, Dr Montserrat Loncá, and Dr Ana González, 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 
Virology Section of the Microbiology Laboratory: Marta Parera Pharmacy: 
Anna Estafell and Begoña Gómez 
Retrovirology and Viral Immunopathology Laboratory of the Infections Service: Alberto Crespo. 
Carmen Alvarez and Sonsoles Sanchez-Palomino 
Biostatistician: Jose Ignacio Pérez 


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Nurse: Merçé Poal 
Laboratory Technician: Pilar Callau 
 
 
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 Trial Unit). 
Monitoring manager: Dr. Anna 
Cruceta. acruceta@clinic.ub.es 
Tel 932275400 ext 4380 fax 932279877 
 
Head of the CTU: 
Dr. Joan Albert Arnaiz. 
Clinical Pharmacology Service. 
Hospital Clínic de Barcelona 
 
 
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 (1, 2). 
 
The combination of efavirenz/tenofovir/emtricitabine has been the most frequently used 
contemporary treatment in clinical trials in people with no prior experience of antiretroviral treatment, 
and no other treatment regimen has shown superiority in efficacy against it 
(3). This combination is available as a fixed-dose combination in a single pill (ATRIPLA),® which 
represents the simplest antiretroviral regimen in Spain today. In the short term, there may be 
tolerability problems, neuropsychological side effects that are usually of little intensity and that in 
many cases resolve after the first four weeks of treatment (4). In addition, a small proportion of 
patients with well-identified risk factors such as older age, low CD4, low weight weight, nephrotoxic 
drugs, and underlying kidney disease may experience a progressive risk of tenofovir-associated 
renal dysfunction (5) that usually improves with discontinuation of tenofovir. There is evidence to 
suggest an association between increased bioavailability of efavirenz or tenofovir and the risk of 
developing side effects due to these drugs. For most patients on chronically stable treatment with 
ATRIPLA®, serious long-term side effects are not expected. ATRIPLA® has shown a better cost-
effectiveness balance than other antiretroviral regimens (6). For all these reasons, ATRIPLA® has 
become one of the most popular antiretroviral regimens. At the end of 2011, approximately 25% of 
active patients (n=4400) treated at the Hospital Clínic de Barcelona were treated with ATRIPLA,® 
making this regimen the most frequently prescribed antiretroviral treatment. Currently, more than 
1000 patients are receiving virologically effective treatment with ATRIPLA® at the Hospital Clínic de 
Barcelona, of which 75% have been on this treatment for more than two years. 


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Since antiretroviral treatment has to be taken indefinitely, the search for strategies to simplify it has 
been an important element in the development of antiretroviral regimens. The simplification of 
antiretroviral treatment in patients with sustained virologic suppression represents a strategy 
accepted by most therapeutic recommendations (7). The longer the viral suppression lasts, the 
greater the probability of maintaining sustained virological success (8-11). In patients with sustained 
virologic suppression, the absolute risk of virologic failure is low, and regimens with non-nucleoside 
reverse transcriptase inhibitors have consistently shown better virologic outcomes than regimens 
with protease inhibitors. Strategies to simplify antiretroviral treatment have aimed to minimize the risk 
of toxicity, seek greater convenience, and more recently reduce the cost of antiretroviral. 
 
Although ATRIPLA® is the simplest antiretroviral regimen at present, there is potential for further 
simplification. Each of the individual components of ATRIPLA® has the longest half-lives of all 
currently available antiretrovirals: 40-55 hours for plasma efavirenz (12), 39 hours for intracellular 
emtricitabine triphosphate, and 150 hours for intracellular tenofovir diphosphate (13). In a 
discontinuation study, efavirenz plasma levels were estimated to exceed the adjusted IC95 for 
protein concentration (46.7 ng/mL) for a median of 6.7 days (IQR 4.7-9.2) after the last dose of 
efavirenz (14). Clinical information is available on the dosing of efavirenz at dose intervals greater 
than once daily (PHOTO study). The FOTO study was a 48-week observational study in which 30 
patients with virologic suppression (<50 copies/mL) for at least three months prior to the study 
switched their usual antiretroviral treatment from a daily dose to a weekly schedule of 5 consecutive 
days on treatment (usually Monday through Friday) followed by 2 days without treatment (usually on 
the weekend) (15). Overall, virologic suppression was maintained in 90% of patients. More 
interestingly, however, ten of the 30 patients included were taking efavirenz along with tenofovir and 
nucleoside reverse transcriptase inhibitors with long half-lives such as didanosine or lamivudine, and 
none of these showed virologic failure. Following these promising results, researchers in the FOTO 
pilot study designed a 24-week open-label randomized study in which treatment with ATRIPLA® for 
five days a week would be compared to the standard dose of ATRIPLA® once a day 
(NCT00414635). So far, we have no information that results of this study have been reported. 
 
