Removal of Doravirine by Hemodialysis in HIV-Infected Patients With End-Stage Renal Disease (ESRD)
Phase: PHASE4
Conditions: HIV-infected Participants With ESRD Undergoing Routine Hemodialysis
Sponsor: Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia

 
 
 
 
 
Removal of Doravirine by Hemodialysis in HIV-Infected Patients with End-Stage Renal Disease 
(ESRD) 
 
 
 
 
Code: Dora-HD 
 
 
Version 1.0, 0.6th October 2020 
 
EudraCT: 2020-004454-30 
 
 
Sponsor:  
 
Fundació FLS de Lluita contra la SIDA, les Malalties Infeccioses  
i la Promoció de la Salut i La Ciència 
 
 
Hospital Universitari Germans Trias i Pujol 
 
 
Carretera de Canyet s/n 
 
 
08916 Badalona (Barcelona) 
 
 
 
 
 
 
Principal / Coordinating Investigator: José Moltó Marhuenda, MD, PhD 
 
 
Co-Investigators: 
Adrià Curran Fàbregas, MD, PhD 
 
 
 
Natàlia Ramos Terrades, MD 
 
 
 
Paula Suanzes Díez, MD 
 
 
 
Arkaitz Imaz Vacas, MD, PhD 
 
 
 
Sofía Scévola, MD 
 
 
 
Ana Coloma López, MD 
 
 
 
Lucia Bailón Álvarez, MD 
 
 
 
 
Fredzzia Amada Graterol Torres, MD 
 
 
 
Jordi Soler Majoral, MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
The information contained in this document is confidential and must not be revealed to third persons without prior 
authorization as contemplated by Law. 
 

 
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SIGNATURES 
 
The coordinating investigator/ Principal Investigator and the sponsor of the study: 
Removal of Doravirine by Hemodialysis in HIV-Infected Patients with End-Stage Renal Disease 
(ESRD)   
 
Declare that this study will be conducted in compliance with the protocol, Good Clinical Practices 
(GCP) published by the International Conference of Harmonization Guideline (ICH), and the 
applicable regulatory requirements. 
 
Modifications to this protocol must be submitted prior agreement of the coordinating / principal 
investigator and sponsor. 
 
 
Principal / Coordinating Investigator: José Moltó Marhuenda, MD, PhD 
 
 
 
Signature and Date: 
 
 
 
 
Sponsor: Bonaventura Clotet, PhD, MD 
Fundació Lluita contra la SIDA 
 
 
 
 
Signature and Date: 
 
 
 
 
 
 
 
 
 
 
 

 
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1 
GENERAL INFORMATION 
1.1 
TITLE 
Removal of Doravirine by Hemodialysis in HIV-Infected Patients with End-Stage Renal Disease 
(ESRD)   
 
1.2 
CODE 
Dora-HD 
 
1.3 
PROTOCOL VERSION AND DATE 
Version 1.0, 06th October 2020 
Any modification of the protocol must also bear the amendment number and date. 
 
1.4 
SPONSOR 
Fundació FLS de Lluita contra la SIDA, les Malalties Infeccioses  i la Promoció de la Salut i La 
Ciència 
Hospital Universitari Germans Trias i Pujol 
Carretera de Canyet s/n 
08916 Badalona (Barcelona) 
T. 93 497 78 97 
F. 93 465 76 02 
 
Person authorized by the sponsor to sign the protocol and amendments:  
Bonaventura Clotet Sala, president of Fundació FLS de Lluita contra la SIDA 
 
1.5 
PRINCIPAL / COORDINATING INVESTIGATOR 
José Moltó Marhuenda, MD, PhD 
Infectious Diseases Department 
Fundació FLS de Lluita contra la SIDA  
Hospital Universitari Germans Trias i Pujol 
Ctra. de Canyet, s/n 
08916 Badalona (Barcelona) 
jmolto@flsida.org 
T. 93 497 88 87 
 
 
 
