Pilot Single-Arm Clinical Trial to Evaluate the Efficacy, PK Interactions and Safety of Dolutegravir Plus 2 NRTIs in HIV-1-Infected Solid Organ Transplant Patients
Phase: PHASE4
Conditions: HIV-1-infection, Solid Organ Transplant
Sponsor: Fundacion Clinic per a la Recerca Biomédica

  
 
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Study Protocol 
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Page  1 out of 56 
 
 
Pilot single-arm clinical trial to evaluate the efficacy, PK interactions and safety of 
dolutegravir plus 2 NRTIs in HIV-1-infected solid organ transplant patients 
 
Code: DTG-SOT 
 
 
Version 1.0, 8th May 2017 
 
EudraCT: 2017-000469-62 
 
 
Sponsor:  
Fundació Clínic per a la Recerca Biomèdica 
C/ Rosselló, 149-153 08036 Barcelona  
Tel.: (93) 227 57 07  
e-mail: fclinic@clinic.ub.es. 
 
 
 
 
 
Principal  Investigators (PIs): 
 
 
Jose M. Miro Meda (PI), MD, PhD,  Consultant, Infectious Diseases Service, 
Hospital Clínic/IDIBAPS, University of Barcelona, Barcelona, Spain 
Villarroel, 170, 08036 Barcelona, Tel. 93 227 5430, Fax: 93 227 9877 E-mail: 
jmmiro@ub.edu 
 
 
Christian Manzardo (Study coordinator): MD, PhD, Associate Investigator, 
Infectious Diseases Service, Hospital Clínic/IDIBAPS, University of Barcelona, 
Barcelona, Spain (e-mail: cmanzard@clinic.ub.es ) 
 
 
 
 
 
 
 
Co-Investigators:  
 
 
 
 
Antonio Rimola, MD, PhD Consultant,  Liver Transplantation Unit/CIBERHD, 
Hospital Clínic, Barcelona, Spain (arimola@clinic.ub.es) 
 

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Frederic Cofan, MD, PhD, Consultant, Kidney Transplant Unit, Hospital Clínic 
Barcelona, Spain (e-mail: fcofan@clinic.ub.es ) 
 
María Teresa Castel, MD, PhD Consultant,  Heart Transplantation Unit, Hospital 
Clínic, Barcelona , Spain (e-mail: macastel@clinic.ub.es ) 
 
Mercè Brunet, MD, PhD Consultant, Bioquímic and Molecular Genétic Unit, Hospital 
Clínic, Barcelona , Spain (email: mbrunet@clinic.ub.es ) 
 
Montserrat Tuset, MD, PhD Hospital Pharmacy Department Hospital Clínic, 
Barcelona , Spain (email: mtuset@clinic.ub.es ) 
 
Juan Ambrosioni, MD, PhD, Associate investigator,  Infectious Diseases Service, 
Hospital Clínic/IDIBAPS, University of Barcelona, Barcelona, Spain (email: 
ambrosioni@clinic.ub.es ) 
 
Asuncion Moreno, MD, PhD, Infectious Diseases Service, Hospital Clínic/IDIBAPS, 
University of Barcelona, Barcelona, Spain (amoreno@clinic.ub.es ) 
 
Elisa de Lazzari, BSc, Statistician, Infectious Diseases Service, Hospital 
Clínic/IDIBAPS, University of Barcelona, Barcelona, Spain (ELAZZARI@clinic.ub.es  
Jose M. Gatell, MD, PhD, Consultant,  Infectious Diseases Service, Hospital 
Clínic/IDIBAPS, University of Barcelona, Barcelona, Spain (jmgatell@clinic.ub.es ).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The information contained in this document is confidential and must not be 
revealed to third persons without prior authorization as contemplated by Law. 

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SIGNATURES 
 
The coordinating investigator and the sponsor of the study: 
 
Pilot single-arm clinical trial to evaluate the efficacy, PK interactions and 
safety of dolutegravir plus 2 NRTIs in HIV-1-infected solid organ transplant 
patients 
 
Declare that this study will be conducted in compliance with the protocol, Good 
Clinical Practices (GCP) and the applicable regulatory requirements. 
 
 
Modifications to this protocol must be submitted prior agreement of the coordinator 
investigator and sponsor. 
 
 
 
Coordinating Investigators:  
 
 
Jose M. Miro Meda (PI), MD, PhD 
Christian Manzardo (Co-PI), MD, PhD 
 
 
Signatures and Date: 
 
 
 
Sponsor: Fundació Clínic per a la Recerca Biomèdica 
              C/ Rosselló, 149-153 08036 Barcelona, Spain 
 
 
 
 
 
Signature and Date: 
 
 
 
 
 

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1 
GENERAL INFORMATION 
 
1.1 TITLE 
Pilot single-arm clinical trial to evaluate the efficacy, PK interactions and safety of 
dolutegravir plus 2 NRTIs in HIV-1-infected solid organ transplant patients. 
 
1.2 CODE 
EudraCT number: 2017-000469-62 
Study Code: DTG-SOT 
 
1.3 PROTOCOL VERSION AND DATE 
Version 1.0, May 8, 2017 
Any modification of the protocol must also bear the amendment number and date. 
 
1.4 SPONSOR 
Fundació Clínic per a la Recerca Biomèdica 
C/ Rosselló, 149-153 08036 Barcelona  
  Tel.: (93) 227 57 07  
  e-mail: fclinic@clinic.ub.es. 
 
Person authorized by the sponsor to sign the protocol and amendments:  
Jose M. Miro Meda, MD, PhD 
 
1.5 MONITOR 
CTU-CLINIC-Clinical Trial Unit  
C/ Rosselló, 138, bajos y  
C/Mallorca 183.  
Fax: 93 227 9877  
e-mail:acruceta@clinic.ub.es.  
 
 
1.6 COORDINATING INVESTIGATOR 
Jose M. Miro Meda, MD, PhD 
 
1.7 SITES AND INVESTIGATORS 
This unicentric study will be performed in: 
 
- Hospital Clínic de Barcelona 

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1.8 TECHNICAL SERVICES INVOLVED 
 
 
Biochemistry; Hematology, quantitative HIV-1 RNA levels and CD4 counts will be 
performed in the Central laboratory of Hospital Clinic (T +34 2275400 Ext 3328). 
 
Dolutegravir, Raltegravir and immunosuppressants plasma levels will be performed 
at CDB (Centre de Diagnòstic Biomèdic) Bioquímic and Molecular Genétic Unit, 
Hospital 
Clínic, 
Barcelona, 
Spain 
(T. 
+34 
2275400 
Ext 
3328, 
email: 
mbrunet@clinic.ub.es ) 
 
 
 
 

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CONTENTS 
1 
GENERAL INFORMATION ................................................................................... 4 
1.1 
TITLE ........................................................................................................ 4 
1.2 
CODE ....................................................................................................... 4 
1.3 
PROTOCOL VERSION AND DATE .................................................................... 4 
1.4 
SPONSOR .................................................................................................. 4 
1.5 
MONITOR .................................................................................................. 4 
1.6 
COORDINATING INVESTIGATOR .................................................................... 4 
1.7 
SITES AND INVESTIGATORS .......................................................................... 4 
1.8 
TECHNICAL SERVICES INVOLVED .................................................................. 5 
CONTENTS ........................................................................................................... 6 
2 
ABBREVIATIONS .............................................................................................. 9 
3 
SUMMARY ..................................................................................................... 11 
4 
BACKGROUND INFORMATION .......................................................................... 12 
4.1 
HYPOTHESIS ............................................................................................ 15 
4.2 
REFERENCES ........................................................................................... 15 
5 
TRIAL OBJECTIVE AND PURPOSE ..................................................................... 18 
5.1 
PRIMARY OBJECTIVES ............................................................................... 18 
5.2 
SECONDARY OBJECTIVES .......................................................................... 18 
6 
TRIAL DESIGN ............................................................................................... 18 
6.1 
TYPE OF TRIAL ......................................................................................... 18 
6.2 
DESCRIPTION OF THE DESIGN .................................................................... 18 
TYPE OF STUDY: SINGLE‐ARM CLINICAL TRIAL. ........................................................ 18 
TWENTY HIV‐INFECTED SOT RECIPIENTS (10 LIVER TRANSPLANT RECIPIENTS, 8 RENAL 
TRANSPLANT RECIPIENTS AND 2 HEART TRANSPLANT RECIPIENTS) RECEIVING TDF/FTC 
OR ABC/3TC PLUS RALTEGRAVIR WILL BE SWITCHED TO DTG PLUS THE SAME 2 NRTIS. 
WHENEVER POSSIBLE, THE ABC+3TC COMBINATION WILL BE THE PREFERRED NRTIS. ALL 
PATIENTS WILL BE FOLLOWED OVER 48 WEEKS. ...................................................... 18 
TO ACCOMPLISH WITH THE PRIMARY OBJECTIVES: .................................................. 19 
1. PHARMACOKINETIC (PK) STUDIES: TEN SOT RECIPIENTS (4 LIVER TRANSPLANT 
RECIPIENTS, 4 RENAL TRANSPLANT RECIPIENTS AND 2 HEART TRANSPLANT RECIPIENTS) 
WILL BE SELECTED TO PERFORM RAL AND IMMUNOSUPPRESSOR DRUGS 24‐HOUR 
PHARMACOKINETIC PROFILES BEFORE THE SWITCH, AND DTG AND IMMUNOSUPPRESSOR 
DRUGS 24‐HOUR PHARMACOKINETIC PROFILES 2 WEEKS AFTER SWITCHING. THE AIM IS 
TO DETECT ANY POSSIBLE DRUG‐DRUG INTERACTIONS BETWEEN DTG AND WIDELY‐USED 
IMMUNOSUPPRESSANT DRUGS (IS)  (CYCLOSPORINE A , TACROLIMUS, SYROLIMUS AND 
MYCOPHENOLIC ACID). ......................................................................................... 19 
6.3 
MEASURES TO AVOID BIAS ......................................................................... 20 
6.3.1 
Randomization ..................................................................................... 20 
6.3.2 
Stratification ......................................................................................... 20 
6.3.3 
Blinding .............................................................................................. 20 
6.4 
FORESEEN CALENDAR .............................................................................. 20 
6.5 
END OF TRIAL .......................................................................................... 20 

