Conditions: AIDS
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 75
Healthy volunteers: no

Brief summary:
A pilot 24-week open-label, randomized, controlled clinical trial to assess the safety, tolerability and efficacy of dual therapy with Raltegravir/Lamivudine combination when replacing standard combination therapy in HIV-infected patients with prolonged virological suppression

Detailed description:

Arms:
arm 1: Raltegravir / 3TC (MK0518B ) (50 patients) arm 2: NNRTI-Based Regimen:

• EFV/TDF/FTC

PI-Based Regimens:

ATV/r + TDF/FTC or DRV/r + TDF/FTC

INSTI-Based Regimens:

DTG+ABC/3TC DTG+TDF/FTC EVG/cobi/TDF/FTC RAL+TDF/FTC

NNRTI-Based Regimens:

EFV plus ABC/3TC or RPV/TDF/FTC

PI-Based Regimen:

ATV/r plus ABC/3TC

PI-Based Regimens:

DRV/r + ABC/3TC or LPV/r + ABC/3TC or LPV/r + TDF/FTC

INSTI-Based Regimen:

RAL plus ABC/3TC

And other ART regimens

Interventions: intervention 1: Raltegravir/3TC intervention 2: EFV/TDF/FTC intervention 3: ATV/r + TDF/FTC or DRV/r + TDF/FTC intervention 4: DTG+ABC/3TC DTG+TDF/FTC EVG/cobi/TDF/FTC RAL+TDF/FTC intervention 5: EFV plus ABC/3TC or RPV/TDF/FTC intervention 6: ATV/r plus ABC/3TC intervention 7: DRV/r + ABC/3TC or LPV/r + ABC/3TC or LPV/r + TDF/FTC intervention 8: RAL plus ABC/3TC intervention 9: Other ART regimens
Intervention descriptions: intervention 1: MK0518B (Raltegravir/3TC) (300mg/150mg) twice daily, administered orally in the 300/150 mg film-coated tablets according to instructions in the prescribing information. intervention 2: standard combination therapy intervention 3: None intervention 4: None intervention 5: None intervention 6: None intervention 7: None intervention 8: None intervention 9: None

Protocol document:
Prot_SAP_000.pdf: 
Protocol 
RALAM 
1 
EudraCT No. 2014-003142-27 
Protocol version 2.0, dated 7 November 2014 
 
 
A pilot 24-week open-label, randomized, controlled clinical trial to assess the safety, 
tolerability and efficacy of dual therapy with Raltegravir/Lamivudine combination when 
replacing standard combination therapy in HIV-infected patients with prolonged virological 
suppression. RALAM Study 
 
CLINICAL TRIAL PROTOCOL WITH MEDICINAL PRODUCTS 
 
 
 
 
 
 
Protocol code: RALAM 
Version and date: version 2.0 dated 7 November 2014 
EudraCT No.: 2014-003142-27 
 
NCT Number: NCT02284035 
 
Sponsor: Fundació Clinic per a la Recerca Biomédica 
Dr. Josep Maria Gatell Artigas 
Principal Investigator: Dr. Esteban Martinez 


Protocol 
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EudraCT No. 2014-003142-27 
Protocol version 2.0, dated 7 November 2014 
 
 
Abbreviations 
3TC 
Lamivudine 
AE 
Adverse event 
AR 
Adverse reaction 
BID 
Twice daily (“bis in die”) 
CKD-EPI 
Change in estimated glomerular filtration rate 
CREC 
Clinical Research Ethics Committee 
CT 
Computed tomography 
CTU 
Clinical Trials Unit 
DSMB 
Data and Safety Monitoring Board 
DXA 
Dual energy X-ray absorptiometry 
FTC 
Emtricitabine 
HOMA-IR 
Homeostasis model assessment-estimated insulin resistance 
(fasting insulin (µU/L) x fasting glucose (nmol/L)/22.5) 
ITT 
Intention-to-treat 
LDL 
Low-density lipoprotein 
LOCF 
Last-Observation-Carried-Forward 
LPV/r 
Lopinavir/ritonavir. 
NNRTI 
Non-nucleoside reverse transcriptase inhibitor 
NRTI 
 Nucleoside reverse transcriptase inhibitor 
PBMC 
Peripheral mononuclear blood cells 
PI/r 
ritonavir-boosted Protease Inhibitor 
PSQI 
Pittsburgh Sleep Quality Index 
QD 
Once a day 
RAL/3TC 
Raltegravir/Lamivudine 
SAE 
Serious adverse event 
SUSAR 
Suspected unexpected serious adverse reaction 
UAR 
Unexpected adverse reaction 
ULN 
Upper limit of normal 
VL 
Viral load 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ............................................................................................. 5 
1. GENERAL INFORMATION ...................................................................................... 8 
1.1 Trial identification ............................................................................................... 8 
1.2 Identification of sponsor and monitor .................................................................. 8 
1.3 Identification of applicant .................................................................................... 8 
1.4 Identification principal investigators of the participating sites ............................. 8 
1.5 Information on other departments involved ........................................................ 8 
2. RATIONALE ............................................................................................................ 9 
2.1 Name and description of the investigational drugs ........................................... 11 
2.2 Summary of known and potential risks and benefits ........................................ 11 
2.3 Route of administration, dose, dosing regimen and treatment period............... 12 
2.4 Statement that the trial will be conducted in compliance with legal 
requirements .......................................................................................................... 12 
2.5 Description of study population ........................................................................ 12 
2.6 References ....................................................................................................... 13 
4. TRIAL DESIGN ...................................................................................................... 15 
4.1 Primary and secondary endpoints .................................................................... 15 
4.2 Type of design ................................................................................................. 16 
4.3 Description of measures taken to minimize or prevent bias ............................. 16 
4.4 Description of trial treatments ........................................................................... 17 
4.5 Trial duration .................................................................................................... 17 
4.6 Criteria for termination and/or discontinuation .................................................. 17 
4.7 Drug accountability ........................................................................................... 18 
4.8 Allocation participant identification codes ......................................................... 18 
4.9 Source data identification ................................................................................. 18 
4.10 End of trial ...................................................................................................... 18 
5. SUBJECT SELECTION AND WITHDRAWAL ........................................................ 19 
5.1 Subject inclusion criteria ................................................................................... 19 
1. Inclusion criteria ............................................................................................. 19 
5.2 Subject exclusion criteria .................................................................................. 19 
5.3 Withdrawal criteria ............................................................................................ 19 
6. SUBJECT TREATMENT ........................................................................................ 20 
6.1 Treatment arms ................................................................................................ 20 
6.2 Concomitant, rescue and nonpermitted medication.......................................... 20 
7. EFFICACY ASSESSMENT .................................................................................... 21 
7.1 Efficacy parameters.......................................................................................... 21 
7.2 Assessment of efficacy parameters .................................................................. 25 
8. SAFETY ASSESSMENT ....................................................................................... 25 
8.1 Safety parameters ............................................................................................ 25 
8.2 Assessment of safety parameters .................................................................... 25 
8.3 Adverse event detection and recording ............................................................ 27 
8.3.1 Procedures for expedited reporting of serious adverse events by the 
investigator ............................................................................................... 28 
8.3.2 Procedures for expedited reporting of serious and unexpected 
adverse reactions by the sponsor .............................................................. 28 
8.4 Follow-up of adverse events ............................................................................ 29 
9. STATISTICS .......................................................................................................... 30 
9.1 Methods ........................................................................................................... 30 


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9.2 Sample size ...................................................................................................... 30 
9.3 Statistical significance and adjustments for multiplicity ..................................... 30 
9.4 Criteria for discontinuation ................................................................................ 30 
9.5 Management of missing data ........................................................................... 31 
9.6 Deviations from statistical plan ......................................................................... 31 
9.7 Analysis population .......................................................................................... 31 
10. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ....................................... 32 
11. ETHICS ............................................................................................................... 32 
12. DATA MANAGEMENT AND RECORD RETENTION .......................................... 33 
13. FUNDING AND INSURANCE .............................................................................. 33 
14. PUBLICATION POLICY ....................................................................................... 33 
 
