Clinical trial NCT04079452
Conditions: HIV-1-infection
Keywords: Doravirine
Sponsor: Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
Start date: 2020-02-18; Completion date: 2020-08-31
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Doravirine is a new HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) that has demonstrated a good efficacy and safety profile in clinical trials. It functions by inhibiting viral replication of both wild-type virus and most common NNRTI variants. It is dosed orally once daily and always given in combination with other HIV-1 active agents as part of highly active antiretroviral therapy. Initial pharmacokinetic studies demonstrated not extensive binding to plasma proteins, which may be crucial determinant for penetration to different reservoirs such as the central nervous system (CNS). This study will address two important issues: The pharmacokinetic profile of Doravirine in cerebrospinal fluid (CSF) as well as the maintenance of HIV suppression in CSF. The assessment of concentrations as well as the antiviral activity of new antiretroviral drugs in compartments such as CNS is relevant to avoid HIV-related neurocognitive disorders as well as for future cure strategies. In addition, the role of unbound ARV drug concentrations has been scarcely evaluated.

Detailed description:
15 asymptomatic, virologically suppressed, HIV infected patients will be offered to switch their antiretroviral treatment to Doravirine+Emtricitabine/TAF. After 4 weeks of treatment all subjects will undergo lumbar puncture and bloods in order to assess CSF and plasma (total and unbound) Doravirine concentrations. HIV RNA also will be assessed. All subjects will complete a follow up visit 4 weeks after

Arms: arm 1: 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 during 4 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 documents:
ICF_002.pdf: 
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 INFORMATION PATIENT SHEET 
 
Title: “Doravirine concentrations and antiviral activity in Cerebrospinal fluid in HIV-1 Infected 
individuals  (“DORACENES 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 introduction of highly active antiretroviral treatment (HAART) has contributed 
significantly to improving the rate of HIV infection, with a drastic reduction in morbidity 
and mortality. 
However, currently available treatments are not capable of eradicating the infection and 
therefore need to be administered indefinitely to achieve permanent viral suppression. 
In some cases, in order to improve adherence or reduce drug toxicity, it is proposed to 
simplify antiretroviral treatment, within the new antiretroviral drugs, to Doravirina. 
Although this drug is not yet commercialized is approved by the American and 
European agencies, in previous studies it has been shown to have a confirmed efficacy 
and a very favorable toxicity profile. It is also important to note that this drug is 
coformulated (in the same pill)  with lamivudine (3TC) and tenofovir (TDF) which would 
constitute a single pill regimen very important when maintaining good adherence and 
that does not interfere with daily activities. 
Despite the effectiveness of current treatments in terms of survival of HIV-infected 
patients, neurological diseases associated with HIV are still relatively common even in 
patients with suppressed plasma viral load.  The penetration of antiretroviral drugs into 
the central nervous system is known to be associated with better control of HIV 
replication in this compartment and a lower incidence of neurocognitive problems. The 
drugs currently considered of choice for the treatment of HIV infection have shown 
great efficacy in reducing the viral load in the plasma, however, not all of them 
penetrate well into the central nervous system. Thus, while simplification strategies 
may have the advantage of reducing or avoiding the toxicity of some drugs, it is 
necessary to know whether they are able to maintain control of HIV replication in the 
central nervous system.  


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The efficacy of treatment within the nervous system reservoir depends on good 
penetration as well as confirmation of virus suppression at that level. 
With new drugs these data are obviously limited and that is why we propose to carry 
out a study in order to know this information. 
 
Objective 
The aim of this study was to determine the pharmacological concentrations of 
Doravirine as well as the viral load of HIV in cerebrospinal fluid in patients with HIV-1 
infection who receive Doravirine+Emtricitabine/Tenofovir alafenamide. 
Study details 
This study will be conducted at the University Hospital of Bellvitge and will involve 15 
patients over 18 years of age, with HIV-1 infection with undetectable plasma viral load 
for at least the previous 6 months. Participants will be offered to change their treatment 
to a single pill containing Doravirine +Emtricitabine/Tenofovir Alafenamide and after 1 
month of treatment they will have a Lumbar Puncture to obtain Cerebrospinal Fluid. 
The duration of the study shall be 4 months. 
 
 
This study has been approved by the Ethics Committee of Drug Research (CEIm) of its 
hospital and by the Spanish Agency for Medicines and Medical Devices (AEMPS) in 
accordance with the current legal regulation of clinical trials in our country, RD 
1090/2015. This study will be carried out following the guidelines and standards of 
Good Clinical Practice, in accordance with Spanish legislation and in accordance with 
the Declaration of Helsinki. 


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Study medication 
 
Doravirina 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. 
 
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®)  
 
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 
 
During the study: 
Study visits:  
A blood test will be performed to determine the viral load of HIV and other parameters 
of clinical utility for monitoring HIV infection and complications of antiretroviral 
treatment. 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), will be performed with the blood samples obtained. After 4 


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weeks with the new treatment, a lumbar puncture will be performed to obtain CSF as 
detailed below.  
 
There is the possibility that it may not be included in the study, because it did not meet 
some or all of the inclusion criteria defined in the study, or that even if it was included in 
the study, it might be decided to exclude it from the study. The possible causes of 
exclusion from the study are: 
- their voluntary withdrawal 
- failure on the part of the investigator to comply with the procedures laid down 
- Grade III or IV laboratory anomalies or adverse events related to the pattern of the 
study which, in the opinion of the researcher, suggest not to continue with the same 
pattern 
- lack of effectiveness of study pattern 
- decision to cancel the trial by the study promoter. 
 
In all the above cases, the study doctor will tell you the reason personally. 
 
In the event that during their participation in the study, any new information regarding 
the drugs used in the study that could affect their decision to continue participating in 
the study, such information shall be communicated to you as soon as possible by the 
study physician and, if necessary, you shall be asked to sign a new consent to 
document it. 
*In compliance with the Biomedical Research Act 14/2007, it is established that 
biological samples (blood and CSF) are to be stored in existing freezers in the HIV Unit 
of the University Hospital of Bellvitge, with the aim of possible further analysis, either 
within the study or for other studies (in this case always requesting their consent again) 
which in no case will include genetic analysis. No further studies shall be conducted 
without prior approval of the Clinical Research Committee.  
These samples may be kept for a period of 10 years before being destroyed. 
These samples will be processed in accordance with Spanish law 14/07 of July 3 on 
Biomedical Research and Royal Decree RD 1716/2011 on biobanks. The samples will 
be stored with a code, that is, a number specific to you. Only study physicians or 
collaborators will have the code key needed to link the data to you. 
If samples are used for purposes other than those described in this study, you will be 
informed of the purpose of the investigation and asked for your consent to use your 
samples. Its results shall be analysed for research purposes only and may not be used 
to diagnose other diseases or ailments. 


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You have the right to revoke your consent to the preservation of the samples, including 
the destruction of the samples. If you wish to request it, contact the study physician. 
You may also revoke your consent to participate in the study. 
 
After 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. 
What are the expected benefits and potential risks of this study? 
Potential benefits: 
It is expected that the study treatment will keep the status of your HIV infection and/or 
its complications stable. It is expected that with this treatment the plasma viral load will 
be maintained below the limits of detectability of the techniques used in clinical practice 
(<40 copies/mL). However, we cannot guarantee that you will get any clinical benefit 
from participating in the study. The information you get in this study can help others in 
the future.  
Your participation in this study will allow to know the concentrations of the new drug 
(Doravirine) and if the treatment with Doravirine+ Emtricitabine/Tenofovir Alafenamide 
allows to achieve an adequate suppression of the viral load of HIV in the CSF, which 
may benefit other people infected with this virus in the future. 
 
Discomforts and risks arising from the study: 
Patients participating in the study will follow a stricter control than usual, with clinical 
and analytical controls at the selection visit, baseline visit (start of treatment with 
Doravirine+Emtricitabine/Tenofovir Alafenamide) and visit in week 4 and week 12 of 
treatment. From this moment on, the usual routine of visits in clinical practice will be 
followed. 
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 
amount of blood extracted will be 20 mL at each of the baseline visits, week 4 and 
week 12 and 10 mL on the day that the lumbar puncture is also performed. 
  
 


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Performing a lumbar puncture 
After 4 weeks of treatment, you will have a lumbar puncture to obtain a sample of CSF. 
CSF is the fluid that surrounds the brain and spinal cord.  
In this case the lumbar puncture will be performed solely and exclusively for the fact of 
participating in this clinical trial, and it is not part of the routine procedures in which they 
are performed in the usual clinical practice. 
The main complication that may occur after a lumbar puncture is headache or nausea. 
In some cases, a post-lumbar puncture syndrome may occur. It results in headaches, 
ringing, or neck pain. These clinical signs usually go away when lying down and usually 
last for 3-5 days at most. 
The fluid that is collected is known as "cerebrospinal fluid (CSF)" CSF circulates 
through the brain and spinal cord area. During a lumbar puncture, fluid samples are 
taken and sent to the lab. This test will evaluate the presence of HIV and levels of 
antiretroviral drugs in the CSF. This research could be very useful to learn more about 
the pharmacological concentrations and efficacy of the antiretroviral treatment regimen 
under study. 
How do I prepare for a lumbar puncture procedure? 
It is advisable to drink plenty of fluid the night before to make sure you are well 
hydrated for the procedure. No further preparation is necessary. 
During the lumbar puncture procedure 
The lumbar puncture will be performed in the Day Hospital of the HIV Unit of the 
hospital. You will be asked to lie on your side with your knees bent to your chest or sit 
on a bed and lean against a raised table in front of you. Pillows may be placed to help 
you maintain posture. The study doctor will clean an area of the skin on your lower 
back (lumbar area) with a special antibacterial soap.  
A narrow hollow needle (to reduce the risk of headache after the procedure) will be 
inserted between two lumbar vertebrae. You may feel pressure on your back during 
part of the procedure. A small amount of cerebrospinal fluid (approximately 9 mLs, two 
teaspoons) will be collected. The needle is then removed. 
 
After the lumbar puncture procedure 
The area where the puncture was done will be covered with an adhesive bandage. You 
may feel discomfort in this area. After the lumbar puncture procedure, you will stay in 
the Day Hospital for approximately 1 hour. You will be asked to lie on your back and 
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not be able to drive home. You will be given medication to relieve pain if necessary 
after the procedure and also to take home if necessary. 
 
After the lumbar puncture 
Care at the puncture point: The adhesive bandage can be removed from the back at 
night. 
Headache: Headache, which occurs in 10% to 30% of patients, is the most common 
complication of the lumbar puncture and is the result of a leakage of cerebrospinal fluid 
(CSF). It’s a headache that can appear when you sit or walk, but goes away when you 
lie down. To relieve it, lie down and drink plenty of fluids. If the headache persists and 
does not improve with bed rest, fluid intake, or pain-relieving medication, then call your 
doctor. 
Back discomfort: Some people feel discomfort in their back after a lumbar puncture. 
Toilet: On the day of the procedure you can shower but not immerse in a bath. 
Limitations on your activities: Rest as much as possible on the day of the procedure. 
Do not participate in strenuous activities on the day or night of the procedure. 
Diet: Go back to your usual diet and fluid intake. 
 
Ask your doctor for more information about this procedure. 
 
In the event of evidence of treatment failure you will receive a new antiretroviral 
treatment that is considered effective based on the results of resistance studies 
conducted.  
 
 
Medication not allowed during the study 
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 study 
Participating patients will be offered the same treatment as they were taking prior to 
starting the study or discussing other options based on the opinion of the investigating 
physician. 
Costs: 
This study does not cost you anything. 


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Compensation: 
A compensation of 100 euros per participant is provided for the loss of time involved in 
participation, 
travel 
and 
other 
unforeseen 
events.


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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. 
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. 
 
Study results 
The results of the study may be communicated to the health authorities and the 
scientific community through congresses and/or publications. 
In none of the publications that are generated at the root of the study results will any 
data identifying the patients participating in the study appear.  
You have the right to request your test results after the study is completed. To do this, 
you need to tell your doctor about the study.  
If during the study, and as part of the research, any information about your medical 
situation that may be relevant to you or your family members arises, the study 
physician will let you know. At that time, you will be advised if any additional tests are 
required if confirmation of such information is required. 


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Also, if you do not wish to be informed of the results of the investigations, your right to 
do so will be respected. 
 
