Evaluation of (Doravirine / Lamivudine / Tenofovir Disoproxil Fumarate) (Delstrigo®) as a New Strategy for Non-occupational Post Exposure Prophylaxis, a Prospective Open Label Study
Phase: PHASE4
Conditions: Hiv
Sponsor: Hospital Clinic of Barcelona

CLINICAL TRIAL PROTOCOL
Protocol Title:
Evaluation of (doravirine / lamivudine / tenofovir disoproxil fumarate) 
(Delstrigo®) as a New Strategy for non-occupational Post Exposure Prophylaxis, a Prospective 
Open Label Study.
Protocol Code: DORAVIPEP
Version:
1.2 fecha 24/04/2020
EudraCT No:
2019-004140-30
Sponsor:
Fundació Clinic per a la Recerca Biomèdica. Barcelona, Spain Chief 
Investigator:
Dr. Josep Mallolas. Hospital Clínic de Barcelona, Spain
EudraCT No. 2019-004140-30                                                                                                                 1
Protocol version 1.2, 24th April  2020

CONTACT DETAILS
Sponsor:
Fundació Clinic per a la Recerca Biomèdica.
Barcelona, Spain
Chief Investigator:
Dr. Josep Mallolas.
Hospital Clínic de Barcelona
Infectious Diseases Department
HIV unit. 
Hospital Clínic de Barcelona, Spain
Mail: mallolas@clinic.cat
Investigator:
Dr. Alexy Iniciarte
Infectious diseases Department-
HIV Unit. 
Hospital Clínic de Barcelona Barcelona, Spain
Mail: ajinciar@clinic.cat
Other Investigators:
Pr François RAFFI, MD, PhD
Head of Infectious Diseases.
Department and HIV & HCV Clinical Research Unit
University Hospital
44093 Nantes cedex 1FRANCE
francois.raffi@wanadoo.fr
Project Manager:
Clinical Trials Unit (CTU Clinic) Hospital Clínic, Barcelona, Spain
Monitoring:
Clinical Trials Unit (CTU Clinic) Hospital Clínic, Barcelona, Spain
Pharmacovigilance:
Clinical Trials Unit (CTU Clinic)
Hospital Clínic, Barcelona, Spain
Statistician:
Elisa de Lazzari 
Hospital Clínic, Barcelona, Spain
EudraCT No. 2019-004140-30                                                                                                                 2
Protocol version 1.2, 24th April  2020

SPONSOR SIGNATURE
I have read and approve this protocol. My signature, in conjunction with the signature of the 
investigator, confirms the agreement of both parties that the clinical study will be conducted
in accordance with the protocol and all applicable local laws and regulations including, but 
not limited to, the International Conference on Harmonization Guideline for Good Clinical 
Practice (ICH GCP), the ethical principles that have their origin in the Declaration of Helsinki 
and applicable privacy laws.
Name of person who signs on behalf of the sponsor: Signature:
Date:
EudraCT No. 2019-004140-30                                                                                                                 3
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
I have thoroughly read and reviewed the trial protocol. I agree:
- To conduct the trial in accordance with GCP and the applicable regulatory 
requirements and with the approved protocol.
- That I am thoroughly familiar with the appropriate use of the investigational 
medicinal products, as described in the Investigator’s Brochure and any other 
information provided by the Sponsor.
- To comply with the procedures for data recording /reporting.
- To ensure that all persons assisting me with the study are adequately informed about 
the study and of their study-related duties and functions.
- To permit monitoring, auditing and inspection and to retain the trial related 
essential documents for the period of time required according to ICH-GCP and local 
regulatory requirements.
Name of Principal Investigator: Signature:
Date:
EudraCT No. 2019-004140-30                                                                                                                 4
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TABLE OF CONTENTS
CONTACT DETAILS...................................................................................................................2
SPONSOR SIGNATURE.............................................................................................................3
INVESTIGATOR PROTOCOL AGREEMENT PAGE.......................................................................4
TABLE OF CONTENTS..............................................................................................................5
ABBREVIATIONS......................................................................................................................6
PROTOCOL  SYNOPSIS.............................................................................................................8
1.INTRODUCTION AND RATIONALE......................................................................................11
2.OBJECTIVES OF THE CLINICAL TRIAL..................................................................................13
3.TRIAL DESIGN.....................................................................................................................14
4.SUBJECT SELECTION AND WITHDRAWAL..........................................................................18
5.TREATMENT OF SUBJECTS.................................................................................................20
6.VISIT SCHEDULE AND STUDY PROCEDURES.......................................................................25
7.STATISTICAL ANALYSIS........................................................................................................30
8.SAFETY ASSESSMENT.........................................................................................................32
9.DATA HANDLING................................................................................................................38
10.QUALITY CONTROL AND QUALITY ASSURANCE..............................................................40
11.ETHICAL AND REGULATORY CONSIDERATIONS...............................................................41
12.FINANCING AND INSURANCE..........................................................................................45
13.PUBLICATION...................................................................................................................46
14.REFERENCES....................................................................................................................47
Appendix I.World Medical Association Declaration of Helsinki Ethical Principles for Medical
Research Involving Human Subjects.....................................................................................49
EudraCT No. 2019-004140-30                                                                                                                 5
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ABBREVIATIONS
3TC
Lamivudine
ABIC
Age, serum Bilirubin, INR, and serum Creatinine score
ADR
Adverse Drug Reaction
ABsup
Superficial Antibody
ABcore
Core Antibody
Agup
Superficial Antigen
AgE
E antigen 
AE
Adverse Event
ALT
Alanine aminotransferase
AP
Alcaline phosphatase
AR
Adverse reaction
AST
Aspartate aminotransferase
ATZ/r
Atazanavir boosted ritonavir
AZT
Zidovudine
CI
Confidence Interval
CK
Creatin Kinase
CRP
C Reactive Protein
CYP3A4
Cytochrome P450 3A4
DSMB
Data Safety Monitoring Board
DRV/r
Darunavir boosted ritonavir
EFV
Efavirenz
EKG
Electrocardiogram
EMA
European Medicines Agency
eNOS
endotelial Nitric Oxide Synthase
EVG/c
Elvitegravir boosted cobicistat
FTC
Emtricitabine
GCP
Good Clinical Practice
HVB
Hepatitis B virus 
HCV
Hepatitis C Virus
HIV
Human immunodeficency virus
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IDIBAPS
Institut d'Investigacions Biomèdiques August Pi i Sunyer
IMP
Investigational Medicinal Products
IQR
Interquartile range
ISF
Investigator Site File
NEV
Nevirapine
LOP/r
Lopinavir boosted ritonavir
EudraCT No. 2019-004140-30                                                                                                                 6
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RAL
Raltegravir
RIL
Rilpivirine 
SAE
Serious Adverse Events
SAP
Statistical Analysis Plan
SD
Standard Deviation 
SMAQ
Simplified medication adherence questionary 
SMT
Standard Medical Therapy
STis
Sexually transmitted diseases 
SUSAR
Suspected Unexpected Serious Adverse Reaction
TDF
Tenofovir disoproxil fumarate
PEP
Post exposure prophylaxis
TMF
Trial master file
UAR
Unexpected Adverse Reaction
WHO
World Health Organization
EudraCT No. 2019-004140-30                                                                                                                 7
Protocol version 1.2, 24th April  2020