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6.5.1 
Early study suspension ............................................................................ 21 
6.6 
SOURCE DATA ......................................................................................... 21 
7 
TRIAL INVESTIGATIONAL PRODUCT(S) ............................................................... 23 
7.1 
TREATMENTS: SUPPLY, PACKAGING, LABELING AND STORAGE ........................ 23 
7.1.1 
All investigational products will be stored at the Pharmacy Service of Hospital Clinic of 
Barcelona. As a Phase 4 Trial, commercial formulations will be administered to patients. ....... 23 
7.2 
DOSE, INTERVAL, ROUTE AND METHOD OF ADMINISTRATION ........................... 23 
7.3 
DRUG ACCOUNTABILITY............................................................................. 23 
7.4 
CONCOMITANT TREATMENTS ..................................................................... 24 
7.4.1 
Other treatments ................................................................................... 24 
7.5 
COMPLIANCE ........................................................................................... 24 
8 
SELECTION AND WITHDRAWAL OF SUBJECTS (INCLUSION/EXCLUSION CRITERIA) .... 25 
8.1 
INCLUSION/EXCLUSION CRITERIA ................................................................ 25 
8.2 
SUBJECT WITHDRAWAL CRITERIA ............................................................... 26 
8.2.1 
Related to Dolutegravir-containing regimens .................................................. 26 
8.2.2 
Early subject withdrawal .......................................................................... 27 
8.2.3 
Medical approach to withdrawal ................................................................. 27 
8.2.4 
Follow-up after early withdrawal ................................................................. 28 
9 
TRIAL CONDUCTION AND RESPONSE EVALUATION .............................................. 29 
9.1 
LONG-TERM FOLLOW-UP............................................................................ 29 
9.2 
PROCEDURES FOR EVALUATION OF RESPONSE ............................................ 30 
9.2.1 
Clinical record and physical exam ............................................................... 30 
9.2.2 
Laboratory tests .................................................................................... 30 
10 
ADVERSE EVENTS ....................................................................................... 33 
10.1 
DEFINITION ........................................................................................... 33 
10.2 
MONITORING, RECORDING AND REPORTING OF ADVERSE EVENTS ................ 34 
10.3 
DOCUMENTATION RELATED TO AE AND SAE ............................................... 35 
10.4 
EVALUATION OF ADVERSE EVENTS ........................................................... 35 
10.4.1 
Seriousness ......................................................................................... 35 
10.4.2 
Severity / Intensity ................................................................................. 37 
10.4.3 
Causality ............................................................................................. 38 
10.4.4 
Duration ............................................................................................. 39 
10.4.5 
Action Taken ........................................................................................ 39 
10.4.6 
Outcome ............................................................................................. 39 
10.5 
ABNORMAL LABORATORY VALUES ............................................................ 40 
10.6 
ALLERGIC REACTIONS ............................................................................ 42 
10.7 
EXPEDITED REPORTING OF ADVERSE EVENTS ........................................... 43 
10.7.1 
Reporting to Regulatory Authorities and the Ethics Committee ............................ 43 
10.7.2 
Immediate reporting by Investigator to Sponsor .............................................. 44 
10.7.3 
Reporting by Sponsor to ViiV Healthcare ...................................................... 44 
10.7.4 
Reporting by Sponsor to Coordinating investigator ........................................... 44 
11 
STATISTICS ................................................................................................ 46 
12 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ............................................. 47 
13 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................ 48 
13.1 
STUDY MONITORING .............................................................................. 48 
13.2 
AUDITS AND INSPECTIONS ...................................................................... 48 

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13.3 
CASE REPORT FORM .............................................................................. 49 
13.4 
ALLOCATION PARTICIPANT IDENTIFICATION CODES ..................................... 49 
14 
ETHICS ...................................................................................................... 50 
14.1 
GENERAL CONSIDERATIONS .................................................................... 50 
14.2 
PATIENT INFORMATION SHEET AND INFORMED CONSENT ............................ 50 
14.3 
PAYMENT TO RESEARCH SUBJECTS ......................................................... 51 
15 
DATA HANDLING AND RECORD KEEPING ......................................................... 52 
15.1 
DATA HANDLING .................................................................................... 52 
15.2 
RECORD KEEPING .................................................................................. 52 
15.2.1 
Investigator file and document retention ....................................................... 53 
15.2.2 
Source documents and basic data .............................................................. 54 
16 
FINANCING AND INSURANCE ......................................................................... 55 
16.1 
SOURCE OF FINANCING .......................................................................... 55 
16.2 
INSURANCE POLICY ............................................................................... 55 
17 
PUBLICATION POLICY .................................................................................. 55 
 
APPENDIX 
 
APPENDIX 1- VHL Standar Protocol Risk  Management & Monitoriting Language for 
Investigator Sponsored Studies (ISS) with Dolutegravir 
 
APPENDIX 2 Patient information sheet and informed consent 
 
APPENDIX 3. Helsinki Declaration 

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2 
ABBREVIATIONS  
 
3TC 
Lamivudine 
ABC 
Abacavir 
AE 
Adverse event 
AEMPS 
Agencia Española de Medicamentos y Productos Sanitarios 
AIDS 
Acquired immune deficiency syndrome 
ALT 
Alanine aminotransferase 
AR  
Adverse reaction 
BP 
blood pressure 
cART 
Combination Antiretroviral Therapy 
CTA 
Clinical Trial Agreement 
DSMB 
Data Safety Monitoring Board 
DTG 
Dolutegravir 
EC 
Ethics Committee 
EMA 
European Medicines Agency 
FDA 
Food and Drugs Administration 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
HAART 
Highly active antiretroviral therapy 
HBsAg 
Hepatitis B virus surface antigen 
HBV 
Hepatitis B virus 
HC 
Clínic Hospital  
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HLA 
Human Leukocyte Antigen 
IB 
Investigator's Brochure 
ICF 
Informed Consent Form 

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ICH 
International Conference of Harmonisation 
IRB/IEC 
Institutional Review Board/Independent Ethic Comitte 
iv 
Intravenous 
MS 
Mass spectrometry 
NRTI 
Nucleoside Reverse Transcriptase Inhibitor 
PBMCs 
Peripheral blood mononuclear cell 
PBS 
Phosphate buffered saline 
PCR 
Polymerase chain reaction 
PK 
Pharmacokinetics 
PI 
Principal Investigator 
PIS 
Participant/ Patient Information Sheet 
pVL 
Plasma viral load 
QD 
Once-a-day 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SOT 
Solid Organ Transplant 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
RAL 
Raltegravir 
TDF 
Tenofovir Fumarate 
TMF 
Trial Master File 
 

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3 
SUMMARY 
 
Objectives:  
 
The aims of this study are to obtain pharmacokinetic data on interactions 
between DTG and immunosuppressant drugs (Cyclosporine A, Tacrolimus, 
Syrolimus and Mycophenolic acid) in SOT   recipients To provide proof of 
principle data that DTG plus 2 NUCs is safe and effective in HIV‐infected SOT 
recipients. 
 
Methods: 
 
Study Design: Single-arm clinical trial. Twenty HIV-infected SOT recipients 
(10 liver transplant recipients,   8 renal transplant recipients and 2 heart 
transplant recipients) receiving TDF/FTC or ABC/3TC plus raltegravir will be 
switched to DTG plus the same 2 NUCs. Depending on the results of the 
proviral genotyping, patients receiving a third drug (e.g. rilpivirine) other than 
raltegravir can be also be considered for switching to DTG plus 2 NUCs.  
Whenever possible, the ABC+3TC combination will be the preferred NUCs. All 
patients will be followed over 48 weeks. All SOT recipients will be proposed to 
perform RAL (or other antiretroviral drug) and immunosuppressor drugs 24-
hour 
pharmacokinetic 
profiles 
before 
the 
switch, 
and 
DTG 
and 
immunosuppressor drugs 24-hour pharmacokinetic profiles 12 weeks after 
switching.  The aim is to detect any possible drug-drug interactions between 
DTG and widely used immunosuppressant drugs (Cyclosporine A, Tacrolimus, 
Syrolimus and Mycophenolic  acid). 
 