Civil liability: 
In case of injury or prejudice, please contact the principal investigator of the study (Dr. 
Daniel Podzamczer, HIV-Infectious Diseases Unit of the University Hospital of Bellvitge 
as the first contact person. 
The promoter of the study has signed a civil liability policy with the company Zurich 
Insurance PLC Branch in Spain, with the number 00000106148950 according to the 
requirements set out in RD 1090/2015, which covers any damages they may 
experience as a result of their participation in the trial. 
If you have a health insurance policy, it may not cover participation in a clinical trial. 
 
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. 
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. 
Daniel Podzamczer 
                           Tel.:   649 630 408 
 
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 
“Doravirine concentrations and antiviral activity in Cerebrospinal fluid in HIV-1 Infected 
individuals  (“DORACENES 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 
 
 
 
I agree that my blood and/or CSF samples will be kept for future 
research outside the main research study, in accordance with 
Spanish law 14/07 of 3 July on Biomedical Research 
 
You will receive a copy of this document, once you have signed it, to keep with your 
records. 
 
 

Prot_000.pdf: 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
 
Doravirine concentrations and antiviral activity in Cerebrospinal 
fluid in HIV-1 Infected individuals 
 
 
 
 
 
Protocol ID: DORACeNeS 
Version: 2.4 (26/06/2019) 
 
EudraCT Number: 2018-003915-24 
 
 
 
 
 
 
 
 
Promoter: Fundació LLuita contra la SIDA 
 
 
 
Source of financing:Lluita contra la SIDA Foundation in collaboration with Merck 
Sharp & Dome. 


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1. PROTOCOL SYNOPSIS 
 
1.0. Study type: 
Pilot study, Phase III, prospective, open label, single arm, single center.  
 
1.1. Promoter Identification: 
Fundació Lluita contra la SIDA 
Hospital Germans Trias I Pujol, 2ª planta maternal 
Carretera del Canyet s/n 
Badalona 08916 
 
  
1.2. Study Title: 
Doravirine concentrations and antiviral activity in Cerebrospinal fluid in HIV-1 
infected Individuals. 
 
1.3. Protocol ID:  
EudraCT Number: 2018-003915-24 
 
1.4. Principal Investigador: 
Daniel Podzamczer, M.D, PhD. 
HIV and STD Unit 
Department of Infectious Diseases. 
Hospital Universitari de Bellvitge. L´Hospitalet de Llobregat. Barcelona. Spain 
 
1.5. Study Center: 
HIV and STD Unit. Department of Infectious Diseases. 
Bellvitge University Hospital. L´Hospitalet de Llobregat. Barcelona. Spain 
 
1.6. Responsible for monitoring  
HIVand STD Unit monitoring team 
HIV and STD Unit. Department of Infectious Diseases. 
Bellvitge University Hospital. L´Hospitalet de Llobregat. Barcelona. Spain 
 
1.7. Referral Ethics Committee: 


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Research Ethics Review Committee of the Bellvitge University Hospital 
 
1.8. Test Product, Dose, and Mode of Administration: 
Doravirine will be administered in combination with a emtricitabine and tenofovir 
alafenamide (FTC/TAF, Descovy®). Each Doravirine tablet contains 100 mg 
of the drug. Descovy®  contains 200 mg of emtricitabine, and 25 mg of 
tenofovir alafenamide. Doravirine+Descovy® will be administered orally, 
once daily, without regard to food.   
 
1.9. Study Phase:   
Phase III 
 
1.10. Objectives: 
The primary objectives of this study are:  
 
- To assess Doravirine concentrations in CSF and to estimate penetration into the 
CNS. 
-To evaluate antiviral activity of a combination of Doravirine+FTC/TAF in CSF. 
 
1.11. Study Design: 
Pilot study, Phase III, prospective, open label, single arm, single center.  
 
1.12. Study Disease: 
HIV-1 infection 
 
1.13. Primary Endpoints: 
- To determine total and unbound Doravirine concentrations in cerebrospinal fluid 
in HIV-1 infected individual receiving ART with Doravirine+FTC/TAF. 
-Total Doravirine concentrations in blood plasma. 
-Doravirine CSF/plasma ratio. 
-HIV-1 RNA in cerebrospinal fluid. 
-HIV-1 RNA in blood plasma. 
 
 


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1.14. Target Population: 
 
HIV-1 infected male and female adults on stable ART. 
 
1.15. Number of Subjects Planned:  
15 HIV infected individuals. 
 
1.16 Study duration: 
4 months 
 
1.17. Anticipated Study Calendar (dates will be confirmed later) 
Anticipated Start Date: 10/09/2019. 
Recruiting Period: 3 months. Anticipated End date of the Recruiting Period: 
10/11/2019. 
Anticipated end date: 10/02/2020 
Analysis: 1/04/2020 
Final Inform: 01/06/2020


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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 ........................................................................................................... 9 
3.11. Study timeline .................................................................................................................................. 9 
4. BACKGROUND .........................................................................................................................................10 
4.1. Backgroung and justification .......................................................................................................10 
4.2 REFERENCES ....................................................................................................................................11 
4.3. Objetives ............................................................................................................................................14 
5. STUDY DESIGN ........................................................................................................................................14 
5.1. STUDY PHASE ..................................................................................................................................14 
5.2. Randomization process .................................................................................................................14 
6. SUBJECT POPULATION .........................................................................................................................14 
6.1.Subjects selection ............................................................................................................................14 
6.2. Inclusión Criteria: .............................................................................................................................14 
6.3. Exclusion Criteria ............................................................................................................................15 
6.4 Sample size ........................................................................................................................................15 
6.5. Study duration ..................................................................................................................................16 
6.6. Treatment of patients at the end of the study ..........................................................................16 
6.7. Criteria for discontinuation of study treatment .......................................................................16 
7. INVESTIGATIONAL MEDICINE PRODUCT .........................................................................................17 
7.1. Study regimen...................................................................................................................................17 
8. STUDY DEVELOPMENT AND EVALUATION OF THE RESPONSE ..............................................20 
8.1. Response evaluation citeria ..........................................................................................................20 
8.2. Procedures ........................................................................................................................................20 
9. ADVERSE EVENTS AND TOXICITY MANAGEMENT .......................................................................22 
10. ETHICAL ASPECTS ...............................................................................................................................26 
10.1 Responsabilities ....................................................................................................................................26 
12. STATISTICAL ANALYSIS .....................................................................................................................28 
 
 


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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: DORACeNeS 
 
EudraCT Number: 2018-003915-24 
 
Study Title: Doravirine concentrations and antiviral activity in Cerebrospinal fluid in 
HIV-1 infected individuals. 
 
3.2. Study Type 
Pilot study, Phase III, prospective, open label, single arm, single center. 
 
 
3.3. Description of the Investigational medicinal products 
Doravirine 100 mg will be administered in combination with emtricitabine and 
tenofovir alafenamide (Doravirine+FTC/TAF). Each Doravirine tablet contains 100 
mg of Doravirine  and Descovy contains 200 mg of emtricitabine, and 25 mg of 
tenofovir alafenamide. Doravirine+FTC/TAF will be administered orally, once daily, 
without regard to food. 
 
3.4.  Promoter Identification 
Fundació Lluita contra la SIDA 
Hospital Germans Trias I Pujol, 2ª planta maternal 
Carretera del Canyet s/n 
Badalona 08916 
Phone: 649893921 
 
3.5. Technical services involved in the study  
- For this trial, we will work the Microbiology Department of the Bellvitge University 
Hospital for the determination of the microbiologic parameters.  
- Haematological and biochemical parameters will be determined in the Clincal 
Analisys Department of the the Bellvitge University Hospital, following the normal 
practice routine.  
- Laboratory sampling managing and storage will be done at the Bellvitge 
University Hospital HIV and STD Unit and Microbiology Department, 


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- Doravirine concentrations will be measured at the University of Liverpool, UK 
 
3.6. Study medication supplier 
Doravirine will be provided by MSD, S.L, the product manufacturer. 
Descovy will not be provided by MSD, which is a commercial medication that will 
be dispensed through the Hospital Pharmacy Service. 
 
3.7. Monitoring 
HIV and STD Unit – Monitoring Team, Infectious Diseases Department 
Bellvitge University Hospital. 
Tel: +34 93 260 76 67 or  +34 93 260 76 68.  Fax: +34 93 260 76 69 
 
3.8. Principal investigator 
Dr. Daniel Podzamczer  
Unidad VIH 
Servicio de Enfermedades Infecciosas.  
Hospital Universitari de Bellvitge.  
C/ Feixa Llarga s/n. 08907  
L´Hospitalet de Llobregat. Barcelona. 
Tfno: 93 260 76 67  ó 93 260 76 68.   Fax:93 260 76 69 
dpodzamczer@bellvitgehospital.cat 
 
3.8. Co-investigators 
Juan M Tiraboschi, M.D, PhD. 
HIV and STD Unit -Infectious Diseases Department 
Bellvitge University Hospital.  
 
Arkaitz Imaz, M.D, PhD. 
HIV and STD Unit -Infectious Diseases Department 
Bellvitge University Hospital.  
 
3.9. Study center  
Bellvitge University Hospital.  


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3.10. Referral Ethics Committee 
Research Ethics Review Committee of the Bellvitge University Hospital 
 
3.11. Study timeline 
Estudy duration: 2 months 
Recritment period: 3 months 
Treatment period: 8 weeks 
Follow up period: 4 weeks 
 
Anticipated Start Date: 10/092019. 
Recruiting Period: 3 months. Anticipated End date of the Recruiting Period: 
10/11/2019. 
Anticipated end date: 10/02/2020Analysis: 1/04/2020 
Final Inform: 01/06/2020 
These dates are yet to be confirmed. 


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4. BACKGROUND 
 
4.1. Backgroung and justification 
Combination antiretroviral therapy (cART) has markedly reduced the morbidity and 
mortality of HIV-1 infection, transforming a generally lethal infection into a chronic 
disease amenable to medical management. Treatment has not only reduced 
systemic disease, but also the various neurological complications, including both 
central nervous system opportunistic infections and AIDS dementia complex 
associtaed with HIV-1 encephalitis. Direct therapeutic effects on HIV replicationm 
within the CNS may have contributed to achieve these goals and it might be 
crucial in some cases. These effects requier of suppressive levels of drug reach 
infected cells within the CNS to inhibit local virus propagation. The blood-brain 
barrier reduces delivery of antiretrovirals to the brain. Most antiretroviral drugs 
penetrate the CNS but the levels of penetration for different ARV drugs may vary. 
 
Doravirine is a new HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) 
that has demonstrated a good efficacy and safety profile in clinical trials [3-5]. It 
functions by inhibiting viral replication of both wild-type virus and most common 
NNRTI variants [6]. It is dosed orally once daily and always given in combination 
with other HIV-1 active agents as part of highly active antiretroviral therapy  
(HAART). Initial pharmacokinetic studies demonstrated a time to maximal  
oncentration of 1–5 h, not extensive binding to plasma proteins, major CYP3A 
metabolism, low renal excretion (< 10%), and an apparent terminal half-life 
of 12–21 h [6, 7]. Doravirine is not a strong inhibitor or inducer of cytochrome  
nzymes but may be prone to drug interactions as a substrate of CYP3A [7]. 
 
These two physicochemical characteristics are crucial determinants of CSF drug 
penetration. 
 
Thus two key issues in the use of Doravirine remain to be addressed: 
1. The pharmacokinetic (PK) profile of Doravirine in CSF when given orally in 
stable, undetectable HIC-1 infected individuals. 
2. Maintenance of HIV suppression in CSF. 
 


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This study will address these unknowns and provide additional evidence for the 
scientific rational for the use of Doravirine in treatment and prevention of HIV 
associated neurocognitive disorders. 
 