 
 

 
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1.6 
CLINICAL RESEARCH ORGANIZATION 
The Sponsor will delegate the study monitoring, regulatory submission to EC and other study tasks to 
the following Clinical Research Organization (CRO):  
 
FLS-Research Support 
Fundació FLS de Lluita contra la SIDA  
Hospital Universitari Germans Trias i Pujol 
Carretera de Canyet s/n 
08916 Badalona 
Phone +34 93 497 84 14 
 
1.7 
SITES AND INVESTIGATORS 
Multicentric trial.   
The trial will be performed at: 
 
Hospital 
PI 
Co- Investigators 
H. U. Germans Trias i Pujols 
José Moltó Marhuenda 
Lucia Bailón Álvarez,  
Fredzzia Amada Graterol Torres,  
Jordi Soler Majoral 
H. Vall d’Hebron 
Adrià Curran Fàbregas 
Natalia Ramos,  
Paula Suanzes 
H. U. Bellvitge 
Arkaiz Imaz Vacas 
Sofía Scévola, Ana Coloma 
López 
 
 
1.8 
TECHNICAL SERVICES AND INSTITUTIONS INVOLVED 
Biochemistry, blood count and dialysis session will be performed in the local facilities of participating 
sites. 
 
Doravirine concentrations in plasma and dialysate fluid will be determined using high-performance 
liquid chromatography tandem mass spectrometry (LC-MS/MS), at the Department of Molecular and 
Clinical Pharmacology of the University of Liverpool, according to a validated method. 
 
Laura Jayne Else Bsc PhD/ Saye Khoo, MD, PhD 
Bioanalytical Facility / Molecular and Clinical Pharmacology 
Royal Liverpool University Hospital 
4th Floor UCD 
Prescot Street 
Liverpool 
L69 3GA 
Tel: +44 (0) 151 706 4076 / +44 (0)151 794 5560 
Fax: +44 (0) 151 706 4084 
Email: l.j.else@liv.ac.uk / S.H.Khoo@liverpool.ac.uk 

 
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TABLE OF CONTENTS 
1 
GENERAL INFORMATION .................................................................................................................. 3 
1.1 
TITLE ..................................................................................................................................................... 3 
1.2 
CODE ..................................................................................................................................................... 3 
1.3 
PROTOCOL VERSION AND DATE .................................................................................................. 3 
1.4 
SPONSOR ............................................................................................................................................ 3 
1.5 
PRINCIPAL / COORDINATING INVESTIGATOR .......................................................................... 3 
1.6 
CLINICAL RESEARCH ORGANIZATION ........................................................................................ 4 
1.7 
SITES AND INVESTIGATORS .......................................................................................................... 4 
1.8 
TECHNICAL SERVICES AND INSTITUTIONS INVOLVED ......................................................... 4 
TABLE OF CONTENTS ............................................................................................................................... 5 
2 
BACKGROUND INFORMATION ......................................................................................................... 8 
2.1 
REFERENCES ..................................................................................................................................... 9 
3 
TRIAL OBJECTIVE AND PURPOSE ................................................................................................ 10 
3.1 
PRIMARY OBJECTIVE ..................................................................................................................... 10 
3.2 
SECONDARY OBJECTIVE .............................................................................................................. 10 
4 
TRIAL DESIGN .................................................................................................................................... 11 
4.1 
TYPE OF TRIAL ................................................................................................................................. 11 
4.2 
DESCRIPTION OF THE DESIGN ................................................................................................... 11 
5 
ENDPOINTS......................................................................................................................................... 12 
5.1.1 
Primary endpoint(s).................................................................................................................... 12 
5.1.2 
Secondary endpoints ................................................................................................................. 12 
5.2 
MEASURES TO AVOID BIAS .......................................................................................................... 12 
5.2.1 
Randomization ............................................................................................................................ 12 
5.2.2 
Stratification ................................................................................................................................ 12 
5.2.3 
Blinding ........................................................................................................................................ 12 
5.3 
FORESEEN CALENDAR .................................................................................................................. 12 
5.4 
END OF TRIAL ................................................................................................................................... 12 
5.5 
SOURCE DATA ................................................................................................................................. 13 
6 
TRIAL INVESTIGATIONAL PRODUCT(S) ....................................................................................... 14 
6.1 
EXPERIMENTAL AND CONTROL TREATMENTS ..................................................................... 14 
6.2 
SUPPLY, PACKAGING, LABELING AND STORAGE ................................................................. 14 
6.3 
DOSE, INTERVAL, ROUTE AND METHOD OF ADMINISTRATION ........................................ 14 
6.4 
DRUG ACCOUNTABILITY ............................................................................................................... 14 
6.5 
ARM DESCRIPTION ......................................................................................................................... 14 
6.6 
MODIFICATION OF THE TREATMENT REGIMEN ..................................................................... 15 
6.7 
CONCOMITANT TREATMENTS ..................................................................................................... 15 
6.8 
COMPLIANCE .................................................................................................................................... 15 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS......................................................................... 16 
7.1 
INCLUSION CRITERIA ..................................................................................................................... 16 
7.2 
EXCLUSION CRITERIA.................................................................................................................... 16 
7.3 
SUBJECT WITHDRAWAL CRITERIA ............................................................................................ 17 
7.3.1 
Early subject withdrawal ............................................................................................................ 17 
7.3.2 
Medical approach to withdrawal ............................................................................................... 17 