PROTOCOL  SYNOPSIS
Protocol code
Evaluation of (doravirine / lamivudine / tenofovir disoproxil fumarate) 
(Delstrigo®) as a New Strategy for non-occupational Post Exposure 
Prophylaxis, a Prospective Open Label Study.
Title of the study
DORAVIPEP
EudraCT No.
2019-004140-30
Sites
Multicenter clinical trial:
-
Hospital Clínic de Barcelona, Barcelona, Spain
-
Hotel-Dieu de France University Hospital, Nantes, France
Study period
The study is expected to begin, once authorizations are obtained, in 
February 2020. The recruitment period will be 6-12 months, and the 
follow-up will last up to 4 months after the inclusion of the last subject.
The study is expected to end by March 2022.
Primary objective
To estimate the proportion of subjects who correctly complete (for 28 
days) the entire antiretroviral treatment proposed in the study.
Secondary 
objectives
Incidence and description of adverse effects (clinical and laboratory) 
that appear during cART.
Description of adherence to cART, including the time until loss of 
adherence .
Proportion of patients that maintain follow-up at 1 and 3 months. 
Rate of HIV Seroconversion
Study population
Adult individuals eligible for post exposure HIV prophylaxis using 
Study Design
A Phase 4, prospective, open, multi-center study on subjects outcomes 
(efficacy and safety) following post exposure prophylaxis.
Number of subjects
400 subjects
EudraCT No. 2019-004140-30                                                                                                                 8
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Study population
Inclusion Criteria
Subjects attending ER due to potential HIV exposition of either sex:
1.
Aged 18 years or more.
2.
Who have been exposed to non-occupational HIV and 
who meet the prerequisites for the current recommendations to 
begin PEP with three antiretroviral drugs.
3.
Who after being fully informed, give their written 
consent to participate in the study and undergo the tests and 
examinations required.
4.
Individuals able to do follow up correctly. 
Exclusion Criteria
1.
Pregnant women or nursing mothers or women trying to
conceive during the study period.
2.
Patients in whom it is known or suspected that the 
source case has a resistance to one of the drugs from the study 
treatment regimens.
3.
Treatment with drugs that are contraindicated in the 
study or products that are in the investigational phase.
4.
Allergic  reactions or intolerance to the compounds of 
the study treatment regiments
Investigational 
Product
Doravirine, Lamivudine and tenofovir disoproxil fumarate (Delstrigo®)
Route and dosage 
form
Oral administration dosage: 1 covered tablet every day (QD)
Dosage
Doravirine / lamivudine / tenofovir disoproxil fumarate (Delstrigo®)
100 mg  doravirine, 300 mg  lamivudine,300 mg  tenofovir disoproxilo 
fumarate equivalen t  to 245 mg de tenofovir disoproxilo.
1 covered tablet for day .( will be administered 28 days maximum)
Duration of 
treatment
The duration of the study treatment will be 28 days.
Outcome measures
Primary outcome will be defined as :
Proportion of subjects with treatment completion at day 28. PEP non-
completion is considered in cases:
1.
If the subject dies.
2.
Does not go to visits (loss of follow-up)
3.
Change or suspend the treatment under study for any 
EudraCT No. 2019-004140-30                                                                                                                 9
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Secondary and 
exploratory 
outcome measures
1.
Assess the baseline characteristics associated to non-
completion.
2.
Incidence and description of adverse effects (clinical and 
laboratory) that appear during cART.
3.
Description of adherence to cART, including the time 
until loss of adherence.
4.
Proportion of subjectsthat maintain follow-up at 1 and 3 
months.
Statistical Methods 
and Planned 
Analyses:
A sample size of 400  individuals from a population of 1400 produces a 
two-sided 95% confidence interval with a precision of 0.04  when the 
actual proportion of non-completion is near 40%. The population size 
considered  corresponds to the yearly number of individuals receiving 
post-exposure profilaxis in our hospital.
Summary statistics will be performed using absolute frequency and 
percentages for qualitative variables and mean and SD or median and 
IQR for quantitative characteristics, at each visit.
The primary outcome will be reported as absolute frequency and 
percentage along with the 95%CI.
The secondary objectives will be assessed as follow:
1.
Baseline characteristics associated to treatment non-
completion will be identified using logistic regression model.
2.
The incidence of adverse effects (AEs) will be reported as
number of AEs per 100/person-time and its 95%CI, differentiating 
those leading to discontinuation or to study withdrawal, those 
caused by laboratory abnormalities (grade 1-2 and 3-4) during 
study treatment and also until week 12 of follow-up. 
3.
Absolute frequency and percentage of individuals who 
showed non-adherence at each follow-up visit. Median (IQR) time 
until loss of adherence. 
4.
Absolute frequency and percentage of individuals who 
performed week 4 assessment and week 12 (retention rate).
5.
The rate of HIV seroconvertion will be reported as the 
number of individuals newly diagnosed of HIV per 100/person-
time and its 95%CI.
EudraCT No. 2019-004140-30                                                                                                                 10
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1. INTRODUCTION AND RATIONALE
According to the Joint United Nations Programme on HIV/AIDS (UNAIDS), in 2017 there were 
2.1 million new HIV infections worldwide, adding up to a total of 36.7 million people living with
HIV1. In this scenario, the use of antiretroviral therapy (ART) has been proposed as a secondary
prevention to avoid infection. This strategy is known as Post-exposure prophylaxis (PEP), which 
is used after either occupational contact or non-occupational contact.
PEP was initially used in the occupational context 2. Data available from animal transmission 
models, perinatal clinical trials, and studies of health-care workers receiving prophylaxis after 
occupational exposures and observational studies indicate that PEP administered within 48-72 
hours and continued for 28 days might reduce the risk for HIV infection3-6. The sooner PEP is 
administered after exposure, the more likely is the interruption of transmission. 
The recommended guidelines in Spain and Europe for PEP consist of two nucleoside reverse 
Transcriptase Inhibitors (NRTI) that can be combined with either an integrase or a protease 
inhibitor7,8.  PEP toxicity is the main reason for poor adherence and the high rate of 
discontinuation in the treatment9. The side effects of PEP that mostly appear with the use of 
three-drug regimens are mainly attributed to protease inhibitors and cause irregular 
compliance and dropouts which ultimately lead to worsen treatment completion10-14. 
This hospital attended in 2018 1,596 cases of Post Exposure Prophylaxis and the evaluation of 
new PEP regimens would be welcome. 
NNRTIs based triple therapy could qualify for PEP regimens, however, DDI potential, treatment 
associated toxicities and lack of convenience (i.e. bedtime dosing or calorie intake 
requirements) have prevented the currently existing NNRTIs to become so. Current guidelines 
recommend the use of integrase inhibitors with raltegravir as core treatment as standard of 
care. 
Guidelines for PEP's treatment suggest a triple treatment with the aim of avoiding the 
development of resistance. Drugs are chosen for their pharmacodynamic characteristics 
(potency), pharmacokinetics (dosage and potential interactions) and convenience of 
administration (single tablet). Among the options is raltegravir, but in this case the dosage is 
not comfortable since it is twice a day. There is elvitegravir, which allows a daily dose but 
presents multiple potential drug interactions, and there is dolutegravir, which is administered 
in a single tablet a day and includes abacavir, which requires a previous test before use and 
therefore invalidates it as PEP. Our proposal is doravirin, a potent, well-tolerated NNRTI that 
allows dosing in a single tablet once a day.
Doravirine, is novel non nucleotide transcriptase inhibitor that has recently arrived on the 
market as an STR in combination with (Lamivudine and tenofovir disoproxil fumarate) 
(Delstrigo®)  and in studies in HIV infected patients have shown a very good toxicity profile 15,16)
Doravirine has an in vitroresistance profile that is distinct from other NNRTIs retaining activity 
against viruses containing the most frequently transmitted NNRTI mutations, K103N, E138K, 
EudraCT No. 2019-004140-30                                                                                                                 11
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Y181C and G190A.  Recent studies show that the prevalence of doravirine resistance associated
mutations in HIV-1-infected ARV-treated patients in the Mediterranean was low(17)
The emerging of Integrase resistance mutations during Initial therapy containing dolutegravir is
reminder that, despite a high barrier to resistance (18), no agent as initial therapy for HIV-1 is 
impervious to resistance, doravirine as a novel agent has a role for HIV prevention. 
Doravirine may be as good a choice as a PEP given its excellent tolerance profile, mechanism of 
action, its potency, the lack of interactions due to mostly being unboosted and also its single 
tablet administration. It is likely that a much better dosage pill and BID to QD could improve 
adherence to medication (19). Current guidelines recommend the use Raltegravir as first line 
regimen,Data available from previous studies show that a 32% of patients occasionally missed 
the second dose of raltegravir (20). Doravirina as a STR regimen might Improve the perception 
of illness and, therefore, its compliance.
EudraCT No. 2019-004140-30                                                                                                                 12
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2. OBJECTIVES OF THE CLINICAL TRIAL
Primary objective
To estimate the proportion of subjects who correctly complete (for 28 days) the entire 
antiretroviral treatment proposed in the study.
Secondary objectives
1. Assess the baseline characteristics associated to non-completion.
2. Incidence and description of adverse effects (clinical and laboratory) that appear during 
cART.
3. Description of adherence to cART, including the time until loss of adherence.
4. Proportion of patients that maintain follow-up at at 4 at 12 weeks. 
5. Rate of HIV Seroconversion.
EudraCT No. 2019-004140-30                                                                                                                 13
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3. TRIAL DESIGN
a.
Primary and secondary endpoints
Primary endpoint:
Primary outcome will be defined as:
Proportion of subjects that achieved treatment completion at day 28. PEP non-completion is 
considered in cases:
1. If subject dies
2. Does not go to visits (loss of follow-up)
3. Changes or suspends the treatment under study for any reason.
4. Consent withdrawal.
Secondary endpoints:
1. Assess the baseline characteristics associated to non-completion.
2. Incidence and description of adverse effects (clinical and laboratory) that appear during 
cART.
3.  Description of adherence to cART, including the time until loss of adherence .
4. Proportion of subjects that maintain follow-up at 1 and 3 months. 
5. Rate of HIV Seroconversion
b. Study design
This is a phase 4, multicenter, open, prospective, on subjects outcomes (efficacy and safety) 
following post exposure prophylaxis.
The study will be developed at two tertiary care centers:
- Hospital Clínic de Barcelona, Barcelona, Spain
- Hotel-Dieu de France University Hospital, Nantes, France
Subjects attending emergency room due to a potential HIV exposition of either sex who meet 
inclusion criteria and none of the exclusion criteria will be included in this trial.
A total of 400 subjects will receivea regimen consisted of  (doravirine / lamivudine / tenofovir 
disoproxil fumarate) (Delstrigo®)  1 covered tablet for day ( will be administered 28 days 
maximum).
EudraCT No. 2019-004140-30                                                                                                                 14
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Subjects will receive the study medication for 28 days.  Follow-up will be performed at  1 to 7 
days after starting PEP and  week 4  and 12.visit consisting in telemedicine, in those sites which 
it is the current clinical practice,evaluation and analysis assessment will be done.
For PEP treatment in some sites the follow up evaluation the clinical practice consist on a 
telemedicine visit. This visit is carried out through a digital platform used in other patients 
evaluations. If the normal clinical practice is by telemedicine in the site, the clinical evaluation 
can be done by telemedicine. 
Figure 1. Flow-chart of the study
 