4.2 REFERENCES 
1. Heaton RK, Clifford DB, Franklin DR, Jr, et al. CHARTER Group. HIV-
associated neurocognitive disorders persist in the era of potent antiretroviral 
therapy: 
CHARTER 
Study. Neurology. 2010; 
75:2087–96. 
[PMC 
free 
article] [PubMed]. 
2. Heaton RK, Franklin DR, Ellis RJ, et al. CHARTER and HNRC Groups. HIV-
associated neurocognitive disorders before and during the era of combination 
antiretroviral 
therapy: 
differences 
in 
rates, 
nature, 
and 
predictors. J 
Neurovirol. 2011;17: 3–16. [PMC free article] [PubMed]. 
3. Spudich S, González-Scarano F. HIV-1-related central nervous system disease: 
current issues in pathogenesis, diagnosis, and treatment. Cold Spring Harb 
Perspect Med. 2012; 2:a007120. [PMC free article][PubMed]. 
4. Canestri A, Lescure FX, Jaureguiberry S, et al. Discordance between cerebral 
spinal fluid and plasma HIV replication in patients with neurological symptoms who 
are receiving suppressive antiretroviral therapy. Clin Infect Dis. 2010; 50:773–
8. [PubMed]. 
5. Edén A, Fuchs D, Hagberg L, et al. HIV-1 viral escape in cerebrospinal fluid of 
subjects on suppressive antiretroviral treatment. J Infect Dis. 2010; 202:1819–
25. [PMC free article] [PubMed]. 
6. Letendre S, Capparelli E, Best B, et al. Better antiretroviral penetration into the 
central nervous system is associated with lower CSF viral load. 13th Conference 
on Retroviruses and Opportunistic Infections, Denver,; 5–8 February; Colorado. 
2006. 
7. Letendre S, Marquie-Beck J, Capparelli E, et al. CHARTER Group. Validation of 
the CNS penetration-effectiveness rank for quantifying antiretroviral penetration 
into the central nervous system. Arch Neurol.2008; 65:65–70. [PMC free 
article] [PubMed]. 
8. Cusini A, Vernazza PL, Yerly S, et al. the Swiss HIV Cohort Study. Higher CNS 
penetration-effectiveness of long-term combination antiretroviral therapy is 


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associated with better HIV-1 viral suppression in cerebrospinal fluid. J Acquir 
Immune Defic Syndr. 2013; 62: 28–35. [PubMed]. 
9. Price RW, Spudich S. Antiretroviral therapy and central nervous system HIV 
type 
1 
infection. J 
Infect 
Dis.2008; 
197(suppl 
3):S294–306. [PMC 
free 
article] [PubMed]. 
10. Gisslen M, Hagberg L, Rosengren L, et al. Defining and evaluating HIV-related 
neurodegenerative disease and its treatment targets: a combinatorial approach to 
use 
of 
cerebrospinal 
fluid 
molecular 
biomarkers. J 
Neuroimmune 
Pharmacol. 2007; 2:112–9. [PubMed]. 
11. Sinclair E, Ronquillo R, Lollo N, et al. Antiretroviral treatment effect on immune 
activation reduces cerebrospinal fluid HIV-1 infection. J Acquir Immune Defic 
Syndr. 2008; 47:544–52. [PMC free article][PubMed]. 
12. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for 
the use of antiretroviral agents in adults and adolescents living with HIV. 
Department of Health and Human Services. 2018. http://aidsi nfo.nih.gov/conte 
ntfil es/lvgui delin es/Adult andAd olesc entGL .pdf. Accessed 28 May 2018. 
13. Usach I, Melis V, Peris J. Non-nucleoside reverse transcriptase inhibitors: a 
review on pharmacokinetics, pharmacodynamics,safety and tolerability. J Int AIDS 
Soc. 2013;16(1):18567. 
14. Molina J, Squires K, Sax PE, Cahn P, Lombaard J, DeJesus E, et al. 
Doravirine versus ritonavir-boosted darunavir in K. J. Wilby, N. A. Eissa 
antiretroviral-naïve adults with HIV-1 (DRIVE-FORWARD): 48-week results of a 
randomised, 
double-blind, 
phase 
3, 
noninferiority 
trial. 
Lancet 
HIV. 
2018;5(5):e211–20. 
15. Squires KE, Molina J, Sax PE, Wong W, Orkin C, Sussmann O, et al. Fixed 
dose 
combination 
of 
doravirine/lamivudine/TDF 
is 
non-inferior 
to 
efavirenz/emtricitabine/TDF in treatment-naïve adults with HIV-1 infection: week 
48 results of the new Phase 3 DRIVE-AHEAD study. IAS 2017. http://progr 
amme.ias20 17.org/ Abstr act/Abstr act/5585. Accessed 28 May 2018. 
16. Anderson M, Gilmartin J, Cilissen C, De Lepeleire I, Van Bortel L, Dockendorf 
MF, et al. Safety, tolerability and pharmacokineticsof doravirine, a novel HIV non-
nucleoside reverse transcriptase inhibitor, after single and multiple doses in 
healthy subjects. Antivir Ther. 2015;20(4):397–405. 


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17. Sanchez R, Fillgrove K, Yee K, Liang Y, Lu B, Tatavarti A, et al. 
Characterisation of the absorption, distribution, metabolism,excretion and mass 
balance of doravirine, a non-nucleoside reverse transcriptase inhibitor in humans. 
Xenobiotica. 2018. https://doi.org/10.1080/00498 254.2018.14516 67. 
18. Colombier MA, Molina JM. Doravirine: a review. Curr Opin HIVAIDS. 
2018;13(4):308–14. 
19. Behm M, Yee K, Fan L, Fackler P. Effect of gender and age on the relative 
bioavailability of doravirine: results of a Phase I trial in healthy subjects. Antivir 
Ther. 2017;22(4):337–44. 
20. Behm M, Yee K, Liu R, Levine V, Panebianco D, Fackler P. The effect of food 
on doravirine bioavailability: results from two pharmacokinetic studies in healthy 
subjects. Clin Drug Investig. 2017;37(6):571–9. 
21. Khalilieh S, Yee KL, Liu R, Fan L, Sanchez RI, Auger P, et al. Moderate 
hepatic impairment does not affect doravirine pharmacokinetics. J Clin Pharmacol. 
2016;57(6):777–83. 
22. Sanchez RI, Filgrove K, Hafey M, Palamanda J, Newton D, Lu B, Bleasby K. In 
vitro evaluation of doravirine potential for pharmacokinetic drug interactions. Drug 
Metab Rev. 2016;48(Suppl 1):73. 
23. Anderson M, Khalilieh S, Yee KL, Liu R, Fan L, Rizk ML, et al. A two-way 
steady-state pharmacokinetic interaction study of doravirine (MK-1439) and 
dolutegravir. Clin Pharmacokinet. 2016;56(6):661–9. 
24. Yee KL, Chatterjee M, Dockendorf M, Lai M, Teppler H, Rizk M, et al. 
Pharmacokinetics (PK) of doravirine and exposure-response analysis: efficacy and 
safety implications. In: Interscience conference on antimicrobial agents and 
chemotherapy, September 5–9, 2014. Washington, DC. 


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4.3. Objetives  
Primary objectives:  
-To assess Doravirine concentrations in CSF and to estimate penetration into The 
CNS.  
 
- To evaluate antiviral activity of a combination of Descovy®+Doravirine in CSF. 
 
5. STUDY DESIGN  
Pilot study, Phase III, prospective, open label, single arm, single center. 
 
 
5.1. STUDY PHASE  
Phase III 
 
5.2. Randomization process 
NA. 
 
6. SUBJECT POPULATION 
 
6.1.Subjects selection 
Male and female HIV-1 infected adults receiving an 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. Inclusión Criteria:  
1. Asymptomatic, HIV-1 infected individuals ≥ 18 years of age  
2. Be on a stable ART continously or ≥3 consecutive months preceding the 
screening visit. Patients already receiving TAF/FTC+DoravirineC for at least three 
consecutive months will be eligible. 
 3. Plasma HIV-1 RNA at screening <40 copies/mL for at least 3 months at the 
Screening visit.  
4. Signed and dated written informed consent prior to inclusion.  


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5. Subjects must agree to utilize a highly effective method of contraception during 
heterosexual intercourse from the screening visit throughout the duration of the 
study. 
 
* Women of childbearing potential must have a negative pregnancy test prior to 
randomization into the study and commitment to use at least one of these birth 
control methods: male or female condom with or without spermicide, cap, 
diaphragm or sponge with or without spermicide, intrauterine device, bilateral 
tubal occlusion, vasectomized partner, sexual abstinence during the study.  
Based on ICH, M3 (R2) 2009 a woman is considered of childbearing potential: 
fertile, following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include tubal ligation, 
hysterectomy, bilateral oophorectomy. 
6.3. Exclusion Criteria  
1. Severe hepatic impairment (Child-Pugh Class C)  
2. Ongoing malignancy  
3. Active opportunistic infection  
4. Primary 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. Adequate renal function: Estimated glomerular filtration rate ≥ 50 mL/min  
8. Females who are pregnant (as confirmed by positive serum pregnancy test) or 
breastfeeding. 
9. Current treatment with antiaggregant or anticoagulant therapy. 
10. History of any neurologic disease/condition/treatment may alter the blood brain 
barrier permeability. 
 
6.4 Sample size 
Fifteen individuals will be included in the study. This is a pilot study designed to 
obtain information about Doravirine concentrations and HIV viral suppression in 
CSF. The study design is similar to other studies evaluating ARV PK and PD in 
this compartment.  


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6.5. Study duration  
The study will have a recruitment period of 12 weeks   The treatment period will be 
of 2 months.  
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  
At the end of the study, participants will be offered to return to their previous 
treatment or to discuss other treatment options depending on investigator´s 
opinion.  
 
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 
5. Lack of treatment efficacy 
 
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 one tablet of Doravirine 100 mg administered in 
combination with FTC and TAF (Descovy®) ).  
Each film-coated tablet contains contains 100 mg of Doravirine. Each tablet of 
Descovy® contains 200 mg of emtricitabine, and 25 mg of tenofovir alafenamide. 
Doravirine+ Descovy® will be administered orally, once daily, without regard to 
food. 
 
7.1.1. Packaging and labelling  
The Monitoring Team will register the study medication lot and expiry date to 
guarantee the treazability, collecting this information in the Case Report Form of 
each participant. 
Medication will be provided by the manufacturer, MSD; and will be sent to the 
Pharmacy of the Bellvitge Hospital. 
Study medication will be re-labelled by the HIV 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: 
 
DORACeNeS Study. EudraCt: 2018-003915-24  
Sponsor: Fight AIDS Foundation (Fundació Lluita contra la SIDA).  
Investigator: Dr. Daniel Podzamczer, 649630408 
(Doravirine) Content: Doravirine 100 mg  
30 film-coated tablets 
Oral administration 
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 


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USE FOR CLINICAL TRIAL 
 
Estudio DORACeNeS . EudraCt: 2018-003915-24  
Promotor: Fundació Lluita contra la SIDA. 
Investigador principal: Dr. Daniel Podzamczer 649630408 
Doravirina 100 mg  
30 cápsulas 
Administracion oral 
Numero de paciente: XXXXXX 
Lote : XXXXXX 
Fecha de caducidad: XXXXXX 
Mantener el envase bien cerrado para protegerlo de la humedad. Mantener lejos 
del alcance de los niños 
USO EXCLUSIVO PARA ENSAYO CLINICO 
 
 
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, 
and the patient will be discontinued from the study. 
At the end of the study, participants will be offered to return to their previous 
treatment or to discuss other treatment options depending on investigator´s 
opinion.  
 
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+FTC/TAF 
 


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Drug Class 
 
 
Agents Disallowed 
 
Use Discouraged and To Be Used 
With Caution 
 
 
Acid Reducing Agents 
Antacids 
Buffered medications 
 
 
Concentration of study drug may 
decrease with antacids. Subjects 
may not take antacids (eg, Tums or 
Rolaids); the ulcer medication 
sucralfate (Carafate); or vitamin or 
mineral supplements that contain 
calcium, iron or zinc for a minimum of 
2 hours before and 6 hours after any 
dose of study drug. 
 
Antiarrhythmic Agent 
 
 
Dofetilide 
 
 
Anticonvulsants 
 
 
Phenobarbital, Phenytoin, 
Carbamazepine, Oxcarbazepine 
 
 
Antimycobacterials 
 
 
Rifampin, Rifapentine 
 
 
Antiretrovirals 
 
 
Any antiretroviral drug that is not part 
of the study regimen 
 
 
GI Motility Agents 
 
 
Cisapride 
 
 
Herbal/Natural 
Supplements 
 
 
St. John’s Wort, Echinaccea 
 
 
Oral Hypoglycemic Agent 
 
 
Metformin: close monitoring is 
recommended. A dose adjustment of 
Metformin may be necessary. Limit 
total daily doses of Metformin to 
1000mg when initiating study 
medication or if initiating metformin 
while on study drug. 
 
 


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7.1.4  Investigational Medicinal Product Management 
Stribild does not have special precautions for storage.  
Following the instructions from de manufacturer Doravirine+FTC/TAF will be 
stored at controlled room temperature of 25°C. 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 
To assess the treatment adherence, a validated adherence questionnaire, 
routinely used in the clinical practice (SMAQ questionnaire) will be provided to the 
participants at each study visit. 
 