In our daily practice, we have detected at least two patients on chronic treatment with ATRIPLA® 
who, for personal reasons, different in each case, decided to take the dose every other day instead 
of the standard daily dosage for more than 6 and 12 months respectively, without the plasma viral 
load having become detectable in any of them. On the other hand, a small preliminary survey of a 
randomly selected sample of 36 consecutive patients treated with ATRIPLA® for more than 2 years, 
who claimed to have no tolerability problems and with a persistently undetectable viral load during 
that period of time, showed that 78% saw a dose reduction to three days per week as more favorable 
than the standard daily dose.  14% did not care, and only 8% did not want to change their dosage, 
their main reasons being the fact that they were already fine as they were and the fear that they 
could lose the undetectability of the plasma viral load. 
We intend to evaluate the possibility of effective simplification by moving from the standard daily 
dose of ATRIPLA® to a three-day-weekly dose in patients with sustained virologic suppression. 
Although antiretroviral treatment regimens have not so far contemplated dosing with intervals greater 
than once a day, the dosing of three times a week in the same way as that proposed in this project 
has been used with a high degree of compliance in the prophylaxis of P. jirovecii  pneumonia in HIV-
infected patients (16,  17). 
 
Reducing the dosage of the most widely used antiretroviral treatment regimen as proposed in this 
project would reduce expenditure by 57%. In the case of the Hospital Clínic alone, this reduction in 
expenditure would mean going from 7.4 to 4.2 million euros per year. Since ATRIPLA® represents 
one of the most widely used regimens, the dose reduction strategy 


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Protocol version 1.0 of 30 October 2012 
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could have a considerable impact on the budget for antiretroviral treatment within the policy of 
containing health expenditure promoted by the Spanish health authorities and more necessary today 
than ever in the current context of economic crisis (18). In addition, it can help reduce your already 
low risk of chronic toxicity. Finally, dose reduction is considered a popular measure and positively 
evaluated by a high proportion of treated patients. If our project obtains favorable results that support 
the dosage reduced to three days per week, the experimental regimen would become the simplest 
and cheapest among all the currently available regimens, including monotherapy with protease 
inhibitors. 
 
Determination of plasma viral load and CD4 and CD8 cell counts have been key tools for clinical 
research and healthcare of HIV-positive patients until now. However, in patients with persistently 
undetectable viral load and relatively high CD4 counts, the simple determination of viral load and cell 
populations is unlikely to allow a fine distinction between the possible virological and immunological 
consequences of the dose reduction strategy to be evaluated. Therefore, viral reservoir analysis by 
determining proviral DNA and especially the proportion of that reservoir that produces viral particles 
can provide more detailed information on the virological safety of the new strategy (19). Similarly, the 
determination of plasma viral load using the most sensitive technique ("single copy assay" (limit of 
detection 1 copy/mL) (20) can discriminate whether this dose-reduction strategy produces any 
impact on viral replication that cannot be detected by the standard technique used in routine clinical 
practice. On the other hand, the extensive immunological study that is intended to be carried out 
(population analysis of the T lineage that includes its activation status and thymic production, among 
others) will allow us to exhaustively monitor the effects of any changes that may occur at this level on 
the study population (21-23). Therefore, we consider that the efficacy and safety of the dose 
reduction strategy of the efavirenz/tenofovir/emtricitabine regimen should be evaluated as 
consistently as possible with the previously mentioned virological and immunological tests. 
 
Our study aims to conceptually confirm whether dose reduction of ATRIPLA® is feasible as a 
strategy and whether it entails any virological or immunological risk. If the results of this study are 
positive, they could form the basis for a randomized clinical trial of sufficient size to attempt to 
validate this strategy for future clinical use. 
 