 
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7.3.3 
Follow-up alter early withdrawal ............................................................................................... 17 
7.3.4 
Replacement of participants ..................................................................................................... 17 
7.4 
PRE-RANDOMIZATION / PRE-BASELINE LOSSES .................................................................. 18 
8 
TRIAL CONDUCTION AND RESPONSE EVALUATION ................................................................ 19 
8.1 
CRITERIA FOR RESPONSE EVALUATION ................................................................................. 19 
8.1.1 
Primary parameter ..................................................................................................................... 19 
8.1.2 
Secondary parameters .............................................................................................................. 19 
8.2 
TRIAL DEVELOPMENT .................................................................................................................... 19 
8.3 
STUDY VISITS ................................................................................................................................... 19 
8.3.1 
Screening visit (day -14 to 0) .................................................................................................... 19 
8.3.2 
Day 1 ............................................................................................................................................ 20 
8.3.3 
Day 6 ............................................................................................................................................ 20 
8.3.4 
Day 20 (+/- 4 days): Safety follow-up / End-of-study visit (Remote visit is accepted) ..... 21 
8.4 
STUDY ASSESMENTS .................................................................................................................... 21 
8.4.1 
Clinical record and physical exam ........................................................................................... 21 
8.4.2 
Laboratory tests .......................................................................................................................... 22 
8.5 
ASSESSMENTS FLOW-CHART ..................................................................................................... 23 
9 
ADVERSE EVENTS ............................................................................................................................ 24 
9.1 
DEFINITION ........................................................................................................................................ 24 
9.2 
DESCRIPTION OF THE IMPUTABILITY CRITERIA ................................................................... 24 
9.3 
ADVERSE EVENTS GRADING....................................................................................................... 25 
9.4 
PROCEDURE FOR  REPORTING ADVERSE EVENTS ............................................................ 26 
9.4.1 
Investigator .................................................................................................................................. 26 
9.4.2 
Sponsor ....................................................................................................................................... 27 
9.5 
HOSPITALIZATION AND FORESEEN PROCEDURES ............................................................. 27 
9.6 
ABNORMAL LABORATORY PARAMETERS ............................................................................... 27 
9.7 
DOCUMENTATION RELATED TO AE AND SAE ........................................................................ 28 
9.8 
SAE FOLLOW-UP ............................................................................................................................. 28 
9.9 
PREGNANCY ..................................................................................................................................... 29 
9.9.1 
Male subjects .............................................................................................................................. 29 
10 
STATISTICS ..................................................................................................................................... 30 
10.1 
SAMPLE SIZE DESCRIPTION .................................................................................................... 30 
10.2 
DEVIATION OF STATISTICAL PLAN ........................................................................................ 30 
11 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ............................................................... 31 
12 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................................. 32 
12.1 
STUDY MONITORING .................................................................................................................. 32 
12.2 
AUDITS AND INSPECTIONS ...................................................................................................... 32 
12.3 
CASE REPORT FORM ................................................................................................................. 33 
13 
ETHICS ............................................................................................................................................. 34 
13.1 
GENERAL CONSIDERATIONS .................................................................................................. 34 
13.2 
PATIENT INFORMATION SHEET AND INFORMED CONSENT .......................................... 34 
12.3 PAYMENT TO RESEARCH PARTICIPANTS .................................................................................. 34 
14 
DATA HANDLING AND RECORD KEEPING............................................................................... 35 
14.1 
DATA HANDLING .......................................................................................................................... 35 
14.2 
RECORD KEEPING ...................................................................................................................... 35 