Inclusion/Exclusion criteria: 
 
Inclusion criteria: 
 
1. HIV patients >18 years old who provide signed and dated informed   consent; 
2. Males and females; 
3. SOT recipients (heart, liver or  kidney); 
4. On stable ART for ≥6 months preceding the screening  visit; 

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5. Plasma HIV RNA <50 cop/ml for 12 months (2 tests separated by at least 12 
months with no viral load >50 between determinations); 
6. Absence of major reverse transcriptase or integrase gene mutations 
affecting study drug efficacy by proviral DNA sequencing. 
 
Exclusion criteria: 
 
1. HIV patients who have stopped ART due to virological  failure; 
2. HIV patients who require treatment with DTG contraindicated medications; 
3. History or presence of an allergy or intolerance to the study  drug; 
4. Active opportunistic infection; 
5. Neoplasms requiring chemotherapy. 
6. Pregnancy or breast feeding or planned pregnancy during the study period         
7. Any other contraindication to study drugs. 
 
Number of Patients 
 
Twenty  (10 liver transplant recipients, 8 renal transplant recipients and 2 heart 
transplant   recipients) 
 
 
4 
BACKGROUND INFORMATION 
With the advent of combined antiretroviral therapy (cART), patients infected with the 
type 1 human immunodeficiency virus (HIV) are now living longer and dying of 
illnesses other than acquired immunodeficiency syndrome. Although the outcome of 
solid organ transplantation (SOT) in HIV-infected recipients was poorer than in 
HIV-negative recipients in the pre-HAART era, more recent evidence has 
demonstrated comparable results in both populations [1-3]. Currently, SOT can be 
performed safely in selected HIV-1-infected patients [4-6]. However, a number of 
issues persist regarding patient selection, postoperative management, and 
pharmacokinetic and pharmacodynamic interactions between antiretroviral and 
immunosuppressive agents. A key challenge in the post-transplant period is the 
management of pharmacokinetic interactions between immunosuppressive and 

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antiretroviral drugs, particularly HIV protease inhibitors (PIs), which involve a higher 
risk of allograft rejection and drug toxicity [7]. Frequent monitoring of the levels of 
calcineurin inhibitors (e.g., tacrolimus or cyclosporine A) is necessary when PIs are 
introduced or withdrawn in HIV-infected SOT recipients, because they are potent 
CYP450 inhibitors. Furthermore, the pharmacokinetics of corticosteroids and mTOR 
inhibitors can be affected by PIs. In contrast, non-nucleoside reverse transcriptase 
inhibitors (NNRTI), such as efavirenz and nevirapine, which are commonly used in 
HAART regimens, are strong CYP450 inducers and decrease serum levels of 
calcineurin inhibitors, resulting in the need to increase their dose to prevent allograft 
rejection. Raltegravir (RAL) was the first HIV-1 integrase inhibitor to be approved for 
clinical practice [8]. A favorable pharmacokinetic profile has been demonstrated in 
HIV-infected SOT recipients co-treated with RAL and calcineurin inhibitors 
(cyclosporine, tacrolimus), mTOR inhibitors, and corticosteroids [7,9], indicating that 
RAL is probably safe and efficacious in HIV-infected SOT recipients [9]. However, 
because of its low genetic barrier, RAL should be administered in general terms with 
two nucleot(s)ide analogs such as TDF/FTC or 3TC/ABC. Tenofovir is an acyclic 
nucleotide analog reverse-transcriptase inhibitor structurally similar to the 
nephrotoxic drugs adefovir and cidofovir. Tenofovir is widely used to treat HIV 
infection and approved for the treatment of the hepatitis B virus. Despite initial cell 
culture and clinical trial results supporting the renal safety of tenofovir, its clinical use 
is associated with a low, albeit significant, risk of kidney injury [10,11]. The proximal 
tubular cell secretion of tenofovir explains the accumulation of the drug in these 
mitochondria-rich cells. Tenofovir nephrotoxicity is characterized by proximal tubular 
cell dysfunction that may be associated with acute kidney injury or chronic kidney 
disease. Withdrawal of the drug leads to an improvement of analytical parameters 
that may only be partial. Newer, structurally-similar molecular derivatives that do not 
accumulate in proximal tubules are under study, but are not yet commercially 
available. SOT recipients are prone to renal dysfunction because of pre-existing 
conditions such as diabetes, hypertension or cirrhosis and because of the 

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nephrotoxicity of immunosuppressive drugs, especially calcineurin inhibitors. In this 
sense, a TDF-free cART regimen would be desirable in the post-transplant period. 
Spanish guidelines consider ABC/3TC plus an integrase inhibitor to be a preferable 
combination for kidney transplant recipients because it does not affect renal function 
[12].  
However, there are no published clinical data supporting this suggestion. 
Dolutegravir (DTG) is a novel QD integrase inhibitor approved by FDA and EMA 
both for antiretroviral-naïve and treatment-experienced patients. It is metabolized 
mainly by the UGTA1 liver enzyme and, only in a small percentage (less than 10%), 
by CYP3A4. For these reasons, it is expected to have a favorable drug-drug 
interaction profile, at least comparable to RAL. DTG+3TC+TDF/ABC may become 
the standard of care for HIV-infected SOT recipients because of its low drug-drug 
interaction potential, its high barrier to resistance (higher than RAL) and its 
convenience (QD vs. BID for RAL). 
 
 
 

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4.1 HYPOTHESIS 
 
1. DTG is safe and effective in HIV- infected SOT treatment. 
 
2. DTG has few PK interactions with commonly used immunosuppressant drugs. 
 
3. ABC/3TC NRTI backbone leads to a better safety profile, especially in terms renal 
safety, compared with TDF/FTC in HIV-infected SOT recipients.  
 
 
4.2 REFERENCES 
1 
Polak WG, Gładysz A. Solid organ transplantation and HIV infection. Ann 
Transplant 2003; 8:16–21. 
2 
Huprikar S. Solid organ transplantation in HIV-infected individuals: an update. 
Rev Med Virol 2009; 19:317–323. 
3 
Roland ME, Stock PG. Solid organ transplantation is a reality for patients with 
HIV infection. Curr HIV/AIDS Rep 2006; 3:132–138. 
4 
Miro JM, Montejo M, Castells L, Rafecas A, Moreno S, Aguero F, et al. 
Outcome of HCV/HIV-coinfected liver transplant recipients: a prospective and 
multicenter cohort study. American journal of transplantation : official journal of 
the American Society of Transplantation and the American Society of 
Transplant Surgeons 2012; 12:1866–1876. 
5 
Trullas JC, Cofan F, Tuset M, Ricart MJ, Brunet M, Cervera C, et al. Renal 
transplantation in HIV-infected patients: 2010 update. Kidney Int 2011; 79:825–
842. 
6 
Castel MA, Pérez-Villa F, Roig E, Miró JM. [Heart transplantation in an HIV-1-
infected patient with ischemic cardiomyopathy and severe pulmonary 
hypertension]. Rev Esp Cardiol 2011; 64:1066–1067. 
7 
van Maarseveen EM, Rogers CC, Trofe-Clark J, van Zuilen AD, Mudrikova T. 
Drug-drug interactions between antiretroviral and immunosuppressive agents in 
HIV-infected patients after solid organ transplantation: a review. AIDS Patient 
Care STDS 2012; 26:568–581. 
8 
Powderly WG. Integrase inhibitors in the treatment of HIV-1 infection. J 
Antimicrob Chemother 2010; 65:2485–2488. 

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9 
Tricot L, Teicher E, Peytavin G, Zucman D, Conti F, Calmus Y, et al. Safety and 
efficacy of raltegravir in HIV-infected transplant patients cotreated with 
immunosuppressive drugs. American journal of transplantation : official journal 
of the American Society of Transplantation and the American Society of 
Transplant Surgeons 2009; 9:1946–1952. 
10 Wyatt CM. Antiretroviral therapy and the kidney. Top Antivir Med 2014; 22:655–
658. 
11 Post F. Adverse events: ART and the kidney: alterations in renal function and 
renal toxicity. J Int AIDS Soc 2014; 17:19513. 
12 Ligtenberg G, Hené RJ. Cardiovascular risk factors in renal transplant patients: 
cyclosporin A versus tacrolimus. Journal of the American Society of Nefrology. 
2001; 12:268-93.  
13 Nicolau-Raducu R, Gitman M, Ganier D, Loss GE, Cohen AJ, Patel H, et al. 
Adverse cardiac events after orthotopic liver transplantation: a cross-sectional 
study in 389 consecutive patients. Liver Transpl 2015; 21:13–21. 
14 Sabin CA, Worm SW, Weber R, Reiss P, El-Sadr W, Dabis F, et al. Use of 
nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in 
HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. 
Lancet 2008; 371:1417–1426. 
15 Costagliola D, Lang S, Mary-Krause M, Boccara F. Abacavir and cardiovascular 
risk: reviewing the evidence. Curr HIV/AIDS Rep 2010; 7:127–133. 
16 EACS European AIDS Clinical Society. Guidelines. Version 8.0 Available at: 
http://www.eacsociety.org/files/guidelines_8_0-english_web.pdf (Accessed 12-
Jun-2016).  
17 Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the 
use of antiretroviral agents in HIV-1-infected adults and adolescents. 
http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/0. 
(Accessed 12-Jun-2016).  
18 UK GUIDELINES FOR KIDNEY AND PANCREAS TRANSPLANTATION IN 
PATIENTS 
WITH 
HIV. 
www.bts.org.uk. 
http://www.bts.org.uk/Documents/Guidelines/Active/DRAFT_UK%20Guidelines
%20for%20Kidney%20and%20Pancreas%20Transplantation%20in%20Patients
%20with%20HIV.pdf (accessed 18 Feb2015). 
19 Górriz JL, Gutierrez F, Trullas JC, Arazo P. Documento de consenso sobre el 
manejo de la patología renal en pacientes con infección por VIH. Nefrología  

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2014; 34 S2. 
 