 
 
4.1 Investigational Drug Identification 
Generic name: efavirenz, emtricitabine, and tenofovir disoproxil (as fumarate). 600 mg/200 mg/245 mg 
Trade name: Atripla ® 
Composition: Each tablet contains 600 mg efavirenz, 200 mg emtricitabine and 245 mg 
tenofovir disoproxil (as fumarate). 
Pharmaceutical form: film-coated tablet. 
 
 
4.2 Investigational Drug Information 
The drug has been definitively approved by the Ministry of Health. 
 
 
4.3 Treatment Regimen 
Adults: The recommended dose of Atripla is one tablet, taken orally, once daily. 


A-TRI-WEEK Trial 
EudraCT number: 2012-004970-24 
Protocol version 1.0 of 30 October 2012 
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Description: 
 
Atripla is a fixed-dose combination of efavirenz, emtricitabine, and tenofovir disoproxil fumarate. It is 
indicated for the treatment of human immunodeficiency virus-1 (HIV-1) infection in adults 18 years of 
age or older with virologic suppression at HIV-1 RNA levels of < 50 copies/mL on their current 
combination antiretroviral therapy for more than three months. 
 
Route of administration: oral 
 
Storage: Keep in the original packaging to protect it from moisture. Keep the bottle tightly 
closed. 
Dosage Schedule: 
 
Atripla ® is given 1 tablet 1 time a day. 
 
 
Study period and treatment: 
Randomization to two treatment groups: A or B 
 
GROUP A (control): ATRIPLA® at standard daily dose (1 tablet daily) for a period of 24 weeks 
GROUP B (experimental): ATRIPLA® at a dose three days per week (1 tablet Monday, Wednesday, 
and Friday) for a period of 24 weeks 
 
 
4.4 Compliance Statement 
The study will be carried out in accordance with the principles emanating from the Declaration of 
Helsinki, and according to the legal regulations in force (Royal Decree 223/2004), and will not begin 
until the approval of the reference CEIC and the approval of the AEMPS have been obtained. 
Patients will be informed orally and in writing and all relevant information tailored to their level of 
understanding will be communicated to participants. 
(See Attachment III: Patient Information Sheet and Attachment III: Written Consent Sheet.) 
 
The patient will be informed that their participation in the study will be treated with the same 
confidentiality as their clinical documentation and that only the people involved in the study will have 
access to their data. The patient's name will not appear in any publication or communication of the 
results of the study. 
PEG + 
 
4.5 Population under study 
Adults with HIV-1 infection controlled on an outpatient basis in the Infectious Diseases Service of the 
Hospital Clinic of Barcelona. 
 
 
4.6 Relevant Bibliography 
1. Mandalia S, Mandalia R, Lo G, et al. Rising population cost for treating people living with HIV in 
the UK, 1997-2013. PLoS ONE 2010; 5: e15677. 
2. Stoll M, Kollan C, Bergmann F, et al. Calculation of direct antiretroviral treatment costs and 
potential cost savings by using generics in the German HIV ClinSurv cohort. PLoS ONE 2011; 6: 
E23946. 
3. Boyd SD. Management of HIV infection in treatment-naive patients: a review of the most current 
recommendations. Am J Health Syst Pharm 2011; 68: 991-1001. 