Day 0
(Treatment
initiation)
Day 7 after
start PEP
Week 4
(End of
treatment)
Week 12
(after start PEP)
Compliance with inclusion 
and exclusion criteria
x
Clinical evaluation
x
x
x
x
Biochemistry, liver and CBC
x (1)
x
x
x
HIV, HAV, HBV, HCV and 
syphilis serology (**)
x (1)
X, Syphilis
serology(2)
x
x
Cholesterol, HDL and LDL 
cholesterol, triglycerides
x (1)
x
x
x
Pregnancy test
x
x
x
Questionnaire on adherence 
to ART(3) 
x
x
Pill Count
x
x
Adverse events
x
x
x
x
(1) This analysis can be performed within the first 10 days after exposure
(2) Lues serology will only be performed in sexual exposures until day 28
(3) Evaluated with a Simplified Medication Adherence Questionnaire SMAQ
EudraCT No. 2019-004140-30                                                                                                                 15
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c.
Trial duration
The duration of the trial will be of 28 days of daily treatment plus 3 follow-up visits at 1-7 days 
after PEP initiation, between day 28 and 60 after PEP initiation, and another  visit  between 12 
and 16 weeks after stopped  the treatment.
d. Criteria for termination and/or discontinuation
The participants will discontinue study participation if they are unwilling or unable to meet the 
protocol requirements in terms of the visit schedule or if the patient or the investigator 
considers it is best to end their participation in the study. All participants have the right to 
withdraw their consent at any time during the study without prejudice to them.
All follow-up terminations of study subjects 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.
Premature termination of the study will occur if subjects are considered to be exposed to an 
unacceptably high risk in the investigators decision. Premature termination will be reported to 
the local Ethics Committee and competent authorities within 15 days in accordance with 
country- specific requirements.
See section 4.4 Withdrawal criteria for specific criteria for treatment discontinuation.
e.
Drug accountability.
The study treatment will be administered to patients who are admitted to the hospital from 
the Pharmacy Service of each participating hospital,  but adherence to treatment will be 
evaluated by the medical researcher.
f.
Allocation participant identification code
All participants will be assigned with a subject number that will allow the patient to be 
identified. Subjects will be identified only by subject number in order to protect 
confidentiality. Each site investigator will keep its own patient log to match the identification 
number with the patient’s personal data, in accordance with applicable regulatory and 
country-specific data protection requirements.
The subject number will be done through an electronic case report form (eCRF) that will be 
created using RedCap. This system is regulatory compliant (GCP, 21CRF11, EC Clinical Trial 
Directive).
EudraCT No. 2019-004140-30                                                                                                                 16
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g.
Source data verification
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, EKG tracings, 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
and signed by the principal investigator is acceptable.
h. End of the trial
The end of the trial is defined as the date of the last visit of last subject undergoing the trial 
(LVLP).
i.
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 in each country.
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 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.
EudraCT No. 2019-004140-30                                                                                                                 17
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4. SUBJECT SELECTION AND WITHDRAWAL
a. Description of study population
Patients eligible for this study will be subjects post HIV exposure prophylaxis attended from 
the hospital participating in the study.
b. Subject inclusion criteria
Patients included into the study must meet all the following criteria:
1.
Patients attending emergency room due to potential HIV exposition of either sex:
2.
Aged 18 years or more.
3.
Who have been exposed to non-occupational HIV and who meet the prerequisites for 
the current recommendations to begin PEP with three antiretroviral drugs.
4.
Who after being fully informed, give their written consent to participate in the study 
and undergo the tests and examinations required.
5.
Individuals able to do follow up correctly. 
c.
Subject exclusion criteria
1.
Pregnant women or nursing mothers or women trying to conceive during the study 
period.
2.
Patients in whom it is known or suspected that the source case has a resistance to one 
of the drugs from the study treatment regimens.
3.
Treatment with drugs that are contraindicated in the study or products that are in the 
investigational phase.
4.
 Allergic  reactions or intolerance to the compounds of the study treatment regiments
5.
Sexual assault victims 
6.
 Past history of PEP use in several occasions without accomplishing Follow-up testing.
d. Withdrawal criteria
Study withdrawal
All patients have the right to withdraw their consent at any time during the study 
without prejudice to them.
EudraCT No. 2019-004140-30                                                                                                                 18
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The patient may also discontinue study participation in the following instances:
1. If the investigator considers in the interest of the subject (i.e intercurrent illness, occurrence 
of adverse events) that it is best for them to stop study medication.
2. The  subject  fails  to  comply  with  the  protocol  requirements  or  fails  to  cooperate  with 
investigator.
3. The individual move to another country being unable to do the follow up. 
All follow-up terminations of study patients and their reasons must be reported 
immediately to monitor and sponsor and be duly documented in both the subject’s CRF and
source document. All patients who discontinue study medication will be asked to do the 
follow up and requested to attend for study visits up until 28 days of treatment. If this is not 
possible or acceptable to the subject or Investigator, the subject may be withdrawn from 
the study and the reason for withdrawal recorded in the CRF. The Early Termination Visit 
(ETV) form in the CRF should be completed.
4. If  a  female  subject  becomes  pregnant  along  the  study,  she  will  discontinue  the  
study treatment.
Specific criteria for study treatment withdrawal
1. If the subject has HIV positivity against HIV .
2. Bad  tolerance or appearance of serious adverse events related to study medication.
3. Patient decision: Risk reconsideration.
4. If the source of the exposure had a HIV negative test by a 4th generation test.
EudraCT No. 2019-004140-30                                                                                                                 19
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5. TREATMENT OF SUBJECTS
A cohort  of 400 subjects will recive  (doravirine, lamivudine, and tenofovir disoproxil fumarate)
tablets, for oral use , (will be administered for 28 days)
a.
Name and description of the investigational products
Farmaceutical form
DELSTRIGO™:  Covered Tablets: 100 mg of doravirine, 300 mg of lamivudine, and 300 mg of 
tenofovir disoproxil fumarate
b. Storage conditions
Store in the original bottle and keep the bottle tightly closed to protect it from
humidity. Do not remove the desiccant. This medication does not require any special 
temperature of conservation.
Stability data from three commercial scale batches of active substance from the proposed 
manufacturer stored in in double LDPE liners within a fiberboard container for up to 36 months
under long term conditions (25 ºC / 60% RH) and for up to 6 months under accelerated 
conditions (40 ºC / 75% RH) according to the ICH guidelines were provided. The results for 
three additional primary commercial stability batches for 12 months at 25°C/60%RH and 6 
months at 40°C/75%RH showed comparable results to prior stability studies.
c.
Summary of known and potential risks and benefits Undesirable 
effects
- Most common adverse reactions (incidence greater than or equal to 5%, all grades) are 
dizziness, nausea, and abnormal dreams.
Others:
-Severe acute exacerbations of hepatitis B (e.g., liver decompensated and liver failure) have 
been reported in patients who are coinfected with HIV-1 and HBV and have discontinued 
products containing lamivudine and/or TDF, and may occur with discontinuation of DELSTRIGO
EudraCT No. 2019-004140-30                                                                                                                 20
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- Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular 
injury with severe hypophosphatemia), has been reported with the use of TDF, a component of
DESLTRIGO
-The concomitant use of DELSTRIGO and certain other drugs may result in known or potentially
significant drug interactions, some of which may lead to.
Loss of therapeutic effect of doravirine, lamivudine, and tenofovir disoproxil fumarate
and possible development of resistance. 
Possible clinically significant adverse reactions from greater exposures of a 
component of doravirine, lamivudine, and tenofovir disoproxil fumarate
- Bone Loss and Mineralization Defects
d. Contraindications
DELSTRIGO is contraindicated when co-administered with drugs that are strong cytochrome 
P450 (CYP)3A enzyme inducers as significant decreases in doravirine plasma concentrations 
may occur, which may decrease the effectiveness of DELSTRIGO. (4) DELSTRIGO is 
contraindicated in patients with a previous hypersensitivity reaction to lamivudine
Renal impairment, including cases of acute renal failure and Fanconi syndrome, have been 
reported with the use of TDF. DELSTRIGO should be avoided with concurrent or recent use of a 
nephrotoxic agent (eg, high-dose or multiple NSAIDs). Cases of acute renal failure after 
initiation of high-dose or multiple NSAIDs have been reported in patients with risk factors for 
renal dysfunction who appeared stable on TDF.
DELSTRIGO is contraindicated in patients with a previous hypersensitivity reaction to 
lamivudine.
Renal impairment, including cases of acute renal failure and Fanconi syndrome, have been 
reported with the use of TDF. DELSTRIGO should be avoided with concurrent or recent use of a 
nephrotoxic agent (eg, high-dose or multiple NSAIDs). Cases of acute renal failure after 
initiation of high-dose or multiple NSAIDs have been reported in patients with risk factors for 
renal dysfunction who appeared stable on TDF.
e.
Drug interactions
Co-administration of DELSTRIGO with a CYP3A inducer decreases doravirine plasma 
concentrations, which may reduce DELSTRIGO efficacy [see Contraindications (4), Warnings 
and Precautions (5.3), and Clinical Pharmacology (12.3)]. Co-administration of DELSTRIGO and 
drugs that are inhibitors of CYP3A may result in increased plasma concentrations of doravirine.
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f.
 Adverse events
The focus of this safety section is the safety outcomes in the phase 3 studies. Potential risks 
include possible adverse effects due to the trial medication. Specifically, these include the renal
effects associated with tenofovir. Doravirine is well tolerated drug but can cause side effects. 
The most commonly observed adverse drug reactions during clinical trials as long term 
treatment in HIV individuals were: headache (13%), diarrhea (14%), sleep disorders (12%), 
nausea (10%), Nasopharyngitis (10%) dizziness (8%), vomiting, fatigue (8%), rash (5%) . Severe 
adverse events were observed in the minority of cases (< 0,01%) as; acute kidney injury, genital
wards, appendicitis, Pneumonia. 
Laboratory abnormalities 
In general, treatment with DOR and DOR/3TC/TDF was well tolerated in the phase 2 and 3 
studies. Few Grade 3 or 4 lab abnormalities were reported. Around 5% de los patients have 
grade I and grade II elevations of bilirubin. The majority of elevations in the laboratory test 
were Grade 1, single, transient elevations, with no pattern of the elevation occurring early or 
late relative to dosing. The duration of treatment limits the possibility of adverse effects that 
appear in the long term.
g.
Labeling of investigational products
Ther are complet IMPD In the Investigator file to consult
Delstrigo ®will be distributed to each Hospital Pharmacy Service  labeled according to the 
current legislation by Pharmacy Service of the study sites.
h. Concomitant, non permitted and permitted medication
Co-administration with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers 
should be avoided: 

Carbamazepine

Oxcarbazepine

Phenobarbital

Phenytoin

Enzalutamide

Rifampin 

Rifapentine

Mitotane.
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
St. John’s wort (Hypericum perforatum))
Co-administration with drugs that are strong cytochrome P450 (CYP)3A enzyme inhibitors 
should be avoided: 