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5 
TRIAL OBJECTIVE AND PURPOSE 
5.1 PRIMARY OBJECTIVES 
 
1. 
To 
obtain 
pharmacokinetic 
data 
on 
interactions 
between 
DTG 
and 
immunosuppressant 
drugs 
(Cyclosporine 
A, 
Tacrolimus, 
Syrolimus 
and 
Mycophenolic acid) in SOT recipients;  
 
2. To provide proof of principle data that DTG plus 2 NRTIs is safe and effective in 
HIV-infected SOT recipients.  
 
5.2 SECONDARY OBJECTIVES 
 
1. To assess the development of viral resistance in subjects experiencing virological 
failure;  
 
2. To assess the changes in CD4+ cell count in peripheral blood; 
 
3. To assess the changes in lipid profile (triglycerides, total, LDL- and 
HDL-cholesterol);  
 
4. To assess renal function in HIV SOT patients. 
 
 
6 
TRIAL DESIGN 
6.1 TYPE OF TRIAL 
Phase IV, single-center, open-label, single arm clinical trial. 
 
 
6.2 DESCRIPTION OF THE DESIGN 
 
Type of Study: Single‐arm clinical trial.  
 
Twenty HIV‐infected SOT recipients (10 liver transplant recipients, 8 renal transplant 
recipients and 2 heart transplant recipients) receiving TDF/FTC or ABC/3TC plus 
raltegravir (or other third drug) will be switched to DTG plus the same 2 NRTIs. 
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for the study. Whenever possible, the ABC+3TC combination will be the preferred 
NRTIs. All patients will be followed over 48 weeks from switching.  
 
 
To accomplish with the Primary Objectives:   
 
1. Pharmacokinetic (PK) studies: All SOT recipients will be proposed to perform 
RAL (or other antiretrovirals) and immunosuppressor drugs 24‐hour pharmacokinetic 
profiles before the switch, and DTG and immunosuppressor drugs 24‐hour 
pharmacokinetic profiles 2 weeks after switching. Patients already receiving 2NRTIs 
plus DTG will be proposed to perform only DTG and IS PK study. The aim is to 
detect any possible drug‐drug interactions between DTG and widely‐used 
immunosuppressant drugs (IS)  (Cyclosporine A , Tacrolimus, Syrolimus and 
Mycophenolic acid).  
 
Procedures:  
 
Patients will be electively admitted to the Hospital (Infectious Disease Service) 
during 24 hours approximately.  
 
1. A 24- hour PK will be performed.  
2. A peripheral venous line will be positioned by a trained nurse.  
3. RAL (or other ARV) or DTG as long as IS plasma concentrations before and 
at 0.5, 1, 2, 4, 8, 10, 12 and 24 hours after the ARV and IS administration will 
be determined.  
Three 10 mL EDTA tubes will be extracted at each timepoint.  
 
 
 
Safety and effectiveness of DTG in SOT setting and Secondary Endpoints ( see 
Section 8 for details) :  
 
• At w0, w12, w24, w36 and w48 physical examination, including blood 
pressure and wheight will be  performed.  
• At same timepoints the following parameters will be measured: 
 
- CD4+/CD8 T cell count  
- Plasma HIV-1 levels.  

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- Blood chemistry (including triglycerides, total, HDL‐ and 
LDL‐cholesterol and CK)                         
- Hematology                                                                                            
-Creatinine, eGFR (CKD‐EPI)  
- Basic urine profile, including glycosuria, proteinuria and 
creatinine/protein. 
 
In case of viral rebound (confirmed detectable viral RNA in 2 susequent determinations > 
50 cp/mL) a genotypic test and viral tropism will be performed.  
 
 
6.3 MEASURES TO AVOID BIAS 
6.3.1 Randomization 
Not applicable, since it is a single arm clinical trial. 
 
6.3.2 Stratification 
Not applicable, since it is a single arm clinical trial. 
 
6.3.3 Blinding 
Not applicable since it is an open clinical trial. 
 
6.4 FORESEEN CALENDAR 
- 
First patient first visit: August 2017 
- 
Inclusion period: 12 months 
- 
Follow-up period: At last 48 weeks (12 months)  
- 
Last patient last visit: August  2019 (End of study) 
- 
Final report submission: November,  2019 
 
6.5 END OF TRIAL 
 
Stopping rules will be based on the observation of an unexpected high proportion of 
individuals experiencing SAE or any grade ≥3 local or systemic events judged 
definitely or probably related to any of the study drugs administration.  
 

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If two or more study participants develop a clinically similar SAE or grade 3 local or 
systemic event, judged definitely, or probably related to the investigational medicinal 
products (IMP)s, a review by the Scientific Committee will be requested. The study 
will be suspended pending review of all safety data. Following this review, the 
Scientific Committee will make a recommendation to the Principal Investigator and 
Sponsor regarding continuation of the study. 
In addition, if more than 50% of participants withdraw from the Scientific Committee 
will discuss a premature stop of the trial.   
 
The date of the end of the trial will be to the last visit of the last patient. 
 
6.5.1 
Early study suspension 
 
If the study must be interrupted prematurely, all non-used materials should be 
returned to the sponsor. The principal investigator will keep the investigator file and 
the completed CRF. 
 
In case there were no patients included in the study, the sponsor will take care of all 
materials. 
 
6.6 SOURCE DATA 
 
Source documents are the patient's medical records including routine laboratory 
results obtained from blood tests. A scanned copy of all source documents will be 
included in the patient’s medical chart, when possible; in all cases, these source 
documents will be included in the investigator site file.  
 
Study data will be collected through the HIV database of the AIDS functional Unit.  
 

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All investigational results from analysis performed from stored samples (virological, 
immunological results as well as PK determinations) will be recorded in electronic 
databases. Once the trial is finished, all databases will be unified.  
 
Information regarding safety and tolerability will be reported by the physician in the 
patient’s electronic medical history, which will be reviewed by the attending physician 
for grading and assessment of causality/imputability.  
 

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7 
TRIAL INVESTIGATIONAL PRODUCT(S) 
7.1 TREATMENTS: SUPPLY, PACKAGING, LABELING AND STORAGE 
7.1.1 All investigational products will be stored at the Pharmacy Service of 
Hospital Clinic of Barcelona.  
 
7.2 DOSE, INTERVAL, ROUTE AND METHOD OF ADMINISTRATION 
 
The drugs under study will be administered orally. The daily doses will be: 
 
- Lamivudine 300 mg + Abacavir 600 mg + dolutegravir  50 mg / 24h (Triumeq®), 1 
tablet once daily; -  
 
-Emtricitabine 200 mg/Tenofovir 245mg (Truvada®, 1 tablet once daily) 
- Dolutegravir 50 mg (Tivicay®, 1 tablet once daily) 
 
 
7.3 DRUG ACCOUNTABILITY 
During the study, an accountability log, dispensing log and log of used boxes will be 
kept for all IMPs. These logs will be monitored according to Good Clinical Practice 
(GPC) guidelines.  
 
Labeling of investigational medicinal drug will be done in according to applicable 
regulations (Directive 2003/94/CE, annex 13 GMP).  
 
Sample of the label: 
 
Código Protocolo: DGT-SOT 
Nº EudraCT: 2017-000469-62 
Promotor: Fundació Clinic per a la Recerca Biomèdica 
Investigador principar: JM Miró 
Contiene:  príncipio activo / (dosificación) mg 
Nombre comercial/ vía oral  / comprimidoss 
Código paciente:_____ 
Lote nº Y fecha de caducidad (consultar en la caja) 
Conservar a temperatura ambiente y fuera del alcance de los niños  
Solo uso en ensayo clínico 
 
 

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7.4 CONCOMITANT TREATMENTS 
 
7.4.1 Other treatments 
 
All participants will be discouraged to initiate any concomitant treatment without the 
knowledge and permission of the investigator. Patients will be discouraged of taking 
strong 
CYP3A4 
inhibitors 
(ritonavir, 
cobicistat, 
atazanavir, 
ketoconazole, 
itraconazole, voriconazole, clarithromycin, telithromycin) or CYP3A4 inducers 
(nevirapie, efavirenz, etravirine, rifampicin, rifabutin, carbamazepine, phenytoin, 
phenobarbitalk, St. John’s Worth). 
 