  
 
8. STUDY DEVELOPMENT AND EVALUATION OF THE RESPONSE 
 
8.1. Response evaluation citeria  
8.1.1.Primary endpoinst: 
- To determine total and unbound Doravirine concentrations in cerebrospinal fluid 
in HIV-1 infected individual receiving ART with TAF/FTC+Doravirine. 
-Total Doravirine concentrations in blood plasma. 
- Doravirine CSF/plasma ratio. 
-HIV-1 RNA in cerebrospinal fluid. 
-HIV-1 RNA in blood plasma. 
 
8.2. Procedures 
 
8.2.1 Study visits 
Eligibility criteria will be assessed in at Screening visit (week -4) before the inclusion of 
patients in the study.  
Patients will be evaluated at baseline (treatment switch, week 0), 
At week 4, clinical review and samples (blood and CSF) will be obtained. 
At week 8 FU visit (end of the study).  


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8.2.2 Clinical records and physical examination 
-At screening a complete physical examination will be performed. At the following visits, a 
physical examination oriented to symptoms will be performed. 
-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 risk 
factor, CDC stage, opportunistic infections, malignancies or previous diseases, 
concomitant treatments). Antiretroviral treatment will be switched to FTC/TAF/Doravirine. 
-At week 4: Inclusion/exclusion criteria review. Blood test and CSF sample will be taken. 
-At week 8 (FU visit): A physical examination oriented to symptoms will be performed. AE 
and concomitant medications review. 
 
At the end of the study, participants will be offered to return to their previous treatment or 
to discuss other treatment options depending on investigator´s opinion.  
 
8.2.3 Laboratory Procedures 
HIV-1 RNA quantification 
At screening, baseline and week 4 visits HIV-1 RNA will be determined in blood plasma 
using a real-time PCR assay (Abbott RealTime HIV-1) with a quantification limit of 40 
copies/mL. 
 
CSF HIV-1 RNA will be assessed at baseline by real-time PCR assay (Abbott Real Time 
HIV-1) with a quantification limit of 40 copies/mL. 
 
All determinations will be performed at the Microbiology lab, Bellvitge University Hospital. 
 
Doravirine concentrations  
At baseline visit Doravirine concentrations will be determined in blood plasma (BP), 
cerebrospinal fluid (CSF). In CSF Doravirine unbound concentrations will be also 
determined. Drug concentrations will be determined at the end of the dosing interval 
(C24h). 
Doravirine concentrations will be quantified using a validated liquid chromatography-
tandem mass spectrometry (‘LC-MS/MS’) method. Drug concentrations will be performed 
at 
the 
Department 
of 
Molecular 
and 
Clinical 
Pharmacology, University 
of 
Liverpool, Liverpool, UK. 
 
 


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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 follow up visit the following parameters will 
be also determined: 
 
 Haematology: red blood cells, haemoglobin, white blood cells, platelets; 
coagulation.   
 
Biochemistry: Glucose, urea, creatinine, bilirrubin, alkaline phosphatase, gamma 
glutamyl transferase, albumin, total cholesterol, HDL cholesterol. LDL cholesterol, 
triclycerides.  
 
T CD4 lymphocites (at baseline and week 8 visits) 
 
Pregnancy test will be performed in all women at each study visit. 
 
 
8.3.4 Biological samples management 
- Blood samples will be obtained by venipuncture.  
- CSF samples will be taken through Lumbar Puncture using a Pencil Point Spinal Needle. 
All samples will be stored at -80ºC in the HIV Unit of the Bellvitge Hospital until the end of 
the study. 
Only the site staff will have access to them. Samples will be stored with a numeric code. 
All the study analysis except CSF and plasma Doravirine concentrations will be performed 
at the Bellvitge Hospital, 
Doravirine determinations in CSF and plasma will be performed at the Department of 
Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of 
Liverpool, Liverpool, UK. Only the principal investigator and delegated personnel will have 
access to the list where the patients and samples are identified. 
 
 
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 unfavourable and unintended sign, symptom, or disease temporally 


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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: 
• 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. 


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9.2 Assessment of Adverse Events 
All AEs will be assessed by the Investigator or qualified designee and recorded on 
the CRF. The AE entry should indicate whether or not the AE was serious, the 
start date 
(AE onset), the stop date (date of AE resolution), whether or not the AE was 
related to investigational medicinal product or to a study procedure, the action 
taken with investigational medicinal product due to the AE, and the severity of the 
AE. The Investigator is responsible for final review and confirmation of accuracy of 
events, relationship and severity confirmed by the signature on the eCRF book. 
The relationship to investigational medicinal product therapy should be assessed 
using clinical judgment and the following considerations: 
• 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. 
 
9.3 Serious Adverse Events 
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 
 
• Life-threatening situation (subject is at immediate risk of death) 


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• 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. 
 
• 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. 
 
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 sponsor 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.  
 
The appendix A contains the Division of AIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events (“DAIDS AE Grading Table”), which  is a 
descriptive terminology that will be utilized for Adverse Event (AE) reporting.  
 


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10. ETHICAL ASPECTS 
The study will follow the Interrnational Conference on Harmonization, ICH 
guidelines and the Royal Decree 1090/2015 and will be initiated once obtained the 
EC 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 peform all the questions they need. 
 
An insurance policiy will be contracted for this study, covering the possible 
damages ocurred to the study as a result of the study  
 
10.1 Responsabilities 
 
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 
protocol/amendments, CRF and query forms, IRB and governmental approval with 
correspondence, informed consent, drug records, and other appropriate 
documents and correspondence.  


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The Principal Investigator will ensure that all the study collaborators will be 
informed 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. 
Patietns’ 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. Only subject 
initials, date of birth and an identification code (i.e., not names) will be recorded in 
the CRF or on any form or biological sample submitted to the external laboratory. 
The Investigator will keep a screening log showing codes, names, and addresses 
for all subjects screened and for all subjects enrolled in the study. 
The study subjects will be informed about the confidentiality in the management of 
their personal data, and that only the study team and eventually, members of the 
hospital EC or an inspector would have access to their clinical records. 
 
Personal information will be treated following the Organic Law 15/1999 of 13 
December on the Protection of Personal Data. 
 
Study participants would be able to exercise their rights in the treatment, 
communication and cesion of their personal data. Following that law, study 


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patients will have the possibility of exercising their rights of access, rectification, 
erasure and objection of data contacting with the study investigators. 
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 that cesion of the study data to third countries the confiendality, this will 
be only with the study purposes and guaranteeing the data confidentiality.   
 
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. 
 
Publication 
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. 
The intellectual property of the study design and results belongs to the Principal 
Investigator, Dr. Daniel Podzamczer Palter. 
 
12. STATISTICAL ANALYSIS 
 
The statistical analysis will be performed by using SPSS 18.0 IBM software. 
- Data will be analysed with descriptive, statistics using standard methods: 
Categorical variables will be described as the number and percentage and 
continuous variables as the median and range or interquartile range (IQR).  
- All adverse events will be listed and analyzed using descriptive statistics.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix A 
 
 
 
 
Division of AIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events 
VERSION 1.0, DECEMBER 2004; CLARIFICATION 
AUGUST 2009 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (“DAIDS 
AE Grading Table”) is a descriptive terminology which can be utilized for Adverse Event (AE) 
reporting. A grading (severity) scale is provided for each AE term. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
PARAMETER  
 
GRADE 1 
MILD  
 
GRADE 2  
MODERATE  
 
GRADE 3  
SEVERE  
 
GRADE 4 POTENTIALLY LIFE-
THREATENING  
 
ESTIMATING SEVERITY GRADE  
Clinical adverse event NOT 
identified elsewhere in this 
DAIDS AE Grading Table  
 
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities  
 
Symptoms causing greater than 
minimal interference with usual 
social & functional activities  
 
Symptoms causing inability to 
perform usual social & functional 
activities  
 
Symptoms causing inability to perform basic 
self-care functions OR Medical or operative 
intervention indicated to prevent permanent 
impairment, persistent disability, or death  
 
SYSTEMIC  
Acute systemic allergic 
reaction 
Localized urticaria wheals) 
with no medical 
intervention indicated 
Localized urticaria with medical 
intervention indicated OR Mild 
angioedema with no medical 
intervention indicated 
Generalized urticaria OR 
Angioedema with medical 
intervention indicated OR 
Symptomatic mild bronchospasm 
Acute anaphylaxis OR Life-threatening 
bronchospasm OR laryngeal edema 
Chills  
 
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities  
 
Symptoms causing greater than 
minimal interference with usual 
social & functional activities  
 
Symptoms causing inability to 
perform usual social & functional 
activities  
 
NA  
 
Fatigue 
Malaise 
Symptoms causing no  
or minimal interference 
with usual social & 
functional activities  
 
Symptoms causing  
greater than minimal interference 
with usual social & functional 
activities  
 
Symptoms causing  
inability to perform usual social & 
functional activities  
 
Incapacitating fatigue/  
malaise symptoms causing inability to 
perform basic self-care functions  
 
Fever (nonaxillary)  
 
37.7 – 38.6°C  
 
38.7 – 39.3°C  
 
39.4 – 40.5°C  
 
> 40.5°C  
 
Pain (indicate body site) DO 
NOT use for pain due to 
injection (See Injection Site 
Reactions: Injection site 
pain) See also Headache, 
Arthralgia, and Myalgia  
 
Pain causing no or minimal 
interference with usual 
social & functional activities  
 
Pain causing greater than minimal 
interference with usual social & 
functional activities  
 
Pain causing inability to perform 
usual social & functional activities  
 
Disabling pain causing inability to perform 
basic self-care functions OR Hospitalization 
(other than emergency room visit) indicated  
 
 
 
 


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PARAMETER  
 
GRADE 1 
MILD  
 
GRADE 2 MODERATE  
 
GRADE 3 SEVERE  
 
GRADE 4 POTENTIALLY LIFE-
THREATENING  
 
Unintentional weight  
loss 
NA 
5 – 9% loss in body  
weight from baseline  
 
10 – 19% loss in body  weight from 
baseline  
 
≥ 20% loss in body  
weight from baseline OR Aggressive 
intervention indicated [e.g., tube feeding or 
total parenteral nutrition (TPN)]  
INFECTION 
Infection (any other  
than HIV infection)  
  
 
Localized, no systemic 
antimicrobial treatment 
indicated AND Symptoms 
causing no or minimal 
interference with usual 
social & functional activities 
Systemic antimicrobial treatment 
indicated OR Symptoms causing 
greater than minimal interference 
with usual social & functional 
activities 
Systemic antimicrobial treatment 
indicated AND Symptoms causing 
inability to perform usual social & 
functional activities OR Operative 
intervention (other than simple 
incision and drainage) indicated 
Life-threatening consequences (e.g., 
septic shock) 
INJECTION SITE REACTIONS 
Injection site pain (pain 
without 
touching) 
Or 
Tenderness (pain when area 
is 
touched) 
Pain/tenderness causing 
no or minimal limitation of 
use of limb 
 
Pain/tenderness limiting use of limb 
OR Pain/tenderness causing 
greater than minimal interference 
with usual social & functional 
activities 
 
Pain/tenderness causing inability to 
perform usual social & functional 
activities 
 
Pain/tenderness causing inability to 
perform basic self-care function OR 
Hospitalization (other than emergency 
room visit) indicated for management of 
pain/tenderness 
Injection site reaction (localized) 
Adult > 15 years 
Erythema OR Induration of 
5x5 cm – 9x9 cm (or 25 
cm2 – 81cm2) 
Erythema OR Induration OR Edema 
> 9 cm any diameter (or > 81 cm2) 
Ulceration OR Secondary infection 
OR Phlebitis OR Sterile abscess 
OR Drainage 
Necrosis (involving dermis and deeper 
tissue) 
Pediatric ≤ 15 Years 
Erythema OR Induration 
OR 
Edema present but ≤ 2.5 
cm 
diameter 
 
Erythema OR Induration OR Edema 
> 2.5 cm diameter but < 50% 
surface area of the extremity 
segment (e.g., upper arm/thigh) 
 