 
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14.2.1 
Investigator file and document retention ................................................................................. 35 
14.2.2 
Source documents and basic data .......................................................................................... 35 
15 
FINANCING AND INSURANCE ..................................................................................................... 36 
15.1 
SOURCE OF FINANCING ............................................................................................................ 36 
15.2 
INSURANCE POLICY ................................................................................................................... 36 
16 
PUBLICATION POLICY .................................................................................................................. 37 
APPENDIX I: CASE REPORT FORM (CRF)............................................................................................ 38 
APPENDIX II: INVESTIGATOR’S BROCHURE ...................................................................................... 39 
APPENDIX III: PATIENT INFORMATION AND WRITTEN INFORMED CONSENT ............................ 40 
APPENDIX IV: INSURANCE ..................................................................................................................... 41 
APPENDIX V: SERIOUS ADVERSE EVENT REPORT .......................................................................... 42 
APPENDIX VI: DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF ADULT AND 
PEDIATRIC ADVERSE EVENTS .............................................................................................................. 43 
 

 
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2 
BACKGROUND INFORMATION 
Progressive improvement in life expectancy of people living with HIV (PLWH)  after the introduction of 
combined antiretroviral therapy (cART) has been accompanied by an increase in the prevalence of 
other non-AIDS defining comorbidities, including chronic kidney disease (CKD).1, 2 Nowadays, CKD 
may be considered epidemic among PLWH, being present in 4.7 to 38% of patients. Similarly, PLWH 
have a 2- to 20-fold greater risk of end stage renal disease (ESRD) compared with the general 
population,3-6  and the number of patients requiring hemodialysis as renal replacement therapy is 
increasing, especially among those with older age.1 Patients on dialysis are subject to extracorporeal 
clearance of small molecules, including many drugs, and management of dosing of antiretrovirals in 
PLWH undergoing hemodialysis may be challenging.7-9 Moreover, hemodialysis is intermittent and it 
has the potential for relatively rapid drug clearance. The extent to which dialysis removes a particular 
compound from plasma varies across different drugs, and it is dependent on drug properties including 
water solubility, molecular weight, protein binding and volume of distribution.10 
 
