Conditions: HIV-1-infection
Keywords: Doravirine
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 30
Healthy volunteers: no

Brief summary:
This study aims to evaluate the ability of Doravirine to penetrate the genital tract and suppress viral replication and provide evidence for the use of Doravirine as part of treatment strategies as prevention.

Detailed description:
Objectives:

* To determine Doravirine concentrations in seminal plasma and cervicovaginal fluid in HIV-1 infected male and female individuals receiving antiretroviral therapy (ATR) with Doravirine plus Descovy®.
* To evaluate HIV-1 viral load in seminal plasma and cervicovaginal fluid in HIV-1 infected male and female individuals receiving ART with Doravirine plus Descovy®.

Study Phase:

Phase II

Study Design:

Open label, single arm, single center, prospective study.

Study Disease:

HIV-1 infection

Study Endpoints:

* Concentration of Doravirine in seminal plasma and cervicovaginal fluid in HIV-1 infected male and female individuals, respectively, 8 weeks after switching to Doravirine plus Descovy®.
* HIV-1 RNA in seminal plasma and cervicovaginal fluid in HIV-1 infected male and female individuals, respectively, 8 weeks after switching to Doravirine plus Descovy®.

Target Population:

Male and female adult HIV-1 infected patients receiving standard ART with tenofovir alafenamide/emtricitabine (TAF/FTC), tenofovir disoproxil fumarate/emtricitabine or abacavir/lamivudine , plus an non-nucleoside reverse transcriptase inhibitor, a boosted protease inhibitor or an integrase inhibitor during at least 3 months, with plasma HIV-1 RNA suppression (\<40 copies/mL) during at least 6 months.

Number of Subjects Planned:

15 male and 15 female individuals.

Study duration:

16 weeks

Arms:
arm 1: Doravirine (MK-1439) 100 mg administered orally once daily in combination with Tenofovir alafenamide (TAF) and emtricitabine (FTC) co-formulated as single tablet (Descovy® TAF/FTC 25/200 mg) and administered orally once daily during 16 weeks

Interventions: intervention 1: Doravirine intervention 2: Descovy
Intervention descriptions: intervention 1: Doravirine 100 mg tablet intervention 2: Tenofovir alafenamide 25 mg / emtricitabine 200 mg tablet

Protocol document:
SAP_002.pdf: 
Statistical Analysis Plan 
 
DORAGEN 
SAP v 1.0: 06/05/2019 
DORAGEN 
 
Statistical Analysis Plan 
 
TRIAL FULL TITLE 
Doravirine concentrations and antiviral activity in genital fluids in 
HIV-1 infected individuals (“DORAGEN Study”) 
SAP VERSION 
1.0 
SAP VERSION DATE 
06/05/2019 
Protocol Version (SAP 
associated with) 
1.2 
 
Principal Investigator 
Daniel Podzamczer, M.D, PhD. 
HIV and STD Unit -Infectious Diseases Department 
Hospital Universitari de Bellvitge  
Author 
Antonio Navarro, MSc 
HIV and STD Unit -Infectious Diseases Department 
Hospital Universitari de Bellvitge  
Protocol identification number: DORAGEN 
ClinicalTrials.gov Identificator: NCT04097925  


Statistical Analysis Plan 
 
DORAGEN 
SAP v 1.0: 06/05/2019 
DORAGEN 
 
Signature page 
 
Principal investigator:    
 
 
 
 
Daniel Podzamczer (06/05/2019) 
 
 
Author:      
 
 
 
 
Antonio Navarro (06/05/2019) 
 
 


Statistical Analysis Plan 
 
DORAGEN 
SAP v 1.0: 06/05/2019 
DORAGEN 
 
Abbreviations 
HIV 
Human Immunodeficiency Virus 
TAF 
Tenofovir Alafenamide Fumarate 
FTC 
Emtricitabine 
ART 
Antirretroviral Treatment 
PK 
Pharmacokinetics 
PD 
Pharmacodynamics


Statistical Analysis Plan 
 
DORAGEN 
SAP v 1.0: 06/05/2019 
DORAGEN 
Table of contents 
1. 
Introduction .......................................................................................................................... 5 
2. 
Study Design .......................................................................................................................... 5 
3. 
Aims and Objectives .............................................................................................................. 6 
4. 
Outcomes .............................................................................................................................. 6 
5. 
Population to be analyzed ..................................................................................................... 6 
6. 
Analyses ................................................................................................................................. 6 
7. 
Missing data .......................................................................................................................... 6 
 


Statistical Analysis Plan 
 
DORAGEN 
SAP v 1.0: 06/05/2019 
DORAGEN 
 
 
1. Introduction 
 
The aim of this project is to assess Doravirine concentrations in seminal plasma and 
cervicovaginal fluid in HIV-1 infected male and female individuals receiving ART with 
Doravirine plus TAF/FTC. 
This statistical analysis plan (SAP) will give more detailed descriptions of the endpoints in the 
study and the corresponding analyses. 
2. Study Design 
 
Study subjects will be selected from the routine control visits in the outpatient clinic of the HIV 
and STD Unit at the Bellvitge University Hospital. Asymptomatic, HIV-1 infected individuals and 
be on stable ART continuously or ≥3 consecutive months and Plasma HIV-1 RNA at <40 
copies/mL for at least 3 months will be recruited. 
This is Pilot study, Open label, single arm, single center, prospective study. Study patients will 
receive one tablet of Doravirine 100 mg administered in combination with FTC and TAF 
(Descovy®) ).  
Clinic visits will be performed at 3 time points: baseline, week 4 and week 8, only in  baseline 
and w8 HIV-1 RNA viral load and Doravirine cervicovaginal fluid and seminal plasma 
concentration will be assessed. 
2.1 Sample Size. 
Fifteen male and fifteen female individuals will be included in the study. This is a study 
designed to obtain information about doravirine concentrations and HIV viral suppression in 
seminal plasma and cervicovaginal fluid. The study design is similar to other studies evaluating 
PK and PD of antiretroviral drugs in these compartments.  
 
 


Statistical Analysis Plan 
 
DORAGEN 
SAP v 1.0: 06/05/2019 
DORAGEN 
3. Aims and Objectives 
This study will address these unknowns and provide additional evidence for the scientific 
rational for the use of Doravirine in treatment and prevention strategies. 
4. Outcomes 
 
- Concentration of Doravirine in seminal plasma and cervicovaginal fluid in HIV-1 infected male 
and female individuals, respectively, 8 weeks after switching to Doravirine plus TAF/FTC. 
- HIV-1 RNA in seminal plasma and cervicovaginal fluid in HIV-1 infected male and female 
individuals, respectively, 8 weeks after switching to Doravirine plus TAF/FTC. 
4.1 Safety outcomes 
Adverse events 
Adverse events are reported at each clinic visit. 
Concomitant medications 
 Usage of medications during study period will be recorded. 
5. Population to be analyzed 
Per Protocol (PP)  
All randomised study subjects completing the whole study period (complete cases). For a 
specific analysis, study subjects with missing data on any of the variables in the model will be 
excluded from the analysis. 
6. Analyses 
All outcomes will be presented using descriptive statistics; normally distributed data by the 
mean and standard deviation (SD) and skewed distributions by the median and interquartile 
range (IQR). Binary and categorical variables will be presented using counts and percentages. 
The primary analysis will determine the Doravirine concentration in cervicovaginal fluid and 
seminal plasma and blood plasma, and the HIV-1 viral load in cervicovaginal fluid and seminal 
plasma and blood plasma. 
7. Missing data 
Subjects with missing data will be excluded for the analysis. 