 
 
Protocol appendices: 
Appendix I 
Case report form: List of variables in CRF 
Appendix II 
Patient information sheet and informed consent form 
Appendix III 
Patient information sheet and informed consent form in case of pregnancy 
Appendix IV 
Declaration of Helsinki 
Appendix V 
SAE reporting form 
Appendix VI 
Serious and unexpected adverse reaction reporting form 
Appendix VII 
Toxicity grading table 
Appendix VIII 
Summary of product characteristics of investigational products 
Appendix IX 
Morisky-Green test 
Appendix X 
Pittsburgh Sleep Quality Index 
Appendix XI 
Financial report 
Appendix XII 
Civil liability insurance 
Appendix XIII 
Protocol agreement document 


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PROTOCOL SYNOPSIS 
A pilot 24-week open-label, randomized, controlled clinical trial to assess the safety, tolerability and 
efficacy of dual therapy with Raltegravir/Lamivudine combination when replacing standard combination 
therapy in HIV-infected patients with prolonged virological suppression. RALAM Study 
SITES: National single center study: Hospital Clínic de Barcelona 
Clinical phase: Phase III 
HYPOTHESIS: Raltegravir /Lamivudine in patients with prolonged virological suppression will be able 
to maintain virological efficacy, while being overall well tolerated and specifically able to improve 
metabolic parameters, body composition, renal function and sleep quality 
OBJECTIVES: 
 
Primary: 
 
• 
efficacy in virological suppression assessed with standard plasma HIV-1 RNA detection 
(limit of detection 37 copies/mL). 
Secondary: 
 
• 
efficacy in virological suppression assessed with ultrasensitive HIV-1 RNA detection (limit 
of detection 1 copy/mL) 
• 
changes in peripheral mononuclear blood cells HIV-1 reservoir 
 
• 
changes in metabolic parameters including fasting plasma lipids and insulin resistance 
(HOMA-IR) 
• 
changes in body fat composition and bone mineral density 
 
• 
changes in plasma 25-OH vitamin D levels 
 
• 
changes in estimated glomerular filtration rate (CKD-EPI) and urine beta-2-microglobulin 
 
• 
changes in immune activation markers including CD38 and HLA-DR 
 
• 
changes in biomarkers of inflammation (IL-6, high sensitivity C-reactive protein) and 
biomarkers of mononuclear activation (SD-14, SD-163) 
• 
changes in sleep quality (Pittsburgh Sleep Quality Index) 
 
• 
changes in adherence in both treatment arms (Morisky-Green Test) overall tolerability 
 
STUDY DESIGN AND DURATION: This is a single center, national, phase III, prospective, open-label, 
randomized, and controlled, 24-week pilot study. 
 
 
SAMPLE SIZE: A total of 75 patients, 18 years or older, will be included in the study, 50 in the study 
arm and 25 in the control arm (randomized 2:1). 


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TREATMENTS, DOSE, POSOLOGY: 
Group 1 (study): 
Raltegravir / 3TC (MK0518B ) (50 patients) 
Group 2 (control): 
Continue current treatment (25 patients) 
 
DOSE: RAL/3TC (300mg/150mg) 
 
 
POSOLOGY: BID single pill 
 
 
EFFICACY MEASUREMENTS: Plasma viral load (HIV-RNA) will be measured at weeks 0, 4, 12 and 
24. 
SAFETY ASSESSMENTS: At each visit, a physical examination and a blood test will be performed. 
 
DATA ANALYSIS: All randomized patients will be included in the intent-to-treat (ITT) population. The 
per protocol population will include all patients from the ITT population except those who did not fulfill 
the inclusion/exclusion criteria or withdrawing from the study or discontinuing study treatment for 
reasons other than virological failure or adverse event. 
Statistical Methods: The baseline patients’ characteristics of the ITT population will be described. 
Continuous variables will be described by their means, standard deviations,medians, Interquartile 
ranges, minimums and maximums. Categorical variables, figures and percentages per class will be 
presented per arm. 
The primary analysis will be done when all patients have reached 24 weeks. Analysis of the primary 
endpoint will be performed on both ITT and per protocol populations. The 95% two sided confidence 
interval of the of the difference in percentage of patients in therapeutic success (RAL/3TC – Current 
regimen) will be calculated. 
The percentage and absolute changes in continous variables between week 4, 12 and 24 versus 
baseline will be compared between arms in the ITT population (LOCF of other imputation method to be 
defined in the statistical analysis plan) using a two-sided non parametric Mann WhitneyTest. 
The categorical endpoints will be compared using Fisher’s exact test or chi-squared test. 
Two sided p-values will be reported. The level of significance will be tested at 0.05. 
Power/Sample Size: 
 
A total of 75 patients will be included in the study with a randomization 2:1 (RAL/3TC and 
Current treatment). The study is not a noninferiority study, in which case the delta should be -15% or 
less. It is a pilot study which tries to see the feasibility of the pattern and to generate data with which to 
design a larger study with a noninferiority design. However, there are security measures in the primary 
end-point is the virologic efficacy. The DSMB will review the data if 4 episodes of treatment failure are 
detected, and then every 4 additional failures detected. The study will be interrupted as early as 5 
episodes of virological failure in experiemental branch are detected (10%). 


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The DSMB will meet not when 8 cases of treatment failure but 4 patients occur. Treatment failure may 
be due to virological failure, but also for other reasons (discontinuation due to toxicity, loss to follow 
rupture of consent, etc). 
However, we are committed to make a thorough study and monitoring of each failure by independent 
researchers to study team to discover the possible reason for it. 
This pilot study is exploratory, and must serve to see whether it is feasible, if the results are good 
enough, to make a large-scale study. 
STUDY TIMETABLE 
 
WEEK 
-2 / -4 
Screening 
0 
Randomization 
4 
12 
24 
Clinical assessment 
√ 
√ 
√ 
√ 
√ 
Physical examination 
√ 
√ 
√ 
√ 
√ 
Informed consent 
√ 
Pregnancy test 
√ 
Hematology 
√ 
√ 
√ 
√ 
√ 
Biochemistry1 
√ 
√ 
√ 
√ 
√ 
Beta-2-microglobulin (urine) 
√ 
√ 
√ 
√ 
Plasma viral load (HIV-RNA) 
√ 
√ 
√ 
√ 
√ 
Ultrasensitive viral load in plasma 
√ 
√ 
√ 
√ 
Immunology2 
√ 
√ 
√ 
√ 
Insulin 
√ 
√ 
Vitamin D 
√ 
√ 
DXA 
√ 
√ 
Stored samples3 
√ 
√ 
Validated Spanish PSQI 
√ 
√ 
Morisky-Green test 
√ 
√ 
√ 
√ 
Genotypic resistance test 
In case of virological failure 
Adverse events 
√ 
√ 
√ 
√ 
1 including lipid profile (total cholesterol, HDL, LDL and TG), creatinine, glucose and vitamin D levels 
2 including CD4 and CD8 
3 stored plasma samples will be taken for the determination of biomarkers of inflammation (IL-6, high 
sensitivity C-reactive protein). Stored cell samples will be taken for the determination of biomarkers of 
mononuclear activation SD-14 and SD-163 and immunology (CD38 and HLA-DR) 


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+34 93 451 55 38 
+34 93 227 54 00 ext. 3310 
estebanm@clinic.ub.es 
jcamacho@clinic.ub.es 
93 2275400 ext. 4386 
93 2279877 
jcamacho@clinic.ub.es 
93 2275400 ext. 4386 
93 2279877 
1. General Information 
 