Doravirine is a novel non-nucleoside reverse transcriptase inhibitor that has demonstrated good 
efficacy, tolerability, and safety for the treatment of patients with HIV infection in phase III clinical 
trials. Doravirine achieved non-inferiority when compared with efavirenz- and darunavir/ritonavir-
based regimens.11, 12 Doravirine is mainly metabolized and eliminated by the liver, with only 6% of the 
drug being excreted unchanged through the urine.13 In a study comparing 8 subjects with severe renal 
disease to 8 subjects without renal impairment, the single dose exposure of doravirine was 43% 
higher in subjects with severe renal function impairment.14 However, according to prescribing 
information, no dosage adjustment of doravirine is required in patients with mild, moderate, or severe 
renal impairment. On the other hand, data on doravirine pharmacokinetics in patients with ESRD on 
dialysis are lacking.15 This may be of special interest because  doravirine has a relatively low 
molecular weight and it is only 76% bound to proteins in plasma.13 These characteristics could make 
possible for hemodialysis to remove doravirine from plasma, potentially leading  to subtherapeutic 
concentrations of doravirine after the dialysis sessions. On the contrary, doravirine volume of 
distribution is about 60 liters,15 what could limit extraction of doravirine by hemodialysis. Since data on 
doravirine pharmacokinetics in PLWH with ESRD on dialysis are lacking, our aim is to evaluate the 
effect of intermittent hemodialysis on doravirine concentrations in HIV-infected patients with ESRD. 
 
Clinical hypotheses:  
Doravirine pharmacokinetics in HIV-infected patients with ESRD is not affected by intermittent 
hemodialysis. 

 
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2.1 
REFERENCES 
1.- Ando M, Yanagisawa N. Epidemiology, clinical characteristics, and management of chronic kidney 
disease in human immunodeficiency virus-infected patients. World J Nephrol 2015;4:388-95. 
 
2.- Nadkarni GN, Konstantinidis I, Wyatt CM. HIV and the aging kidney. Curr Opin HIV AIDS 
2014;9:340-5. 
 
3.- Bansi L, Hughes A, Bhagani S, et al. Clinical epidemiology of HIV-associated end-stage renal 
failure in the UK. AIDS. 2009;23(18):2517–2521.  
 
4.-  Jotwani V, Li Y, Grunfeld C, Choi AI, Shlipak MG. Risk factors for ESRD in HIV-infected 
individuals: traditional and HIV-related factors. Am J Kidney Dis. 2012;59(5):628–635.  
 
5.-  Bickel M, Marben W, Betz C, et al. End-stage renal disease and dialysis in HIV-positive patients: 
observations from a long-term Cohort Study with a follow-up of 22 years. HIV Med. 2013;14(3):127–
135.  
 
6.-  Lucas GM, Mehta SH, Atta MG, et al. End-stage renal disease and chronic kidney disease in a 
Cohort of African-American HIV-Infected and at-risk HIV-seronegative participants followed between 
1988 and 2004. AIDS. 2007;21(18):2435–2443.  
 
7.- Wearne N, Davidson B, Blockman M, et al. HIV, drugs and the kidney. Drugs Context. 2020 Mar 
10;9:2019-11-1 
 
8.- Izzedine H, Launay-Vacher V, Baumelou A, et al. An appraisal of antiretroviral drugs in 
hemodialysis. Kidney Int 2001;60:821-30. 
 
9.- Tourret J, Tostivint I, Tézenas Du Montcel S, et al. Antiretroviral drug dosing errors in HIV-infected 
patients undergoing hemodialysis. CI Clin Infect Dis. 2007 Sep 15;45(6):779-84. 
 
10.- Weir MR, Fink JC. Safety of medical therapy in patients with chronic kidney disease and end-
stage renal disease. Curr Opin Nephrol Hypertens 2014;23:306-13. 
 
11.- Gatell JM, Morales-Ramirez JO, Hagins DP, et al. Doravirine dose selection and 96-week safety 
and efficacy versus efavirenz in antiretroviral therapy-naive adults with HIV-1 infection in a Phase IIb 
trial. Antivir Ther. 2019;24(6):425-435. 
 
12.- Molina JM, Squires K, Sax PE, et al. Doravirine versus ritonavir-boosted darunavir in 
antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 96-week results of a randomised, double-
blind, non-inferiority, phase 3 trial.Lancet HIV. 2020 Jan;7(1):e16-e26.  
 
13.- Boyle  A, Moss CE, Marzolini C, Khoo S. Clinical Pharmacodynamics, Pharmacokinetics, and 
Drug Interaction Profile of Doravirine. Clin Pharmacokinet. 2019 Dec;58(12):1553-1565. 
 