 
7.5 COMPLIANCE 
 
Antiretroviral treatment adherence will be self-reported. No pill count will be 
performed to assess compliance.  
  
 
 

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8 
SELECTION AND WITHDRAWAL OF SUBJECTS (INCLUSION/EXCLUSION 
CRITERIA) 
 
 
8.1 INCLUSION/EXCLUSION CRITERIA 
 
 
 Inclusion criteria:     
                                                                               
1. HIV patients >18 years old who provide signed and dated informed consent;         
2. Males and females;     
3. SOT recipients (heart, liver or kidney); 
4. On stable ART for ≥6 months preceding the screening visit;  
5. Plasma HIV RNA <50 cop/ml for 12 months (2 tests separated by at least 12 
months with no viral load >50 between determinations); 
6. Negative HLA B5701 in recipient (and donor, if available); 
7. Absence of major reverse transcriptase or integrase gene mutations affecting 
study drug efficacy by proviral DNA sequencing.    
 
Exclusion criteria:         
1. HIV patients who have stopped ART due to virological failure;  
2. HIV patients who require treatment with DTG contraindicated medications (i.e., 
current treatment with rifampin, phenytoin, phenobarbital, carbamazepine, 
oxcarbazepine);  
3. History or presence of an allergy or intolerance to the study drug; 
4. Active opportunistic infection;  
5. Neoplasms requiring chemotherapy;   
6. Pregnancy or breast feeding or planned pregnancy during the study period         
7. Any other contraindication to study drugs. 
 
* Female subjects of childbearing potential must not be pregnant, not be planning a 
pregnancy or breast-feeding. Sexually active women must be willing to use two 
approved methods of contraception (including condoms, diaphragm, spermicides, 
hormonal methods and/or intrauterine devices) from screening until 28 days after 
last immunization. Sexually active men in heterosexual relationships must be willing 

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to use two approved method of contraception with their partners from screening until 
28 days after last immunization. 
 
8.2 SUBJECT WITHDRAWAL CRITERIA 
 
8.2.1 
Related to Dolutegravir-containing regimens 
 
 
Any individual for who is being considered for discontinuation or postponement of 
vaccinations will be discussed with the trial team.  
 
• Ineligibility (either arising during the study or retrospective having been 
overlooked at screening). 
• A disease, condition or an adverse event (including clinically significant 
abnormal laboratory values; see below) that develops, regardless of 
relationship to the study products, if, in the opinion of the principal investigator 
or designee, further vaccinations would jeopardize the safety of the patient.  
• Hematology 
 Hemoglobin < 8.0 g/dl 
 Absolute Neutrophil Count (ANC) ≤ 1000 /mm3 (≤ 1 x 109 /l) 
 Absolute Lymphocyte Count (ALC) ≤ 500 /mm3 (≤ 1 x 109 /l) 
 Platelets ≤ 50.000 /mm3, ≥ 550,000 /mm3 (≤ 50 /L, ≥ 550 /l) 
 
• Biochemistry 
 Creatinine > 1.5 x ULN 
 AST > 5 x ULN 
 ALT > 5x ULN 
 
• Pregnancy. 
• Significant non-compliance with cART regimen or study requirements. 
• A serious adverse event judged to be possibly, probably or definitely 
related to vaccination. 
• An adverse event which requires discontinuation of the study product or 
results in inability to continue to comply with study procedures. 

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• Loss to follow up. 
• The safety of the volunteer would be jeopardized in the opinion of the 
investigator or sponsor. 
• Investigator discretion. 
• Significant protocol deviation. 
• Disease progression, including virological failure (defined as a rebound in 
at least two consecutive determinations of pVL > 2,000 copies/ml after 
suppression), which requires discontinuation or modification of the study 
medication or results in inability to continue to comply with study procedures.  
• Consent withdrawn. 
 
8.2.2 
Early subject withdrawal 
 
The patients will complete the clinical study before the stipulated time in the 
following circumstances:  
 
 
Concurrent process or illness which in the opinion of the investigator requires 
the withdrawal of the patient. 
 
 
Protocol deviation which in the opinion of the sponsor requires the withdrawal 
of the patient. 
 
 
The patient does not wish to continue in the study. 
 
 
Other 
 
8.2.3 
Medical approach to withdrawal 
 
In all cases, ‘end of study form’ is to be filled. Detailed information will be given 
about the date and reasons of the discontinuation to the sponsor. The investigator 
will facilitate the necessary medical support to the patient. 
 

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8.2.4 
Follow-up after early withdrawal 
 
That is, as a general rule, all patients who discontinue treatment prematurely will 
undergo a clinical examination and all tests specified in the visit.  
 
In case early withdrawal happens while patient is receiving IMP, a follow-up of 28 
days after the last IMP dose will be performed for AEs collection.  
 

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9 
TRIAL CONDUCTION AND RESPONSE EVALUATION 
 
 
Clinical Procedures:  Physical examination, assessment of adverse events, and 
adherence to treatment at each study visit. 
 
Laboratory Tests:      
 
- Proviral HIV DNA sequencing before switching therapy: w0 
- Plasma HIV RNA: w0, w4, w12, w24, and w48. HIV RNA will be 
monitored in a central laboratory                 
- Resistance testing: Any patient with a viral load above 50 copies/mL 
will have an attempted phenotype/genotype testing on day 1 (first day 
with a viral load >50 copies/mL) and at the time of confirmed failure 
samples 
(including 
those 
with 
<400 
c/mL)                      
                                     
- CD4+ cell count at w0, w12, w24, w36 and w48 
- Blood 
chemistry 
(including 
triglycerides, 
total, 
HDL‐ 
and 
LDL‐cholesterol)                         
- Hematology                                                                                            
-Creatinine, eGFR (CKD‐EPI)  
- 
Basic 
urine 
profile, 
including 
glycosuria, 
proteinuria 
and 
creatinine/protein. 
- RAL and immunosuppressant 24‐hour PK profile before the switch, 
and DTG and immunosuppressant 24‐hour pharmacokinetic profile 2 
weeks after switching in SOT recipients. 
 
 
9.1 LONG-TERM FOLLOW-UP 
After end-of-study, participants will continue with cART and return to standard 
clinical care in consultation with their doctor, in HIV units from HGTIP and HC. All 
participants will be followed-up annually for 5 years in regards to: 
 
- Safety 
- HIV related information 
 
 

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9.2 PROCEDURES FOR EVALUATION OF RESPONSE 
9.2.1 
Clinical record and physical exam 
 
Demographic and HIV infection-related data will be collected in order to characterize 
the study population (sex, age, time since HIV transmission to treatment initiation, 
Fiebig stage at HIV diagnosis, risk factor and history of opportunistic infections or 
tumors). 
 
Appearance of clinical adverse events will be recorded all over the study. A 
complete physical examination will be performed at the baseline visit, including 
weight and height. In the follow-up visits, a physical exam will be performed following 
schedule described in attachment J (Schedule of procedures). 
 
9.2.2 
Laboratory tests 
Patients will fast for at least 8 hours prior to assessment, in the points specified in 
the schedule of procedures of the study (attachment J), except for RMD1 
assessment that will be performed in the evening previous RMD1 administration. 
The following parameters will be quantified, as needed: 
 
 
Hematology: 
Hematocrit 
Red blood cell count 
Hemoglobin 
Leucocytes 
Lymphocyte  
Platelet count 
 
 
Blood biochemistry:  
Glucose 
Urea  
Creatinine 
Ionogramme: sodium, potassium 
Total Bilirubin 
Total protein 

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Albumin 
Liver 
enzymes: 
aspartate 
aminotransferase 
(AST), 
alanine 
aminotransferase (ALT), gamma-GT, alkaline phosphatase 
Estimated glomerular filtration rate (CKD-EPI) 
Creatinin Kinase (CK) 
 
Lipid profile: Triglycerides, Cholesterol (HDL, LDL and total)  
 
Extra ions: Magnesium, phosphate and calcium  
 
 
 
 
Pregnancy test in women (test strip) 
 
 
Immunology: 
CD4 lymphocytes count 
CD4 lymphocytes percentage 
CD8 lymphocytes count  
CD8 lymphocytes percentage. 
 
           Virology.: Viral Load  (HIV-RNA) 
 
 
 
Note: Before the beginning of the study, all labs will facilitate to the sponsor 
and to the investigator a list of the reference normal values of the parameters 
assessed. 
 
 
Specific Lab Procedures 
 
Laboratory techniques used for PK: 
 
CsA and MPA levels will be determined by immunoassay (EMIT200, Siemens).  
TAC and sirolimus (or everolimus) whole blood concentrations FK levels will be 
determined using a validated ultra-High performance liquid chromatography–tandem 
mass spectrometry analytical method 
chemiluminescent microparticle immunoassay (ARCHITECT i 2000 SR, Abbott).  
 