1.1 Trial identification 
Title: A pilot 24-week open-label, randomized, controlled clinical trial to assess the safety, tolerability and efficacy 
of dual therapy with Raltegravir/Lamivudine combination when replacing standard combination therapy in HIV- 
infected patients with prolonged virological suppression. RALAM Study 
 
 
Protocol code: RALAM 
Version and date: version 1.0 dated 17 July 2014 
EudraCT No.: 2014-003142-27 
 
1.2 Identification of sponsor and monitor 
Sponsor: Fundació Clinic per a la Recerca Biomédica – Fiscal Identity No.: G59319681 
Dr. José Mª Gatell Artigas 
Address: C/ Villarroel, 170 
Town/City: Barcelona (Spain) 
Zip Code: 08036 
 
Monitor: 
CTU (Clinical Trials Unit) 
Department of Clinical Pharmacology 
Hospital Clínic C/Villarroel 170, 08036 Barcelona (Spain). 
Phone: 
Fax: 
E-mail: 
 
1.3 Identification of applicant 
Applicant: 
Address: CTU (Clinical Trials Unit). Clinical Pharmacology 
Hospital Clínic C/Villarroel 170, 08036 Barcelona (Spain). 
Phone: 
Fax: 
E-mail: 
 
1.4 Identification principal investigators of the participating sites 
Dr. Esteban Martinez 
Hospital Clínic 
Villarroel, 170 
08036 Barcelona 
E-mail: 
Phone: 
Fax. 
 
1.5 Information on other departments involved 
 
Clinical research ethics committees 
The trial has been submitted for approval to the CREC of Hospital Clínic. 
Jaime Camacho 
Jaime Camacho 


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2. Rationale 
Treatment of HIV infection typically consists of a combination of antiretroviral drugs. 
Normally, it is a combination of three drugs which are both inhibitors of nucleoside analogue 
reverse transcriptase and the third is a drug of another family. However, there have been 
treatment options with two drugs where one of them is usually a protease inhibitor boosted 
with low dose ritonavir; these dual patterns have shown similar efficacy to standard triple 
patterns not only in naive patients but in patients already treated with sustained suppression 
of viral replication as are the patients be targeted by the study RALAM. These dual patterns 
are contained in the "Recommendations for Antiretroviral Therapy GESIDA 2014". In real life, 
there are also patients treated with the monotherapy, which in this case are provided with an 
inhibitor boosted protease, but these patterns have a suboptimal efficacy and therefore 
patients on monotherapy are not considered candidates for RALAM study. 
Effective antiretroviral therapy leads not only to undetectable plasma HIV-1 RNA, but to a decrease in 
the body HIV-1 burden. The longer virological suppression in HIV-infected patients, the more likely 
virological suppression will persist. This may be particularly evident in therapeutically suboptimal 
ritonavir-boosted protease (PI/r) monotherapy studies, in which initial PI/r monotherapy (Monark 
Study1) of HIV infection performed worst, induction-maintenance (613 Study2, triple PI/r-based therapy 
followed by PI/r monotherapy) performed better, and simplification (OK Study3, PI/r monotherapy in 
virologically suppressed patients) performed best out of these three possibilities. 
We are guiding therapy of HIV infection based on studies in antiretroviral-naïve subjects. Triple therapy 
including two nucleoside reverse transcriptase inhibitors plus a third drug is the standard therapy for 
initial HIV infection. Follow-up of studies in antiretroviral-naïve patients is usually two years and very 
few up to five years. Many patients in our clinical units are virologically suppressed and virological 
suppression may have been lasting for years, as we saw in the SPIRAL study4. For these patients, 
triple antiretroviral therapy may not be needed. In fact, a subanalysis of SPIRAL5 study looking back at 
patients with previous resistance failure and genotypic resistance tests available in their history 
database showed than a proportion of patients were on functional dual or even monotherapy both in 
the PI/r and raltegravir arm. A subanalysis of the BENCHMRK6 study also suggested that some 
patients in the raltegravir arm had no other drugs active as shown by the genotypic sensitivity score. 
Until now, regimens containing less than 3 drugs should have a PI/r included7. However, preliminary 
data8 suggests that dual combinations of a non-nucleoside reverse transcriptase inhibitor such as 
etravirine or nevirapine plus raltegravir in virologically suppressed patients may maintain virological 
efficacy while improving tolerability9. In addition, the Latte study10 has recently shown the capability of 
744 (an integrase inhibitor) plus rilpivirine (a low genetic barrier non-nucleoside reverse transcriptase 
inhibitor) to maintain virological suppression after only 6 months induction therapy. 
Lamivudine is probably the safest antiretroviral drug. It is now available as a generic drug, and 
therefore its cost is relatively low. It has shown potentially useful data when combined with a PI/r in 


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both naive and experienced HIV patients. Raltegravir is also a well-tolerated antiretroviral drug. 
Because a co-formulation of raltegravir plus lamivudine is already planned meaning that it will be 
available in the near future, it will represent a very convenient regimen (a BID single pill) that will 
prevent selective lack of adherence. 


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2.1 Name and description of the investigational drugs 
 
Patients will be randomized 2:1 to: 
 
1. Switch to MK0518B (Raltegravir/3TC) (50 patients) 
 
2. Continue current treatment (25 patients) 
The study treatment period will be 24 weeks. 
The study medication MK0518B (Raltegravir/3TC) will be supplied by Merck for 24 weeks. After the 
study, MSD will provide MK0518B (RAL/3TC) until it is available commercially. If not possible, 
RAL/3TC will be switched to RAL + 3TC or any other antiretroviral regimen considered appropriate for 
the patient at the discretion of the investigator. 
The rest of antiretroviral medication will be obtained through the standard prescription and dispensing 
route in which antiretroviral drugs are dispensed on an outpatient basis by the pharmacy service of the 
center. 
Raltegravir/3TC (MK0518B) 
 
Integrase inhibitor/nucleoside analogue reverse transcriptase inhibitor 
Therapeutic group: JO5AE10 
Manufacturing laboratory: MSD (Merck Sharp & Dohme) 
The main characteristics of Raltegravir/3TC are detailed in the summary of product characteristics (see 
Appendix VIII: Summary of product characteristics of investigational products) 
 
 
Raltegravir/3TC will be supplied by Merck as a fixed-dose combination for the whole duration of the 
study. The medication will be packed and labeled by Merck in accordance with European regulations. 
 
 
 
2.2 Summary of known and potential risks and benefits 
The potential risks of a clinical trial with drugs include the possible occurrence of adverse events 
attributable to the study drugs. However, this simplification study does not add a new drug but 
withdraws or not one of them from the current regimen, and therefore an increase in potential toxicity is 
not expected. 
 
The risk of virological failure in patients with inclusion criteria similar to those in the study who are 
switched to dual therapy are subjected is actually very small, similar to that expected with triple 
standard combinations (references 8 y 9). In addition, virological monitoring in this study will be more 
frequent than in clinical practice and the results of HIV RNA measurements in plasma will be available 
one or two days after blood sampling. 


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The reduction in the number of drugs could be associated with improved tolerability and less toxicity, 
as well as improved treatment compliance, which could result in superior effectiveness. 
 
 
2.3 Route of administration, dose, dosing regimen and treatment period 
A randomization list will be generated with a computer program according to a 2:1 allocation scheme. 
The randomization procedure will result with a code that will allow the treatment of each patient 
(patient code) to be identified. Randomization will be performed using the electronic case report form 
for the study. 
 
1. Study group : MK0518B (Raltegravir/3TC) (300mg/150mg) twice daily 
 
it will be administered orally in the 300/150 mg film-coated tablets according to instructions in 
the prescribing information. 
2. Control group: All drug products included in the antiretroviral regimen will be part of the 
standard prescription and will be used according to the prescribing information. 
 
The study treatment period will be 24 weeks. 
 