Erythema OR Induration OR Edema 
involving ≥ 50% surface area of the 
extremity segment (e.g., upper 
arm/thigh) OR Ulceration OR 
Secondary infection OR Phlebitis 
OR 
Sterile abscess OR Drainage 
Necrosis (involving dermis and deeper 
tissue) 
Pruritis associated with 
injection See also Skin: 
Pruritis (itching - no 
skin lesions) 
Itching localized to injection 
site AND Relieved 
spontaneously or with < 48 
hours treatment 
 
Itching beyond the injection site but 
not generalized OR Itching localized 
to injection site requiring ≥ 48 hours 
treatment 
Generalized itching causing inability 
to perform usual social & functional 
activities 
NA 
 


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PARAMETER  
 
GRADE 1 
MILD  
 
GRADE 2 MODERATE  
 
GRADE 3 SEVERE  
 
GRADE 4 POTENTIALLY LIFE-
THREATENING  
 
SKIN – DERMATOLOGICAL 
Alopecia  
 
Thinning detectable by 
study participant (or by 
caregiver for young 
children and disabled 
adults) 
Thinning or patchy hair loss 
detectable by health care provider 
 
Complete hair loss 
NA 
Cutaneous reaction – rash  
 
Localized macular rash 
Diffuse macular, maculopapular, or 
morbilliform rash OR Target lesions 
Diffuse macular, maculopapular, or 
morbilliform rash with vesicles or 
limited number of bullae OR 
Superficial ulcerations of mucous 
membrane limited to one site 
Extensive or generalized bullous 
lesions OR Stevens-Johnson syndrome 
OR Ulceration of mucous membrane 
involving two or more distinct mucosal sites 
OR Toxic epidermal necrolysis (TEN) 
Hyperpigmentation  
Slight or localized 
Marked or generalized 
NA 
NA 
Hypopigmentation 
Slight or localized 
Marked or generalized 
NA 
NA 
Pruritis (itching – no skin 
lesions) (See also Injection 
Site Reactions: Pruritis 
associated with injection) 
Itching causing no or 
minimal 
interference with usual 
social & functional activities 
 
Itching causing greater than 
minimal interference with usual 
social & functional activities 
Itching causing inability to perform 
usual social & functional activities 
NA 
NA 
CARDIOVASCULAR 
Cardiac arrhythmia (general) 
(By ECG or physical exam) 
Asymptomatic AND No 
intervention indicated  
Asymptomatic AND Non-urgent 
medical intervention indicated 
Symptomatic, non-life-threatening 
AND Non-urgent medical 
intervention 
 ndicated 
Life-threatening arrhythmia OR Urgent 
intervention indicated 
Cardiac-ischemia/infarction  
NA 
NA 
Symptomatic ischemia (stable 
angina) OR Testing consistent with 
ischemia 
Unstable angina OR Acute myocardial 
infarction 
Hemorrhage (significant 
acute blood loss) 
 
NA 
Symptomatic AND No transfusion 
indicated 
 
Symptomatic AND Transfusion of ≤ 
2 units packed RBCs (for children ≤ 
10 cc/kg) indicated 
Life-threatening  hypotension OR 
Transfusion of > 2 units packed RBCs (for 
children >10 cc/kg) indicated 
HYPERTENSION 
Adult > 17 years 
(with repeat testing at same 
visit) 
140 – 159 mmHg systolic 
OR 
90 – 99 mmHg diastolic 
160 – 179 mmHg systolic 
OR 
100 – 109 mmHg diastolic 
≥180 mmHg systolic 
OR 
≥ 110 mmHg diastolic 
Life-threatening consequences (e.g., 
malignant hypertension) OR 
Hospitalization indicated (other than 
emergency room visit) 


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PARAMETER  
 
GRADE 1 
MILD  
 
GRADE 2 MODERATE  
 
GRADE 3 SEVERE  
 
GRADE 4 POTENTIALLY LIFE-
THREATENING  
 
Pediatric ≤ 17 Years 
(with repeat testing at same 
visit) 
NA  
 
91st – 94th percentile adjusted for 
age, height, and gender (systolic 
and/or diastolic) 
95th percentile adjusted for age, 
height, and gender (systolic and/or 
diastolic) 
 
Life-threatening consequences (e.g., 
malignant hypertension) OR Hospitalization 
indicated other than 
emergency room visit) 
Hypotension  
 
NA 
Symptomatic, corrected with oral 
fluid replacement 
Symptomatic, IV fluids indicated 
Shock requiring use of vasopressors or 
mechanical assistance to maintain 
blood pressure 
Pericardial effusion  
 
Asymptomatic, small 
effusion requiring no 
intervention 
Asymptomatic, moderate or larger 
effusion requiring no intervention 
 
Effusion with non-life threatening 
physiologic consequences OR 
Effusion with non-urgent 
intervention indicated 
Life-threatening consequences (e.g., 
tamponade) OR Urgent intervention 
indicated 
PROLONGED PR INTERVAL 
Adult > 16 years 
 
PR interval 
0.21 – 0.25 sec 
PR interval 
> 0.25 sec 
Type II 2nd degree AV block OR 
Ventricular pause > 3.0 sec 
Complete AV block 
Pediatric ≤ 16  
 
Years 1st degree AV block 
(PR > normal for age and 
rate) 
Type I 2nd degree AV block 
Type II 2nd degree AV block 
Complete AV block 
PROLONGED QTC 
Adult > 16 years 
 
Asymptomatic, QTc 
interval 0.45-0.47 sec OR 
Increase interval <0.03 sec 
above baseline 
Asymptomatic, QTc interval 
0.48-0.49 sec OR Increase in 
interval 0.03 – 0.05 sec above 
baseline 
Asymptomatic, QTc interval ≥ 0.50 
sec OR Increase in interval ≥ 0.06 
sec above baseline 
 
Life-threatening consequences, e.g. 
Torsade de pointes or other associated 
serious ventricular dysrhythmia 
Pediatric ≤ 16 years  
Life-threatening 
consequences, e.g. 
Asymptomatic, QTc 
interval 0.450–0.464 sec 
 
Asymptomatic, QTc intervalo 0.465-
0.479 sec 
 
Asymptomatic, QTc 
interval ≥ 0.480 sec 
 
Torsade de pointes or other associated 
serious ventricular dysrhythmia 
Thrombosis/embolism 
NA 
Deep vein thrombosis AND No 
intervention indicated (e.g.,  
nticoagulation, lysis filter, 
invasiveprocedure) 
Deep vein thrombosis AND 
Intervention indicated (e.g., 
anticoagulation, lysis filter, invasive 
procedure) 
Embolic event (e.g., pulmonary 
embolism, life-threatening thrombus 
Vasovagal episode 
(associated with a procedure 
of any kind) 
 
Present without loss of 
Consciousness 
Present with transient loss of 
consciousness 
 
NA 
NA 
Ventricular dysfunction 
(congestive heart failure) 
 
NA 
Asymptomatic diagnostic finding 
AND intervention indicated 
 
New onset with symptoms OR 
Worsening symptomatic congestive 
heart failure 
Life-threatening congestive heart 
failure 


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PARAMETER  
 
GRADE 1 
MILD  
 
GRADE 2 MODERATE  
 
GRADE 3 SEVERE  
 
GRADE 4 POTENTIALLY LIFE-
THREATENING  
 
GASTROINTESTINAL 
Anorexia  
 
Loss of appetite without 
decreased oral intake 
Loss of appetite associated with 
decreased oral intake without 
significant weight loss 
 
Loss of appetite associated with 
significant weight loss 
 
Life-threatening consequences OR 
Aggressive intervention indicated [e.g., 
tube feeding or total 
Comment: Please note that, while the grading scale provided for Unintentional Weight Loss may be used as a guideline when grading anorexia, this is not a requirement and should 
not be used as a substitute for clinical judgment. 
Ascites  
 
Asymptomatic 
Symptomatic AND Intervention 
indicated (e.g., diuretics or 
therapeutic paracentesis) 
Symptomatic despite intervention 
Life-threatening consequences 
Cholecystitis  
 
NA 
Symptomatic AND Medical 
intervention indicated 
Radiologic, endoscopic, or operative 
intervention indicated 
Life-threatening consequences 
Constipation  
 
NA 
Persistent constipation requiring 
regular use of dietary modifications, 
laxatives, or enemas 
Obstipation with manual evacuation 
Indicated 
 
Life-threatening consequences (e.g., 
obstruction) 
Diarrhea 
Adult and 
Pediatric ≥ 1 year 
 
Transient or intermittent 
episodes of unformed 
stools OR Increase of 3 
stools over baseline per 
24-hour period 
 
Persistent episodes of unformed to 
watery stools OR Increase of 4 – 6 
stools over baseline per 24-hour 
period 
 
Bloody diarrhea OR Increase of 7 
stools per 24-hour period OR IV 
fluid replacement indicated 
 
Life-threatening consequences 
Pediatric < 1 year  
 
Liquid stools (more 
unformed than usual) 
but usual number of stools 
Liquid stools with increased number 
of stools OR Mild dehydration 
 
Liquid stools with moderate 
dehydration 
 
Liquid stools resulting in severe 
dehydration with aggressive 
rehydration indicated OR Hypotensive 
shock 
Dysphagia- 
Odynophagia 
 
Symptomatic but able to 
eat usual 
diet 
 
Symptoms causing altered dietary 
intake without medical intervention 
indicated 
 
Symptoms causing severely altered 
dietary intake with medical 
intervention indicated 
 
Life-threatening reduction in oral intake 
 
 
 
 


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PARAMETER  
 
GRADE 1 
MILD  
 
GRADE 2 MODERATE  
 
GRADE 3 SEVERE  
 
GRADE 4 POTENTIALLY LIFE-
THREATENING  
 
Mucositis/stomatitis 
(clinical exam) 
Indicate site (e.g., larynx, 
oral) 
See Genitourinary for 
Vulvovaginitis 
See also Dysphagia-
Odynophagia and 
Proctitis 
Erythema of the mucosa  
 
Patchy pseudomembranes or 
ulcerations 
Confluent pseudomembranes or 
ulcerations OR Mucosal 
bleeding with 
minor trauma 
 
Tissue necrosis OR Diffuse 
spontaneous mucosal bleeding OR 
Life-threatening consequences (e.g., 
aspiration, choking) 
Nausea  
 
Transient (< 24 hours) 
or intermittent nausea 
with no or minimal 
interference with oral 
intake 
Persistent nausea resulting in 
decreased oral intake for 24 – 
48 hours 
 
Persistent nausea resulting in 
minimal oral intake for > 48 
hours OR Aggressive 
rehydration indicated (e.g., IV 
fluids) 
Life-threatening consequences (e.g., 
hypotensive shock) 
Pancreatitis  
 
NA 
Symptomatic AND 
Hospitalization not indicated 
(other than emergency room 
visit) 
Symptomatic AND 
Hospitalization indicated (other 
than emergency room visit) 
 
Life-threatening consequences (e.g., 
circulatory failure, hemorrhage, sepsis 
Proctitis (functional-
symptomatic) 
Also see  
 
Rectal discomfort AND 
No 
intervention indicated 
 
Mucositis/stomatitis for 
clinical exam  
Symptoms causing greater than 
minimal interference with usual 
social & functional activities OR 
Medical intervention indicated 
Symptoms causing inability to 
perform usual social & functional 
activities OR Operative 
intervention 
indicated 
 
Life-threatening consequences (e.g., 
perforation) 
Vomiting  
 
Transient or intermittent 
vomiting with no or 
minimal interference 
with oral intake 
Frequent episodes of vomiting 
with no or mild dehydration 
 
Persistent vomiting resulting in 
orthostatic hypotension OR 
Aggressive rehydration indicated 
(e.g., IV fluids) 
 
Life-threatening consequences (e.g., 
hypotensive shock) 
 
 


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PARAMETER  
 
GRADE 1 
MILD  
 
GRADE 2 MODERATE  
 
GRADE 3 SEVERE  
 
GRADE 4 POTENTIALLY LIFE-
THREATENING  
 
NEUROLOGIC 
Altered Mental Status 
For Dementia, see Cognitive 
and 
behavioral/attentional 
disturbance (including 
dementia and attention 
deficit disorder) 
Changes causing no or 
minimal 
interference with usual 
social & 
functional activities 
 
Mild lethargy or somnolence 
causing greater than minimal 
interference with usual social & 
functional activities 
 
Confusion, memory impairment, 
lethargy, or somnolence causing 
inability to perform usual social & 
functional activities 
 
Delirium OR obtundation, OR coma 
Ataxia  
 
Asymptomatic ataxia 
detectable on exam OR 
Minimal ataxia causing no 
or minimal interference 
with usual social & 
functional activities 
Symptomatic ataxia causing greater 
than minimal interference with usual 
social & functional activities 
 