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Protocol version 1.0 of 30 October 2012 
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4. Gazzard B, Balkin A, Hill A. Analysis of neuropsychiatric adverse events during clinical trials of 
efavirenz in antiretroviral-naive patients: a systematic review. AIDS Rev 2010; 12: 67-75. 
5. Hall AM, Hendry BM, Nitsch D, Connolly JO. Tenofovir-associated kidney toxicity in HIV-infected 
patients: a review of the evidence. Am J Kidney Dis 2011; 57: 773-780. 
6. Blasco AJ, Arribas JR, Clotet B, et al. Cost and cost/efficacy analyses of the preferred GESIDS 
regimens for initial antiretroviral therapy. Enferm Infecc Microbiol Clin 2011; 29: 721-730. 
7. McKinnon JE, Mellors JW, Swindells S. Simplification strategies to reduce antiretroviral drug 
exposure: progress and prospects. Antivir Ther 2009; 14: 1-12. 
8. Benzie AA, Bansi LK, Sabin CA, et al. Increased duration of viral suppression is associated with 
lower viral rebound rates in patients with previous treatment failures. AIDS 2007; 21: 1423-1430. 
9. Geretti AM, Smith C, Haberl A, et al. Determinants of virological failure after successful viral load 
suppression in first-line highly active antiretroviral therapy. Antivir Ther 2008; 13: 927-936. 
10. Rosenblum M, Deeks SG, van der Laan M, Bangsberg DR. The risk of virologic failure 
decreases with duration of HIV suppression, at greater than 50% adherence to antiretroviral therapy. 
PLoS ONE 2009; 4: E7196. 
11. Reekie J, Mocroft A, Ledergerber B, et al. History of viral suppression on combination 
antiretroviral therapy as a predictor of virological failure after a treatment change. HIV Med 2010; 11: 
469-478. 
12. Vrouenraets SM, Wit FW, van Tongeren J, Lange JM. Efavirenz: a review. Expert Opin 
Pharmacother 2007; 8: 851-871. 
13. Anderson PL, Kiser JJ, Gardner EM, et al. Pharmacological considerations for tenofovir and 
emtricitabine to prevent HIV infection. J Antimicrob Chemother 2011; 66: 240-250. 
14. Ribaudo HJ, Haas DW, Tierney C, et al. Pharmacogenetics of plasma efavirenz exposure after 
treatment discontinuation: an adult AIDS Clinical Trials Group Study. Clin Infect Dis 2006; 42: 401- 
407 
15. Cohen CJ, Colson AE, Sheble-Hall AG, McLaughlin KA, Morse GD. Pilot study of a novel short-
cycle antiretroviral treatment interruption strategy: 48-week results of the Five-Days-On, Two-Days-
Off (PHOTO) study. HIV Clin Trials 2007; 8: 19-23. 
16. El-Sadr W.M., Luskin-Hawk R, Yurik TM, et al. A randomized trial of daily and thrice-weekly 
trimethoprim-sulfamethoxazole for the prevention of Pneumocystis carinii pneumonia in human 
immunodeficiency virus-infected persons. Clin Infect Dis 1999; 29: 775-783. 
17. CDC. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults 
and adolescents. Recommendations from CDC, the National Institutes of Health, and the HIV 
Medicine Association of the Infectious Diseases Society of America. MMWR 2009; 58: 1-207. 
18. Rivero A. Does the cost of medicines influence the choice of antiretroviral treatment regimens? 
Enferm Infecc Microbiol Clin 2011; 29: 719-720. 
19. Boulassel MR, Chomont N, Pai NP et al. CD4 T cell nadir independently predicts the magnitude 
of the HIV reservoir after prolonged suppressive antiretroviral therapy. J Clin Virol 2012; 53: 29-32. 
20. Palmer S, Wiegand AP, Maldarelli F, et al. New real-time reverse transcriptase-initiated PCR 
assay with single-copy sensitivity for human immunodeficiency virus type 1 RNA in plasma. J Clin 
Microbiol 2003; 41: 4531-4536. 
21. Moore RD, Keruly JC. CD4+ cell count 6 years after commencement of higly active antiretroviral 
therapy in persons with sustained virologic suppression. Clin Infect Dis 2007; 44: 441-446. 
22. Aiuti F, Mezzaroma I. Failure to reconstitute CD4+ T-cells despite suppression of HIV replication 
under HAART. AIDS Rev 2006; 8: 88-97. 
 
 
5.  Objective and Purpose of the Trial 
Main: 
The primary objective of this study is to determine the feasibility of maintaining virologic suppression 
on standard plasma viral load (limit of detection 37 copies/mL) of a once-daily dose reduction 
strategy of ATRIPLA® to three tablets per week in HIV-1-infected patients with sustained standard 
plasma viral load suppression for more than 2 years. 


A-TRI-WEEK Trial 
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Protocol version 1.0 of 30 October 2012 
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Side: 
● 
Virological study including: ultrasensitive viral load in plasma (limit of detection 1 copy/mL), and 
HIV-1 reservoir in peripheral blood mononucellar cells, 
 
● 
Immunological study including: production of TRECs, immune profile of activation (CD38 and 
HLA-DR) and senescence (CD57 and CD28) in CD4 and CD8 lineages, apoptosis (annexin V 
staining), and ratios of naïve T cells and effectors and memory cells (CCR7 and CD45RA). 
 