2.4 Statement that the trial will be conducted in compliance with legal 
requirements 
 
The trial will be conducted in accordance with the principles of the Declaration of Helsinki, and 
according to applicable regulations (Royal Decree 223/2004). The study will not start until obtaining the 
favorable opinion of the reference CREC, authorization from the Spanish Agency for Medicinal 
Products and Medical Devices, and approval from the Management of the site. 
By signing the investigator's agreement, the investigator undertakes to comply with the provisions 
contained in applicable legislation on clinical trials and agrees to conduct the study in an efficient and 
diligent manner in accordance with good clinical practice guidelines, applicable European, Spain and 
local regulations, as well as the guidelines or regulations relating to clinical trial management. 
The investigator must prepare and keep adequately study documentation according to good clinical 
practice, and applicable local and national regulations. 
 
 
2.5 Description of study population 
The study will be conducted in HIV-1 infected patients with virological suppression. 
 
A total of 75 patients will be included in the study, 50 in the study arm and 25 in the control arm. 


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2.6 References 
 
1. Delfraissy JF, Flandre P, Delaugerre C et al. Lopinavir/ritonavir monotherapy or plus zidovudine 
and lamivudine in antiretroviral-naïve HIV-infected patients. AIDS 2008; 22: 385–93. 
2. Cameron DW, da Silva BA, Arribas JR, Myers RA, Bellos NC, Gilmore N, et al. A 96-week 
comparison of lopinavir-ritonavir combination therapy followed by lopinavir-ritonavir monotherapy 
versus efavirenz combination therapy. J Infect Dis 2008; 198: 234-240 
3. Arribas JR, Pulido F, Delgado R, et al. Lopinavir/ritonavir as single-drug therapy for maintenance 
of HIV-1 viral suppression: 48-week results of a randomized, controlled, open-label, proof-of- 
concept pilot clinical trial (OK Study). J Acquir Immune Defic Syndr 2005; 40: 280-287 
4. Martínez E, Larrousse M, Llibre JM, et al. Substitution of raltegravir for ritonavir- 
boosted protease inhibitors in HIV-infected patients: the SPIRAL study. AIDS 2010; 24: 1697-1707 
5. Blanco JL, Gonzalez-Cordón A, Llibre JM, et al. Impact of prior virologic failure and nucleos(t)ide 
genotypic  resistance  mutations  on  the  efficacy  of  switching  from  ritonavir- 
boosted protease inhibitors to raltegravir. Antivir Ther 2014 (in press) 
6. Gatell JM, Katlama C, Grinsztejn B, et al. Long-term efficacy and safety of the HIV integrase 
inhibitor raltegravir in patients with limited treatment options in a phase II study. J Acquir Immune 
Defic Syndr 2009; 53(4):456-463 
7. Günthard HF, Aberg JA, Eron JJ, et al. Antiretroviral Treatment of Adult HIV Infection2014 
Recommendations of the International Antiviral Society–USA Panel. JAMA 2014; 312: 410-425 
8. Reliquet V, Chirouze C, Allavena C, et al. Nevirapine-raltegravir combination, an NRTI and PI/r 
sparing regimen, as maintenance antiretroviral therapy in virologically suppressed HIV-1-infected 
patients. Antivir Ther 2014; 19:117-123 
9. Monteiro P, Perez I, Laguno M, et al. Dual therapy with etravirine plus raltegravir for virologically 
suppressed HIV-infected patients: a pilot study. J Antimicrob Chemother 2014; 69: 742-748 
10. Margolis D, Brinson CC, Eron JJ, et al. 744 and rilpivirine as two-drug oral maintenance therapy: 
LAI116482 (LATTE) week 48 results. 21st Conference on Retroviruses and Opportunistic 
Infections (CROI 2014). March 3–6, 2014. Boston. Abstract 91LB. 


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3. Objective and Purpose of the Trial 
General objective: 
 
A pilot 24-week open-label, randomized, controlled clinical trial to assess the safety, tolerability and 
efficacy of dual therapy with Raltegravir/Lamivudine combination when replacing standard combination 
therapy in HIV-infected patients with prolonged virological suppression. 
Randomization: 
 
1. to simplify to MK0518B (Raltegravir / 3TC) (50 patients) 
 
2. to continue current treatment (25 patients) 
 
 
Primary: 
 
• 
efficacy in virological suppression assessed with standard plasma HIV-1 RNA detection 
(limit of detection 37 copies/mL). 
Secondary: 
 
• 
efficacy in virological suppression assessed with ultrasensitive HIV-1 RNA detection (limit 
of detection 1 copy/mL) 
• 
changes in peripheral mononuclear blood cells HIV-1 reservoir 
 
• 
changes in metabolic parameters including fasting plasma lipids and insulin resistance 
(HOMA-IR) 
• 
changes in body fat composition and bone mineral density 
 
• 
changes in plasma 25-OH vitamin D levels 
 
• 
changes in estimated glomerular filtration rate (CKD-EPI) and urine beta-2-microglobulin 
 
• 
changes in immune activation markers including CD38 and HLA-DR 
 
• 
changes in biomarkers of inflammation (IL-6, high sensitivity C-reactive protein) and 
biomarkers of mononuclear activation (SD-14, SD-163) 
• 
changes in sleep quality (Pittsburgh Sleep Quality Index) 
 
• 
changes in adherence in both treatment arms (Morisky-Green Test) 
 
• 
overall tolerability 


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4. Trial Design 
 
4.1 Primary and secondary endpoints 
Primary variable: 
 
• 
The primary variable is the proportion of patients free of therapeutic failure at week 24. 
Therapeutic failure includes virological failure, change in treatment for any reason, consent 
withdrawal, loss to follow-up or death. 
Virological failure is defined as two consecutive measurements of plasma viral load above 37 
copies/ml (current detection limit in hospital lab) separated at least by 2 weeks during the assigned 
treatment, using the FDA snapshot method. 
Secondary variables: 
 
• 
Proportion of patients with viral load below 37copies/ml at 24 weeks 
 
• 
Proportion of patients with viral load below ultrasensitive HIV-1 RNA detection limit (limit of 
detection 1 copy/mL) at 24 weeks 
• 
Changes from baseline in peripheral mononuclear blood cells HIV-1 reservoir at 24 weeks 
 
• 
Changes from baseline in metabolic parameters including fasting plasma lipids (cholesterol 
total, LDL, HDL and triglycerides) and insulin resistance (HOMA-IR) at 24 weeks 
• 
Changes from baseline in body fat composition at 24 weeks 
 
• 
Changes from baseline in lumbar and femoral bone mineral density at 24 weeks 
 
• 
Changes from baseline in plasma 25-OH vitamin D levels at 24 weeks 
 
• 
Changes from baseline in estimated glomerular filtration rate (CKD-EPI) and urine beta-2- 
microglobulin at 24 weeks 
• 
Changes from baseline in immune activation markers including CD38 and HLA-DR at 24 
weeks 
• 
Changes from baseline in biomarkers of inflammation (IL-6, high sensitivity C-reactive protein) 
and biomarkers of mononuclear activation (SD-14, SD-163) at 24 weeks 
• 
Changes from baseline in sleep quality (Pittsburgh Sleep Quality Index) at 24 weeks 
 
• 
Incidence of adverse events in both treatment arms 
 
• 
Proportion of patients discontinuing study treatment due to adverse events related to 
medication 
• 
Proportion of patients with serious adverse events related to study medication 
 
• 
Changes in treatment adherence during all the study duration (Morisky-Green test) 


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4.2 Type of design 
This is a single center, national, phase III, prospective, open-label, randomized, controlled, 24-week 
pilot study. 
Eligible participants will be randomized (2:1) to one of the following arms: 
 
1. to simplify to to switch to Raltegravir / 3TC (MK0518B) (50 patients) 
 
2. to continue current treatment (25 patients) 
The study treatment period will be 24 weeks. 
A randomization list will be generated with a computer program according to a 2:1 allocation scheme. 
The randomization procedure will result with a code that will allow the treatment of each patient 
(patient code) to be identified. Randomization will be performed using the electronic case report form 
for the study. 
 