ICF_003.pdf: 
 
 
 
 
 
 
 
 
 
PATIENT INFORMATION SHEET 
 
AND 
 
 
INFORM CONSENT FORM 


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INFORM PATIENT SHEET 
 
Title: “Doravirine concentrations and antiviral activity in genital fluids in HIV-1 
infected individuals(“DORAGEN Study”) 
Sponsor: Fundació Lluita contra la SIDA 
 
The Infectious Diseases Service - HIV Unit of the University Hospital of Bellvitge through 
Dr. Daniel Podzamczer (Principal Investigator of the study) is conducting a clinical 
research study to which he is invited to participate. (Contact: 93 260 7667) 
 
The male and female genital tract act as reservoirs for HIV and also contribute to the 
transmission of the virus sexually due to the presence of HIV in semen and cervical fluid. 
Effective antiretroviral treatment (ART) for people with human immunodeficiency virus 
(HIV) infection significantly lowers the risk of sexually transmitted infection among patients 
treated with their sexual partners. Transmission of HIV through sexual intercourse is 
intimately related to the presence of virus with infective capacity in genital secretions and 
rectal tissue/fluid and the effectiveness of ART in preventing new sexually transmitted 
infections is associated with reduction of viral load in these compartments. Therefore, the 
ability of different antiretroviral drugs to reach genital secretions and reach sufficient 
concentrations to suppress viral replication in this compartment is of particular importance 
in the prevention of new HIV infections. The levels of each antiretroviral drug and its 
antiviral activity in the genital tract and rectum may vary depending on the characteristics 
of each drug. On the other hand, higher or lower concentrations of drugs and their antiviral 
activity may influence the time needed to achieve viral suppression, which may also be 
important in reducing the risk of sexual transmission of HIV. 
 
Doravirine is a new drug in the family of non-nucleoside reverse transcriptase inhibitors 
(ITINN) which is active against viruses with resistance to other ITINN and which, due to its 
pharmacokinetic properties, can be administered once a day. Doravirine in combination 
with 2 nucleoside/nucleotide analog reverse transcriptase inhibitors (ITIAN) has been 
shown to be no less effective than another ITINN (efavirenz) and a protease inhibitor drug 
(darunavir), 
both 
also 
in 
combination 
with 
2 
ITIAN 
(tenofovir/emtricitabine 
oabacavir/lamivudine), as well as a good safety profile and tolerable, in phase III clinical 
trials, in adult patients with type 1 HIV infection who had not previously received 
treatment. 


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Therefore, Doravirine is a new option for the treatment of HIV infection, effective and with 
a favorable safety profile. However, as it is a newly introduced drug, there is no 
information about Doravirine concentrations and its effectiveness in maintaining viral 
suppression in genital fluids in patients with HIV infection. 
This study can provide information on these issues, which will allow a better 
understanding of the drug and its potential both for the treatment of HIV infection and to 
prevent its transmission. 
 
Objectives 
 
The objectives of this study are:: 
1- To determine the concentrations of Doravirine in seminal plasma and 
cervicovaginal fluid in men and women with HIV-1 infection who modify their 
antiretroviral treatment to Doravirine in combination with tenofovir alafenamide and 
emtricitabine (Descovy®). 
2- Study the viral load of HIV in seminal plasma and cervical fluid in men and women 
with HIV-1 infection who modify their antiretroviral treatment to Doravirine in 
combination with tenofovir alafenamide and emtricitabine (Descovy®). 


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Details of the study 
 
This study will involve 15 men and 15 women over the age of 18, with HIV-1 infection, 
who are already receiving antiretroviral treatment and maintain undetectable plasma viral 
load for at least the previous 6 months. Participants will be offered to change their 
treatment to Doravirine + Tenofovir Alafenamide/Emtricitabine. At 8 weeks of treatment 
with Doravirine + Tenofovir Alafenamide/Emtricitabine concentrations of Doravirine and 
viral load of HIV in blood plasma and seminal plasma in male participants and in blood 
plasma and cervical fluid in the women participants. All study procedures will be 
developed at the University Hospital of Bellvitge. 
The duration of the study shall be 3 months. 
 
In accordance with the current legal regulations of clinical trials in our country, RD 
1090/2015, this study has been approved by the Spanish Agency for Medicines and 
Medical Devices (AEMPS) and by a Clinical Research Ethics Committee with medicines 
(CEIm), an independent committee that oversees the rights, safety and well-being of 
people involved in clinical trials.  This study will be carried out following the guidelines and 
standards of Good Clinical Practice, in accordance with Spanish legislation and the 
Declaration of Helsinki. 
 
Discomforts and risks arising from the study: 
Patients participating in the study will follow a stricter control than usual, with clinical 
controls at the baseline visit, week 4 and week 8, and analytical in the baseline visit and 
week 8. In addition, an additional follow-up visit will be performed one month after the end 
of the study. 
 
Before starting the study: 
Screening visit: 
If you decide to participate in the study, we will ask you to sign this informed consent 
before being included.  
In this visit we will make: 
 
A review of your medical history 
 
A physical examination  
 
A review of your medication 
 
Signature of consent 
 


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During the study: 
Study visits:  
At the baseline visit and week 8 visit of the study, a blood draw will be done to determine 
the viral load of HIV. In addition, other tests, similar to those carried out for the follow-up of 
patients with HIV infection in routine clinical practice (blood count, basic biochemistry and 
CD4 lymphocyte count)  
Male patients will be asked at baseline and at week 8 to provide a semen sample, which 
should be delivered within 2 to 4 hours of collection. 
In the case of female patients, a sample of cervical vaginal fluid will be obtained at each of 
these visits (baseline and week 8). 
 
Collection of blood samples:  
It consists of obtaining a blood sample from the vein in the anterior area of the elbow. 
Risks associated with a blood draw are pain, bruising, bleeding, or other discomfort at the 
location of the prick. In rare cases anemia, fainting or infection of the spot of the prick may 
appear. Precautions will be taken to avoid or minimize these problems. 
The blood extractions will be carried out by the nursing staff of the HIV and STI Unit of the 
University Hospital of Bellvitge. The amount of blood to be drawn at each of the study 
visits shall be 30 mL. 
Obtaining the cervical fluid samples:  
A speculum (commonly used for gynaecological examinations) will be used to obtain 
cervical fluid to locate the vaginal fornix (located in the deepest part of the vaginal wall) 
and a small amount of flow is aspirated through a syringe. 
These procedures will be performed by doctors experienced in the use of these 
techniques.  
 
*In compliance with the Biomedical Research Act 14/2007, it is noted that the storage of 
biological samples (blood, semen and cervical fluid) is plannedin existing freezers in the 
HIV and STI Unit and/or the Microbiology Service of the University Hospital of Bellvitge, 
for the purpose of possible further analysis, either within the study or for other studies (in 
this case always requesting your consent again) which in no case will include genetic 
analysis. 
Study medication 
Doravirine is approved by the European Medicines Agency (EMA) for the treatment of 
HIV-1 infection, under the trade name Pifeltro, although it is not yet marketed in Spain. 


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In previous clinical trials Doravirine has been well tolerated serious adverse reactions 
were very rare.  
 
The most commonly reported adverse reactions (5% or higher) are: 
 
-  Nausea (7%) 
-  Headache (6%) 
-  Fatigue (6%) 
-  Diarrhea (5%) 
-  Abdominal pain (5%) 
-  Dizziness (3%) 
 
(Source: Datasheet of Doravirina (Pifeltro®)  
 
 
Medication Not allowed during the study 
The use of some other drugs is contraindicated or should be performed with caution when 
administered simultaneously with Doravirine/FTC/TAF. For this reason, the following 
drugs are not allowed during the study: 
 Androgen receptor inhibitors: enzalutamide. 
 • Anticomycials: carbamazepine, oxcarbazepine, phenobarbital, phenytoin. 
 • Antimycobacterians: rifampicin, rifapentin.  
 • Ctotoxics: mitotane.  
 • Antiretrovirals: efavirenz, nevirapine, etravirin.  
 • Herbalist products: San Juan herb (Hypericum perforatum).  
 
Do not use medicines (both over-the-counter and over-the-counter) without consulting the 
study doctor. The study physician will explain the need to avoid certain medications during 
the study, including contraindications. New drugs may be identified later that need to be 
added to the list of drugs not to be taken during the study 
 
After the study 
Once the study is completed, your doctor will decide on the most appropriate antiretroviral 
treatment regimen for you, either Doravirine + FTC/TAF or another combination in the 
event that Doravirine is not yet commercially available in Spain or at our center. 