Clarithromycin

Telithromycin

Nefazodone

Itraconazole

Ketoconazole
A closer patient follow up of the investigator team will be needed for patients in treatment 
with moderate and weak CYP3A inhibitors and inducers.
All the medication listed above had a significant decrease in doravirine plasma concentrations, 
which may decrease the effectiveness of DELSTRIGO.
i.
Monitoring of compliance
The researcher's health staff will be in charge
Assessment of compliance by a health staff will be performed in the first and second follow-up 
consultation at day 7 and 4- 8 weeks, with the SMAQ questionnaire. 
The SMAQ questionnaire was developed as a modification of the Morisky-Green questionnaire 
to measure adherence to antiretroviral treatment in patients with acquired immunodeficiency 
syndrome (AIDS). The questionnaire provides good levels of validity and interobserver 
agreement. An enhanced sensitivity is advantageous to better detect non-adherent patients for
a better follow-up.
This questionnaire consists of six questions that evaluate different aspects of patient 
compliance with treatment: forgetfulness, routine, adverse effects, and a quantification of 
omissions. A patient is classified as non-compliant if he/she responds to any of the questions 
with a non-adherence answer, and in terms of quantification, if the patient has lost more than 
two doses during the last week or has not taken medication during more than two complete 
days during the last three months. 
This validated questionnaire for HIV compliance  is written as follows.
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“SIMPLIFIED MEDICATION ADHERENTE QUESTIONNARIE (SMAQ)
This questionnaire refers to the level of compliance that you hold with the post exposure 
prophylaxis treatment prescribed by your doctor please answer the entire question, indicating 
the correct response in each case. Please remember that you answers are confidential, and 
that you should respond to the question in as truthful a manner as possible. THANK YOU. 
1. - Do you always take your medication at the appropriate time?
YES ____
NO ____
2. - When you feel bad, have you ever discontinued taking your medication?
YES _____
NO _____
3.- Have you ever forgotten to take your medication?
YES _____
NO______
4. - Have you ever forgotten to take your medications during the weekend?
YES _____
NO______
5. - In the last week, how many times did you fail to take you prescribed dose? 
Never _____
1-2 times______
3-5 times _____
6-10 times ______
More than 10 times _____
6. - Since your last visit, how many whole days have gone by in which you did not take your 
medication?
Days ______ “
Continuation of treatment after the end of the trial
At day 28, the study medication will be stopped and the investigator will decide the best 
management for each patient.
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6. VISIT SCHEDULE AND STUDY PROCEDURES
a.
Assessment at each visit
Table 1 shows the summary of visits and procedures that will take place during the study.
Day 0. 
After providing informed consent, all subjects will undergo screening assessments:
-
Risk assessment, establishing better PEP should be indicated (high, 
intermediate, low)
-
Review inclusion and exclusion criteria.
-
Obtain written informed consent.
-
Medical history and physical examination (including vital signs). 
Demographics: Age, Sex (male, female, no binary), Sexual orientation 
(heterosexual, homosexual, Transexual), Origin (North America, Latin 
America, Europe, Asia, Africa, Oceania)
-
Register comorbidities. (ICD-10)
-
Register concomitant medication.
-
Register allergies
-
Previous Hep B vaccination. 
-
Previous PEP episodes (yes/no). Regimen: Back bone (TDF/FTC or AZT/3TC), 
third agent (EVG, LOP/r, RAL, ATZ/r, RIL, EFV, NEV), other. When (year). 
-
Previous PREP use (yes/no).
-
Previous STIs (yes/no). Type: Herpes, Gonococal uretritis, Clamidia uretritis, 
Unknow uretritis, Sifilis, Linfrogranulom venereum. When (year of diagnosis).
-
Last HIV test performed (date)
-
Use of abuse drugs (cocaine, GHB, ketamine, Tina, mefedrone, Speed, Extasis,
MDMA, Poppers, Viagra, Cannabis).
-
Hours from the exposure.
-
HIV status of the source (HIV+, HIV -, Unknown)
-
Anal sex (yes/no), vaginal sex (yes/no), oral sex (yes/no).
-
Condom less sex (yes/no), Blood (yes/no), Semen (yes/no), broken condom.
-
Adverse events. 
-
Antimicrobial prophylaxis (yes/no).
-
Hepatitis B prophylaxis (yes/no).
-
Counseling. 
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-
Blood tests for (further detailed in 6.2.1):
o
Hematology. 
o
Creatinine  levels,  glomerular  filtration  rate,  sodium  and  
potassium levels.
o
Liver tests: ALT, AST, Bilirubin, AP, albumin.
o
Leukocyte count.
o
Serologies: HIV antibody.
-
Evaluation of other activities (HBV prophylaxis, STDs). 
-
Pregnancy test in urine will be performed in all fertile women.
-
Recommendations on contraception methods during participation in the 
clinical trial will be provided.
Total required amount of blood at Day 0 visit: 70mL. Total required amount of urine at Day 0 
visit (applies only to women with childbearing potential): 100mL.
Day 7 after PEP initiation  (day 1-7)
The  following  procedures  will  be completed:
-
Complete physical examination, vital signs.
-
Register of comorbidities.
-
Register concomitant medications.
-
Investigation of PEP tolerance and initial adherence.
-
Adverse events
-
Blood tests for (further detailed in 6.2.1):
o
Hematology 
o
Creatinine  levels,  glomerular  filtration  rate,  sodium  and  
potassium levels
o
Liver tests: ALT, AST, Bilirubin, AP, albumin.
o
Leukocyte count 
o
Serologies: HIV antibody, HCV, HAV, HBV, Syphilis.
-
Simplified Medication Adherence Questionnaire (should be expressed as a 
percentage) and the level of tolerance, with the questioning directed towards
body changes and changes in daily routines. These parameters will be graded 
on a 0 to 10 analog scale.
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-
Pill Count
-
Baseline laboratory testing with kidney and liver function, hemogram, lipids 
(cholesterol, fractions and triglycerides).
-
Simplified Medication Adherence Questionnaire. 
Total required amount of blood for Day 7 visit: 70mL.
Study follow-up visit: Week 4  (4-8 weeks). End of treatment
-
Medical history and physical examination (including vital signs ).
-
Register comorbidities.
-
Register concomitant medication.
-
 Counseling. 
-
Assesment of development of adverse Events 
-
Blood tests for (further detailed in 6.2.1):
o
Hematology and coagulation tests.
o
Creatinine  levels,  glomerular  filtration  rate,  sodium  and  
potassium levels
o
Liver tests: ALT, AST, Bilirubin, AP, albumin.
o
Leukocyte count and CRP.
o
Serologies: HIV antibody. Syphilis Test 
-
Simplified Medication Adherence Questionnaire.
-
Pill Count
-
Evaluation of other activities (HBV prophylaxis, tetanus, STDs, gynecological 
evaluation in cases of sexual assault. 
-
Pregnancy test in urine will be performed in all fertile women.
-
Recommendations  on  contraception  methods  during  participation  in  
the clinical trial will be provided.
Total required amount of blood at week 4 visit: 70 mL. Total required amount of urine at 
week 4 visit (applies only to women with childbearing potential and amenorrea): 100 mL.
-
Clinical interview, investigating treatment adherence using Simplified 
Medication Adherence Questionnaire (should be expressed as a percentage) 
and the level of tolerance, with the questioning directed towards body 
changes and changes in daily routines. These parameters will be graded on a 
0 to 10 analog scale.
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Study follow-up visit: Week 12 (weeks 12-16)
-
Medical history and physical examination (including vital signs ).
-
Register comorbidities.
-
Register concomitant medication (incluiding LVP).
-
Assesment of development of adverse Events 
-
Blood tests for (further detailed in 6.2.1):
o
Hematology Creatinine  levels,  glomerular  filtration  rate,  sodium  
and  potassium levels
o
Live r tests: ALT, AST, Bilirubin, , albumin.
o
Leukocyte count..
o
Serologies: HIV antibody. Syphilis test, HCV antibodies
-
Evaluation of other activities (HBV prophylaxis, tetanus, STDs, gynecological 
evaluation in cases of sexual assault
-
Pregnancy test in urine will be performed in all fertile.
Total required amount of blood at week 12 visit: 70mL. Total required amount of urine 
(applies only to women with childbearing potential and amenorrea): 100mL.
Early termination 
In case of early termination of a participant, a termination should be done. The 
evaluations and procedures will be the same as the Standard of Care.
6.2.1 Blood and urine samples for laboratory assessments during the study
Blood samples to determine hematology, biochemistry and coagulation and serology  tests 
will be analyzed at the local laboratory of each participating center. After analysis the 
samples will be destroyed locally.
The following parameters will be evaluated:
- Hematology: Hemoglobin (g/L), Hematocrit 0.48 L/l, Platelets 10^9L, White cell count10^9L, 
Lymphocytes10^9L, Neutrophils10^9L. Total required amount of blood: 5mL
- Biochemistry: Glucose mg/dl, Bilirubin mg/dl, Direct bilirubin mg/dl, Indirect bilirubin 
mg/dl, AST U/l, ALT U/L, Alkaline phosphatase U/L, GGT U/L, Creatinine mg/dl, Na mg/dl, K 
EudraCT No. 2019-004140-30                                                                                                                 28
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mg/dl, Total cholesterol mg/dl, High density cholesterol mg/dl, low density cholesterol 
mg/dl,Total required amount of blood: 5mL.
-HIV test: Total required amount of blood: 5 mL
-Hepatitis A, Hepatitis B IgM, IgG, Asup, ABsup, ABcore AgE,  and hepatitis C antibodies and 
Syphilis test (VDRL, IgM, IgG): total required amount of blood: 10 mL
-Pregnancy test (applies to women with childbearing potential in case of amenorrea): 
Total required amount of urine: 13.5 mL
Samples for analysis at the end of the study (stored samples)
No samples will be stored for the study
EudraCT No. 2019-004140-30                                                                                                                 29
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7. STATISTICAL ANALYSIS
General remarks
The statistical analysis will be carried out in accordance with the principles specified in the
International Conference on Harmonization (ICH) Topic E9 (CPMP / ICH / 363/96) (1). 
Data analysis will be performed using the statistical software: Stata version 15 (2). 
A summary of the overall approach to statistical analysis is presented hereafter.
Sample size
A sample size of 400  individuals from a population of 1400 produces a two-sided 95% 
confidence interval with a precision of 0.04  when the actual proportion of non-completion is 
near 40%. The population size considered  corresponds to the yearly number of individuals 
receiving post-exposure profilaxis in our hospital.
The sample size calculation was performed using PASS 15 (3). 
Criteria for evaluation Analysis populations
The population considered for this study will be the ITT (intention-to-treat): all patients who 
have received the first dose of the investigational product after signing the informed consent 
will be included in the ITT population.
Statistical  Methods
Summary statistics will be performed using absolute frequency and percentages for 
qualitative variables and mean and SD or median and IQR for quantitative characteristics, at 
each visit.
The primary outcome, proportion of subjects who achieved treatment completion at day 28, 
will be reported as absolute frequency and percentage along with the 95%CI.
The secondary objectives will be assessed as follow:
1.
Baseline characteristics associated to treatment non-completion will be identified using 
logistic regression model selecting variables in a stepwise fashion.
2.
The incidence of adverse effects (AEs) will be reported as number of AEs per 
100/person-time and its 95%CI, differentiating those leading to discontinuation or to 
study withdrawal, those caused by laboratory abnormalities (grade 1-2 and 3-4) during 
study treatment and also until week 12 of follow-up. 
3.
Absolute frequency and percentage of individuals who showed non-adherence at each 
follow-up visit. Median (IQR) time until loss of adherence. 
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4.
Absolute frequency and percentage of individuals who performed week 4 assessment 
and week 12 (retention rate).
5.
The rate of HIV seroconvertion will be reported as the number of individuals newly 
diagnosed of HIV per 100/person-time and its 95%CI.
   Subgroups
No subgroup analyses are planned in the protocol. In case of any post-hoc subgroup analysis, 
they will be justified and identified as data-driven.
   Inferential Analysis
No inferential analyses are planned in the protocol.
Multiplicity adjustment and interim analysis
No multiplicity adjustment neither interim analysis are planned in the protocol.
Procedures to account for missing data
The primary outcome includes the missing value in the non-completer category. No formal 
imputations will be performed for the rest of variables and the analyses will be based on the 
Available Data Only (ADO) approach.
Data Review (DR) will be performed before lock of database. Data will be examined for 
compliance with the trial protocol by the monitor and the data manager. Deviations will be 
sent to the project statistician to plan listings for the Data Review. The objective is to carry out 
the population selection and definition of the final study populations as well as a preliminary 
assessment of the quality of the trial data.
Statistical references
(1) (1) European Medicines Agency. International Conference on Harmonisation (ICH) Topic E9 
(CPMP/ICH/363/96)
(2) (2) StataCorp. 2017. Stata: Release 15. Statistical Software. College Station, TX: StataCorp LLC
(3) (3) PASS 15 Power Analysis and Sample Size Software (2017). NCSS, LLC. Kaysville, Utah, USA, 
ncss.com/software/pass.
EudraCT No. 2019-004140-30                                                                                                                 31
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8. SAFETY ASSESSMENT
Definitions
Adverse
 