 
SCREENING OF POTENTIAL CANDIDATES 
 
 
INFORMATION AND CONSENT SIGNATURE 
 
DOES NOT MEET SELECTION 
MEETS SELECTION 
CRITERIA 
CRITERIA 
 
 
2:1 RANDOMIZATION 
 
 
RALTEGRAVIR /3TC 
 
CONTINUE 
(300/150mg) BID 
CURRENT TREATMENT 
 
 
Patients will attend the selection and randomization visit (baseline) and visits 4, 12 and 24 weeks. 
A total of 75 patients will be included in the study, 50 in the study arm and 25 in the control arm. 
 
4.3 Description of measures taken to minimize or prevent bias 
A randomization list will be generated with a computer program according to a 2:1 allocation scheme. 
The randomization procedure will result with a code that will allow the treatment of each patient 
(patient code) to be identified. The same randomization procedure will result in the generation of a 


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code that will allow the treatment of each patient (patient code) to be identified. Randomization will be 
performed centralised at Coordinating Center (CTU). 
 
 
4.4 Description of trial treatments 
Patients will be randomized 2:1 to: 
1. to simplify to Raltegravir / 3TC (MK0518B) 300/150mg BID 
2. to continue current treatment 
 
The study treatment period will be 24 weeks. 
The study medication (Raltegravir/3TC) will be supplied by Merck as a fixed-dose combination for 24 
weeks. The medication will be packed and labeled by Merck in accordance with European regulations. 
After the study, MSD will provide RAL/3TC until it is available commercially. If not possible, RAL/3TC 
will be switched to RAL + 3TC or any other antiretroviral regimen considered appropriate for the 
patient at the discretion of the investigator 
The study medication for the control group will be obtained through the standard prescription and 
dispensing route in which antiretroviral drugs are dispensed on an outpatient basis by the pharmacy 
department of the hospital. There are no plans to re-label the samples of this group. Patients will 
continue under the same treatment that they are already receiving. 
The study will assure the traceability of samples by recording the lot number and expiry date of the 
antiretroviral drugs. In addition, treatment adherence will be assessed at each visit through Morisky- 
Green test. 
 
4.5 Trial duration 
The total duration of the study will be 24 weeks. The recruitment period will be 6 months followed by a 
follow-up period of 24 weeks. 
End of study will coincide with the last follow-up visit of the last patient included in the study. 
 
 
4.6 Criteria for termination and/or discontinuation 
The patient will discontinue study participation if he/she is unwilling or is unable to meet the protocol 
requirements in terms of the visit schedule or if the patient or the investigator considers it best to end 
his/her participation in the study. All patients have the right to withdraw their consent at any time during 
the study without prejudice to them. 
All follow-up terminations of study patients and the reasons for them must be reported immediately to 
the study monitor and be duly documented both in the medical records and the case report form. 


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The DSMB will review the data if 4 episodes of treatment failure are detected, and then every 4 
additional failures detected. The study will be interrupted as early as 5 episodes of virological failure in 
experiemental branch are detected (10%). 
The DSMB will meet not when 8 cases of treatment failure but 4 patients occur. Treatment failure may 
be due to virological failure, but also for other reasons (discontinuation due to toxicity, loss to follow 
rupture of consent, etc). 
 
 
 
4.7 Drug accountability 
Drug accountability will not be performed. 
 
 
 
4.8 Allocation participant identification codes 
A randomization list will be generated with a computer program according to a 2:1. allocation scheme. 
As this is an open-label study, unblinding of the randomization codes is not necessary. 
The randomization procedure will result with a code that will allow the treatment of each patient 
(patient code) to be identified. The same randomization procedure will result in the generation of a 
code that will allow the treatment of each patient (patient code) to be identified 
 
 
4.9 Source data identification 
Source documents are defined as all observations or notes recorded on the clinical interventions, and 
all reports and notes required for assessment and reconstruction of the research study. Accordingly, 
source documents include but are not limited to laboratory reports, ECG tracings, echocardiography 
reports, hospital reports, patient progress notes, radiologist reports, or any other reports or records of 
any procedure according to this protocol. 
Whenever possible the original document should be kept as the source document; however, provision 
of a photocopy which is clear, legible and an exact duplicate of the original document is acceptable. 
 
 
4.10 End of trial 
End of trial will coincide with the date of the last follow-up visit of the last patient included in the study. 


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5. Subject Selection and Withdrawal 
 
5.1 Subject inclusion criteria 
 
1. Inclusion criteria 
The study population will consist of 75 adults who meet the following selection criteria: 
 
a. Eligible patients will be males or females at least 18 years of age. Women of 
childbearing potential must have a negative pregnancy test within 10 days prior to 
randomization into the study. 
b. Patients seropositive for HIV-1 using standard diagnostic criteria. 
c. Patients virologicaly suppressed during at least 12 months prior to inclusion (viral load 
<50 copies/mL). 
d. Patients on combination antiretroviral therapy (at least 2 antiretroviral drugs) for at 
least 12 months before being randomized in this study. 
e. Patients who are clinically stable in the opinion of the investigator at study entry 
(clinical status and chronic medication must not have not been modified at least 14 
days prior to randomization). 
f. 
Patients who have signed informed consent to participate in the study. 
 
*Women of childbearing potential must agree to sexual abstinence or use of barrier 
contraceptive methods during the study. 
 
 
5.2 Subject exclusion criteria 
The study population must not meet the following exclusion criteria: 
 
a. Pregnancy, lactation, or planned pregnancy during the study period. 
b. Previous failure to an integrase inhibitor-containing regimen. 
c. Previous failure to a 3TC or FTC-containing regimen. 
d. Resistance mutations to 3TC or integrase inhibitor if any resistance test had been 
previously performed. 
e. Any disease or history of disease which, in the opinion of the investigator, might 
confound the results of the study or pose additional risk to patient treatment. 
f. 
Chronic hepatitis B. 
g. Current therapy with RAL+3TC 
 
 
5.3 Withdrawal criteria 
Treatment discontinuation 
 
If a clinical or laboratory adverse event requiring an interruption in the antiretroviral regimen occurs, all 
drugs may be stopped or one of the drugs may be discontinued selectively if there is a clear causal 
relationship to the event. 
Discontinuation of therapy will be at the discretion of the investigator or the patient. If so, the reasons 
for discontinuing treatment will be recorded both in the medical records and the case report form and 


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patient follow-up will be continued. If the medication is discontinued permanently, the investigator will 
start the treatment judged appropriate in his opinion and maintain the planned follow-up according to 
the study. 
 
 
Study withdrawal 
 
The patient may discontinue study participation if he/she is unwilling or unable to meet the protocol 
requirements in terms of the visit schedule or if the patient or the investigator considers it best to end 
his/her participation in the study. All patients have the right to withdraw their consent at any time during 
the study without prejudice to them. 
If a female participant becomes pregnant along study, she will discontinue the study, but will be asked 
for consent for the pregnancy and delivery follow up (Appendix III). 
All follow-up terminations of study patients and the reasons for them must be reported immediately to 
the study monitor and be duly documented both in the medical records and the case report form. 
Should this prematurely terminated patient withdraw the study more than 2 months apart previous visit, 
a termination visit would need to be completed following w24 procedures as termination visit. 
 
 
 
6. Subject Treatment 
 
6.1 Treatment arms 
Patients who meet all inclusion criteria and no exclusion criteria will be randomized to one of the two 
treatment arms: 
 
1. to simplify to to switch to Raltegravir / 3TC (MK0518B) (50 patients) 
2. to continue current treatment (25 patients) 
The study treatment period will be 24 weeks. 
 