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What are the expected benefits and potential risks of this study? 
Possible benefits: 
By participating in this study, you will receive antiretroviral treatment that has 
demonstrated high efficacy and excellent tolerability in different clinical trials. It is 
expected that with this treatment its plasma viral load is reduced and the objective of the 
treatment is to achieve a plasma viral load level lower than the limits of detectability of the 
techniques used in clinical practice (<40 copies/mL). In this sense, it is possible that 
Doravirine does not provide a clinical benefit superior to that achieved with other 
combinations of antiretrovirals.  
Their participation in this study will allow to know if the drug Doravirine reaches adequate 
concentrations in semen and cervical fluid and if the combination of Doravirine with 
TAF/FTC allows to achieve an adequate suppression of the viral load of HIV in these 
reservoirs, which may benefit other people infected with HIV in the future. 
Possible risks: 
The derivatives of procedures for extracting blood samples from rectal tissue samples.  
According to the selection criteria for the study, in which the possibility of resistance to the 
study drugs should be ruled out, a failure of treatment with Doravirine and TAF/FTC due 
to lack of efficacy is not foreseeable. However, if this happens, your doctors will decide 
which treatment is best for you in that situation.   
 
Costs: 
This study does not cost you anything.  
 
Compensation: 
Financial compensation is foreseen for their participation in the study of €175. 
 
Confidentiality 
The confidentiality of the personal information of the participants will be guaranteed in 
accordance with current legal regulations (EU Regulation 2016/679 General Data 
Protection (GDPR) of the European Parliament and of the Council of 27 April 2016). 
During this study, study physicians will record information about you, your health, and 
your participation in the study in forms called data collection notebooks. 
In order to ensure that the data collected during the study is treated confidentially, your 
data shall be identified by a code, your name and any other information which allows you 
to be identified directly in the data collection logbooks. 


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Only your study doctors/collaborators will be able to relate such data to you and your 
medical history. 
Moreover, as stipulated in current legal regulations, you can exercise your rights of 
access, rectification, cancellation or opposition (ARCO rights) with respect to your 
personal data collected, for which you must contact your study doctor. Likewise, you can 
exercise your rights of access, rectification, cancellation, opposition, limitation of the 
processing of data that are incorrect, request a copy or be transferred to a third party 
(portability) of the patient on the data you have provided for the study (PARSOL rights). 
To exercise their rights, the participant may contact the researcher or the data protection 
officer of the institution (josue.sallent@ticsalutsocial.com).           
In case the study data are transferred to third countries outside the EU or EEA (European 
Economic Area), the promoter guarantees a level of data protection at least equivalent to 
that granted by European legislation. 
 
Civil liability: 
We inform you that if you have a health insurance policy, it may not cover participation in 
a clinical trial. 
Likewise, it is possible that your participation in this clinical trial may modify the general 
and individual conditions (coverage) of your insurance policies (life, health, accident) and, 
therefore, we recommend that you contact your insurance company and inform you of 
your participation in it to determine could affect your current insurance policy or in the 
event that you will contract a new policy.  
The promoter of the study has signed a civil liability insurance policy with the company 
Zurich Insurance PLC branch in Spain in accordance with the requirements set out in RD 
1090/2015, which covers any damages they may experience as a result of their 
participation in the trial. Policy No: 00000105553366. 
 
Study participation: 
To participate in the study you do not need to make the decision at this time, you can take 
this Information Sheet home and meditate on it long enough and consult your participation 
with your family or regular doctor.  
You participate in this study on a voluntary basis and may withdraw from the study at any 
time without having to explain or be affected by your subsequent attendance at our 
Consultation.  
Once you have signed the Informed Consent, you will keep a copy of this document. 
 
There is the possibility of exclusion from the trial by the sponsor or the researchers, in 
case of safety problems or non-compliance with the procedures established in the study. 


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In the event of cancellation of the trial by the sponsor, participants shall be informed of the 
reasons. 
Any new information regarding drugs used in the study that may affect your decision to 
continue the study will be communicated to your doctor as soon as possible and, if 
necessary, a new consent will be signed. 
Contact for information: 
In case of any questions or problems related to your infection or the treatment 
administered, outside of working hours, you can contact the principal investigator of the 
study:   (Please insert name and telephone of the investigator) 
                           Dr. ........................................ 
                           Tel.:   .................................. 
 
If you agree to participate in this study, please express your consent by signing on the 
appropriate site:


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INFORM CONSENT 
 
Me, (name and surname).............................................................................., after having 
read the information sheet that has been given to me, about the study "Concentrations of 
Doravirine and antiviral activity in genital fluids in patients with HIV-1 infection (DORAGEN 
Study)" and ask the clarifying questions about it to the Dr.................................... from 
Hospital.................................................................................................................................
 
 
 
I agree with everything related to this study and freely agree to participate in it and that my 
data can be used for research purposes as stated in the patient information sheet. 
Comprendo que mi participación es voluntaria. 
 
I understand that I can withdraw from the studio: 
Anytime. 
Without having to explain. 
Without any impact on my medical care. 
 
 
Patient signature  
 
 
 
 
 
Investigator signature  
Date 
 
 
 
 
 
 
 
Date 
 
 
You will receive a copy of this document, once you have signed it, to keep with your 
records. 

Prot_000.pdf: 
Protocol 
Version 1.2 (06/05/2019) 
 
DORAGEN Study 
 
 
EudraCT 2018-003921-27 
 
 
 
 
 
 
1 
 
CLINICAL STUDY PROTOCOL 
 
 
 
 
 
Doravirine concentrations and antiviral activity in genital fluids in 
HIV-1 infected individuals 
(“DORAGEN Study”) 
 
 
Protocol ID: DORAGEN 
Version: 1.2 (06/05/2019) 
 
EudraCT Number: 2018-003921-27 
 
 
 
 
 
 
 
 
Promoter: 
Lluita contra la SIDA Foundation  
 
 
 
Principal Investigator: Daniel Podzamczer Palter. Hospital Universitari de Bellvitge 
 
Source of financing:Lluita contra la SIDA Foundation in collaboration with Merck 
Sharp & Dome. 
 


Protocol 
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1. PROTOCOL SYNOPSIS 
 
1.1. Promoter Identification: 
Lluita contra la SIDA Foundation (Fundació Lluita contra la SIDA); Hosp. Univ. 
Germans Trias i Pujol. Badalona Barcelona, Spain 
 
1.2. Study Title: 
Doravirine concentrations and antiviral activity in genital fluids in HIV-1 infected 
individuals (“DORAGEN Study”). 
 
1.3. Protocol ID:  
EudraCT Number: 2018-003921-27 
 
1.4. Principal Investigador: 
Daniel Podzamczer, M.D, PhD. 
HIV and STI Unit 
Department of Infectious Diseases. 
Hospital Universitari de Bellvitge. L´Hospitalet de Llobregat. Barcelona. Spain 
 
1.5. Study Center: 
HIV and STI Unit. Department of Infectious Diseases. 
Hospital Universitari de Bellvitge. L´Hospitalet de Llobregat. Barcelona. Spain 
 
1.6. Responsible for monitoring  
HIV Unit monitoring team 
HIV ans STI Unit. Department of Infectious Diseases. 
Hospital Universitari de Bellvitge. L´Hospitalet de Llobregat. Barcelona. Spain 
 
1.7. Referral Ethics Committee: 
Clinical Investigation Ethics Committe of the Hospital Universitari de Bellvitge  
 
1.8. Test Product, Dose, and Mode of Administration: 
- Doravirine (MK-1439) 100 mg administered orally once daily in combination with  
Tenofovir alafenamide (TAF) and emtricitabine (FTC) coformulated as single tablet 
(Descovy® TAF/FTC 25/200 mg) and administered orally once daily.  


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1.9. Objectives: 
- To determine Doravirine concentrations in seminal plasma and cervicovaginal 
fluid in HIV-1 infected male and female individuals receiving ART with Doravirine 
plus TAF/FTC. 
 
-To evaluate HIV-1 viral load in seminal plasma and cervicovaginal fluid in HIV-1 
infected male and female individuals receiving ART with Doravirine plus TAF/FTC. 
 