RAL  plasma levels will quantified by a validated method of liquid chromatography 
coupled with fluorescence detection after liquid-liquid extraction.and  
 

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DTG Plasma concentrations will be analyzed by liquid chromatography coupled with 
Triple quadrupol mass spectrometer detection after liquid-liquid extraction. The lower 
limit of quantification  and the higher limit of quantification for DTG are  20 ng/mL 
and 
20.000 
ng/mL, 
respectively.plasma 
levels 
will 
quantified 
by 
liquid 
chromatography coupled with fluorescence detection after liquid-liquid extraction. 
 

  
 
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Schedule of programmed clinical and laboratory evaluation  
 
 
Week 
-2 
Selection 
0 
Enrollment 
4 
12 
24 
48 
Clinical assesment 
√ 
√ 
√ 
√ 
√ 
√ 
B/C events 
√ 
 
 
 
 
 
Adherence  
 
√ 
√ 
√ 
√ 
CD4+ / CD8+ 
√ 
√ 
√ 
√ 
√ 
√ 
Viral Load  (HIV-RNA) 
√ 
√ 
√ 
√ 
√ 
√ 
Hematology 
√ 
√ 
√ 
√ 
√ 
√ 
Biochemistry 
√ 
√ 
√ 
√ 
√ 
√ 
Total, LDL, HDL and Tryglicerids,  
√ 
√ 
√ 
√ 
Plasma 
Creatinine 
CPK 
and 
Seric 
Phosfate 
√ 
√ 
√ 
√ 
√ 
√ 
Proviral 
Genotyping 
(if 
not
previously performed) 
√ 
Genotipic 
resistance 
test 
and viral
tropism 
Viral Rebound 
Adverse events 
√ 
√ 
√ 
√ 
PK Studies * (selected patients) 
24-hour admisión for pk studies before and 2 weeks after 
treatment switching 

  
 
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10 ADVERSE EVENTS 
10.1 DEFINITION 
Adverse event: (AE) Medical event presented by a patient or clinical research 
subject administered a pharmaceutical product, and which does not necessarily 
have a causal relation to the treatment. 
  
Serious adverse event: (SAE) Medical event classified as such and which, 
regardless of the dose involved: 
 
 
causes patient death, 
 
produces a life-threatening situation for the patient, 
 
requires or prolongs in hospital admission, 
 
produces important or persistent incapacitation/handicap, or constitutes a 
congenital defect or anomaly, 
 
needs action to prevent any of above situations. 
 
is considered medically significant 
 
Examples of such events are intensive care in an Emergency Service or in the home 
in a patient with allergic bronchospasm; blood dyscrasias or seizures not giving rise 
to hospital admission, or the development of drug dependency or abuse.  
 
Unexpected adverse event: (UAE) AE related to the product in investigation the 
nature or intensity of which does not coincide with the information available on the 
product administered (IB or SmPC). 
 
Serious unexpected adverse reaction: (SUSAR) SAE related to the product in 
investigation the nature or intensity of which does not coincide with the information 
available on the product administered (IB or SmPC). 

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10.2 MONITORING, RECORDING AND REPORTING OF ADVERSE EVENTS 
An AE is any noxious, unintended, or untoward medical occurrence that may appear 
or worsen in a subject during the course of a study. It may be a new intercurrent 
illness, a worsening concomitant illness, an injury, or any concomitant impairment of 
the subject’s health, including laboratory test values (as specified by the criteria 
below), regardless of etiology. Any worsening (i.e., any clinically significant adverse 
change in the frequency or intensity of a pre-existing condition) should be 
considered an AE. A diagnosis or syndrome should be recorded on the AE page of 
the CRF rather than the individual signs or symptoms of the diagnosis or syndrome.  
 
An overdose, accidental or intentional, whether or not it is associated with an AE, or 
abuse, withdrawal, sensitivity or toxicity to an investigational product should be 
reported as an AE. If an overdose is associated with an AE, the overdose and AE 
should be reported as separate terms. 
 
All subjects will be monitored for AEs during the study. Assessments may include 
monitoring of any or all of the following parameters: the subject’s clinical symptoms, 
laboratory, pathological, radiological or surgical findings, physical examination 
findings, or other appropriate tests and procedures. 
 
All AEs will be recorded by the Investigator from the time the subject signs informed 
consent until the last study visit or to 28 days after the last dose of IMP in case of 
early withdrawal while patient is receiving IMP. AEs and SAEs will be recorded on 
the AE page of the CRF and in the subject’s source documents. All SAEs must be 
reported to the Sponsor (see contact details at the end of the paragraph) within 24 
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method, using the SAE Report Form (attachment N, can be found in the 
Investigator’s File), or approved equivalent form. 
 
 
10.3 DOCUMENTATION RELATED TO AE AND SAE 
Each AE and SAE to take place during the study should be documented in the 
medical records of the patient in accordance with standard clinical practice of the 
researcher, and in the CRF. For each SAE, an independent set of SAE form will be 
used independently. Only if there are multiple SAE at the time of the initial report 
and these are temporary and / or clinically interrelated can be registered on the 
same set of SAE form. 
 
 
The researcher should try to make a diagnosis of the event based on the signs, 
symptoms and / or other clinical information. An AE diagnosis has to be recorded 
per line or a sign/symptom if the diagnosis is not available. If a diagnosis 
subsequently becomes available, this then should be entered and the sign/symptom 
crossed out, initialed and dated by the investigator.  
 
SAE pages found in the investigator’s file shall be completed as precisely as 
possible, printed and shall be signed by the investigator before being sent to the 
sponsor. It is very important that the initial page SAE researcher provide its opinion 
in regard to the relationship of the event to the study drug. 
 
 
10.4 EVALUATION OF ADVERSE EVENTS 
A qualified Investigator will evaluate all AEs as to:  
 
10.4.1 Seriousness  
A SAE is any AE occurring at any dose that: 

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 
Results in death; 
 
 
Is life-threatening (i.e., in the opinion of the Investigator, the subject is at 
immediate risk of death from the AE); 
 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of 
stay); 
 
 
Results in persistent or significant disability/incapacity (a substantial 
disruption of the subject’s ability to conduct normal life functions); 
 
 
Is a congenital anomaly/birth defect; 
 
 
Constitutes an important medical event. 
 
Important medical events are defined as those occurrences that may not be 
immediately life threatening or result in death, hospitalization, or disability, but may 
jeopardize the subject or require medical or surgical intervention to prevent one of 
the other outcomes listed above. Medical and scientific judgment should be 
exercised in deciding whether such an AE should be considered serious. 
 
Events not considered to be SAEs are hospitalizations for: 
 
 
A standard procedure for protocol therapy administration. However, 
hospitalization or prolonged hospitalization for a complication of therapy 
administration will be reported as an SAE.  
 
 
Routine treatment or monitoring of the studied indication not associated with 
any deterioration in condition. 
 
 
A procedure for protocol/disease-related investigations (e.g., surgery, scans, 
endoscopy, sampling for laboratory tests, bone marrow sampling). However, 
hospitalization or prolonged hospitalization for a complication of such 
procedures remains a reportable SAE. 
 
 
Hospitalization or prolongation of hospitalization for technical, practical, or 
social reasons, in absence of an AE. 
 

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 
A procedure that is planned (i.e., planned prior to starting of treatment on 
study); must be documented in the source document and the CRF. 
Hospitalization or prolonged hospitalization for a complication remains a 
reportable SAE. 
 
 
An elective treatment of a pre-existing condition unrelated to the studied 
indication.  
 
 
Emergency outpatient treatment or observation that does not result in 
admission, unless fulfilling other seriousness criteria above. 
 
If an AE is considered serious, both the AE page/screen of the CRF and the SAE 
Report Form must be completed. 
 
For each SAE, the Investigator will provide information on severity, start and stop 
dates, relationship to IP, action taken regarding IP, and outcome. 
 
10.4.2 Severity / Intensity 
For both AEs and SAEs, the Investigator must assess the severity / intensity of the 
event.  
 
Intensity will be assessed by the investigator using the following terms according to 
the Division of AIDS table for grading the severity of adult and pediatric adverse 
events (Attachment O):  
 
 
Grade 1 = Mild  
 
 
Grade 2 = Moderate  
 
 
Grade 3 = Severe  
 
 
Grade 4 = Life threatening  
 
 
Grade 5 = Death 
 

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The term “severe” is often used to describe the intensity of a specific event (as in 
mild, moderate or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe headache). This criterion is not 
the same as “serious” which is based on subject/event outcome or action criteria 
associated with events that pose a threat to a subject’s life or functioning.  
 
Seriousness, not severity, serves as a guide for defining regulatory obligations. 
 
10.4.3 Causality  
The causal relation will be established according to the algorithm of the Spanish 
Pharmacovigilance System, which contemplates the following categories: 
 
Definitive: 
 
A plausible time sequence exists in relation to administration of the drug or its 
plasma or tissue concentrations. 
 
The observed manifestation coincides with the known adverse reactions 
profile of the implicated drug. 
 
The event cannot be explained by the concurrent disease or by other drugs or 
chemical substances. 
 
Response to withdrawal must be clinically plausible, i.e., the condition 
improves on discontinuing administration of the drug. 
 
A positive response to repeat exposure is observed. 
 