 
6.2 Concomitant, rescue and nonpermitted medication 
Concomitant medication 
 
Any concomitant medication used during the study will be duly recorded in case report form for that 
purpose. The data to be recorded will be the name of the drug, dose, and date of dosing as well as the 
reason or indication for administration. 
Rescue medication 
 
Rescue medication will be at the investigator's discretion. 


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Nonpermitted medication 
 
Investigational drugs. 
 
Cytotoxic systemic chemotherapy. 
 
Administration of the drugs formally contraindicated in the prescribing information of the investigational 
 
 
 
6.3 Monitoring of compliance 
Compliance will be monitored by the Morisky-Green test (Appendix IX). 
 
 
7. Efficacy Assessment 
 
7.1 Efficacy parameters 
Primary endpoint 
 
• 
The primary variable is the proportion of patients free of therapeutic failure at week 24. 
Therapeutic failure includes virological failure, change in treatment for any reason, consent 
withdrawal, loss to follow-up or death. 
Virological failure is defined as two consecutive measurements of plasma viral load above 37 
copies/ml (current detection limit in hospital lab) separated at least by 2 weeks during the assigned 
treatment, using the FDA snapshot method. 
Secondary variables: 
 
• 
Proportion of patients with viral load below 37copies/ml at 24 weeks 
 
• 
Proportion of patients with viral load below ultrasensitive HIV-1 RNA detection limit (limit of 
detection 1 copy/mL) at 24 weeks 
Screening visit 
 
The visit will be performed within 2-4 weeks prior to study start. 
 
At the screening visit, the principal investigator or designated collaborator will obtain written informed 
consent from each patient before tests and assessments specific to the protocol are started. 
Demographic data, medical history, complete physical examination, and laboratory tests (including 
hematology, biochemistry and plasma viral load) will be obtained and assessed to confirm the eligibility 
of the patient. 
Women of childbearing age will undergo a pregnancy rest (urine test) within 10 days prior to study start 
and will only be able to participate in the study if they obtain a negative result. If a female participant 
become pregnant along study, she will discontinue the study, but will be asked for consent for the 
pregnancy and delivery follow up (Appendix III). 


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Baseline visit (randomization) 
 
During the randomization visit, the investigator will ensure that all subject selection procedures were 
performed and the results confirm that the patient is eligible for participation in the study. 
After sign informed consent, eligible patients will be allocated to the study treatment according to the 
randomization list which will be by blocks. Randomization will be performed using the electronic case 
report form for the study. 
During the visit, a complete physical exam, measurement of viral load, ultrasensible viral load, CD4 
and CD8, a laboratory test (including hematology, biochemistry, lipid profile, glucose, creatinine, insulin 
and 25-OH vitamin D levels) and an urine sample (for the determination of Beta-2-microglobulin) will 
be obtained. 
In addition, a DXA examination will be performed to determine body composition. Also the Morisky- 
Green test and PSQI will fulfilled by the patient (see Appendices IX and X). 
 
 
Follow-up visits 
 
Patients will return to the center in weeks 4, 12 and 24 of the study. 
 
At each follow-up visit, a complete physical examination, measurement of viral load, ultrasensible viral 
load, CD4 and CD8 and laboratory tests (including hematology, biochemistry, lipid profile, and 
creatinine) will be performed. 
Viral load controls will be made at baseline, 4, 12, and 24 weeks. This frequency of controls is greater 
than that corresponding to a stable patient with undetectable viral load (currently performed controls 
viral load every 6 months): However, control after 4 weeks is a reasonable practice and recommended 
in the "Antiretroviral Treatment recommendations 2014 GESIDA" for any patient changes medication 
in real life. Antiretroviral medication is dispensed with a frequency of 3 months or less, so that the 
control after 12 weeks, not constitute an additional visit (and therefore an additional expense) for the 
patient to participate in the study. 
At each follow-up visit, tolerability of antiretroviral therapy and the presence of potential adverse events 
will be assessed. 
 
 
At the visit in week 24 insulin and 25-OH vitamin D levels and urine sample (for the determination of 
Beta-2-microglobulin) will be obtained. 
In addition, a DXA examination will be performed to determine body composition. Also the Morisky- 
Green test and PSQI will fulfilled by the patient (see Appendices IX and X). 
 
 
Stored samples 


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During the baseline visit and week 24 visits, a plasma sample will be taken and stored frozen for 
determination of biomarkers of inflammation (IL-6, high sensitivity C-reactive protein). In addition, a 
PBMC sample will be taken and stored frozen for determination of biomarkers of mononuclear 
activation SD-14 and SD-163 and immunology (CD38 and HLA-DR). 
If a patient experiences a plasma viral load above 37 copies/mL, the patient will need to repeat the test 
within 2 weeks. If viral load remains above 37 copies/mL the patient will be considered a virological 
failure: Genotypic resistance tests will be done in this case. 
The investigator will freely decide the most appropriate therapeutic option. Any change in antiretroviral 
therapy must be recorded in the case report form. 
All patients will continue follow-up according to the protocol during 24 weeks as planned in the study 
timetable. 
 
Table 1. Study timetable 
 
 
 
WEEK 
-2 / -4 
Screening 
0 
Randomization 
4 
12 
24 
Clinical assessment 
√ 
√ 
√ 
√ 
√ 
Physical examination 
√ 
√ 
√ 
√ 
√ 
Informed consent 
√ 
Pregnancy test 
√ 
Hematology 
√ 
√ 
√ 
√ 
√ 
Biochemistry1 
√ 
√ 
√ 
√ 
√ 
Beta-2-microglobulin (urine) 
√ 
√ 
√ 
√ 
Plasma viral load (HIV-RNA) 
√ 
√ 
√ 
√ 
√ 
Ultrasensitive viral load in plasma 
√ 
√ 
√ 
√ 
Immunology2 
√ 
√ 
√ 
√ 
Insulin 
√ 
√ 
Vitamin D 
√ 
√ 
DXA 
√ 
√ 
Stored samples3 
√ 
√ 
Validated Spanish PSQI 
√ 
√ 
Morisky-Green test 
√ 
√ 
√ 
√ 
Genotypic resistance test 
In case of virological failure 
Adverse events 
√ 
√ 
√ 
√ 


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1 including lipid profile (total cholesterol, HDL, LDL and TG), creatinine, glucose and vitamin D levels 
2 including CD4 and CD8 
3 stored plasma samples will be taken for the determination of biomarkers of inflammation (IL-6, high 
sensitivity C-reactive protein). Stored cell samples will be taken for the determination of biomarkers of 
mononuclear activation SD-14 and SD-163 and immunology (CD38 and HLA-DR) 


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7.2 Assessment of efficacy parameters 
- 
Blood tests will be performed for the determination of viral load, ultrasensible viral load, CD4 
and CD8. 
- 
The laboratory test will be performed during the screening and baseline and visits in week 4, 
12, and 24. 
- 
Resistance determination in patients with virological failure. 
 
8. Safety Assessment 
 
8.1 Safety parameters 
The investigator is responsible for detecting and documenting any event that meets the criteria and 
definitions of adverse event (AE) or serious adverse event (SAE) per this protocol. 
 
8.2 Assessment of safety parameters 
During the conduct of the study, the presence of adverse events, whether or nonserious, will be 
verified according to the adverse event definitions given in this section of the protocol. 
Minimum information 
 
Definitions: 
 
An adverse event (AE) is any untoward occurrence to the health of a patient or clinical trial subject 
treated with a medicinal product and which does not necessarily have a causal relationship with this 
treatment. 
It may be a new concomitant disease, a worsening of a concomitant disease, an injury, or any 
concomitant deterioration in the patient's health status, including laboratory values, regardless of 
etiology. Any medical condition that was present before the study treatment and that remains 
unchanged or improves should not be considered or recorded as an AE. A worsening of that medical 
condition will be considered as an AE. 
An adverse reaction (AR) is any noxious and unintended reaction to an investigational drug, 
regardless of the dose administered. 
A serious adverse event (SAE) is any adverse event that, at any dose, results in death, is life- 
threatening, requires or prolongs hospitalization of the subject, causes persistent or significant 
disability or incapacity, or gives rise to a congenital anomaly or birth defect. Life-threatening is defined 
as the situation in which, in the opinion of physician, the patient would have died if it had not been for a 
timely therapeutic intervention. 
For reporting purposes, any suspected adverse events considered medically important will be 
classified as serious even if they do not meet the above criteria. 