● 
Pharmacokinetic study, including baseline plasma levels of efavirenz at the beginning and end of 
the study. 
 
● 
Safety study, including: sleep quality test (Pittsburgh Sleep Quality Index), vitamin 25OH-D 
levels, estimated glomerular filtration rate (CPK-EPI) and plasma lipids (triglycerides, total 
cholesterol and HDL) at the beginning and end of the study, as well as general tolerability. 
 
 
6.  Trial Design 
Open-label study, Phase IV, pilot, prospective single-center. 
 
 
6.1 Primary and Secondary Endpoints 
Primary Endpoint: 
The primary endpoint of the study will be the proportion of patients who continue to have a standard 
plasma viral load (<37 copies/mL) at 24 weeks by intention-to-treat analysis. 
 
Secondary endpoints: 
1) The proportion of patients with ultrasensitive viral load (<1 copy/mL) after 24 weeks. 
 
2) The change from baseline to 24 weeks in the viral reservoir of peripheral blood mononuclear 
cells 
 
3) Changes from baseline to 24 weeks in TREC production, immune profile of activation (CD38 
and HLA-DR) and senescence (CD57 and CD28) in CD4 and CD8 lineages, in naïve and effector 
and memory T cell ratios (CCR7 and CD45RA), and changes in apoptosis levels in vitro by 
annexin V staining. 
 
4) Changes in plasma levels of efavirenz. 
 
5) Changes in sleep quality (Pittsburgh Sleep Quality Index), plasma levels of vitamin D and lipids, 
and estimated glomerular filtration rate. 
 
6) Overall safety (reporting side effects, serious side effects, and discontinuation of treatment due 
to side effects) 
 
 
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 
virological and immunological efficacy of the ATRIPLA® dose reduction strategy, we are not 
absolutely certain that an unacceptably high virological failure rate (standard viral load ≥37 
copies/mL on two consecutive occasions) can occur in the arm 


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Protocol version 1.0 of 30 October 2012 
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experimental. 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 
 
 
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 1 
(#) 
S 2 
(#) 
S 4 
(#) 
S 6 
(#) 
S 8 
(#) 
S 12 
S 24 
Meet Inclusion and Exclusion 
Criteria 
X 
Signed Informed Consent 
X 
Vital signs 
X 
Weight 
X 
X 
Physical examination 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Simplified Compliance 
Questionnaire 
X 
X 
X 
X 
X 
X 
X 
Test sobre calidad del sueño 
(Pittsburgh Sleep Quality 
Index) 
X 
X 
Haematology 
X 
X 
Blood biochemistry 
X 
X 


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Clinical Evaluations 
Basal 
Day 
0 
S 1 
(#) 
S 2 
(#) 
S 4 
(#) 
S 6 
(#) 
S 8 
(#) 
S 12 
S 24 
Standard plasma viral load 
X 
X 
X 
X 
X 
X 
X 
X 
Ultrasensitive plasma viral load 
($) 
X 
X 
HIV-1 reservoir of PBMCs 
X 
X 
Immunology (CD4/CD8) 
X 
X 
X 
Immunology Sample 
X 
X 
Pregnancy test (women only) 
Y(&) 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetics 
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 
* Genotypic resistance testing will be performed if the patient has virologic failure (defined by HIV-1 
plasma viral load >50 copies/mL confirmed on two consecutive occasions) 
Blood biochemistry: lipids (TG, total cholesterol and HDL), creatinine and estimated glomerular 
filtration rate (CPK-EPI), levels of 25OH vitamin D. 
Hematology: Blood count 
 
 
 
6.3 Guidelines for Dose Modification 
Grade 1 and 2 AEs require close follow-up but no change in treatment. 
 
All grade 3 toxicities will be treated by the facility investigator as appropriate. 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. 
 