Probable: 
 
A reasonable time sequence exists in relation to administration of the drug. 
 
The observed manifestation coincides with the known adverse reactions 
profile of the implicated drug. 
 
The event is unlikely to be explained by the concurrent disease or by other 
drugs or chemical substances. 
 
Response to withdrawal is clinically plausible, i.e., the condition improves on 
discontinuing administration of the drug. 
 
No repeat exposure is required to complete this definition. 
 
Possible: 
 
A reasonable time sequence exists in relation to administration of the drug. 
 
The observed manifestation coincides with the known adverse reactions 
profile of the implicated drug. 

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 
The event might be attributable to the clinical condition of the patient or to 
other concomitantly administered drugs or chemical substances. 
 
Information concerning drug withdrawal may be unavailable or confusing. 
 
Improbable:  
 
A clinical event, including anomalous laboratory test findings, with a time 
relation to administration of the drug which makes a causal association 
unlikely, and where other drugs, chemical substances or intercurrent disease 
afford plausible explanations for the observed event. 
  
Unrelated: 
 
None of the above criteria are met. 
10.4.4 Duration 
For both AEs and SAEs, the Investigator will provide a record of the start and stop 
dates of the event. 
 
10.4.5 Action Taken 
The Investigator will report the action taken with IMP as a result of an AE or SAE, as 
applicable (e.g., discontinuation or reduction of IMP, as appropriate) and report if 
concomitant and/or additional treatments were given for the event.  
 
10.4.6 Outcome 
 
SAE will be followed preferably until: 
 
Resolution of the event; 
 
Stabilization of the event; or 
 
Resetting the baseline situation of the event, in case baseline situation is 
available. 
 
Otherwise, they will continue until: 
 
The event can be attributed to products other than the study medication or 
factors unrelated to the study; or 
 
It is unlikely to obtain further information. 
 
 

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10.5 ABNORMAL LABORATORY VALUES 
An abnormal laboratory value is considered to be an AE if the abnormality: 
 
 
results in discontinuation from the study; 
 
 
requires treatment, modification/ interruption of IP dose, or any other 
therapeutic intervention; or 
 
 
is judged to be of significant clinical importance. 
 
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness 
criterion need to be documented as a serious adverse event.  
 
If a laboratory abnormality is one component of a diagnosis or syndrome, then only 
the diagnosis or syndrome should be recorded on the AE page/screen of the CRF. If 
the abnormality was not a part of a diagnosis or syndrome, then the laboratory 
abnormality should be recorded as the AE. 
 
Liver Chemistry Stopping and Follow up Criteria  
 
Liver chemistry threshold stopping criteria have been designed to assure subject 
safety and to evaluate liver event etiology during administration of IP and the follow-
up period. IP will be stopped if any of the following liver chemistry criteria are met:  
 
• ALT ≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin; bilirubin fractionation 
required)  
• NOTE: serum bilirubin fractionation should be performed if testing is 
available. If testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. If testing is 
unavailable and a subject meets the criterion of total bilirubin ≥ 2xULN, then the 
event meets liver stopping criteria;  
 
• ALT ≥8xULN; 
 
• ALT ≥3xULN (if baseline ALT is < ULN) with symptoms or worsening of acute 
hepatitis or hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, or eosinophilia, OR;  
 

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• ALT ≥3x baseline ALT with symptoms or worsening of acute hepatitis or 
hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, or eosinophilia;  
 
• ALT ≥5xULN and 2 weeks (with bilirubin 2 weeks; Subjects who develop ALT 
≥5xULN should be followed weekly until resolution or stabilization (ALT <5xULN on 2 
consecutive evaluations). 
  
When liver chemistry stopping criterion is met, do the following: 
 
• Immediately discontinue DTG and withdraw the subject from the study. 
Subjects should not restart DTG due to the risk of a recurrent reaction. 
 
• Report the event to the study Sponsor within 24 hours of learning its 
occurrence (see 
• [See Section 10.7  Expedited Reporting of Adverse Events).  
• Complete the liver event CRF and SAE CRF, where applicable, (see Section 
 10.7.3 Reporting by Sponsor to ViiV Healthcare).  
• Complete the liver imaging and/or liver biopsy CRFs if these tests are 
performed; 
• Perform liver event follow up assessments (described below), and monitor the 
• subject until liver chemistries resolve, stabilize, or return to baseline values as 
• described below; 
• Make every reasonable attempt to have subjects return to clinic within 24 
hours for 
• repeat liver chemistries, liver event follow up assessments (see below), and 
close monitoring; 
• A specialist or hepatology consultation is recommended; 
• Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
• phosphatase, bilirubin) resolve, stabilize or return to within baseline values; 
 
Consider the following additional tests to further evaluate the liver event: 
 
1. 
Viral hepatitis serology including: 
• Hepatitis A IgM antibody; 
• HBsAg and Hepatitis B Core Antibody (IgM) and DNA; 
• Hepatitis C RNA; 
• Hepatitis E IgM antibody and RNA; 
• Cytomegalovirus IgM antibody and DNA; 
• Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing and DNA); 
 
2. Syphilis screening 

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3. Drugs of abuse screen including alcohol 
 
4. Serum acetaminophen test (APAP adduct test) 
 
5. Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH); 
 
6. Fractionate bilirubin, if total bilirubin is greater than 1.5xULN; 
 
7. Obtain complete blood count with differential to assess eosinophilia; 
8. Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver 
kidney microsomal antibodies; 
 
9. Liver imaging (ultrasound, magnetic resonance, or computerized tomography) 
to evaluate liver disease; 
 
10. Record the appearance or worsening of clinical symptoms of hepatitis, or 
hypersensitivity, fatigue, decreased appetite, nausea, vomiting, abdominal 
pain, jaundice, fever, or rash as relevant on the AE report form; 
 
11. Record use of concomitant medications, acetaminophen, herbal remedies, 
other over the counter medications, or putative hepatotoxins, on the 
concomitant medications report form. Record alcohol use on the liver event 
alcohol intake case report form. 
 
10.6 ALLERGIC REACTIONS 
 
Subjects may continue investigational product(s) for Grade 1 or 2 allergic reactions 
at the discretion of the Investigator. The subject should be advised to contact the 
Investigator immediately if there is any worsening of symptoms or if further systemic 
signs or symptoms develop. Antihistamines, topical corticosteroids, or antipruritic 
agents may be prescribed. 
 
Subjects with Grade ≥3 allergic reactions that are considered to be possibly or 
probably related to the investigational product(s) should permanently discontinue the 
investigational product regimen and the subject should be withdrawn from the study. 
Subjects should be treated as clinically appropriate and followed until resolution of 
the AE. 
 
If ABC- containing products will be regularly used as background ART, then subjects 
should be managed in terms of a clinically suspected ABC hypersensitivity reaction. 
 

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10.7 EXPEDITED REPORTING OF ADVERSE EVENTS 
10.7.1 Reporting to Regulatory Authorities and the Ethics Committee 
The sponsor will inform the Spanish Medicines Agency (Ministry of Health), the 
competent authorities of the autonomous region and the Ethics Committees 
implicated in the clinical trial about any important information of security of the IMPs. 
 
The sponsor will inform the Spanish Medicines Agency (Ministry of Health) of any 
SUSAR which may be related to the study treatment. 
 
The sponsor will inform competent authorities of the implicated autonomous region 
of any SUSAR which may be related to the study treatment, and that have been 
happened in patients in its autonomous region. 
 
The sponsor will inform the Ethics Committee of any SUSAR which may be related 
to the study treatment, and that have been happened in patients included in its 
sphere of action. 
 
The Sponsor will inform relevant Regulatory Authorities and Ethics Committees; 
 
 
Of all relevant information about SUSAR that are fatal or life-threatening as 
soon as possible and in any case no later than 7 days after knowledge of 
such a case. Relevant follow-up information for these cases will be 
subsequently be submitted within an additional eight days 
 
 
Of all other SUSAR as soon as possible, but within a maximum of 15 days of 
first knowledge by the investigator. 
 
 

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10.7.2 Immediate reporting by Investigator to Sponsor  
The investigator will inform the Sponsor of all SAEs within 24 hours in order that the 
sponsor can fulfill their regulatory reporting obligations within the required 
timeframes. 
 
Contact details for Sponsor 
 
CTU-Clinical Trial Unit  
C/ Rosselló, 138, bajos y  
C/Mallorca 183.  
Tel: 93 227 9877 e-mail:acruceta@clinic.ub.es. FAX 932279877 
10.7.3 Reporting by Sponsor to ViiV Healthcare 
 
The Sponsor will supply ViiV Healthcare with a copy of all SAEs which involve 
exposure to Dolutegracvir within 24 hours of being made aware of the event 
regardless of whether or not the event is listed in the reference document (e.g. IB, 
SmPC) and with a copy of the annual periodic safety report e.g. Development 
Update Safety Report (DSUR) at the time of submission to the Regulatory Authority 
and Ethics Committee. 
Contact details for ViiV Healthcare:  
GSK’s Case management Group: Fax +44.20-8754-7822 . 
 