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Medically important events are defined as those events that may not be immediately life-threatening or 
cause death, hospitalization, or disability, but may jeopardize the patient or require medical or surgical 
intervention to prevent one of the other outcomes listed above. Examples of such events include 
allergic bronchospasm requiring intensive treatment at an emergency room or at home, blood 
dyscrasias or convulsions not requiring hospitalization, or the development of drug dependency or 
drug abuse. 
Medical and scientific judgment should be used to decide if other situations that have resulted in one of 
the outcomes listed in the above definitions should be reported as a SAE. 
Hospitalization or prolongation of an existing hospitalization are a criterion for considering that an AE is 
serious. Only admission when the patient stays overnight in the hospital should be considered 
hospitalization. The following situations do not meet the criteria for a SAE: 
 
- if hospitalization or prolongation of hospitalization is required for completing a procedure 
required by the protocol (for instance day or night visits are performed for biopsies or surgery 
required by the protocol). 
 
- if hospitalization or prolongation of hospitalization is part of the routine procedure at the site 
(such as withdrawal of a stent after surgery) 
 
- if hospitalization was scheduled prior to patient entry in the study 
 
- if hospitalization was scheduled for a preexisting condition that has not worsened 
 
 
An unexpected adverse reaction (UAR) is defined as any adverse reaction whose nature or severity 
is not consistent with product information (e.g., Investigator’s Brochure for an unapproved 
investigational drug or the summary of product characteristics for an approved medicinal product). 
A suspected unexpected serious adverse reaction (SUSAR) is an adverse reaction that is both 
serious and unexpected. 
 
Attributability criteria 
 
The causal relationship of the investigational product to the occurrence of the AE/SAE will be 
established based on a clinical judgment. For this, other causes will be considered and studied, such 
as the natural history of underlying diseases, concomitant treatment, other risk factors, and temporal 
relationship of the event to the investigational product. In addition, the summary of product 
characteristics of the products will be reviewed. 
To analyze the possible cause-effect relationship, the temporal relationship between drug 
administration and the AE, possible alternative explanations, the outcome (complete remission, partial 
recovery, death, sequelae, persistence), persistence or not after discontinuation of the study drug, 


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recurrence on drug rechallenge, or previous knowledge of the event consistent with the known or 
expected pattern of response to the study drug will be considered. 
The causal relationship of an AE to the study drug will be described according to the following 
definitions: 
Unlikely related: The adverse event does not occur after a plausible temporal sequence from 
administration of the study product and/or can be reasonably explained by other factors such as the 
patient's clinical state, toxic or environmental factors, or other concomitant therapies. In addition, it 
does not follow the known or expected pattern of response to the drug. 
Possible relationship: The adverse event occurs after a plausible temporal sequence from 
administration of the study product, but can also be explained by the patient's clinical state, toxic or 
environmental factors, or other concomitant therapies. In addition, it does not follow the known or 
expected pattern of response to the drug. 
Probable relationship: The adverse event occurs after a plausible temporal sequence from 
administration of the study product, cannot be reasonably explained by the patient's clinical state, toxic 
or environmental factors, or other concomitant therapies, and after withdrawal or dose reduction of the 
suspect drug, the event follows a logical clinical sequence. In addition, it follows the known or expected 
pattern of response to the drug. 
Clear relationship: The adverse event occurs after a plausible temporal sequence from administration 
of study product, cannot be reasonably explained by the patient's clinical state, toxic or environmental 
factors or other concomitant therapies, after withdrawal or dose reduction of the suspect drug, the 
event follows a logical clinical sequence, and the adverse event recurs after reintroduction of the 
suspect drug. In addition, it follows the known or expected pattern of response to the drug. 
No relationship: The adverse event is clearly due to causes unrelated to the study drug, and the 
criteria for another causal relationship are not met. 
Nonassessable relationship: Any report suggesting an adverse effect which cannot be judged 
because the information is insufficient or contradictory, and which cannot be supplemented or verified. 
 
8.3 Adverse event detection and recording 
AEs will be recorded at each visit based on careful clinical observation of the patient, laboratory tests, 
spontaneous reports by the patient and also by open-ended questioning by the investigator. 
All AEs (serious or not) occurring during the study must be noted in the medical history and recorded 
in the CRF. The investigator will also decide whether the adverse event is, based on his/her judgment, 
related or not to the study drug—this decision should also be noted in the medical history and CRF. 
At each visit, all AEs experienced by the patient since the previous visit should be recorded in the 
specific adverse event form of the CRF. 
The following will be recorded for each event: description, severity (grade 1, 2, 3, 4 and 5), duration 
(start and end dates), causal relationship with the drug (according to the previously attributability 


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criteria) and study drug(s) for which this causal relationship is suspected, need for treatment (if 
applicable) or the actions taken, possible alternative explanations, predisposing factors, and outcome. 
For a preexisting AE that has worsened in terms of severity or frequency, the meaning of the change 
should be specified. 
The degree of severity of an adverse event provides a qualitative assessment of the extent or intensity 
of an adverse event elicited by the investigator or reported by the patient. Severity does not reflect the 
clinical seriousness of the event, only the grade or extent of the complaint or incidence. 
The severity of an AE will be rated based on the Division of AIDS toxicity table (AppendixVII) 
 
 
8.3.1 Procedures for expedited reporting of serious adverse events by the investigator 
The principal investigator will report immediately to the Coordinating Center (CTU Clinic: telephone 93 
227 5400 ext 4386, fax 93 227 9877, e-mail jcamacho@clinic.ub.es) all serious adverse events 
regardless of their degree of causal relationship with the study drug. All SAEs occurring from signing of 
informed consent and up to 30 days after receiving the last dose of the study drug should be reported. 
The initial report of SAE should be written and as complete as possible including details of the current 
disease and SAE and assessment of the causal relationship between the AE and the investigational 
product. Reporting will be made using the Serious Adverse Event Report Form included in Appendix V 
of this protocol within 24 hours from first knowledge by the investigator, completing all information on 
the form in the following two days. 
The information missing at the time of the initial report must be reported in the SAE follow-up form. 
 
For SAEs, the investigator will provide the Coordinating Center with all documentation related to the 
event (additional laboratory tests, discharge reports, etc.). 
The investigator must also follow up SAEs and similarly report information related to the event until it 
has subsided, returned to baseline, can be attributed to products other than the study medication or to 
factors unrelated to conduct of the study, it is unlikely to obtain additional information, or in case of 
permanent impairment, until the condition stabilizes. 
In the event of death, the investigator must provide the sponsor and/or Coordinating Center, the Ethics 
Committee, and the relevant regulatory authorities with all additional information requested by them. 
 
 
8.3.2 Procedures for expedited reporting of serious and unexpected adverse reactions 
by the sponsor 
 
The study sponsor will report any events that are serious and unexpected that may be related to the 
investigational products (i.e., suspected unexpected serious adverse reactions, SUSARs) to the 
Spanish Regulatory Agency, the competent bodies of the Autonomous Communities involved (the 
communities in whose territory the trial is being conducted) and to the EC involved (EC of the site 
where the SUSAR occurred). 


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Reporting will be made using Suspected Adverse Reaction Report Form. 
 