 
6.4 Trial Treatments 
DRUG SUPPLY AND LABELLING 
 
This study will use a drug already on the market and authorized for use in HIV-infected patients; The 
study drug is already taken regularly by these patients and 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 24 weeks 


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6.6 Termination and/or discontinuation criteria 
The treatment will be compulsorily terminated during the study for any of the following reasons: 
 
● 
Virologic failure, defined by two consecutive determinations of standard viral load >37 copies/mL 
separated by one week from each other. 
● 
I express the patient's wish. 
● 
Medical decision. 
● 
Death. 
● 
Pregnancy detection during the study. 
 
Treatment may be terminated during the study for any of the following reasons: 
● 
The medical investigator determines that a SAE is possibly or likely related to the study drug. 
● 
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. 
All other virologic studies and immunological studies should be determined exclusively at baseline 
and 24 weeks (except if there is earlier virologic failure, in which case it would be performed at the 
time of confirmation of failure rather than at 24 weeks), and their determination should be deferred at 
the end of the study. To this end, plasma and peripheral blood mononuclear cell samples should be 
stored appropriately at -80°C until the planned determinations are made. 
 
 
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. HIV-1 infection, clinical stability, and treatment with ATRIPLA® during the last two years. 
 
3. Standard plasma viral load below the detection limit for at least the last 2 years. 
 
4. CD4 count greater than 350/mm3 at the time of study consideration. 


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Protocol version 1.0 of 30 October 2012 
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5. 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. 
6. Patients must have given written informed consent 
 
7. In the opinion of the researcher, to be able to follow the design of the protocol visits. 
 
 
 
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 efavirenz, tenofovir, or emtricitabine 
 
3. Use of any other chronic treatment besides ATRIPLA that has been introduced in the 6 months 
prior to the patient's entry into the study 
 
4. Any co-indications to the study drug 
 
5. Any condition that does not allow correct adherence to the study to be ensured at the discretion 
of the patient's attending physician 
 
6. Uncontrolled pre-existing psychiatric illness 
 
7. Any current signs of alcoholism or other drug use. 
 
 
 
7.3 Withdrawal criteria (endpoints) 
Treatment with the study drug will be terminated immediately during the study for any of the following 
reasons: 
 
● 
Patient with virologic failure 
● 
Pregnancy during the study. 
 
● 
Express wish of the patient 
 
● 
Medical criteria 
 
● 
Exitus 
 
 
Treatment with the study drug may be terminated during the study for any of the following reasons: 
 
● 
The medical investigator determines that a SAE is possibly or likely related to the study drug. 
● 
Failure to administer, evaluate, or other study requirements. 


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Protocol version 1.0 of 30 October 2012 
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8.  Treatment of Subjects 
8.1 Treatment Branches 
Randomization to two treatment groups: A or B 
 
GROUP A (control): ATRIPLA® at standard daily dose (1 tablet daily) for a period of 24 weeks 
 
GROUP B (experimental): ATRIPLA® at a dose three days per week (1 tablet Monday, Wednesday 
and Friday) for a period of 24 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: 
The administration of treatments that are contraindicated with the study drugs will not be allowed. 
(see annex 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 (detection limit 37 copies/mL) Virologic failure will be 
defined as: 
In case of detection of plasma viral load (≥37 copies/mL), the determination of plasma viral 
load should be repeated during the following week for confirmation. If the result of the 
confirmatory determination is ≥37 copies/mL 
 
 
 
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. 


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Protocol version 1.0 of 30 October 2012 
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Ultrasensitive viral load (detection limit 1 copy/mL) 
 
By ultracentrifugation (170000g, 30 minutes, 4ºC) the HIV-1 virions present in 7mL of plasma will be 
concentrated, a volume to which will have been added a known concentration of an RNA transcript 
used as a non-competitive internal control for the monitoring of ultracentrifugation, extraction and 
amplification processes. The supernatant will be removed leaving a residual volume of 200 L, from 
which the viral RNA will be extracted using the commercial QIAamp MinElute Virus Spin (QIAGEN) 
kit, following the manufacturer's recommendations. The RNA obtained will be aliquoted and frozen at 
-80ºC until use. The ultrasensitive quantification of the HIV-1 viral load will be performed by means of 
a one-step RT-PCR duplex in real time, using the STRATAGENE Mx3005P platform. For the 
amplification and detection of a conserved region of the HIV-1 gag gene, the primers and probes 
previously described by Palmer et al (2003) will be used. To detect the non-competitive internal 
control added to the sample, a set of specific primers and probe described above will be used 
(Almansa et al [PMID 21880131], Anton et al [PMID 20955912]). To carry out the quantification of 
the HIV-1 viral load and the internal control, two standard lines of serial dilutions from a known 
concentration of a standard will be amplified in parallel, one for the determination of the HIV-1 viral 
load and the other for internal control. Each quantification test will be performed in triplicate for each 
of the samples and for each of the dilutions of the standard line. In each of the tests, negative 
plasma samples will be used as a target to minimize the impact of possible contaminations in some 
of the steps of the process. For the quantification (copies/mL) of HIV-1 viral load, only those results 
within the linear range of the assay (R>0.95) will be considered. Initially, the result of the HIV-1 viral 
load will be validated in those samples where the recovery of internal control is greater than 55%, as 
described by Palmer et al (20), although this must be previously demonstrated in the process of 
optimizing our methodology. 
 