1.10. Study Phase: 
Phase II  
 
1.11. Study Design: 
Open label, single arm, single center, prospective study.  
 
1.12. Study Disease: 
HIV-1 infection 
 
1.13. Study Endpoints: 
- Concentration of Doravirine in seminal plasma and cervicovaginal fluid in HIV-1 
infected male and female individuals, respectively, 8 weeks after switching to 
Doravirine plus TAF/FTC. 
-HIV-1 RNA in seminal plasma and cervicovaginal fluid in HIV-1 infected male and 
female individuals, respectively, 8 weeks after switching to Doravirine plus 
TAF/FTC. 
 
1.14. Target Population: 
Male and female adult HIV-1 infected patients receiving standard ART with 
TAF/FTC, tenofovir disoproxil fumarate/emtricitabine or  abacavir/lamivudina , plus 
an non-nucleoside reverse transcriptase inhibitor, a boosted protease inhibitor or 
an integrase inhibitor during at least 3 months, with plasma  HIV-1 RNA 
suppression (<40 copies/mL) during at least 6 months. 
 


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1.15. Number of Subjects Planned:  
15 male and 15 female individuals. 
 
1.16 Study duration: 
16 weeks  
 
1.17. Anticipated Study Calendar 
Anticipated Start Date: May 2019 
Recruiting Period: 4 weeks. Anticipated end date of the Recruiting Period:  June 
2019 
Anticipated end date: September 2019 
Analysis: October and November 2019 
Final Inform: January 2020  
These dates are yet to be confirmed.


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2. TABLE OF CONTENTS  
 
1. PROTOCOL SYNOPSIS ........................................................................................................................... 2 
3. GENERAL INFORMATION....................................................................................................................... 7 
3.1. Protocol ID ........................................................................................................................................... 7 
3.2. Study Type ........................................................................................................................................... 7 
3.3. Description of the Investigational medicinal products .................................................................... 7 
3.4.  Promoter Identification ...................................................................................................................... 7 
3.5. Technical services involved in the study ......................................................................................... 7 
3.6. Study medication supplier…………………………………………………………………………….. 8 
3.7. Monitoring ............................................................................................................................................. 8 
3.8. Principal investigator .......................................................................................................................... 8 
3.8. Co-investigators .................................................................................................................................. 8 
3.9. Study center ......................................................................................................................................... 8 
3.10. Referral Ethics Committee ............................................................................................................... 8 
3.11. Study timeline .................................................................................................................................... 8 
4.1. Backgroung and justification ............................................................................................................. 9 
4.2 References .......................................................................................................................................... 11 
4.3. Objetives............................................................................................................................................. 13 
5. STUDY DESIGN ....................................................................................................................................... 13 
5.1. STUDY PHASE ................................................................................................................................. 13 
6. SUBJECT POPULATION ........................................................................................................................ 13 
6.1.Subjects selection .............................................................................................................................. 13 
6.2. Inclusion Criteria................................................................................................................................ 13 
6.3. Exclusion Criteria .............................................................................................................................. 14 
6.4 Sample size ......................................................................................................................................... 14 
6.6. Treatment of patients at the end of the study ............................................................................... 15 
6.7. Criteria for discontinuation of study treatment .............................................................................. 15 
7. INVESTIGATIONAL MEDICINE PRODUCT ........................................................................................ 16 
7.1. Study regimen ................................................................................................................................... 16 
8. STUDY DEVELOPMENT AND EVALUATION OF THE RESPONSE ............................................. 18 
8.1. Response evaluation citeria ............................................................................................................ 18 
8.2. Procedures ......................................................................................................................................... 18 
8.3. Clinical Trial Management ............................................................................................................... 21 
9. ADVERSE EVENTS AND TOXICITY MANAGEMENT ...................................................................... 22 
10. ETHICAL ASPECTS .............................................................................................................................. 26 
10.1 Responsabilities and Study Management ........................................................................................ 27 
12. STATISTICAL ANALYSIS .................................................................................................................... 29 
Appendix A .................................................................................................................................................... 31 
 
 


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APPENDIX 
 
 
Appendix A GRADING SCALE FOR SEVERITY OF ADVERSE EVENTS AND 
LABORATORY ABNORMALITIES 
 


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3. GENERAL INFORMATION 
 
3.1. Protocol ID 
Study ID: DORAGEN 
 
EudraCT Number: 2018-003921-27 
 
Study Title: Doravirine concentrations and antiviral activity in genital fluids in HIV-1 
infected individuals (“DORAGEN Study”). 
 
3.2. Study Type 
Phase II, open label, single arm, single center, prospective study.  
 
3.3. Description of the Investigational medicinal products 
Doravirine (MK-1439) 100 mg administered orally once daily.  
Doravirine will be administered in combination with Tenofovir alafenamide (TAF) 
and emtricitabine (FTC) coformulated as single tablet (Descovy® TAF/FTC 25/200 
mg) and administered orally once daily.  
Doravirine and TAF/FTC tablets are capsule-shaped, film-coated tablets 
 
3.4.  Promoter Identification 
Fight AIDS Foundation (Fundació Lluita contra la SIDA). Hosp. Univ. Germans 
Trias i Pujol. Badalona • Barcelona, Spain 
 
3.5. Technical services involved in the study  
The HIV-1 RNA analyses will be performed in the Microbiology Department of the 
Hospital Universitari de Bellvitge.  
The analysis of tenofovir-diphosphate (TFV-DP) concentrations in SMC and 
PBMC as well as tenofovir (TFV) concentrations in SP and BP will be performed at 
the laboratory of the Division of Pharmacotherapy and Experimental Therapeutics, 
UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill 
(Chapel Hill, NC, USA).  
Haematological and biochemical parameters will be determined in the Clincal 
Analisys Department of the Hospital Universitari de Bellvitge, following the routine 
clinical practice.  


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3.6. Study medication supplier 
- Doravirine 100 mg tablets will be provided by Merck Sharp & Dome, the product 
manufacturer. 
- Descovy® (TAF/FTC 25/200 mg) will be provided by the Pharmacy of the 
Hospital Universitari de Bellvitge. 
 
3.7. Monitoring 
HIV and STI Unit – Monitoring Team, Infectious Diseases Department 
Hospital Universitari de Bellvitge. 
Tel: +34 93 260 76 67 or  +34 93 260 76 68.  Fax: +34 93 260 76 69 
 
3.8. Principal investigator 
Daniel Podzamczer, MD, PhD. 
HIV Unit -Infectious Diseases Department. Hospital Universitari de Bellvitge. 
 
3.8. Co-investigators 
Arkaitz Imaz, MD, PhD. 
Juan M Tiraboschi, MD, PhD. 
HIV and STI Unit - Infectious Diseases Department. Hospital Universitari de 
Bellvitge.  
 
3.9. Study center  
Hospital Universitari de Bellvitge  
 
3.10. Referral Ethics Committee 
Clinical Investigation Ethics Committe of the Hospital Universitari de Bellvitge  
 
3.11. Study timeline 
16 weeks 
Recruitment: 4 weeks 
Study period: 8 weeks 
Follow-up after the study end: 4 weeks 


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4. BACKGROUND 
 
4.1. Backgroung and justification 
 
The 
HIV-1/AIDS 
epidemic 
remains 
a 
global 
health 
problem 
of 
unprecedented dimensions, with approximately 37 million people living with HIV-1 
in 2015 [1].  
The advent of potent combined antiretroviral therapy (ART) led to a 
substantial mortality reduction in HIV infected patients, transforming HIV-1 
infection into a chronic disease in those patients who have access to treatment 
and who achieve durable virologic suppression [2]. In addition, the more 
favourable safety profile and simpler dosage of modern antiretroviral (ARV) drugs 
and combinations, have contributed to improve the efficacy of ART and the quality 
of life of HIV-infected individuals. 
The treatment of HIV-infected patients with currently available cART 
reduces the risk of HIV acquisition by their sexual partners [3-4]. However, the 
number of new infections has continued stable and even increased in particular 
groups such as men who have sex with men [5]. HIV transmission during 
unprotected sexual intercourse is associated with the presence of HIV in genital 
fluids, and the efficacy of ART in preventing new infection is based on the ability to 
reduce HIV viral load in these fluids [6-10]. On the other hand HIV suppression in 
cervicovaginal fluid (CVF) is also a key factor to prevent mother-to-child 
transmission during childbirth, which is extremely important taking into account 
that women represent more than half of all people living with HIV-1 worldwide, and 
nearly 60% of HIV-1 infections in sub-Saharan Africa [1]. 
Furthermore, HIV persistence in reservoirs constitutes a barrier for HIV 
eradication [11] and the male and female genital tract constitutes separate 
reservoirs for HIV [12].  
Therefore, the capability of antiretroviral (ARV) drugs to penetrate in the 
male and female genital tract is a key factor for achieving HIV suppression in 
these reservoirs, as well as for preventing sexual transmission of the virus [13-14] 