10.7.4 Reporting by Sponsor to Coordinating investigator  
The Sponsor will inform the Coordinating investigator of all SAEs within 24 hours in 
order that the Coordinating investigator can call the scientific committee to assess 
trial stopping rules. 
 
Contact details for Coordinating investigator 
 
Jose M. Miro Meda (PI), MD, PhD,  Consultant, Infectious Diseases Service, 
Hospital Clínic/IDIBAPS, University of Barcelona, Barcelona, Spain 
 

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Villarroel, 170, 08036 Barcelona, Tel. 93 227 5430, Fax: 93 227 9877 E-mail: 
jmmiro@ub.edu 

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11 STATISTICS 
Statistical Analysis Plan  (JO) 
The number of cases to perform the DDI studies range between 5 and 10. For the 
efficacy and safety study, since this is an exploratory single-arm clinical trial there is 
no formal power calculation. although 20 patients will be included in the study 
To assess the effects of DTG on the pharmacokinetics of immunosuppressant drugs 
(Cyclosporine A, Tacrolimus, Syrolimus and Mycophenolic acid), the 90% CI for the 
geometric mean of the test (after drug administration with DTG)/reference (before 
drug administration with DTG) ratio for the parameters Cmax, Cmin, Tmax and AUC 
were computed using two one-sided t tests. 
The changes are expressed as mean (standard deviation) or median [interquartile 
range] according to normal and non normal distributions. To assess intragroup 
changes, we were used repeated measures t-test or Wilkoxon signed rank test, as 
appropriated. 
To assess the efficacy and safety of dolutegravir-based antiretroviral treatment, a 
descriptive analysis will be performed, showing the the proportion of patients with 
plasma VL<50 copies at 24 and 48 weeks, the median (IQR) CD4 T cell counts at 
the same time points and the proportion of patients who needed to stop dolutegravir 
due to WHO grade III or IV adverse events.  
 

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12 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
Researchers and institutions will allow the monitoring, and audits by the Health 
Authorities or the Sponsor giving direct access to data and original source 
documents. 
 
Access to personal patient information will be restricted to the Study physician / 
staff. To allow monitoritings, audits and inspections, access to data to Health 
Authorities (Spanish Agency for Medicines and Health Products), the Ethics 
Committee and personnel authorized by the Sponsor, is guaranteed while 
maintaining the confidentiality thereof according to current legislation. 

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13 QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 STUDY MONITORING 
In accordance with applicable regulations and Good Clinical Practice (GCP), the 
monitor will visit or contact the center on a regular basis. The duration, nature and 
frequency of visits / contacts depend on the monitoring plan. 
 
During these contacts, the monitor shall: 
 
 
monitor and evaluate the progress of the study; 
 
examining the data collected; 
 
carry out a verification of the source documents; 
 
identify any problems and find solutions; 
 
The goal of the monitoring activity is to verify that: 
 
 
the rights and welfare of subjects are respected; 
 
survey data are accurate, complete and verifiable with the help of original 
documents; 
 
the study is performed according to the protocol and any amendment 
adopted, GCPs and regulations. 
 
The investigator must agree to: 
 
 
grant to monitor direct access to all relevant documentation; 
 
devote part of his/her time and staff time to the monitor in order to discuss the 
results of the monitoring, as well as any other possible aspect. 
 
The monitor should also contact the center before starting the study with the aim to 
discuss with staff the Protocol and procedures for data collection. 
 
13.2 AUDITS AND INSPECTIONS 
Sponsor can carry out an audit of quality control at its sole discretion. In this case, 
the investigator should agree to grant the auditor direct access to all relevant 
documentation and devote part of his/her time and staff time to the auditor in order 
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Moreover, regulatory authorities may also inspect the study. In this case, the 
investigator should agree to give the inspector direct access to all relevant 
documentation and devote part of his/her time and staff time to the inspector in 
order to discuss the results of the supervision, as well as any other possible aspect. 
 
13.3 CASE REPORT FORM 
Data collection will be done through an electronic Medical History with a system of 
access by username and password. The application has track changes (recording 
the user that has performed). 
 
Accurate and reliable data collection is ensured by checking and cross checking the 
Medical History front site records conducted by the study monitor (verification of 
source documents). The data collected will be added to a computer database which 
will be reviewed for possible inconsistencies to be resolved by the research team of 
the study in site. 
 
 
13.4 ALLOCATION PARTICIPANT IDENTIFICATION CODES 
 
All participants will be assigned with a code that will allow the patient to be identified. 
The patient code will be assigned correlative at the inclusion of the study (program 
code centralized, formed by letters and numbers)  

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14 ETHICS 
14.1 GENERAL CONSIDERATIONS 
The study will be performed in accordance with the local national laws (Royal 
Decree 1090/2015), the guidelines of the International Conference on Harmonization 
(ICH), and the guidelines of the Declaration of Helsinki adopted by the 18th World 
Medical Assembly in Helsinki, Finland in 1964 and amended by subsequent 
assemblies (last in Fortaleza, Brazil in 2013.  
This study will be conducted according to Spanish regulations and the required 
documentation prior to the start will be: 
 
 
Protocol acceptance by the sponsor and the coordinating investigator  
 
Protocol approval by the Ethics Committee. 
 
Protocol authorization from the Spanish Drug Agency (Ministry of Health) 
 
Approval by the Direction of the Institution 
 
All subjects will be guaranteed continued medical and nursing supervision 
throughout the duration of the study. 
 
This study will conform to the standards of "Good Clinical Practice". 
 
Also, following the “Good participatory practice guidelines” (published by the Joint 
United Nations Programme on HIV/AIDS (UNAIDS), representatives of the 
community-based detection centres have participated in the design of the protocol 
and the Participant Information Sheet, through the Community Advisory Committee 
(CAC).  
 
 
14.2 PATIENT INFORMATION SHEET AND INFORMED CONSENT 
Informed consent will be obtained before including the patient in the trial. The 
investigator is to inform the patient of the nature, duration and purpose of the study, 

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as well as of all the obstacles and inconveniences which – within reason – may be 
expected from it. Furthermore, the patient is to receive information in writing. The 
participating patients must be legally competent to give informed consent, with the 
possibility of taking decisions at his/her own free will. The patient has the right to 
leave the study at any time. 
 
 
14.3 PAYMENT TO RESEARCH SUBJECTS 
No reimbursement to patients has been planned. 

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15 DATA HANDLING AND RECORD KEEPING 
 
15.1 DATA HANDLING 
The processing of the data to be compiled by the study sponsor during the trial will 
be subject to current legislation as regards data protection (LOPD, Ley Orgánica 
15/1999, de 13 de diciembre de protección de datos de carácter personal). The 
patient will be identified in the records by the corresponding code only. The patient is 
to be guaranteed anonymity, and is to be informed that all communication will take 
place between him/her and the investigator – not the sponsor of the trial. 
 
Data transmitted to third countries and other countries will in no case contain 
personal data. In the event that such transfer occurs, it will be for the same purposes 
of the study described and ensuring confidentiality at least to the level of protection 
of the law in Spain. 
 
 
15.2 RECORD KEEPING 
 
CONFIDENTIALITY 
 
Subjects will be codified with a serial numeration. The PI and duly authorized 
collaborators will compromise to maintain personal data strictly confidential, 
according to the corresponding National Legislation (Ley de Protección de Datos de 
Carácter Personal 15/99). The link between the numeric code and real personal 
data from subjects will be rigorously kept by the PI.  
 
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 

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the site CREC, 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. 
Participants may exercise their right to processing, reporting, and transfer of the 
personal data pursuant to Organic Act 15/1999, of 13 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. 
 
 
15.2.1 Investigator file and document retention 
The investigator must keep the investigator file with the proper and accurate records 
to enable the study to be fully documented and data subsequently verified. 
 

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The Investigator's study file will contain the protocol and its amendments, CRFs, 
questionnaires’ forms, EC approval and authorization from the health authorities, 
samples of the patient information sheet and informed consent, staff curriculum, 
signatures’ delegation log and listing of subjects, as well as other appropriate 
documents and correspondence. 
 
Clinical source documents from subjects (usually predefined by the project to record 
key efficacy and safety parameters or documents that are not in the clinical record of 
the hospital) will be filed indicating the number of patient without personal data. 
 
The investigator should retain these documents at least 25 years, according to with 
Royal Decree 1090/2015, provided that the promoter does not express a greater 
period. 
 
15.2.2 Source documents and basic data  
 
The information contained in the Medical History will be considered as primary data, 
except for patient filiation data and lab tests. Patient participation in the study will be 
collected on medical records, including assigned code number and identification of 
the different study visits that will take place throughout the study. At the end of the 
study, a copy of the CRF will be placed on the site. 
 

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16 FINANCING AND INSURANCE 
16.1 SOURCE OF FINANCING 
 
The study will be funded partially by ViiV Healthcare.  
 
16.2 INSURANCE POLICY 
In accordance with Royal Decree 1090/2015, the sponsor has taken out civil liability 
insurance for this study (see Investigator file)  
 
 
17 PUBLICATION POLICY 
The publication of the trial results shall meet the requirements of Royal Decree 
1090/2015 and will follow the consort guidelines.