  event
 
  (AE)
 
 : an AE is any untoward medical occurrence in a clinical study 
subject administered a medicinal (investigational or non-investigational) product. An AE 
does not necessarily have a causal relationship with the treatment. An AE can therefore be
any unfavorable and unintended sign (including an abnormal finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational or non-
investigational) product, whether or not related to that medicinal (investigational or non-
investigational) product (Definition per International Conference on Harmonization [ICH]).
This includes any occurrence that is new in onset or aggravated in severity or frequency 
from the baseline condition, or abnormal results of diagnostic procedures, including 
laboratory test abnormalities.
Serious
 
  adverse
 
  event
 
  (SAE)
 
 : an SAE is any untoward medical occurrence that at any 
dose: Results in death, is life-threatening, requires inpatient hospitalization or prolongation 
of existing hospitalization, results in persistent or significant disability/incapacity, is a 
congenital anomaly/birth defect, is a suspected  transmission of any infectious agent via a
medicinal product, is medically important (according to the treating physician), other 
important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed in the definition above.
If a serious and unexpected AE occurs for which there is evidence suggesting a causal 
relationship between the study drug and the event (eg, death from anaphylaxis), the 
event must be reported as a serious and unexpected suspected adverse reaction even 
if it is a component of the study endpoint (eg, all-cause mortality).
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during 
the course of a subject's participation in a study must be reported as an SAE, except 
hospitalizations for the following: hospitalizations not intended to treat an acute illness or 
AE (eg, social reasons such as pending placement in long-term care facility), surgery or 
procedure planned before entry into the study.
Adverse
 
  reaction
 
 : An AR is an AE suspected to be causally related to a medicinal product.
An ADR is a response to a medicinal product which is noxious and unintended. Response in 
this context means that a causal relationship between a medicinal product and an adverse 
event is at least a reasonable possibility (i.e. the relationship cannot be ruled out). 
Adverse reactions may arise from use of the product within or outside the terms of the 
marketing authorization or from occupational exposure. Conditions of use outside the 
marketing authorization include overdose, misuse, abuse and medication errors. [Sources 
EMA GVP Annex I, and ICH E2A].
EudraCT No. 2019-004140-30                                                                                                                 32
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Unexpected
 
  Adverse
 
  Reaction
 
  (UAR)
 
 : Any adverse reaction, whose nature or severity of 
which is not consistent with the applicable product information (e.g. investigator's 
brochure for an unauthorized investigational product or summary of product 
characteristics for an authorized product).
Suspected
 
  Unexpected
 
  Serious
 
  Adverse
 
  Reaction
 
  (SUSAR)
 
 : An adverse reaction that is 
both serious and unexpected.
Assessment of intensity
An assessment of intensity grade will be made using the general categorical descriptors 
outlined in the WHO Toxicity Grading Scale (see Appendix 4). The investigator should 
use clinical judgment in assessing the severity of events not directly experienced by the 
subject (eg, laboratory abnormalities).
Assessment of causality
- Possible: An AE that might be due to the use of the drug. An alternative explanation, eg,
concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
- Probable: An AE that might be due to  the use of the drug. The relationship in time is 
suggestive (eg, confirmed by dechallenge). An alternative explanation is less likely, eg, 
concomitant drug(s), concomitant disease(s).
- Very Likely: An AE that is listed as a possible adverse reaction and cannot be reasonably 
explained by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). 
The relationship in time is very suggestive (eg, it is confirmed by dechallenge and 
rechallenge).
- AE related: The relationship in time of the AE with the study drug indicates a possible causal
relationship and it cannot be explained by factors such as the patient's clinical condition 
or therapeutic interventions.
- AE unrelated: The relationship in time of the AE with the study drug indicates an unlikely
causal relationship, or other factors (concomitant medication or conditions) or other 
therapeutic interventions provide a satisfactory explanation for the AE.
Collection and follow up of adverse events
AEs may be recorded at each visit based on careful clinical observation of the patient, 
laboratory tests or spontaneously reports by the participant discovered as a result of 
general questioning by the study staff. All AEs will be recorded on the medical history and 
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.
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The following will be recorded for each event: description, severity (grade 1, 2, 3, 4 and 
5), duration (start and end dates), intensity, causal relationship with the drug (according 
to the previously attributability criteria) and study drug(s) for which this causal 
relationship is suspected, actions taken and outcome, using choices given on the patient’s
medical history. The investigator should report the underlying condition when a surgical or 
medical procedure is required as the event term, and the procedure as an action taken. For 
a preexisting AE that has worsened in terms of severity or frequency, the meaning of the 
change should be specified.
For all AEs, the Investigator must pursue and obtain information adequate both to 
determine the outcome of the AE and to assess whether it meets criteria for classification
as a serious adverse event (SAE) requiring immediate notification (see section 8.3). Follow-
up of the AE is required if the AE persists until the event resolves or stabilizes at a level 
acceptable to the Investigator.
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.
Adverse events (including pre-treatment adverse events) must be recorded on an 
Adverse Event Report Form. The investigator must provide information on the adverse 
event, preferably with a diagnosis, or at least with signs and symptoms; start and stop 
dates (and start and stop time if the adverse event lasts less than 24 hours); intensity; 
causal relationship to IMP; action taken; and outcome. If the adverse event is an 
overdose, the nature of the overdose must be stated (for example, medication error, 
accidental overdose, or intentional overdose) and the investigator shall notify sponsor or 
whoever assumes the tasks delegated by the sponsor, within 24 hours from the time of 
knowing about the event. The reporting circuit and form will be the same as for the SAE.
In order to avoid vague, ambiguous, or colloquial expressions, all AEs should be recorded 
in standard medical terminology using MedDRA dictionary, rather than the patient’s own 
words. The SAEs that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be 
followed until any of the following occurs: the event resolves, the event stabilizes, the 
event returns to baseline, if a baseline value/status is available, the event can be 
attributed to agents other than the study drug  or  to  factors  unrelated  to  study  
conduct,  it  becomes  unlikely  that  any  additional information can be obtained (subject 
or health care practitioner refusal to provide additional information, lost to follow-up after 
demonstration of due diligence with follow-up efforts).
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.
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The sponsor will keep a record of all AEs reported by investigators. These records will 
be submitted to the competent authorities when requested.
Pregnancy
Subjects will be instructed to notify the investigator if the subject or partner becomes 
pregnant.
If any pregnancy occurs during the course of the study, the investigator shall  notify  the 
sponsor or whoever assumes the tasks delegated by the sponsor within 24 hours of 
knowing about the event. Also, a follow-up of the pregnancy will be performed to document
its outcome and the state of health of the newborn. If the pregnancy outcome meets 
the SAE.
criteria or if the newborn presents a serious event, the procedures for reporting an SAE will 
be followed.
The report shall be made using the specific form for the notification of pregnancy, which 
must be sent by fax or email to the same contact who receives the SAE notifications .
Procedure for expedited reporting of serious adverse events and serious 
unexpected adverse reactions
Phamacovigilance activities will be delegated by the sponsor to Pharmacovigilance center 
(PV center) located at Hospital Clínic Barcelona CTU (Clinical Trial Unit),Barcelona , Spain.
8.3.1 Serious Adverse Events (SAEs)
The principal investigator or delegates will report immediately any SAE occurring during 
the study to the PV center regardless of their degree of causal relationship with the study
drug. Any such serious adverse event due to any cause, whether or not related to the study 
medication, occurring from signing of informed consent and up to 30 days after 
receiving initiating the study, must be reported within 24 hours of occurrence or when the 
investigator becomes aware of the event.
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 3 of this protocol within 24 hours from first 
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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.
SAEs forms should be sent immediately by fax or email to: CTU )clinical Trial Unit) . 
Farmacologia Clínica.Hospital Clínic Barcelona
Fax number: 93 2279877
Email address: cencinas@clinic.cat
 