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and also, in the case of the female genital tract, to prevent mother-to-child 
transmission, and also to control.  
All ART regimens currently used in clinical practice have demonstrated high 
efficacy in terms of HIV-1 RNA suppression in blood plasma. However, the activity 
or certain ARV drugs in the male and female GT may be limited by the presence of 
natural barriers to drug penetration into these compartments. The ability of drugs 
to penetrate into the genital fluids depends on many variables including molecular 
size, lipophilicity, electric charge, plasma protein binding and active transport [13-
14].  
Doravirine is new NNRTI with activity against common NNRTI-resistant 
mutants that has demonstrated non-inferior efficacy campared to  efavirenz (both 
in combination with tenofovir/emtricitabine) and boosted darunavir (both in 
combination with tenofovir/emtricitabine or abacavir/lamivudine) as well as good 
tolerability profile in randomized, double-blind, phase III studies in ART-naïve HIV-
1-positive adult patients [15-16].  
However, a number of key issues regarding the capability of Doravirine to 
suppress HIV replication in male and female genital tract remain to be addressed, 
including: 
1. The pharmacokinetic (PK) profile of Doravirine given orally in stable, 
undetectable HIV-1 infected individuals in male and female genital fluids (semen 
and cervicovaginal)  
2. Maintenance of HIV suppression in male and female genital fluids. 
3. The correlation between blood plasma and male and female genital fluids 
Doravirine drug levels. 
This study will address these unknowns and provide additional evidence for 
the scientific rational for the use of Doravirine in treatment and prevention 
strategies. 
 


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4.2 References 
1. UN Joint Programme on HIV/AIDS (UNAIDS), Global AIDS Update 2016, 
available: 
http://www.unaids.org/sites/default/files/media_asset/global-AIDS-
update-2016_en.pdf [accessed 2 January 2016] 
2. Palella F, Delaney K, Moorman A, et al. Declining morbidity and mortality 
among patients with advanced HIV infection. HIV Outpatient Study Investigators. 
N Engl J Med. 1998;338:853-60. 
 
3. Donnell D, Baeten JM, Kiarie J, Thomas KK, Stevens W, Cohen CR, et al; 
Partners in Prevention HSV/HIV Transmission Study Team. Heterosexual HIV-1 
transmission after initiation of antiretroviral therapy: a prospective cohort analysis. 
Lancet. 2010;375:2092-8.  
4. Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy 
N, et al; HPTN 052 Study Team. Prevention of HIV-1 infection with early 
antiretroviral therapy. N Engl J Med. 2011;365:493-505. 
5. Kirby T. New HIV diagnoses in MSM in high-income countries. Lancet Infect 
Dis. 2015;15:23-4. 
6. Baeten JM, Kahle E, Lingappa JR, et al; Partners in Prevention HSV/HIV 
Transmission Study Team. Genital HIV-1 RNA predicts risk of heterosexual HIV-1 
transmission. Sci Transl Med. 2011;3:77ra29.  
7. Anderson JA, Ping LH, Dibben O, et al; Center for HIV/AIDS Vaccine 
Immunology. HIV-1 Populations in Semen Arise through Multiple Mechanisms. 
PLoS Pathog. 2010 Aug 19;6(8):e1001053. 
8. Zhang H, Dornadula G, Beumont M, et al. Human immunodeficiency virus type 
1 in the semen of men receiving highly active antiretroviral therapy. N Engl J Med. 
1998;339:1803-9. 
9. Lambert-Niclot S, Tubiana R, Beaudoux C, ET al. Detection of HIV-1 RNA in 
seminal plasma samples from treated patients with undetectable HIV-1 RNA in 
blood plasma on a 2002-2011 survey. AIDS. 2012;26:971-5. 
10. Chan DJ, Ray JE, McNally L, Batterham M, Smith DE. Correlation between 
HIV-1 RNA load in blood and seminal plasma depending on antiretroviral 
treatment status, regimen and penetration of semen by antiretroviral drugs. Curr 
HIV Res. 2008;6:477-84 


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11. Martinez-Picado J, Deeks SG. Persistent HIV-1 replication during antiretroviral 
therapy. Curr Opin HIV AIDS. 2016;11:417-23;   
12. Galvin SR, Cohen MS. Genital tract reservoirs. Curr Opin HIV AIDS. 
2006;1:162-6;   
13. Taylor S, Davies S. Antiretroviral drug concentrations in the male and female 
genital tract: implications for the sexual transmission of HIV. Curr Opin HIV AIDS. 
2010;5:335-43.  
14. Else LJ, Taylor S, Back DJ, Khoo SH. Pharmacokinetics of antiretroviral drugs 
in anatomical sanctuary sites: the male and female genital tract. Antivir Ther. 
2011;16:1149-67. 
15. Molina JM, Squires K, Sax PE, et al; DRIVE-FORWARD Study Group. 
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;5:e211-e220.  
16. Orkin C, Squires KE, Molina JM, et al; DRIVE-AHEAD Study Group. 
Doravirine/Lamivudine/Tenofovir 
Disoproxil 
Fumarate 
is 
Non-inferior 
to 
Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate in Treatment-naive Adults 
With Human Immunodeficiency Virus-1 Infection: Week 48 Results of the DRIVE-
AHEAD Trial. Clin Infect Dis. 2018. doi:10.1093/cid/ciy540. [Epub ahead of print]  
 
 
 


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5. STUDY DESIGN  
Open label, single arm, single center, prospective study.  
 
5.1. STUDY PHASE  
Phase II 
 
5.2. Objetives  
- To determine Doravirine concentrations in seminal plasma and cervicovaginal 
fluid in HIV-1 infected male and female individuals receiving ART with Doravirine 
plus TAF/FTC. 
 
-To evaluate HIV-1 viral load in seminal plasma and cervicovaginal fluid in HIV-1 
infected male and female individuals receiving ART with Doravirine plus TAF/FTC. 
 
6. SUBJECT POPULATION 
 
6.1.Subjects selection 
Male and female HIV-1 infected adults receiving an antiretroviral therapy ART. 
Subjects will be selected from the routine control visits in the outpatient clinic of 
the HIV and STD Unit at the Bellvitge University Hospital. 
 
6.2. Inclusion Criteria  
1. Asymptomatic, HIV-1 infected individuals ≥ 18 years of age.  
2. Be on a stable ART consisting of TAF/FTC, tenofovir disoproxil 
fumarate/emtricitabine or  abacavir/lamivudina, plus an non-nucleoside reverse 
transcriptase inhibitor, a boosted protease inhibitor or an integrase inhibitor, 
continously for at least 3 consecutive months preceding the screening visit.  
 3. Plasma HIV-1 RNA <40 copies/mL for at least 6 months at the Screening visit.  
4. Signed and dated written informed consent prior to inclusion.  
5. Female Subjects of Childbearing Potential* must agree to utilize a highly 
effective** method of contraception during heterosexual intercourse from the 
screening visit throughout the duration of the study. 