Symptomatic ataxia causing inability 
to perform usual social & functional 
activities 
 
Disabling ataxia causing inability to 
perform basic self-care functions 
Cognitive and 
behavioral/attentional 
disturbance (including 
dementia and attention 
deficit disorder) 
 
Disability causing no or 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources not indicated 
Disability causing greater than 
minimal interference with usual 
social & functional activities OR 
Specialized resources on part-time 
basis indicated 
 
Disability causing inability to 
perform usual social & functional 
activities OR Specialized resources 
on a full-time basis indicated 
 
Disability causing inability to perform 
basic self-care functions OR 
Institutionalization indicated 
CNS ischemia (acute)  
NA 
NA 
Transient ischemic attack 
Cerebral vascular accident (CVA, 
stroke) with neurological deficit 
Developmental delay 
– Pediatric ≤ 16 Years 
 
 
Mild developmental delay, 
either motor or cognitive, 
as determined 
by comparison with a 
developmental screening 
tool 
appropriate for the setting 
Moderate developmental delay, 
either motor or cognitive, as 
determined by comparison with a 
developmental screening tool 
appropriate for the setting 
 
Severe developmental delay, either 
motor or cognitive, as determined 
by comparison with a 
developmental screening tool 
appropriate for the setting 
 
Developmental regression, either motor or 
cognitive, as determined by 
comparison with a developmental 
screening tool appropriate for the setting 
 
 
 
 
 
 
 
 


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PARAMETER  
 
GRADE 1 
MILD  
 
GRADE 2 MODERATE  
 
GRADE 3 SEVERE  
 
GRADE 4 POTENTIALLY LIFE-
THREATENING  
 
Headache  
 
Symptoms causing no or 
minimal interference with 
usual social & 
 unctional activities 
Symptoms causing greater than 
minimal interference with usual 
social & functional activities 
 
Symptoms causing inability to 
perform usual social & functional 
activities 
 
Symptoms causing inability to perform 
basic self-care functions OR 
Hospitalization indicated (other than 
emergency room visit) OR Headache 
with significant impairment of alertness 
Insomnia  
 
NA 
Difficulty sleeping causing greater 
than minimal interference with usual 
social & functional activities 
Difficulty sleeping causing inability 
to perform usual social & functional 
activities 
 
Disabling insomnia causing inability to 
perform basic self-care functions 
Neuromuscular weakness 
(including myopathy & 
neuropathy) 
 
Asymptomatic with 
decreased strength on 
exam OR  Minimal muscle 
weakness causing no or 
minimal interference with 
usual social & functional 
activities 
Muscle weakness causing greater 
than minimal interference with usual 
social & functional activities 
 
Muscle weakness causing inability 
to perform usual social & functional 
activities 
 
Disabling muscle weakness causing 
inability to perform basic self-care 
functions OR Respiratory muscle 
weakness impairing ventilation 
Neurosensory Alteration 
(including paresthesia and 
painful neuropathy) 
 
Asymptomatic with sensory 
alteration on exam or 
minimal 
paresthesia causing no or 
minimal interference with 
usual social & 
functional activities 
Sensory alteration or paresthesia 
causing greater than minimal 
interference with usual social & 
functional activities 
 
Sensory alteration or paresthesia 
causing inability to perform usual 
social & functional activities 
 
Disabling sensory alteration or 
paresthesia causing inability to perform 
basic self-care functions 
Seizure: (new onset) 
– Adult ≥ 18 years 
See also Seizure: (known 
preexisting seizure disorder) 
NA 
1 seizure 
2 – 4 seizures 
Seizures of any kind which are 
prolonged, repetitive (e.g., status 
epilepticus), or difficult to control (e.g., 
refractory epilepsy) 
Seizure: (known pre-existing 
seizure disorder) 
– Adult ≥ 18 years 
For worsening of existing 
epilepsy the grades should 
be based on an increase 
from previous level of control 
to any of these levels. 
NA 
Increased frequency of pre-existing 
seizures (non-repetitive) without 
change in seizure character OR 
Infrequent break-through seizures 
while on stable medication in a 
previously controlled seizure 
disorder 
 
Change in seizure character from 
baseline either in duration or quality 
(e.g., severity or focality) 
 
Seizures of any kind which are 
prolonged, repetitive (e.g., status 
epilepticus), or difficult to control (e.g., 
refractory epilepsy) 
 


Protocol  
 
 
 
 
 
 
EudraCT Number: 2018-003915-24 
Version 2.4 (26/06/2019) 
 
DORACeNeS Study 
 
 
 
 
38
PARAMETER  
 
GRADE 1 
MILD  
 
GRADE 2 MODERATE  
 
GRADE 3 SEVERE  
 
GRADE 4 POTENTIALLY LIFE-
THREATENING  
 
Seizure 
– Pediatric < 18 years 
 
Seizure, generalized onset 
with or without secondary 
generalization, lasting < 5 
minutes with < 24 hours 
post ictal state 
Seizure, generalized onset with or 
without secondary generalization, 
lasting 5 – 20 minutes with <24 
hours post ictal state 
 
Seizure, generalized onset with or 
without secondary generalization, 
lasting >20 minutes 
 
Seizure, generalized onset with or 
without Secondary generalization, 
requiring intubation and sedation 
Syncope (not associated 
with a procedure) 
NA 
Present 
NA 
NA 
Vertigo  
 
Vertigo causing no or 
minimal interference with 
usual social & functional 
activities 
Vertigo causing greater than 
minimal interference with usual 
social & functional activities 
 
Vertigo causing inability to perform 
usual social & functional activities 
 
Disabling vertigo causing inability to 
perform basic self-care Functions 
RESPIRATORY 
Bronchospasm (acute)  
 
FEV1 or peak flow reduced 
to 70-80% 
FEV1 or peak flow 50–69% 
FEV1 or peak flow 25–49%  
Cyanosis OR  FEV1 or peak flow < 25% 
OR Intubation 
Dyspnea or respiratory distress 
Adult ≥ 14 years Dyspnea 
on exertion with no or 
minimal interference with 
usual social & functional 
activities 
 
Dyspnea on exertion with 
no or minimal interference 
with usual social & 
functional activities 
 
Dyspnea on exertion causing 
greater than minimal interference 
with usual social & functional 
activities 
 
Dyspnea at rest causing inability to 
perform usual social & functional 
activities 
 
Respiratory failure with ventilatory 
support Indicated 
Pediatric < 14 years  
 
Wheezing OR minimal 
increase in respiratory rate 
for age 
Nasal flaring OR Intercostal 
retractions OR Pulse oximetry 90 – 
95% 
 
Dyspnea at rest causing inability to 
perform usual social & functional 
activities OR Pulse oximetry < 90% 
 
Respiratory failure with ventilatory 
support indicated 
MUSCULOSKELETAL 
Arthralgia 
See also Arthritis 
 
Joint pain causing no or 
minimal nterference with 
usual social & functional 
activities 
Joint pain causing greater than 
minimal interference with usual 
social & functional activities 
 
Joint pain causing inability to 
perform 
usual social & functional activities 
 
Disabling joint pain causing inability to 
perform basic self-care Functions 
Arthritis 
See also Arthralgia 
 
Stiffness or joint swelling 
causing no or minimal 
interference with usual 
social & functional activities 
Stiffness or joint swelling causing 
greater than minimal interference 
with usual social & functional 
activities 
 
Stiffness or joint swelling causing 
inability to perform usual social & 
functional activities 
 
Disabling joint stiffness or swelling 
causing inability to perform basic selfcare 
functions 
 
 


Protocol  
 
 
 
 
 
 
EudraCT Number: 2018-003915-24 
Version 2.4 (26/06/2019) 
 
DORACeNeS Study 
 
 
 
 
39
PARAMETER  
 
GRADE 1 
MILD  
 
GRADE 2 MODERATE  
 
GRADE 3 SEVERE  
 
GRADE 4 POTENTIALLY LIFE-
THREATENING  
 
Bone Mineral Loss 
Adult ≥ 21 years  
 
BMD t-score -2.5 to -1.0 
BMD t-score < -2.5 
Pathological fracture (including loss 
of vertebral height) 
Pathologic fracture causing lifethreatening 
Consequences 
Pediatric < 21 years  
 
BMD z-score -2.5 to -1.0 
BMD z-score < -2.5 
Pathological fracture (including loss 
of vertebral height) 
Pathologic fracture causing lifethreatening 
consequences 
Myalgia (non-injection site)  
 
Muscle pain causing no or 
minimal interference with 
usual social & functional 
activities 
Muscle pain causing greater than 
minimal interference with usual 
social & functional activities 
Muscle pain causing inability to 
perform usual social & functional 
activities 
 
Disabling muscle pain causing inability 
Osteonecrosis  
 
NA 
Asymptomatic with radiographic 
findings AND No operative 
intervention indicated 
Symptomatic bone pain with 
radiographic findings OR Operative 
intervention indicated 
Disabling bone pain with radiographic 
findings causing inability to perform basic 
self-care functions 
GENITOURINARY 
Cervicitis (symptoms) 
(For use in studies 
evaluating topical study 
agents) 
For other cervicitis see 
Infection: Infection (any 
other than HIV infection) 
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities 
 
Symptoms causing greater than 
minimal interference with usual 
social & functional activities 
 
Symptoms causing inability to 
perform usual social & functional 
activities 
 
Symptoms causing inability to perform 
basic self-care functions 
Cervicitis (clinical exam) 
(For use in studies 
evaluating topical study 
agents) 
For other cervicitis see 
Infection: Infection (any 
other than HIV 
infection) 
Minimal cervical 
abnormalities on 
examination (erythema, 
Mucopurulent discharge, or 
friability) OR Epithelial 
disruption < 25% of total 
surface 
 
Moderate cervical abnormalities on 
examination (erythema, 
mucopurulent discharge, or 
friability) OR Epithelial disruption of 
25 – 49% total surface 
 
Severe cervical abnormalities on 
examination (erythema, 
mucopurulent discharge, or friability) 
OR Epithelial disruption 50 – 75% 
total surface 
 
Epithelial disruption > 75% total 
surface 
Inter-menstrual bleeding 
(IMB)  
 
Spotting observed by 
participant 
OR Minimal blood 
observed during clinical or 
colposcopic examination 
Inter-menstrual bleeding not greater 
in duration or amount than usual 
menstrual cycle 
 
Inter-menstrual bleeding greater in 
duration or amount than usual 
menstrual cycle 
 
Hemorrhage with life-threatening 
hypotension OR Operative intervention 
indicated 
 
 
 


Protocol  
 
 
 
 
 
 
EudraCT Number: 2018-003915-24 
Version 2.4 (26/06/2019) 
 
DORACeNeS Study 
 
 
 
 
40
PARAMETER  
 
GRADE 1 
MILD  
 
GRADE 2 MODERATE  
 
GRADE 3 SEVERE  
 
GRADE 4 POTENTIALLY LIFE-
THREATENING  
 
Urinary tract obstruction 
(e.g., 
stone) 
 
NA  
 
Signs or symptoms of urinary tract 
obstruction without hydronephrosis 
or renal dysfunction 
Signs or symptoms of urinary tract 
obstruction with hydronephrosis or 
renal dysfunction 
Obstruction causing life-threatening 
consequences 
Vulvovaginitis (symptoms) 
(Use in studies evaluating 
topical study agents) 
For other vulvovaginitis see 
Infection: Infection (any 
other than HIV infection) 
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities 
 
Symptoms causing greater than 
minimal interference with usual 
social & functional activities 
 
Symptoms causing inability to 
perform usual social & functional 
activities 
 
Symptoms causing inability 
Vulvovaginitis (clinical exam) 
(Use in studies evaluating 
topical 
study agents) 
For other vulvovaginitis see 
Infection: Infection (any 
other than HIV infection) 
Minimal vaginal 
abnormalities on 
examination OR Epithelial 
disruption <25% of total 
surface 
 
Moderate vaginal abnormalities on 
examination OR Epithelial 
disruption of 25 - 49% total surface 
 
Severe vaginal abnormalities on 
examination OR Epithelial disruption 
50 - 75% total surface 
 
Vaginal perforation OR Epithelial 
disruption > 75% total surface 
OCULAR/VISUAL 
Uveitis  
 
Asymptomatic but 
detectable on 
Exam 
Symptomatic anterior uveitis OR 
Medical intervention indicated 
 