   and  copy  acruceta@clinic.cat/ 
For SAEs, the investigator will provide the PV 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 fatal or life-threatening, the investigator should be required to provide with 
all additional information requested by the study coordinator, the EC and regulatory 
authorities to PV center..
The PV center shall keep detailed records of all the SAEs or the events of special interest 
which are notified by the investigators.
In the case of a medication error or if the investigational medicinal product is used outside 
the provisions of the protocol, while conducting the study, the investigator shall notify 
the PV center within 24 hours from the time of knowing about the event. The reporting 
circuit and form will be the same as for the SAE.
In the case of documenting medication errors or overdose, the sponsor will carry out 
the necessary actions for its management and prevention (specify when necessary).
Suspected Unexpected Serious Adverse Reactions (SUSARs)
The PV center will report any events that are serious and unexpected that may be related 
to the investigational products to the competent authorities in accordance with local 
regulations.
Reporting will be made using the SAE 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,
EudraCT No. 2019-004140-30                                                                                                                 36
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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.
Expedited reporting of other relevant safety information:
The FV center shall notify regulatory authorities, as soon as possible and no later than 15 
days after having knowledge of it, any information that could alter the benefit/risk 
relationship of the investigational medicinal product (e.g. an increase in the rate of 
occurrence of the expected SAR, SUSARs that occur after the completion of a clinical trial, 
new events related to the conduct of the trial or the development of the investigational
medicinal product, etc.).
Annual safety report
During the course of the study, the FV center will prepare periodic safety reports 
annually following the recommendations outlined in the ICH E2F guidelines, and they 
must be submitted to the regulatory authorities and the ECs involved following the 
timetable established in the legislation.
Opening of the blind and unmasking:  Not Aplicable 
8.6 Report to the invest igators
The sponsor shall present the safety information that could affect the safety of the patients
included in the study to the investigators as soon as possible.
The SUSAR information will be sent annually through a line listing, together with a summary 
of the data analysis. For masked studies, the SUSAR line listing will present worldwide 
SUSAR information, rather than by investigational medicinal product, in order not to break 
the blind for the investigator.
In addition, the investigator will be informed throughout the study about all safety 
aspects, including amendments to the protocol due to safety reasons.
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9. DATA HANDLING
Recording of data
Data generated and/or collected will be registered in participating centers using an 
electronic data management system with remote data entry. Completeness and 
plausibility checks will ensure the collection of high quality data. An electronic case report 
form (eCRF) will be designed, validated and implemented with REDCap electronic data 
capture tools (1,2) hosted at Hospital Clinic and will provide electronic data capture 
functionality (EDC) to the investigators. The system complies with the relevant 
international standards and provides the capability to perform all major data 
management activities within a consistent, auditable and integrated electronic 
environment (query management, data entry, data validation, report generation). An e-
CRF for each patient will be completed by authorized personnel.
Each centre will have access to their patients, and access will be secured by the use of 
unique personal logins. Each data recording or editing event will be logged in the 
database to allow better monitoring and database coordination.
The Sponsor or his delegates must ensure that data are recorded in the eCRF correctly 
and completely by authorized personnel. The investigator has to confirm the integrity of 
the data transferred to the eCRF by signature.
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 Ethics Committee if they request to inspect the study.
Source documents will be stored in the Investigators´s File. These documents will be kept for 
a minimum period of 25 years by the PI, after which they will be destroyed.
Data management
The Investigator must ensure the accuracy, completeness, legibility and  timelines of data 
reported in the CRF and all required reports. Any change or correction to the CRF must 
be dates, initialled and explained (if necessary).
All documentation derived from this study must be stored for 25 years.
Archiving and storage of data
The investigator is responsible for maintaining all records which enable the conduct of 
the clinical trial at the site to be fully documented, in compliance with ICH GCP filing 
standard. Timeliness and completeness of the documentation will be regularly checked by
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the clinical monitor. The documentation of the clinical trial including all the relevant 
correspondence should be kept by the investigator for the minimum period required by 
applicable regulatory and country-specific requirements.
All completed study related documents (e.g. eCRF, Informed consent forms, drug 
accountability logs, staff signature lists, Subject identification log, …) must be archived by 
25 years.
9.5 Audit and inspection
The investigators agree to comply with the requirements of the sponsor and the 
relevant authority for an audit or an inspection of the study.
The audit can apply to all stages of the study, from development of the protocol to 
publication of the results and filing the data used or produced in the study.
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10. QUALITY CONTROL AND QUALITY ASSURANCE
According to ICH/GCP guidelines, the sponsor should ensure that the trial is adequately 
monitored.
The purpose of monitoring is to verify that the rights and wellbeing of human subjects 
are protected; that the trial is accurate, complete and verifiable with source data and that 
the trial is conducted in compliance with the protocol, GCP and the applicable regulatory 
requirements. A monitoring plan will be designed by the lead CTU. The monitoring plan 
will establish the guideline for conducting all the monitoring activities.
To ensure homogeneity and the same quality standards, monitors in all study countries will 
be trained with the same procedures.
Source data will be verified during on-site monitoring visits. During the visits, the monitor 
will compare the data entered into the eCRF with the source documents. The nature and 
location of all source documents will be identified to ensure that all sources of original data 
required to complete the eCRF are known to the monitor and study-site personnel and are
accessible for verification. During monitoring visits, the relevant study-site personnel 
should be available, the source documentation accessible, and a suitable environment 
provided for review of suty- related documents. The monitor will meet the investigator The 
number of visits will be described in detail in the monitoring plan.
A close-out visits will be performed before the final closure of each centre. During this 
visit, medication accountability will be checked and arranged according to the indications
of the final version of the protocol.  Besides, a general overview and a final revision  of 
pending queries will be implemented, ensuring that all data and corresponding source 
documents are in place before the site closure.
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11. ETHICAL AND REGULATORY CONSIDERATIONS
Ethics approval
This study will be conducted in accordance with the protocol and ethical principles stated 
in the Declaration of Helsinki or the applicable guidelines on GCP, and all applicable local 
laws, rules, and regulations.
Requirements for ethical review as set forth in Directive 2001/20/EC of the European 
Parliament and of the Council of 4 April 2001 on the approximation of the laws, 
regulations.
and administrative provisions of the Member States relating to the implementation of 
good clinical practice (GCP) in the conduct of clinical trials on medicinal products for 
human use or other relevant local regulations for institutional review will be followed. 
The Protocol, informed consent form, Investigator’s Brochure and other required 
documents must be approved by the Ethics Committee before enrolment of subjects in 
the study. The letter of approval from the Ethics Committee, as well as a list of 
documents reviewed, will be filed in the Investigator Site File (ISF) and a copy will be filed 
in the trial master file (TMF) held by the Sponsor.
The Sponsor and his delegates, in collaboration with the investigator, will be responsible 
for reporting to the Ethics Committee all changes in research activity, including protocol 
amendments, updates of Investigator’s Brochures, annual safety reports, all 
unanticipated problems involving risks to human subjects, and study termination.
Regulatory considerations
In parallel to the submission to the Ethics Committee, the Sponsor has to obtain an 
authorization from the appropriate competent authority to conduct the clinical study. 
Subjects must not be entered into the study until the relevant Ethics Committee has issued 
its opinion and the CA has given authorization to conduct the study.
All substantial amendments must be submitted to the Ethics Committee and/or to the 
Competent authorities for approval.
Neither the investigator nor the sponsor will modify this protocol without a formal 
amendment by the sponsor. All protocol amendments must be issued by the sponsor, 
and signed and dated by the investigator. Protocol amendments must not be implemented 
without prior Ethics Committee approval, or when the relevant competent authority has 
raised any grounds for non-acceptance, except when necessary to eliminate immediate 
hazards to the subjects, in which case the amendment must be promptly submitted to the 
Ethics Committee and relevant competent authority.
Documentation of amendment approval by the investigator and Ethics Committee must 
be provided to the sponsor. During the course of the study, in situations where a departure 
from the protocol is unavoidable, the investigator or other physician in attendance will 
contact the appropriate sponsor representative. Except in emergency situations, this 
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contact should be made before implementing any departure from the protocol. In all 
cases, contact with the sponsor must be made as soon as possible to discuss the situation 
and agree on an appropriate course  of  action.  The  data  recorded  in  the  eCRF  and  
source  documents  will  reflect  any
departure from the protocol, and the source documents will describe this departure and 
the circumstances requiring it.
Responsibilities of the investigators
The investigator is responsible for ensuring that the study is performed in accordance with 
the protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable 
regulatory and country-specific requirements. Good Clinical Practice is an international 
ethical and scientific quality standard for designing, conducting, recording, and reporting 