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(*)  A woman of Childbearing Potential is considered following menarche and until becoming post-
menopausala unless permanently sterileb.  
a) A postmenopausal state is defined as amenorrhea for 12 months without an alternative medical 
cause. 
d) Permenent sterility is defined as Documented hysterectomy, bilateral salpingectomy or bilateral 
oophorectomy 
(**) Highly effective methods of contraception as defined by the Clinical Trial Facilitation Group 
(CTFG) (“Recommendations related to contraception and pregnancy testing in clinical trials”, 
version 15/09/2014): 1. Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, transdermal); 2. Progestogen-only 
hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable); 3. 
Intrauterine device (IUD); 4. Intrauterine hormone-releasing system (IUS); 5. Bilateral tubal 
occlusion; 6. Vasectomised partner; 7. Sexual abstinence. 
 
6.3. Exclusion Criteria  
1. Severe hepatic impairment (Child-Pugh Class C)  
2. Ongoing malignancy  
3. Active opportunistic infection  
4. Resistance to any of the ARV included in the study or history of virologic failure 
with risk of resistance selection to any of the study drugs.  
5. Any verified Grade 4 laboratory abnormality  
6. ALT or AST ≥ 3xULN and/or bilirubin ≥ 1.5xULN  
7. Severe renal impairment (Estimated creatinine filtration rate <50mL/min).  
8. Females who are pregnant (as confirmed by positive serum pregnancy test) or 
breastfeeding. 
 
6.4 Sample size 
Fifteen male and fifteen female individuals will be included in the study. This is a 
study designed to obtain information about doravirine concentrations and HIV viral 
suppression in seminal plasma and cervicovaginal fluid. The study design is 
similar to other studies evaluating PK and PD of antiretroviral drugs in these 
compartments.  
 
6.5. Study duration  
The study will have a recruitment period of 4 weeks. 


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The study treatment period will be of 8 weeks.  
A follow up visit will be performed 4 weeks after the end of the study treatment 
period.  
 
6.6. Treatment of patients at the end of the study  
If at the end of the study doravirine is marketed in Spain, and the study treatment 
has resulted aeefective and safe, participants will be offered continue the same 
study treatment. 
If at the end of the study, participants refuse to continue taking the same treatment 
or doravirine is not yet marketed in Spain, participants will be offered to return to 
their previous treatment or to discuss other treatment options.  
 
6.7. Criteria for discontinuation of study treatment  
 
1. Grade III or IV laboratory abnormalities or Adverse Events related to the study 
drug, or that in the investigator’s opinion, advise against continuing taking the 
study drugs. 
2. Subject request to discontinue for any reason (withdrawal of consent). 
3. Protocol non compliance. 
4. Lost of follow up or death 
 
6.7.1. Managing of a study patient withdrawal 
In case of any study withdrawal, the information must be recorded in the Case 
Report Form. 
Detailed information about the date and reasons for discontinuation will be 
recorded. 
As a general rule, for all the premature discontinued patients, a clinical 
examination and all the tests specified in the final visit will be performed. 
The investigator will provide the appropiated medical care to the premature 
discontinued patient for any reason.  
 


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7. INVESTIGATIONAL MEDICINE PRODUCT 
 
7.1. Study regimen 
Study patients will receive Doravirine (MK-1439) 100 mg administered in 
combination with Tenofovir alafenamide (TAF) and emtricitabine (FTC) orally once 
daily.  
Doravirine 100 mg will be administered as a film-coated tablet, orally, once daily, 
without regard to food.  
TAF/FTC will be administered co-formulated as single tablet (Descovy® TAF/FTC 
25/200 mg).  Each film-coated tablet contains 25 mg of tenofovir alafenamide and 
200 mg of emtricitabine. TAF/FTC will be administered orally, once daily, without 
regard to food. 
 
7.1.1. Packaging and labelling  
The Promoter will register the study medication lot and expiry date to guarantee 
the treazability, collecting this information in the Case Report Form of each 
participant. 
The study medication (Doravirine) will be provided by the manufacturer, Merck 
Sharp & Dome, and will be sent to the Pharmacy of the Hospital University de 
Bellvitge. 
Descovy® (TAF/FTC 25/200 mg) will be provided by the Pharmacy of the Hospital 
Universitari de Bellvitge. 
Study medication (Doravirine) will be rellabelled by the HIV and STI Unit 
monitoring team once received at the hospital pharmacy. The lable will be in 
Spanish, as requested by the applicable Spanish Law. 
The information in the label will be: 
 
Study. EudraCT: 2018-003921-27 
Sponsor: Fight AIDS Foundation (Fundació Lluita contra la SIDA).  
Investigator: Dr. Daniel Podzamczer 
Content: Doravirine 100 mg. 
Oral administration 


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Patient number: XXXXXX 
Lot number: XXXXXX 
Expiry date: XXXXXX 
To be stored in the original package in order to protect from moisture. Keep the 
bottle tightly closed.  
Keep away form children 
USE FOR CLINICAL TRIAL 
 
7.1.2. Criteria for changing the treatment regimen during the study  
No changes in the ARV treatment regimen are expected during the study period. 
In case of virological failure, the appropiated treatment will be given to the patient 
in base to the genotypical resistence study. 
In case of Adverse Reactions related to the study drugs, the investigator will 
provide the patient with the treatment that he considers appropiate for the patient, 
anf the patient will be discontinued from the study. 
At the end of the study, if doravirine is marketed in Spain, and the study treatment 
has resulted aeefective and safe, participants will be offered continue the same 
study treatment. If participants refuse to continue taking the same treatment or 
doravirine is not yet marketed in Spain, participants will be offered to return to their 
previous treatment or to discuss other treatment options.  
 
7.1.3 Prior and concomitant medications 
 
Concomitant medication should only be used during patient participation in the 
study only when medically necessary. 
All the concomitant medications should be listed in the Case Report Form. 
 
MEDICATION DISALLOWED WITH DORAVIRINE 
 

• Androgen Receptors inhibitors: enzalutamide. 
• anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin. 
• antimycobacterials: rifampicin, rifapentine.  
• Cytotoxic Agents: mitotane.  
• HIV Antiviral Agents: efavirenz, nevirapine, etravirine.  


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• herbal products: St. John’s wort (Hypericum perforatum).  
 
7.1.4  Investigational Medicinal Product Management 
Doravirine will be stored at controlled room temperature. It will be stored in the 
original package in order to protect from moisture. The bottle sould be tightly 
closed. Until dispensed to the subjects, all bottles of study drugs should be stored 
in a secure area, accessible only to authorized site personnel. 
 
7.1.5. Compliance assessment test 
Adherence to the study treatment will be assessed at each study visit by the study 
investigators. 
 
8. STUDY DEVELOPMENT AND EVALUATION OF THE RESPONSE 
 
8.1. Evaluation criteria  
.Primary study endpoints: 
- Concentration of Doravirine in seminal plasma and cervicovaginal fluid in HIV-1 
infected male and female individuals, respectively, 8 weeks after switching to 
Doravirine plus TAF/FTC. 
-HIV-1 RNA in seminal plasma and cervicovaginal fluid in HIV-1 infected male and 
female individuals, respectively, 8 weeks after switching to Doravirine plus 
TAF/FTC. 
 
8.2. Procedures 
Eligibility criteria will be evaluated in a screening visit before the inclusion of 
patients in the study.  
Patients will be evaluated at baseline, weeks 4 and 8 (end of the study), and 4 
weeks after the end of the study (follow up visit).  
 
8.2.1. Clinical records and physical examination 
At baseline, demographic data of interest related to HIV infection will be collected 
to characterize the study population: gender, date of birth, HIV diagnosis date, HIV 


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risk factor, CDC stage, opportunistic infections, malignancies or previous 
diseases, concomitant treatments).  
At baseline a complete physical examination will be performed. At the following 
visits, a physical examination oriented to symptoms will be performed. 
 
8.2.2. Laboratory Procedures 
 
HIV-1 RNA quantification 
At baseline and week 8 visits HIV-1 RNA will be determined in paired blood 
plasma and seminal plasma samples in male participants, and paired blood 
plasma and cervicovaginal fluid samples in female participants. HIV-1 RNA will be 
assessed by real-time PCR assay (Abbott Real Time HIV-1) with a quantification 
limit of 40 copies/mL. 
 