Posterior or pan-uveitis OR 
Operative 
intervention indicated 
Disabling visual loss in affected eye(s) 
Visual changes (from 
baseline)  
 
Visual changes causing no 
or minimal interference 
with usual 
social & functional activities 
Visual changes causing greater 
than minimal interference with usual 
social & functional activities 
 
Visual changes causing inability to 
perform usual social & functional 
activities 
 
Disabling visual loss in affected eye(s) 
ENDOCRINE/METABOLIC 
Abnormal fat accumulation 
(e.g., 
back of neck, breasts, 
abdomen) 
 
Detectable by study 
participant (or by caregiver 
for young children and 
disabled adults) 
Detectable on physical exam by 
health care provider 
 
Disfiguring OR Obvious changes on 
casual visual inspection 
 
NA 
Diabetes mellitus  
 
NA 
New onset without need to initiate 
medication OR Modification of 
current medications to regain 
glucose control 
New onset with initiation of 
medication indicated OR Diabetes 
uncontrolled despite treatment 
modification 
Life-threatening consequences (e.g., 
ketoacidosis, hyperosmolar non-ketotic 
coma) 
 
 


Protocol  
 
 
 
 
 
 
EudraCT Number: 2018-003915-24 
Version 2.4 (26/06/2019) 
 
DORACeNeS Study 
 
 
 
 
41
 
PARAMETER  
 
GRADE 1 
MILD  
 
GRADE 2 MODERATE  
 
GRADE 3 SEVERE  
 
GRADE 4 POTENTIALLY LIFE-
THREATENING  
 
Gynecomastia  
 
Detectable by study 
participant or caregiver (for 
young children and 
disabled adults) 
Detectable on physical exam by 
health care provider 
 
Disfiguring OR Obvious on casual 
visual inspection 
 
NA 
Hyperthyroidism 
 
Asymptomatic  
 
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid suppression therapy 
indicated 
Symptoms causing inability to 
perform usual social & functional 
activities OR Uncontrolled despite 
treatment modification 
 
Life-threatening consequences (e.g., 
thyroid storm) 
Hypothyroidism  
 
Asymptomatic 
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid replacement therapy 
indicated 
Symptoms causing inability to 
perform usual social & functional 
activities OR Uncontrolled despite 
treatment modification 
 
Life-threatening consequences (e.g., 
myxedema coma) 
Lipoatrophy (e.g., fat loss 
from the 
face, extremities, buttocks) 
 
Detectable by study 
participant (or by caregiver 
for young children and 
disabled adults) 
Detectable on physical exam by 
health care provider 
 
Disfiguring OR Obvious on casual 
visual inspection 
 
NA 
 
 
 
 
 


 
 
 
 
 
 
 
LABORATORY 
PARAMETER 
 
GRADE 1 
MILD 
 
GRADE 2 
MODERATE 
 
GRADE 3 SEVERE 
 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
 
HEMATOLOGY 
Absolute CD4+ 
count 
– Adult and 
Pediatric 
> 13 years 
(HIV NEGATIVE 
ONLY) 
300 – 400/mm3 
300 – 400/μL 
 
200 – 299/mm3 
200 – 299/μL 
 
100 – 199/mm3 
100 – 199/μL 
 
< 100/mm3 
< 100/μL 
Absolute lymphocyte 
count 
– Adult and 
Pediatric 
> 13 years 
(HIV NEGATIVE 
ONLY) 
 
600 – 650/mm3 
0.600 x 109 – 
0.650 x 109/L 
 
500 – 599/mm3 
0.500 x 109 – 
0.599 x 109/L 
 
350 – 499/mm3 
0.350 x 109 – 
0.499 x 109/L 
 
< 350/mm3 
< 0.350 x 109/L 
Comment: Values in children ≤ 13 years are not given for the two parameters above because the 
absolute counts are 
variable. 
Absolute neutrophil count (ANC) 
Adult and 
Pediatric, 
> 7 days 
 
1,000 – 
1,300/mm3 
1.000 x 109 – 
1.300 x 109/L 
 
750 – 999/mm3 
0.750 x 109 – 
0.999 x 109/L 
 
500 – 749/mm3 
0.500 x 109 – 
0.749 x 109/L 
 
< 500/mm3 
< 0.500 x 109/L 
Infant*†, 2 – ≤ 7 
days 1,250 – 
 
1,500/mm3 
1.250 x 109 – 
1.500 x 109/L 
 
1,000 – 1,249/mm3 
1.000 x 109 – 
1.249 x 109/L 
 
750 – 999/mm3 
0.750 x 109 – 
0.999 x 109/L 
 
< 750/mm3 
< 0.750 x 109/L 
Infant*†, ≤1 day  
 
4,000 – 
5,000/mm3 
4.000 x 109 – 
5.000 x 109/L 
3,000 – 3,999/mm3 
3.000 x 109 – 
3.999 x109/L 
 
1,500 – 2,999/mm3 
1.500 x 109 – 
2.999 x 109/L 
 
< 1,500/mm3 
< 1.500 x 109/L 
Fibrinogen, 
decreased 100 – 
200 mg/dL 
 
1.00 – 2.00 g/L 
OR 
0.75 – 0.99 x 
LLN 
 
75 – 99 mg/dL 
0.75 – 0.99 g/L 
OR 
0.50 – 0.74 x LLN 
 
50 – 74 mg/dL 
0.50 – 0.74 g/L 
OR 
0.25 – 0.49 x LLN 
 
< 50 mg/dL 
< 0.50 g/L 
OR 
< 0.25 x LLN 
OR 
Associated with 
gross 
bleeding 
LABORATORY 
PARAMETER 
 
GRADE 1 
MILD 
 
GRADE 2 
MODERATE 
 
GRADE 3 SEVERE 
 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
 
HEMATOLOGY 
Absolute CD4+ 
count 
– Adult and 
Pediatric 
> 13 years 
(HIV NEGATIVE 
ONLY) 
300 – 400/mm3 
300 – 400/μL 
 
200 – 299/mm3 
200 – 299/μL 
 
100 – 199/mm3 
100 – 199/μL 
 
< 100/mm3 
< 100/μL 
Absolute lymphocyte 
count 
– Adult and 
Pediatric 
> 13 years 
(HIV NEGATIVE 
ONLY) 
 
600 – 650/mm3 
0.600 x 109 – 
0.650 x 109/L 
 
500 – 599/mm3 
0.500 x 109 – 
0.599 x 109/L 
 
350 – 499/mm3 
0.350 x 109 – 
0.499 x 109/L 
 
< 350/mm3 
< 0.350 x 109/L 
Comment: Values in children ≤ 13 years are not given for the two parameters above because the 
absolute counts are 
variable. 
Absolute neutrophil count (ANC) 
Adult and 
Pediatric, 
> 7 days 
 
1,000 – 
1,300/mm3 
1.000 x 109 – 
1.300 x 109/L 
 
750 – 999/mm3 
0.750 x 109 – 
0.999 x 109/L 
 
500 – 749/mm3 
0.500 x 109 – 
0.749 x 109/L 
 
< 500/mm3 
< 0.500 x 109/L 
Infant*†, 2 – ≤ 7 
days 1,250 – 
 
1,500/mm3 
1.250 x 109 – 
1.500 x 109/L 
 
1,000 – 1,249/mm3 
1.000 x 109 – 
1.249 x 109/L 
 
750 – 999/mm3 
0.750 x 109 – 
0.999 x 109/L 
 
< 750/mm3 
< 0.750 x 109/L 
Infant*†, ≤1 day  
 
4,000 – 
5,000/mm3 
4.000 x 109 – 
5.000 x 109/L 
3,000 – 3,999/mm3 
3.000 x 109 – 
3.999 x109/L 
 
1,500 – 2,999/mm3 
1.500 x 109 – 
2.999 x 109/L 
 
< 1,500/mm3 
< 1.500 x 109/L 
Fibrinogen, 
decreased 100 – 
200 mg/dL 
 
1.00 – 2.00 g/L 
OR 
0.75 – 0.99 x 
LLN 
 
75 – 99 mg/dL 
0.75 – 0.99 g/L 
OR 
0.50 – 0.74 x LLN 
 
50 – 74 mg/dL 
0.50 – 0.74 g/L 
OR 
0.25 – 0.49 x LLN 
 
< 50 mg/dL 
< 0.50 g/L 
OR 
< 0.25 x LLN 
OR 
Associated with 
gross 
bleeding 


Protocol  
 
 
 
 
 
 
EudraCT Number: 2018-003915-24 
Version 2.4 (26/06/2019) 
 
DORACeNeS Study 
 
 
 
 
43
 
 
LABORATORY 
PARAMETER 
 
GRADE 1 
MILD 
 
GRADE 2 
MODERATE 
 
GRADE 3 SEVERE 
 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
 
Hemoglobin (Hgb) 
Adult and Pediatric 
≥ 57 days 
(HIV POSITIVE 
ONLY) 
 
8.5 – 10.0 g/dL 
5.24 – 6.23 
mmol/L 
 
7.5 – 8.4 g/dL 
4.62 – 5.23 mmol/L 
 
6.50 – 7.4 g/dL 
4.03 – 4.61 mmol/L 
 
< 6.5 g/dL 
< 4.03 mmol/L 
Adult and Pediatric 
≥ 57 days 
(HIV NEGATIVE 
ONLY) 
 
10.0 – 10.9 g/dL 
6.18 – 6.79 
mmol/L 
OR 
Any decrease 
2.5 – 3.4 g/dL 
1.58 – 2.13 
mmol/L 
9.0 – 9.9 g/dL 
5.55 – 6.17 mmol/L 
OR 
Any decrease 
3.5 – 4.4 g/dL 
2.14 – 2.78 mmol/L 
 
7.0 – 8.9 g/dL 
4.34 – 5.54 mmol/L 
OR 
Any decrease 
≥ 4.5 g/dL 
≥ 2.79 mmol/L 
 
< 7.0 g/dL 
< 4.34 mmol/L 
Infant*†, 36 – 56 
days 
(HIV POSITIVE OR 
NEGATIVE) 
8.5 – 9.4 g/dL 
5.24 – 5.86 
mmol/L 
 
7.0 – 8.4 g/dL 
4.31 – 5.23 mmol/L 
 
6.0 – 6.9 g/dL 
3.72 – 4.30 mmol/L 
 
< 6.00 g/dL 
< 3.72 mmol/L 
Infant*†, 22 – 35 
days 
(HIV POSITIVE OR 
NEGATIVE) 
9.5 – 10.5 g/dL 
5.87 – 6.54 
mmol/L 
 
8.0 – 9.4 g/dL 
4.93 – 5.86 mmol/L 
 
7.0 – 7.9 g/dL 
4.34 – 4.92 mmol/L 
 
< 7.00 g/dL 
< 4.34 mmol/L 
Infant*†, ≤21 days 
(HIV POSITIVE OR 
NEGATIVE) 
 
12.0 – 13.0 g/dL 
7.42 – 8.09 
mmol/L 
 
10.0 – 11.9 g/dL 
6.18 – 7.41 mmol/L 
 
9.0 – 9.9 g/dL 
5.59 – 6.17 mmol/L 
 
< 9.0 g/dL 
< 5.59 mmol/L 
International 
Normalized 
Ratio of prothrombin 
time 
(INR) 
 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 3.0 x ULN 
> 3.0 x ULN 
Methemoglobin  
5.0 – 10.0% 
10.1 – 15.0% 
15.1 – 20.0% 
> 20.0% 
Prothrombin Time 
(PT)  
1.1 – 1.25 x 
ULN 
1.26 – 1.50 x ULN 
1.51 – 3.00 x ULN 
> 3.00 x ULN 
Partial 
Thromboplastin 
Time (PTT) 
 
1.1 – 1.66 x 
ULN 
1.67 – 2.33 x ULN 
2.34 – 3.00 x ULN 
> 3.00 x ULN 
Platelets, decreased  
 
100,000 – 
124,999/mm3 
100.000 x 109 – 
124.999 x 109/L 
50,000 – 
99,999/mm3 
50.000 x 109 – 
99.999 x 109/L 
 
25,000 – 
49,999/mm3 
25.000 x 109 – 
49.999 x 109/L 
 
< 25,000/mm3 
< 25.000 x 109/L 
WBC, decreased  
 
2,000 – 
2,500/mm3 
2.000 x 109 – 
2.500 x 109/L 
1,500 – 1,999/mm3 
1.500 x 109 – 
1.999 x 109/L 
 