The specific PCR product obtained with the primers specific for a conserved region of the gag gene 
previously described by Palmer et al (20) will be cloned into a pGEM-T Easy Vector (PROMEGA) 
plasmid that will be linearized by the restriction enzyme SpeI (NEW ENGLAND BIOLABS). This 
plasmid, which contains a T7 promoter for RNA polymerase, will be transcribed in vitro using the 
commercial MEGAscript Kit (AMBION). Purification of the RNA transcript obtained as a standard 
control for HIV-1 quantification will be performed using the commercial MEGAclear Kit (AMBION). 
The concentration and integrity of the RNA transcript obtained will be determined using the 
BioAnalyzer (AGILENT) platform. From a known concentration of this standard standard, a bank of 
dilutions will be generated to determine the efficiency, linearity range and lower limit of sensitivity. 
 
The RNA transcript used as an internal control, based on a conserved region of the coding sequence 
of the M1 protein of the influenza A virus, has previously been used in the quantification of the 
influenza A (H1N1) pdm09 virus in our laboratory (Almansa et al [PMID 21880131], Anton et al 
[PMID 20955912]). For its synthesis, the methodology described in the previous section was 
followed. The percentage of internal control, added to the plasma sample prior to ultracentrifugation, 
which is recovered and from which we will consider the results of the HIV-1 viral load valid, will be 
validated in our laboratory, initially considering as good the 55% recovery previously described by 
Palmer et al (20). 
B) HIV-1 viral reservoir study: 
The study of the viral reservoir will be determined based on the methodology initially described by 
the group of Nicholas Chomont (19) modified by the Laboratory of Dr José Alcamí. It will be made 
from 50 X 106 frozen peripheral blood mononuclear cells. A purification of CD4+ T-cells by negative 
depletion will be performed. These purified cells will be activated in the presence of anti-CD3/CD28. 
The culture should be maintained for 9 days in the presence of a cocktail of antiretrovirals 
(zidovudine, efavirenz, and raltegravir) to prevent further rounds of infection and a reactivation of 
viral production. Finally, viral production will be quantified at 3, 6 and 9 days, from the supernatant of 
the cultures, by ultrasensitive RT-qPCR and p24 antigen assessment by capture ELISA. 


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Protocol version 1.0 of 30 October 2012 
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C) Immunological studies: 
 
The study of activation markers in the different CD4 and CD8 lymphocyte subpopulations will be 
carried out by extracellular staining with conjugated antibodies for subsequent analysis by flow 
cytometry. 
 
The detection of cleaved circular DNA (TRECs) after genetic rearrangement of the T cell receptor 
(TCR) will be carried out by the usual methods (real-time PCR). 
Determination of apoptosis will be performed using the annexin V staining method. 
D) Pharmacokinetics 
 
All patients will be proposed to be included in the pharmacokinetic substudy. At baseline, each of 
them should have their plasma levels determined in efavirenz in the morning before the next daily 
dose. 
 
This determination will be repeated at week 24 of treatment. For patients who continue with the daily 
treatment, the extraction will be carried out any day in the morning; and for those randomized to 
receive ATRIPLA® on Monday, Wednesday and Friday, the extraction will be carried out on a 
Monday morning because it is the day of the week when the plasma concentration of efavirenz must 
be lower due to the maximum dose interval. 
 