The maximum deadline for reporting will be 15 calendar days from the time the sponsor is aware of the 
SUSAR. For SUSARs causing death or that are life-threatening for the subject, the maximum reporting 
time will be 7 calendar days from the time the sponsor is aware of them. This information will be 
completed, when possible, in the following 8 days (Appendix VI). 
Information on adverse events that are not serious or unexpected and on those considered unrelated 
to the study treatment will be collected in tabular form at the end of the clinical trial or at the time of 
interim analyses when these are planned. 
The Coordinating Center will keep a record of all AEs reported by investigators. These records will be 
submitted to the Spanish Regulatory Agency when requested. 
 
 
8.4 Follow-up of adverse events 
The investigator must also follow up SAEs and similarly report information related to the event until it 
has subsided, returned to baseline, can be attributed to products other than the study medication or to 
factors unrelated to conduct of the study, it is unlikely to obtain additional information, or in case of 
permanent impairment, until the condition stabilizes. 
Although not considered an adverse event, it is the responsibility of the investigator and his/her 
coinvestigators to report immediately any pregnancy or suspected pregnancy (including positive 
pregnancy tests) occurring during the study or within 28 days after the end of the study. 


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9. Statistics 
 
9.1 Methods 
The baseline patients’ characteristics of the ITT population will be described. Continuous variables will 
be described by their means, standard deviations,medians, Interquartile ranges, minimums and 
maximums. Categorical variables, figures and percentages per class will be presented per arm. 
The primary analysis will be done when all patients have reached 24 weeks. Analysis of the primary 
endpoint will be performed on both ITT and per protocol populations. The 95% two sided confidence 
interval of the of the difference in percentage of patients in therapeutic success (RAL/3TC – Current 
regimen) will be calculated. 
The percentage and absolute changes in continuous variables between week 4, 12 and 24 versus 
baseline will be compared between arms in the ITT population (LOCF of other imputation method to be 
defined in the statistical analysis plan) using a two-sided non parametric Mann WhitneyTest. 
The categorical endpoints will be compared using Fisher’s exact test or chi-squared test. 
Two sided p-values will be reported. The level of significance will be tested at 0.05. 
DSMB will review the data if 4 episodes of treatment failure are detected and subsequently every 4 
new episodes of treatment failure. Study will be interrupted as soon as 5 episodes (10%) of confirmed 
virological failure are detected in the experimental arm. 
 
9.2 Sample size 
A total of 75 patients will be included in the study with a randomization 2:1 (RAL/3TC and Current 
treatment). 
This study is not a noninferiority study, in which case the delta should be -15% or less. It is a pilot 
study which tries to see the feasibility of the pattern and to generate data with which to design a larger 
study with a noninferiority design. However, there are security measures in the primary end-point is the 
virologic efficacy. The DSMB will review the data if 4 episodes of treatment failure are detected, and 
then every 4 additional failures detected. The study will be interrupted as early as 5 episodes of 
virological failure in experiemental branch are detected (10%). 
This pilot study is exploratory, and must serve to see whether it is feasible, if the results are good 
enough, to make a large-scale study. 
 
9.3 Statistical significance and adjustments for multiplicity 
In all cases, all tests will be performed with a two-sided type I error of 5%. For the primary endpoint, 
adjustment is not necessary to preserve the type I error. 
 
9.4 Criteria for discontinuation 
The study will be completed when these two premises are met: 


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- Inclusion of the number of patients needed for the sample size in each randomized group 
 
- End of clinical monitoring 
 
No interim analyses are planned. 
 
 
 
9.5 Management of missing data 
In case of missing values, the Last Observation Carried forward (LOCF) method will be used. 
 
 
 
9.6 Deviations from statistical plan 
A statistical analysis plan will be prepared during the course of the study and before closing the 
database and unblinding which will describe in detail the statistical methods to be used, the approach 
to be followed in case of missing values and the tables and charts to be included in the statistical 
report. In addition, a data blind review will be made to define the subjects who will enter each study 
population. 
Any deviation from the original statistical plan must be reported and justified in the final report, if 
necessary. 
 
 
 
9.7 Analysis population 
Study analysis will be performed in the per protocol population (PP). In addition the primary endpoint 
will also be assessed in the intent-to-treat population (ITT), including all randomized subjects who have 
been administered study medication. 


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10. Direct Access to Source Data/Documents 
Investigators will ensure access to the source documents of the staff responsible for guaranteeing data 
quality and data analysis. In addition, access to documentation will be provided, if necessary, to the 
staff duly authorized by the sponsor (study monitors), to regulatory authorities and to CRECs if they 
request to inspect the study. 
 
11. Ethics 
General considerations 
The clinical trial will be conducted in accordance with the principles contained in the Declaration of 
Helsinki, and according to applicable regulations (Royal Decree 223/2004) and will be started once 
approval is obtained from the reference CREC, authorization from the Spanish Agency for Medicinal 
Products and Medical Devices, and approval by the Director of the Institution. 
The investigator agrees to comply with the rules set forth in the applicable clinical trial regulations: 
Medicines Act 29/2006 (Official State Journal No. 178, 27-07-06) and Royal Decree 223/2004 on 
Clinical Trials. 
 
Subject information 
 
Patients will be informed verbally and in writing and all relevant information will be reported to the 
participants adapted to their level of understanding. 
(See Appendix II: Patient Information Sheet and Patient Informed Consent) 
 
 
 
Confidentiality 
 
Patient will be informed that their participation in the trial will be treated with the same confidentiality as 
their clinical documentation, but, if necessary, a member of the site Ethics Committee, an inspector 
designated by the health authorities, or the clinical trial monitor may have access to those records. 
In the case report form, the patient will only be identified by the assigned study code. The name of 
patients will not appear in any publication or report of the study results. 
The participation of the patient in the trial will be noted in their medical records. 
 
The investigator will complete a list which will include the names of the patients participating in the trial, 
the number of inclusion in the study, and their medical history. Only investigators and the staff 
responsible for guaranteeing data quality and data analysis will have access to the clinical 
documentation of the participants. 
Duly authorized persons by the sponsor and the health authorities and the Clinical Research Ethics 
Committee may audit or inspect the trial. Personal information will not be publicly available, in 
compliance with Organic Act 15/1999, of 13 December, on Personal Data Protection. 


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Participants may exercise their right to processing, reporting, and transfer of the personal data 
pursuant to Organic Act 15/1999, of 13 December (Spanish Royal Decree 1720/2007, of 21 
December), on Personal Data Protection. According to the above law, patients can exercise their rights 
to data access, rectification, opposition, and cancellation, for which they must contact the study doctor. 
Only data collected for the study that does not bear any information that could directly identify the 
patient will be transferred to third parties or other countries. Should this transfer occur, it will be for the 
same purposes as the study and guarantee confidentiality with at least the level of protection afforded 
by applicable regulations in Spain. 
 
 
 
12. Data Management and Record Retention 
The processing, reporting, and transfer of personal data from all participating subjects will comply with 
the provisions in Organic Act 15/1999, of December 13 (Spanish Royal Decree 1720/2007, of 21 
December), on Personal Data Protection. 
According to this regulation, all data collected in the case report form should be verifiable against the 
source documents. In addition, the sponsoring investigator will have a file that will contain all case 
report forms, data correction forms, templates, source documents, monitoring records and visit 
scheduling, regulatory filings (e.g. signed protocol, amendments, correspondence with Ethics 
Committee, approval, approved version of patient information sheet, signed patient consents, 
investigator agreement, regulatory agency authorization, etc.). These files must be kept as established 
by regulations. 
 
 
 
13. Funding and Insurance 
The study was financed by a grant provided by Merck. 
 
In accordance with Royal Decree 223/2004, the sponsor has taken out civil liability insurance for this 
study (see Appendix XII). 
 
 
14. Publication Policy 
The investigators, in agreement with the Coordinating Center for the study, will publish the results of 
the trial in internationally indexed journals. Authorship will take into account members of the study 
management, participating investigators and persons responsible for coordination, data analysis and 
article writing.