studies that involve the participation of human subjects. Compliance with this standard 
provides public assurance that the rights, safety, and well-being of study subjects are 
protected, consistent with the principles that originated in the Declaration of Helsinki (and 
updated according to its last version, Fortaleza, Brazil, 2013), and that the study data are 
credible.
In addition, the investigator is responsible for giving information about the study to all 
staff members involved in the study or in any element of subject management, before and
during the course of the study.
The investigator is also responsible for ensuring the privacy, health, and welfare of the 
subjects during and after the study. The investigator(s) must be familiar with the 
background and requirements of the study and with the properties of the investigational 
product as described in the Investigator’s Brochure.
Before the start of the study, the investigator (or sponsor where required) will provide 
the Ethics Committee with current and complete copies of the following documents (as 
required by local regulations).
Informed consent
Each subject must give written consent according to local requirements after the nature of 
the study has been fully explained. The ICF(s) must be signed before performance of any 
study related activity. The ICF(s) that is/are used must be approved by both the sponsor 
and by the reviewing Ethics Committee and be in a language that the patient can read 
and understand. The informed consent should be in accordance with principles that 
originated in the Declaration of Helsinki (updated according to its last version, Fortaleza, 
Brazil, 2013), current ICH and GCP guidelines, applicable regulatory and country-specific 
requirements, and sponsor policy. Before enrollment in the study, the investigator or an 
authorized member of the study- site personnel must explain to potential subjects the 
aims, methods, reasonably anticipated benefits, and potential hazards of the study, and 
any discomfort that the participation in the study may entail.
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Subjects will be informed that their participation is voluntary and that they may 
withdraw consent to participate at any time. They will be informed that choosing not to 
participate will
not affect the care the subject will receive for the treatment of his or her disease. Subjects 
will be told that alternative treatments are available if they refuse to take part and 
that such refusal will not prejudice future treatment. Finally, they will be told that the 
investigator will maintain a subject identification register and that their records may be 
accessed by health authorities and authorized sponsor personnel without violating the 
confidentiality of the subject, to the extent permitted by the applicable law(s) or 
regulations. By signing the ICF the subject is authorizing such access, including permission 
to obtain information about his or her survival status, and agrees to allow his or her study 
physician to recontact the subject for the purpose of obtaining consent for additional 
safety evaluations, if needed, and subsequent disease-related treatments, or to obtain 
information about his or her survival status.
The subject will be given sufficient time to read the ICF and the opportunity to ask 
questions. After this explanation and before entry into the study, consent should be 
appropriately recorded by means of the subject’s personally dated signature. After 
having obtained the consent, a copy of the ICF must be given to the subject.
Patient confidentiality
The collection and processing of personal data from subjects enrolled in this study will 
be limited to those data that are necessary to fulfill the objectives of the study. Patient 
data will be under a patient code to ensure confidentiality and compliance with 
applicable data privacy protection laws and regulations.
Subjects will be codified with a study code that prevents their identity from being deduced.
The PI and duly authorized collaborators will compromise to maintain personal data 
strictly confidential, according to the corresponding country-specific requirements. The link
between the numeric code and real personal data from subjects will be rigorously kept by 
the PI. The informed consent obtained from the subject includes explicit consent for the 
processing of personal data and for the investigator/institution to allow direct access to 
his or her original medical records (source data/documents) for study-related monitoring, 
audit, Ethics Committee review, and regulatory inspection.
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.
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Duly authorized persons by the sponsor and the health authorities and the Ethics 
Committee may audit or inspect the trial. Personal information will not be publicly available, 
in compliance with Personal Data Protection regulation.
The subject has the right to request through the investigator access to his or her personal 
data and the right to request rectification of any data that are not correct or complete 
pursuant to European requirements (EU Directive 2016/679, on data protection). According
to the above law, patients can exercise their rights to data access, rectification, 
opposition, cancellation, request a copy and  portability, for which they must contact the 
study doctor.
In addition, the sponsor cannot make decisions as to the significance of any findings 
resulting from exploratory research. Therefore, exploratory research data will not be 
returned to subjects or investigators, unless required by law or local regulations. Privacy 
and confidentiality of data generated in the future on stored samples will be protected by 
the same standards applicable to all other clinical data.
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.
Patients will be informed that their clinical data will be incorporated into an automated 
study- specific file after and the results of the clinical trials and different studies 
conducted with samples can be communicated at scientific meetings, medical 
conferences or publications. However, patient’s identity or identifiable data will never be 
disclosed.
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12. FINANCING AND INSURANCE
Financing
This study is funded by a grant received from MSD  Sponsored Research grants
Insurance
It is considered a low-intervention  because complies with the following conditions:
a)
the investigational medicinal products, excluding placebos, are authorised;
b)
the use of the investigational medicinal products is evidence-based and supported by 
published scientific evidence on the safety and efficacy of those investigational medicinal 
products in any of the Member States concerned; and 
c)
the additional diagnostic or monitoring procedures do not pose more than minimal 
additional risk or burden to the safety of the subjects compared to normal clinical 
practice in any Member State concerned;
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13. PUBLICATION
The main results will be published according regulatory Spanish requirements.
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14. REFERENCES
- 1. GLOBAL AIDS UPDATE — Joint United Nations Programme on HIV/AIDS | 2016 
http://www.unaids.org/sites/default/files/media_asset/global-AIDS-update-2017_en.pdf
- 2. Cardo DM, Culver DH, Abiteboul D, et al. A case-control study of HIV seroconversion in 
health care workers after percutaneous exposure. N Engl J MEd 1997; 337(21):1485-1490.
- 3. CDC. Management of possible sexual, injecting-drug-use, or other nonoccupational 
exposure to HIV, including considerations related to antiretroviral therapy: Public Health 
Service statement. MMWR 1998;47(No. RR-17).
- 4. Black RJ. Animal studies of prophylaxis. Am J Med 1997; 102:39--44.
- 5. Sperling RS, Shapiro DE, McSherry GD. et al. Maternal viral load, zidovudine treatment, and
the risk of transmission of human immunodeficiency virus type 1 from mother to infant. N 
Engl J Med 1996; 335:1621--9.
- 6. Shaffer N, Chuachoowong R, Young NL, et al. Short-course zidovudine for perinatal HIV-1 
transmission in Bangkok, Thailand: a randomised controlled trial. Lancet 1999; 353:773--80.
- 7. Expert Advisory Group on AIDS (EAGA). Change to Recommended Regimen for Post-
exposure Prophylaxis. https://www.gov.uk.
- 8. Gesida. Documento de Consenso sobre Profilaxis post exposición ocupacional y no 
ocupacional en al VIH,. 2015. http://www.gesida-seimc.org/guias_clinicas.php
- 9. Puro V. Post-exposure prophylaxis for HIV infection. Italian Registry of Post-Exposure 
Prophylaxis [letter]. Lancet 2000; 355(9214):1556-1557.
- 10. Parkin JM, Murphy M, Pinching AJ, et al. Tolerability and side-effects of post-exposure 
prophylaxis for HIV infection [letter]. Lancet 2000; 355(9205):722-723.
- 11. Wang SA, Panlilio AL, Saah A, et al. Experience of healthcare workers taking postexposure 
prophylaxis after occupational HIV exposures: findings of the HIV Postexposure Prophylaxis 
Registry. Infect Control Hosp Epidemiol 2000; 21(12):780-785.
- 12. Rabaud C, Bevilacqua S, May T, et al. Tolerability of postexposure prophylaxis with 
zidovudine, lamivudine, and nelfinavir for human immunodeficiency virus infection. Clin 
Infect Dis 2001; 32(10):1494-1495.
- 13. Rabaud C, Burty C, Beguinot I, et al. Tolerability of postexposure prophylaxis with the 
combination of zidovudine-lamivudine and lopinavir-ritonavir for HIV infection. Clin Infect Dis 
2005; 40(2):303-305. 
- 14. Diaz-Brito V, Leon A, Clotet B, et al. Post-exposure prophylaxis for HIV infection: a clinical 
trial comparing lopinavir/ritonavir versus atazanavir each with zidovudine/lamivudine. Antivir
Ther 2012; 17(2):337-46. 
- 15. Orkin C1,2, Squires KE3,  Martin EAet al.  Doravirine/Lamivudine/Tenofovir Disoproxil 
Fumarate is Non-inferior to Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate in 
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Treatment-naive Adults With Human Immunodeficiency Virus-1 Infection: Week 48 Results of 
the DRIVE-AHEAD Trial. Clin Infect Dis. 2018 Aug 31. doi: 10.1093/cid/ciy540. 
-    16. Molina JM, Squires K, Hwang C et al.  Doravirine versus ritonavir-boosted darunavir in 
antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a randomised, 
double-blind, phase 3, non-inferiority trial. Lancet HIV. 2018 May;5(5):e211-e220. doi: 
10.1016/S2352-3018(18)30021-3. Epub 2018 Mar 25.
-  17. _ Sterrantino, G., Borghi, V., Callegaro, A. P., Bruzzone, B., Saladini, F., Maggiolo, F., … 
Zaccarelli, M. (2019). Prevalence of predicted resistance to Doravirine in HIV-1 positive 
patients after exposure to non-nucleoside reverse transcriptase inhibitors. International 
Journal of Antimicrobial Agents. doi:10.1016/j.ijantimicag.2019.02.007 
- 18. Wandeler, G., Buzzi, M., Anderegg, N., Sculier, D., Béguelin, C., Egger, M., & Calmy, A. 
(2019). Virologic failure and HIV drug resistance on simplified, dolutegravir-based 
maintenance therapy: Systematic review and meta-analysis. F1000Research, 7, 1359. 
doi:10.12688/f1000research.15995.2 
- 19 Inciarte A, Leal L, González E, León A, Lucero C, Mallolas J, Torres B, Laguno M, Rojas J, 
Martínez-Rebollar M, González-Cordón A, Cruceta A, Arnaiz JA, Gatell JM, García F; STRIBPEP 
Study Group.J Antimicrob Chemother. 2017 Oct 1;72(10):2857-2861. doi: 
10.1093/jac/dkx246.
- 20. Mayer KH, Mimiaga MJ, Gelman M, Grasso C. Raltegravir, tenofovir DF, and emtricitabine 
for postexposure prophylaxis to prevent the sexual transmission of HIV: safety, tolerability, and
adherence. J Acquir Immune Defic Syndr. 2012;59:354–359.
 