1,000 – 1,499/mm3 
1.000 x 109 – 
1.499 x 109/L 
 
< 1,000/mm3 
< 1.000 x 109/L 


Protocol  
 
 
 
 
 
 
EudraCT Number: 2018-003915-24 
Version 2.4 (26/06/2019) 
 
DORACeNeS Study 
 
 
 
 
44
 
 
LABORATORY 
PARAMETER 
 
GRADE 1 
MILD 
 
GRADE 2 
MODERATE 
 
GRADE 3 SEVERE 
 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
 
CHEMISTRIES Standard International Units are listed in italics 
Acidosis  
 
NA 
pH < normal, but ≥ 
7.3 
pH < 7.3 without 
lifethreatening 
consequences 
pH < 7.3 with 
lifethreatening 
consequences 
Albumin serum, low 
 
3.0 g/dL – < LLN 
30 g/L – < LLN 
2.0 – 2.9 g/dL 
20 – 29 g/L 
< 2.0 g/dL 
< 20 g/L 
NA 
Alkaline 
Phosphatase  
1.25 – 2.5 x 
ULN† 
2.6 – 5.0 x ULN† 
5.1 – 10.0 x ULN† 
> 10.0 x ULN† 
Alkalosis  
 
NA 
pH > normal, but ≤ 
7.5 
pH > 7.5 without 
lifethreatening 
consequences 
pH > 7.5 with 
lifethreatening 
consequences 
ALT (SGPT)  
1.25 – 2.5 x 
ULN 
2.6 – 5.0 x ULN 
5.1 – 10.0 x ULN 
> 10.0 x ULN 
AST (SGOT) 
 1.25 – 2.5 x 
ULN 
2.6 – 5.0 x ULN 
5.1 – 10.0 x ULN 
> 10.0 x ULN 
Bicarbonate, serum,  
 
low 16.0 mEq/L 
– < LLN 
16.0 mmol/L – < 
LLN 
11.0 – 15.9 mEq/L 
11.0 – 15.9 mmol/L 
 
8.0 – 10.9 mEq/L 
8.0 – 10.9 mmol/L 
 
< 8.0 mEq/L 
< 8.0 mmol/L 
Bilirubin (Total) 
Adult and Pediatric 
>14 days 
1.1 – 1.5 x ULN 
1.6 – 2.5 x ULN 
2.6 – 5.0 x ULN 
> 5.0 x ULN 
Infant*†, ≤ 14 days 
(non-hemolytic) 
NA  
 
20.0 – 25.0 mg/dL 
342 – 428 μmol/L 
25.1 – 30.0 mg/dL 
429 – 513 μmol/L 
 
> 30.0 mg/dL 
> 513.0 μmol/L 
nfant*†, ≤ 14 days 
(hemolytic) 
NA 
NA 
20.0 – 25.0 mg/dL 
342 – 428 μmol/L 
 
> 25.0 mg/dL 
> 428 μmol/L 
Calcium, serum, high (corrected for albumin) 
Adult and Pediatric 
≥ 7 days 
 
10.6 – 11.5 
mg/dL 
2.65 – 2.88 
mmol/L 
11.6 – 12.5 mg/dL 
2.89 – 3.13 mmol/L 
 
12.6 – 13.5 mg/dL 
3.14 – 3.38 mmol/L 
 
> 13.5 mg/dL 
> 3.38 mmol/L 
Infant*†, < 7 days  
 
 
11.5 – 12.4 
mg/dL 
2.88 – 3.10 
mmol/L 
12.5 – 12.9 mg/dL 
3.11 – 3.23 mmol/L 
13.0 – 13.5 mg/dL 
3.245 – 3.38 
mmol/L 
 
> 13.5 mg/dL 
> 3.38 mmol/L 
Calcium, serum, low 
Adult and Pediatric 
≥ 7 days 
7.8 – 8.4 mg/dL 
1.95 – 2.10 
mmol/L 
7.0 – 7.7 mg/dL 
1.75 – 1.94 mmol/L 
 
6.1 – 6.9 mg/dL 
1.53 – 1.74 mmol/L 
 
< 6.1 mg/dL 
< 1.53 mmol/L 
Infant*†, < 7 days  
 
6.5 – 7.5 mg/dL 
1.63 – 1.88 
mmol/L 
6.0 – 6.4 mg/dL 
1.50 – 1.62 mmol/L 
 
5.50 – 5.90 mg/dL 
1.38 – 1.51 mmol/L 
 
< 5.50 mg/dL 
< 1.38 mmol/L 
Cardiac troponin I 
(cTnI) NA NA NA  
NA 
NA 
NA 
Levels consistent 
with myocardial 
infarction or 
unstable angina as 
defined by the 
manufacturer 
Continued 


Protocol  
 
 
 
 
 
 
EudraCT Number: 2018-003915-24 
Version 2.4 (26/06/2019) 
 
DORACeNeS Study 
 
 
 
 
45
 
 
 
1. ∗ Values are for term infants. Preterm infants should be assessed using local normal ranges.2. † Use age 
and sex appropriate values (e.g., bilirubin). 
 
LABORATORY 
PARAMETER 
 
GRADE 1 
MILD 
 
GRADE 2 
MODERATE 
 
GRADE 3 SEVERE 
 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
 
Cardiac troponin T 
(cTnT) 
 
NA 
NA 
NA 
≥ 0.20 ng/mL 
OR 
Levels consistent with 
myocardial infarction 
or 
unstable angina as 
defined by the 
manufacturer 
Cholesterol (fasting) 
Adult ≥ 18 years  
 
 
200 – 239 mg/dL 
5.18 – 6.19 
mmol/L 
240 – 300 mg/dL 
6.20 – 7.77 mmol/L 
> 300 mg/dL 
> 7.77 mmol/L 
 
NA 
Pediatric < 18 years  
 
 
170 – 199 mg/dL 
4.40 – 5.15 
mmol/L 
200 – 300 mg/dL 
5.16 – 7.77 mmol/L 
> 300 mg/dL 
> 7.77 mmol/L 
 
NA 
Creatine Kinase  
3.0 – 5.9 x ULN† 
6.0 – 9.9 x ULN† 
10.0 – 19.9 x ULN† 
≥ 20.0 x ULN† 
Creatinine  
1.1 – 1.3 x ULN† 
1.4 – 1.8 x ULN † 
1.9 – 3.4 x ULN† 
≥ 3.5 x ULN† 
Glucose, serum, high 
Nonfasting  
 
116 – 160 mg/dL 
6.44 – 8.88 
mmol/L 
161 – 250 mg/dL 
8.89 – 13.88 
mmol/L 
 
251 – 500 mg/dL 
13.89 – 27.75 mmol/L 
 
> 500 mg/dL 
> 27.75 mmol/L 
Fasting  
 
110 – 125 mg/dL 
6.11 – 6.94 
mmol/L 
126 – 250 mg/dL 
6.95 – 13.88 
mmol/L 
 
251 – 500 mg/dL 
13.89 – 27.75 mmol/L 
 
> 500 mg/dL 
> 27.75 mmol/L 
Glucose, serum, low 
Adult and Pediatric 
≥ 1 month 
 
55 – 64 mg/dL 
3.05 – 3.55 
mmol/L 
40 – 54 mg/dL 
2.22 – 3.06 mmol/L 
 
30 – 39 mg/dL 
1.67 – 2.23 mmol/L 
 
< 30 mg/dL 
< 1.67 mmol/L 
Infant*†, < 1 month  
 
50 – 54 mg/dL 
2.78 – 3.00 
mmol/L 
40 – 49 mg/dL 
2.22 – 2.77 mmol/L 
 
30 – 39 mg/dL 
1.67 – 2.21 mmol/L 
 
< 30 mg/dL 
< 1.67 mmol/L 
Lactate  
 
ULN - < 2.0 x ULN 
without acidosis 
≥ 2.0 x ULN 
Without acidosis 
 
Increased lactate with 
pH < 
7.3 without life-
threatening 
consequences 
Increased lactate with 
pH 
<7.3 with life-
threatening 
consequences 
LDL cholesterol (fasting) 
Adult ≥ 18 years 
 
130 – 159 mg/dL 
3.37 – 4.12 
mmol/L 
160 – 190 mg/dL 
4.13 – 4.90 mmol/L 
 
≥ 190 mg/dL 
≥ 4.91 mmol/L 
 
NA 
Pediatric > 2 - < 18 
years 
 
110 – 129 mg/dL 
2.85 – 3.34 
mmol/L 
130 – 189 mg/dL 
3.35 – 4.90 mmol/L 
 
≥ 190 mg/dL 
≥ 4.91 mmol/L 
 
NA 
Lipase 
1.1 – 1.5 x ULN 
1.6 – 3.0 x ULN 
3.1 – 5.0 x ULN 
> 5.0 x ULN 
 

SAP_001.pdf: 
Statistical Analysis Plan 
DORACENES 
SAP v 1.0: 26/06/2019 
DORACENES 
 
 
 
 
  
Statistical Analysis Plan 
 
 
 
 
TRIAL FULL TITLE 
Doravirine concentrations and antiviral activity in Cerebrospinal 
fluid in HIV-1 Infected individuals (“DORACENES Study”) 
SAP VERSION 
1.0 
SAP VERSION DATE 
26/06/2019 
Protocol Version (SAP 
associated with) 
2.4 
 
 
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: DORACENES 
 
ClinicalTrials.gov Identificator: NCT04079452 


Statistical Analysis Plan 
DORACENES 
SAP v 1.0: 26/06/2019 
DORACENES 
 
 
Signature page 
 
 
 
Principal investigator: 
 
 
 
 
 
 
Author: 
 
 
Daniel Podzamczer (26/06/2019) 
 
 
 
 
 
 
Antonio Navarro (26/06/2019) 


Statistical Analysis Plan 
DORACENES 
SAP v 1.0: 26/06/2019 
DORACENES 
 
 
Abbreviations 
 
HIV 
Human Immunodeficiency Virus 
CNS 
Central Nervous System 
CSF 
Cerebrospinal Fluid 
ARV 
Antirretroviral 
TAF 
Tenofovir Alafenamide Fumarate 
FTC 
Emtricitabine 
ART 
Antirretroviral Treatment 
PK 
Pharmacokinetics 
PD 
Pharmacodynamics 


Statistical Analysis Plan 
DORACENES 
SAP v 1.0: 26/06/2019 
DORACENES 
 
 
Table of contents 
1. 
Introduction .......................................................................................................................... 5 
2. 
Study Design .......................................................................................................................... 5 
3. 
Aims and Objectives .............................................................................................................. 5 
4. 
Outcomes .............................................................................................................................. 6 
5. 
Population to be analyzed ..................................................................................................... 6 
6. 
Analyses ................................................................................................................................. 6 
7. 
Missing data .......................................................................................................................... 6 
 


Statistical Analysis Plan 
DORACENES 
SAP v 1.0: 26/06/2019 
DORACENES 
 
 
 
 
1. Introduction 
 
The aim of this project is to assess doravirine concentrations in CSF and to estimate 
penetration into the CNS and to evaluate antiviral activity of a combination of 
Doravirine+FTC/TAF in CSF in people live with HIV. 
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, Phase III, prospective, open label, single arm, single center. 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 w4 HIV-1 
RNA concentration and Doravirine CSF concentration will be assessed. 
2.1 Sample Size. 
 
Fifteen individuals will be included in the study. This is a pilot study designed to obtain 
information about Doravirine concentrations and HIV viral suppression in CSF. The study 
design is similar to other studies evaluating ARV PK and PD in this compartment. 
 
 
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 of HIV associated 
neurocognitive disorders. 


Statistical Analysis Plan 
DORACENES 
SAP v 1.0: 26/06/2019 
DORACENES 
 
 
4. Outcomes 
- Total and unbound Doravirine concentrations in cerebrospinal fluid in HIV-1 infected 
individual receiving ART with TAF/FTC+Doravirine. 
-Total Doravirine concentrations in blood plasma. 
 
- Doravirine CSF/plasma ratio. 
 
-HIV-1 RNA in cerebrospinal fluid. 
 
-HIV-1 RNA in blood plasma. 
 
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. 
SAS 9.4 will be used for all statistical analysis. 
The primary analysis will determine the Doravirine concentration in CSF and blood plasma, and 
the HIV-1 viral load in CSF and blood plasma. 
 
 
7. Missing data 
Subjects with missing data will be excluded for the analysis.