Doravirine concentrations  
At week 8 visit doravirine concentrations will be determined in paired blood plasma 
and seminal plasma samples in male participants, and paired blood plasma and 
cervicovaginal fluid samples in female participants.  
Drug concentrations will be determined at the end of the dosing interval (C24h). 
Doravirine concentrations (total and protein-unbound) will be quantified using a 
validated liquid chromatography-tandem mass spectrometry (‘LC-MS/MS’) 
method. Drug concentrations analyses will be performed at the laboratory of the 
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman 
School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 
USA. 
 
General laboratory parameters 
As part of the routine clinical follow up of HIV-infected patients and also for safety 
surveillance during the study, at baseline and week 8 visits the following 
parameters will be also determined:  
 Haematology: red blood cells, hemoglobin, hematocrit, white blood cells, 
platelets.  


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 Biochemistry: Glucose, urea, creatinine, bilirrubin, alkaline phosphatase, 
gamma glutamyl transferase, albumin, total cholesterol, HDL cholesterol. 
LDL cholesterol, triclycerides.  
 T CD4 lymphocites. 
Pregnancy test will be performed in all women at each study visit. 
 
 
 
8.2.4 Biological samples management 
 
Blood samples:  
Blood samples will be obtained by venopuncture. Samples will be processed in the 
Microbiology laboratory within 2 hours after collection (centrifugation and plasma 
separation) and stored at -80°C until analysis.  
 
Semen samples: 
Semen samples will be obtained by self-collection in a sterile, pre-labelled urine 
sample pot (study name, number, initials, date of birth, date of collection, visit 
number and type of sample) and kept on wet ice while being transferred to the 
Microbiology laboratory, where they will processed within 2 hours after collection 
(centrifugation and plasma separation) and stored at -80°C until analysis.  
 
Cervicovaginal fluid samples: 
Cervicovaginal fluid samples will be will be collected via intra-vaginal aspiration 
using 
a 
sterile 
volumetric 
aspiration 
device 
(CarTika 
Medical 
INC 
(www.cartikamedical.com)). Specimens will kept on wet ice while being transferred to 
the Microbiology laboratory, where they will processed within 2 hours after 
collection (centrifugation and plasma separation) and stored at -80°C until 
analysis.  
 
The study samples will be stored in -80ºC freezers, in the HIV and STI Unit and 
the Microbiology Department of the Hospital Universitari de Bellvitge. Samples will 
be stored with a numeric code. Only the site staff will have access to stored 


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samples. Only the principal investigator and delegated personnel will have access 
to the list where the patients and samples are identified. 
 
HIV-1 RNA analyses will be performed at the Microbiology Department of the 
Hospital Universitari de Bellvitge. 
 
Doravirine concentrations analyses will be performed at the Division of 
Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of 
Pharmacy, University of North Carolina at Chapel Hill (Chapel Hill, NC, USA.) 
 
8.3. Clinical Trial Management 
- The study will take place in the Bellvitge Hospital – HIV and STI Unit  
- For each of the study participants a selection visit will be performed, where 
thesigned informed consent form will be obtained, the investigators will review the 
inclusion / exclusion criteria and the patients will be informed about the study 
procedures and the study flowchart. 
At the study visits the procedures indicated in the below flowchart will be followed 
 
8.3.1. Study Flowchart 
 
                                            
Procedures  
                                            
Screening 
visit 
(-2 to -4 
weeks ) 
Day 0 
 
W 4 
 
 
W8 
 
Follow 
up visit 
Inclusion / exclusion 
criteria  
X 
 
 
 
 
Informed Consent  
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Physical Examination 
X 
X 
X 
X 
X 
Haematology, 
Biochemistry, CD4 count 
 
 
X 
 
 
 
X 
 
 
BP HIV-1 RNA 
 
X 
 
X 
 
SP HIV-1 RNA  
 
X 
 
X 
 
CVF HIV-1 RNA 
 
X 
 
X 
 


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Doravirine concentrations 
in BP, SP and CVF 
 
 
 
 
 
X 
 
AEs 
and 
concomitant 
medication 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Adherence assessment 
 
X 
X 
X 
X 
Medication dispensation 
 
X 
X 
X 
 
 
BP: blood plasma; CVF: cervicovaginal fluid; SP: seminal plasma.  
 
9. ADVERSE EVENTS AND TOXICITY MANAGEMENT  
 
9.1 Definition Adverse Events 
 
An adverse event (AE) is any untoward medical occurrence in a clinical 
investigation subject administered a medicinal product and which does not 
necessarily have a causal relationship with this treatment. An AE can therefore be 
any unfavorable and unintended sign, symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
 
AEs also include the following: 
• Pre- or post-treatment complications that occur as a result of protocol mandated 
procedure (e.g. such as venipuncture, biopsy) during or after screening (before the 
administration of study investigational medicinal product). 
• Any pre-existing condition that increases in severity, or changes in nature during 
or as a consequence of the study investigational medicinal product phase of a 
human clinical trial, will also be considered an AE. 
• Complications and termination of pregnancy  
• All AEs that occur from the study screening visit onwards and throughout the 
duration of the study, including the follow-up off study medication period should be 
recorded as an AE. 
 
An AE does not include the following: 


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• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
transfusion) performed; the condition that leads to the procedure is an adverse 
event. 
• Pre-existing diseases or conditions or laboratory abnormalities present or 
detected before the screening visit that do not worsen. 
• Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalization for elective surgery, social and/or convenience admissions). 
• Overdose without clinical sequelae  
• Any medical condition or clinically significant laboratory abnormality with an onset 
date before the consent form is signed and not related to a protocol-associated 
procedure is not an AE. It is considered to be pre-existing and should be 
documented on the medical 
history eCRF. 
• Uncomplicated pregnancy. 
• An induced elective abortion to terminate a pregnancy without medical reason. 
 
9.2 Assessment of Adverse Events 
The investigator is responsible for the detection and documentation of events 
meeting the criteria and definition of an AE or SAE. During the study, in case of a 
safety evaluation, the investigator or site staff will be responsible for reporting AEs 
and SAEs, as detailed in this section of the protocol.  
 
Severity of AEs will be assessed according to “Division of AIDS table for grading 
the severity of adult and pediatric adverse events”, version 2.0 of November 2014.  
Patients will be asked to report all AEs as part of the procedures performed at 
each study visit. The site personnel will document all AEs in the patient’s medical 
record. All AEs subsequently must be recorded in the appropriate eCRF sections.  
The following points must be recorded for each event:   A description
 of the event in medical terms  Date of onset (start date); 
  Date of resolution (stop date); 
  The time of onset with respect to administering the inv
estigational product;  


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  The severity of the sign/symptom or clinically significant abnormal laboratory 
value according to CTC AE Classification;   The causal relationship between the investigational product and the occurrence 
of each AE. This will be assessed by each investigator using clinical judgment. 
Alternative causes, such as natural history of the underlying diseases, concomitant 
medications, other risk factors and the temporal relationship of the event to the 
investigational product will have to be considered.  
• No: Evidence exists that the adverse event has an etiology other than the 
investigational medicinal product. For SAEs, an alternative causality must 
be provided (e.g., pre-existing condition, underlying disease, intercurrent 
illness, or concomitant medication). 
• Yes: A temporal relationship exists between the AE onset and 
administration of the investigational medicinal product that cannot be readily 
explained by the subject’s clinical state or concomitant therapies. 
Furthermore, the AE appears with some degree of certainty to be related, 
based on the known therapeutic and pharmacologic actions or adverse 
event profile of the investigational medicinal product. In case of cessation or 
reduction of the dose, the AE abates or resolves and reappears upon 
rechallenge. It should be emphasized that ineffective treatment should not 
be considered as causally related in the context of adverse event reporting. 
  Action taken regarding the investigational product: 
 
o No action;  
o Temporary discontinuation;  
o Permanent discontinuation;  
o Patient’s outcome:  
o Recovered without sequelae  
o Resolved with sequelae;  
o Recovering/Resolving;  
o On-going;  
o Fatal (for SAEs only).  
 