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Appendix I.
World Medical Association Declaration of Helsinki 
Ethical Principles for Medical Research Involving Human Subjects
World Medical Association
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by 
the: 29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983 41st WMA General Assembly, Hong 
Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 52nd 
WMA General Assembly, Edinburgh, Scotland, October 2000 53rd WMA General Assembly, 
Washington, DC, USA, October 2002 (Note of  Clarification added) 55th WMA General 
Assembly, Tokyo, Japan, October 2004 (Note of Clarification added)
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 64th WMA General 
Assembly, Fortaleza, Brazil, October 2013
Preamble
1-
The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data.
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should be applied with consideration of all other relevant paragraphs.
2-
Consistent with the mandate of the WMA, the Declaration is ad- dressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving 
human subjects to adopt these principles.
General Principles
3-
The Declaration of Geneva of the WMA binds the physician with the words, “The health 
of my patient will be my first consideration,” and the International Code of Medical Ethics
declares that, “A physician shall act in the patient's best interest when providing medical 
care.”
4-
It is the duty of the physician to promote and safeguard the health, well-being and rights 
of patients, including those who are involved in medical research. The physician's 
knowledge and conscience are dedicated to the fulfilment of this duty.
5-
Medical progress is based on research that ultimately must include studies involving 
human subjects.
6-
The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
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therapeutic interventions (methods, procedures and treatments). Even the best proven 
interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality.
7-
Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights.
8-
While the primary purpose of medical research is to generate new knowledge, this goal 
can never take precedence over the rights and interests of individual research subjects.
9-
It is the duty of physicians who are involved in medical research to protect the life, 
health, dignity, integrity, right to self- determination, privacy, and confidentiality of 
personal information of research subjects. The responsibility for the protection of 
research subjects must always rest with the physician or other health care professionals 
and never with the research subjects, even though they have given consent.
10- Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal or 
regulatory requirement should reduce or eliminate any of the protections for research 
subjects set forth in this Declaration.
11- Medical research should be conducted in a manner that minimises possible harm to the 
environment.
12- Medical research involving human subjects must be conducted only by individuals with 
the appropriate ethics and scientific education, training and qualifications. Research on 
patients or healthy volunteers requires the supervision of a competent and appropriately
qualified physician or other health care professional.
13- Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research.
14- Physicians who combine medical research with medical care should involve their patients
in research only to the extent that this is justified by its potential preventive, diagnostic 
or therapeutic value and if the physician has good reason to believe that participation in 
the research study will not adversely affect the health of the patients who serve as 
research subjects.
15- Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured.
Risks, Burdens and Benefits
16- In medical practice and in medical research, most interventions involve risks and 
burdens.
Medical research involving human subjects may only be con- ducted if the importance of 
the objective outweighs the risks and burdens to the research subjects.
17- All medical research involving human subjects must be pre- ceded by careful assessment 
of predictable risks and burdens to the individuals and groups involved in the research in 
comparison with foreseeable benefits to them and to other individuals or groups 
affected by the condition under investigation.
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Measures to minimise the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher.
18- Physicians may not be involved in a research study involving human subjects unless they 
are confident that the risks have been adequately assessed and can be satisfactorily 
managed.
When the risks are found to outweigh the potential benefits or when there is 
conclusive proof of definitive outcomes, physicians must assess whether to continue, 
modify or immediately stop the study.
Vulnerable Groups and Individuals
19- Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm.
All vulnerable groups and individuals should receive specifically considered protection.
20- Medical research with a vulnerable group is only justified if the research is responsive to 
the health needs or priorities of this group and the research cannot be carried out in a 
non- vulnerable group. In addition, this group should stand to benefit from the 
knowledge, practices or interventions that result from the research.
Scientific Requirements and Research Protocols
21- Medical research involving human subjects must conform to generally accepted scientific
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and adequate laboratory and, as appropriate, ani- mal 
experimentation. The welfare of animals used for research must be respected.
22- The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol.
The protocol should contain a statement of the ethical considerations involved and 
should indicate how the principles in this Declaration have been addressed. The protocol 
should include information regarding funding, sponsors, institutional affiliations, 
potential conflicts of interest, incentives for subjects and information regarding 
provisions for treating and/or compensating subjects who are harmed as a consequence 
of participation in the research study.
In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions.
Research Ethics Committees
23- The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This 
committee must be transparent in its functioning, must be independent of the re- 
searcher, the sponsor and any other undue influence and must be duly qualified. It must 
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take into consideration the laws and regulations of the country or countries in which the 
research is to be performed as well as applicable international norms and standards but 
these must not be allowed to reduce or eliminate any of the protections for research 
subjects set forth in this Declaration.
The committee must have the right to monitor ongoing studies. The researcher must 
provide monitoring information to the committee, especially information about any 
serious adverse events. No amendment to the protocol may be made without 
consideration and approval by the committee. After the end of the study, the researchers
must submit a final report to the committee containing a summary of the study’s 
findings and conclusions.
Privacy and Confidentiality
24- Every precaution must be taken to protect the privacy of re- search subjects and the 
confidentiality of their personal information.
Informed Consent
25- Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members 
or community leaders, no individual capable of giving informed consent may be enrolled 
in a research study unless he or she freely agrees.
26- In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding,
any possible conflicts of interest, institutional affiliations of the re- searcher, the 
anticipated benefits and potential risks of the study and the discomfort it may entail, 
post-study provisions and any other relevant aspects of the study. The potential subject 
must be informed of the right to refuse to participate in the study or to withdraw 
consent to participate at any time without reprisal. Special attention should be given to 
the specific information needs of individual potential subjects as well as to the methods 
used to deliver the information.
After ensuring that the potential subject has understood the in- formation, the physician 
or another appropriately qualified individual must then seek the potential subject’s 
freely-given in- formed consent, preferably in writing. If the consent cannot be expressed
in writing, the non-written consent must be formally documented and witnessed.
All medical research subjects should be given the option of being informed about the 
general outcome and results of the study.
27- When seeking informed consent for participation in a research study the physician must 
be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress. In such situations the informed con- sent must 
be sought by an appropriately qualified individual who is completely independent of this 
relationship.
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28- For a potential research subject who is incapable of giving in- formed consent, the 
physician must seek informed consent from the legally authorised representative. These 
individuals must not be included in a research study that has no likelihood of benefit for 
them unless it is intended to promote the health of the group represented by the 
potential subject, the research cannot in- stead be performed with persons capable of 
providing in- formed consent, and the research entails only minimal risk and minimal 
burden.
29- When a potential research subject who is deemed incapable of giving informed consent 
is able to give assent to decisions about participation in research, the physician must 
seek that assent in addition to the consent of the legally authorised representative. The 
potential subject’s dissent should be respected.
30- Research involving subjects who are physically or mentally in- capable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition 
that prevents giving informed consent is a necessary characteristic of the research group.
In such circumstances the physician must seek informed consent from the legally 
authorised representative. If no such representative is available and if the research 
cannot be delayed, the study may proceed without informed consent provided that the 
specific reasons for involving subjects with a condition that renders them unable to give 
informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research must be 
obtained as soon as possible from the subject or a legally authorised representative.
31- The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never adversely affect the patient-physician relationship.
32- For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek 
informed consent for its collection, storage and/or reuse. There may be exceptional 
situations where consent would be impossible or impracticable to obtain for such 
research. In such situations the re- search may be done only after consideration and 
approval of a research ethics committee.
Useof Placebo
33- The benefits, risks, burdens and effectiveness of a new inter- vention must be tested 
against those of the best proven inter- vention(s), except in the following circumstances:
Where no proven intervention exists, the use of placebo, or no intervention, is 
acceptable; or
Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no 
intervention is necessary to determine the efficacy or safety of an intervention
and the patients who receive any intervention less effective than the best proven one, 
placebo, or no intervention will not be sub- ject to additional risks of serious or 
irreversible harm as a result of not receiving the best proven intervention.
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Extreme care must be taken to avoid abuse of this option.
Post-Trial Provisions
34- Inadvanceofaclinicaltrial, sponsors,researchersandhostcoun- try governments should 
make provisions for post-trial access for all participants who still need an intervention 
identified as ben- eficial in the trial. This information must also be disclosed to par- 
ticipants during the informed consent process.
Research Registration and Publication and Dissemination of Results
35- Every research study involving human subjects must be registered in a publicly accessible
database before recruitment of the first subject.
36- Researchers, authors, sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research. Researchers have 
a duty to make publicly available the results of their research on human subjects and are 
accountable for the completeness and accuracy of their reports. All parties should 
adhere to accepted guidelines for ethical reporting. Negative and inconclusive as well as 
positive results must be published or otherwise made publicly avail- able. Sources of 
funding, institutional affiliations and conflicts of interest must be declared in the 
publication. Reports of re- search not in accordance with the principles of this 
Declaration should not be accepted for publication.
Unproven Interventions in Clinical Practice
37- In the treatment of an individual patient, where proven inter- ventions do not exist or 
other known interventions have been ineffective, the physician, after seeking expert 
advice, with in- formed consent from the patient or a legally authorised repre- sentative, 
may use an unproven intervention if in the physi- cian's judgement it offers hope of 
saving life, re-establishing health or alleviating suffering. This intervention should subse- 
quently be made the object of research, designed to evaluate its safety and efficacy. In all
cases, new information must be re- corded and, where appropriate, made publicly 
available.
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