E) Safety 
To evaluate sleep quality, the "Pittsburgh Sleep Quality Index" will be carried out, available in its 
validated Spanish version (http://www.medigraphic.com/pdfs/gaceta/gm-2008/gm086e.pdf). 
 
The plasma concentration of vitamin 25OHD3 will be determined by immunoassay. 
 
The estimated glomerular filtration rate will be calculated using the usual formula, available in 
http://www.nephron.com/MDRD_GFR.cgi . 
 
 
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. 


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● 
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. 
 
The criteria for subject treatment, dose discontinuation, dosage adjustment, withdrawal, or treatment 
changes will only apply to toxicities attributable to the study drugs (i.e., efavirenz, tenofovir, and 
emtricitabine). 
 
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) 


A-TRI-WEEK Trial 
EudraCT number: 2012-004970-24 
Protocol version 1.0 of 30 October 2012 
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- 
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. 
 
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 adverse event 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. 


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Protocol version 1.0 of 30 October 2012 
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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. 
 
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 the development of the investigational 
medicinal product and likely to affect the safety of the 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. 


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EudraCT number: 2012-004970-24 
Protocol version 1.0 of 30 October 2012 
23 
 
 
 
10.3 Evaluation of toxicity parameters 
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/. 
 
Treatment of ATRIPLA side effects 
 
 
The dose reduction levels of ATRIPLA® are indicated in the summary of product characteristics. (see annexes to 
the protocol) 
 
 
 
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 
11.1 Sample 
The study will be carried out in 60 patients. This is a proof of concept and does not require an ad-hoc 
sample size calculation. 
 
11.2 Sample size 
 
11.3 Analysis 
 
Comparison of patient 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 after 24 weeks, as well as absolute and relative changes at 24 
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 test. 


A-TRI-WEEK Trial 
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Protocol version 1.0 of 30 October 2012 
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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: 
 
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 ATRIPLA® dose reduction strategy, 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 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. 
 
 
11.4 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. 
 
11.5 Processing of lost data 
Missing data imputation techniques will not be used. Only the available data will be analyzed. 
 
11.6 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. 
11.7 Population under analysis 
The population analyzed in the study 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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Protocol version 1.0 of 30 October 2012 
25 
 
 
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. 
 
Prior to the start of treatment, a clinical examination, electrocardiogram and blood and urine sample 
will be taken (SEE TABLE OF DAILY DETERMINATIONS). 
 
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. 


BOC-HIV Trial 
EudraCT number: 2012-003984-23 
Protocol version 1.0 of 18 September 2012 
26 
 
 
 
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 1 
(#) 
S 2 
(#) 
S 4 
(#) 
S 6 
(#) 
S 8 
(#) 
S 12 
S 24 
Meet Inclusion and 
Exclusion Criteria 
X 
Signed Informed 
Consent 
X 
Vital signs 
X 
Weight 
X 
X 
Physical examination 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
Simplified Compliance 
Questionnaire 
X 
X 
X 
X 
X 
X 
X 
Test sobre calidad del sueño 
(Pittsburgh Sleep Quality 
Index) 
X 
X 
Haematology 
X 
X 
Blood biochemistry 
X 
X 
Standard plasma viral load 
X 
X 
X 
X 
X 
X 
X 
X 
Ultrasensitive plasma viral 
load ($) 
X 
X 
HIV-1 reservoir of 
PBMCs 
X 
X 
Immunology (CD4/CD8) 
X 
X 
X 
Immunology Sample 
X 
X 


BOC-HIV Trial 
EudraCT number: 2012-003984-23 
Protocol version 1.0 of 18 September 2012 
27 
 
 
 
Clinical Evaluations 
Basal 
Day 
0 
S 1 
(#) 
S 2 
(#) 
S 4 
(#) 
S 6 
(#) 
S 8 
(#) 
S 12 
S 24 
Pregnancy test (women 
only) Y(&) 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetics 
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 
* Genotypic resistance testing will be performed if the patient has virologic failure (defined by 
HIV-1 plasma viral load >50 copies/mL confirmed on two consecutive occasions) 
Blood biochemistry: lipids (TG, total cholesterol and HDL), creatinine and estimated glomerular 
filtration rate (CPK-EPI), levels of 25OH vitamin D. 
Hematology: Blood count