 


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9.3 Serious Adverse Events 
Throughout the study, the reporting of SAEs to the Sponsor or its designee will be 
done through the SAE forms in the eCRF.  
It is the investigator’s responsibility to ensure that the SAE report is reported within 
24 hours after knowledge of the event(s). The SAE forms or paper report forms 
should be completed as thoroughly as possible, with all the available details of the 
event and signed by the investigator or designee. An assessment of causality 
should always be provided at the time of the initial report.  
A serious adverse event (SAE) is defined as follows: 
Any adverse drug experience occurring at any dose that results in any of the 
following outcomes: 
 
• Death. NOTE: Death is an outcome of an AE, and not an AE in itself. 
Event which led to death should be recorded with fatal outcome.  
 
 
• Life-threatening situation.NOTE: The term 'life-threatening' in the definition 
of 'serious' refers to an event in which the patient was at risk of death at the time of 
the event. It does not refer to an event, which hypothetically might have caused 
death, if it were more severe.  
 
 
• In-patient hospitalization or prolongation of existing hospitalization 
(excluding  those for study therapy or placement of an indwelling catheter, 
unless associated  with other SAEs).  
 
• Persistent or significant disability/incapacity. NOTE: The term disability 
means a substantial disruption of a person’s ability to conduct normal life 
functions. This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption.  
 
 
 
• Congenital anomaly/birth defect in the offspring of a subject who received 
 
investigational medicinal product. 
 
• Other: medically significant events that may not be immediately life-
threatening or result in death or hospitalization, but based upon appropriate 
medical and scientific judgment, may jeopardize the subject or may require 
medical or surgical intervention to prevent one of the outcomes listed above. 


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Examples of such events are as follows: 
 
• Intensive treatment in an emergency room or at home for allergic 
bronchospasm 
 
• Blood dyscrasias or convulsions that do not result in hospitalization 
 
• Development of drug dependency or drug abuse 
. 
A distinction should be drawn between seriousness and severity of AEs. An AE 
that is assessed as Grade 4 (potentially life-threatening) should not be confused 
with an SAE. Severity is a category utilized for rating the intensity of an event; and 
both AEs and SAEs can be assessed as Grade 4. An event is defined as “serious” 
when it meets one of the predefined outcomes described above in Section. 
 
The HIV and STD Unit monitoring team will inform about all the Suspected 
Unexpected Serious Adverse Reactions (SUSARs) to the applicable authorities in 
accordance the the applicable law in Spain regarding Clinical Trials.  
  
 
10. ETHICAL ASPECTS  
The study be conducted in compliance with the study protocol  and will follow the 
Interrnational Conference on Harmonization, ICH guidelines, Declaration of 
Helsinki and its amendments and the Royal Decree 1090/2015 and will be initiated 
once obtained the hospital Clinical Research Ethics Committee and Spanish MOH 
(Agencia Española de Medicamentos y Productos Sanitarios) corresponding 
approvals. 
The signed Informed Consent will be obtained for all the study participants 
previously to perform any study related procedure. 
Before the study ICF signature, the patients will have enough time to read the 
Patient Information Sheet and to perform all the questions they need. 
It is the responsibility of the investigator to give, to each patient, full and adequate 
verbal and written information regarding the aims, methods, anticipated benefits 
and potential hazards. The patient must be informed that participation is voluntary, 
and that they are free to withdraw from the study at any time without any 


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disadvantages for their subsequent care. Although a patient is not obliged to give 
her/his reason(s) for withdrawing prematurely from the trial, the investigator should 
make a reasonable effort to ascertain the reason(s), while fully respecting the 
patient's rights. Written consent (signed and dated by the patient and the 
investigator) must be obtained prior to admission. The patient must be provided 
with a copy of the patient information and informed consent.  
The data collected in this study will be processed anonymously.  
 
The patient must be informed of and consent in writing that personal data relating 
to the trial may be subject to audits by Health Authorities and the sponsor. 
However, personal data will be kept strictly confidential and will not be made 
publicly available 
 
 
10.1 Responsabilities and Study Management 
The investigator will ensure that the study is conducted in accordance with the 
approved protocol. All protocol modifications must be submitted to the EC for 
approval if necessary. The Investigator will ensure that this study is conducted in 
accordance with the principles of the “Declaration of Helsinki”, International 
Conference on Harmonisation (ICH) guidelines, and with the laws and regulations 
applicable in Spain 
 
The Investigator is responsible for obtaining written informed consent from each 
individual participating in this study after adequate explanation of the aims, 
methods, objectives, and potential hazards of the study and before undertaking 
any study-related procedures. The Investigator must utilize an EC approved 
consent form for documenting written informed consent. Each informed consent 
will be appropriately signed and dated by the subject or the subject’s legally 
authorized representative and the person obtaining consent. 
 
The Investigator and the Promoter must maintain adequate and accurate records 
to enable the conduct of the study to be fully documented and the study data to be 
subsequently verified.  At least the following documents will be kept: the 


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protocol/amendments, CRF and query forms, IRB and governmental approval with 
correspondence, informed consent, drug records, and other appropriate 
documents and correspondence. Study documents will be retained until a 
 
 
The Principal Investigator will ensure that all the study collaborators will be 
informaed about the study procedures and about their responsabilities. 
 
 
Drug Handling 
The Investigator or designee is responsible for ensuring adequate accountability of 
all 
used 
and 
unused 
investigational 
medicinal 
product. 
This 
includes 
acknowledgment of receipt of each shipment of study product (quantity and 
condition) at the hospital pharmacy and subject dispensing records and returned 
or destroyed study product. Dispensing records will document quantities 
dispensed to subjects, including lot number, date dispensed, subject identifier 
number, and the initials of the person dispensing the medication. The medication 
will be dispensed individually to each patient subject after being relabelled with the 
study information and patient’s number. See section 7.1.1 
 
 
Confidentiality 
 
Study subjects will be informed that their participation in the study will be treated 
with the same confidentiality than their clinical records. 
Patients’ participation in the study will be reflected in their clinical records. 
The Investigator must assure that subjects’ anonymity will be strictly maintained 
and that their identities are protected from unauthorized parties.  
 
Personal information will be treated following the Regulation (EU) 2016/679 of the 
European Parliament and the Council of 27 April 2016 on the protection of natural 
persons with regard to the processing of personal data and on the free movement 
of such data (Implementation date 25 May 2018). 


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Also according to the current European Regulation participants will Possibility of 
exercising the rights of access, rectification, cancellation and objection regarding 
their personal data (ARCO rights) contacting with the study investigators.  
In case of that cesion of the study data to third countries, this will be only 
according to the study purposes and guaranteeing the data confidentiality. There 
will only be transmitted to third parts or other countries the study collected data 
dissociated and without information that could identify directly the patient. In case 
of the study data would be transferred to other countries out of the EU and EEA 
(European Economic Area) the study promoter will warrantee the protection of 
personal data at less at the same level as required by European regulation. 
 
. 
.   
 
The investigator will keep a coded list that will allow to identify to all the study 
patients (subject name study number). This list will be kept at the site. 
 
Condiciones de publicación 
A clinical study report will be prepared and provided to the regulatory agency and 
the EC. 
The study results will be published in internationally indexed publications. 
 
12. STATISTICAL ANALYSIS 
 
The statistical analysis will be performed by using SPSS 21.0 software. 
1. A descriptive analysis of the baseline characteristic will be performed. 
Quantitative variable will be described as median and range. Qualitative 
variables will be described as frequencies and percentages. 
2. The study endpoints will be expressed as mean and standard deviation or 
median and range for quantitative variables and as frequencies and 
percentages for qualitative variables. For comparisons, Chi Square or Fisher 
exact test were used for quantitative variables and the non-parametric Mann 


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Whitney U test for qualitative variables. For intra-group comparisons McNemar 
and Wilcoxon tests were used when appropriate. 
3.  All adverse events will be listed and analyzed  
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix A 
 
Division of AIDS table for grading the severity of 
adult and pediatric adverse events  
The severity of adverse events will be assessed using the division of AIDS table 
for grading the severity of adult and pediatric adverse events, version 2.0 of 
November 2014. A copy can be downloaded from the internet web site below  
 
http://rsc.techres.com/Document/safetyandpharmacovigilance/DAIDS_AE_Gradin
g_Table_v2_NOV2014.pdf