14.- Ankrom W, Yee KL, Sanchez RI, et al. Severe Renal Impairment Has Minimal Impact on 
Doravirine Pharmacokinetics. Antimicrob Agents Chemother. 2018 Jul 27;62(8):e00326-18.  
 
15.- Doravirine (Pifeltro) prescribing information. Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210806s000lbl.pdf 
 

 
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3 
TRIAL OBJECTIVE AND PURPOSE 
3.1 
PRIMARY OBJECTIVE 
- 
To assess the hemodialysis extraction ratio of doravirine in HIV-infected patients with ESRD 
undergoing intermittent hemodialysis.   
 
3.2 
SECONDARY OBJECTIVE 
 
- 
To evaluate the safety of doravirine in HIV-infected participants with ESRD on hemodialysis.   
 
- 
To evaluate the effect of a hemodialysis session on doravirine concentrations in plasma in 
HIV-infected participants with ESRD. 
 
 
 
 
 

 
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4 
TRIAL DESIGN 
4.1 
TYPE OF TRIAL 
This is a multi-centre, single-arm, open-label, pilot study in HIV-infected participants with ESRD 
undergoing routine hemodialysis 
 
4.2 
DESCRIPTION OF THE DESIGN 
After enrolment (on day 1), doravirine (Pifeltro, MSD) will be added to participant’s cART (100 mg 
once daily) for 5 days. On day 6, blood samples from the pre-dialyzer line (‘in’) will be collected from 
each participant at the beginning (‘Cpre’) and at the end (‘Cpost’) of a dialysis session. Additionally, 
paired samples of blood entering (‘Cin’) and leaving (‘Cout’) the dialyzer and resulting dialysate fluid will 
be collected during the dialysis session, approximately one hour after the start of the session.  
 
 
 
 
 
 

 
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5 
ENDPOINTS 
5.1 
ENDPOINTS 
5.1.1    Primary endpoint(s) 
- 
To calculate the hemodialysis extraction ratio for doravirine in HIV-infected participants with 
ESRD 
 
5.1.2 
Secondary endpoints 
- 
To assess the safety (adverse events grade 3-4) of doravirine in HIV-infected patients with 
ESRD undergoing hemodialysis 
 
- 
To assess changes in concentrations of doravirine in plasma from the beginning to the end of 
a dialysis session 
 
5.2 
MEASURES TO AVOID BIAS 
 
5.2.1 
Randomization 
Not applicable since it is an open clinical trial.  
 
5.2.2 
Stratification 
Not applicable since it is an open clinical trial.  
 
5.2.3 
Blinding 
Not applicable since it is an open clinical trial.  
 
5.3 
FORESEEN CALENDAR 
- 
First subject first visit: January 2021 
- 
Inclusion period: 2 months 
- 
Follow-up period: 20 days 
- 
Last subject last visit: March 2021 (End of study) 
- 
Final report submission: March 2022 
 
5.4 
END OF TRIAL 
The date of the end of the trial will be the last subject’s last visit. 
 
If the study had to be interrupted prematurely, all non-used materials should be returned to the 
sponsor, at the Lluita Contra la SIDA Foundation. The principal investigator will keep the investigator 
file and a copy of the completed CRF. 
 
In case there were no subjects included in the study, the sponsor will take care of all materials. 

 
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5.5 
SOURCE DATA 
The source data are the subject’s electronic health records including the results from blood test. 
 
Study data will be collected through a study-specific Case Report Form (see annex 1). 
 
 
 

 
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6 
TRIAL INVESTIGATIONAL PRODUCT(S) 
6.1 
EXPERIMENTAL AND CONTROL TREATMENTS 
The investigational treatment will be doravirine. Open-label supplies of doravirine (100mg) will be 
required from MSD. 
 
There is not control treatment in this trial.  
 
6.2 
SUPPLY, PACKAGING, LABELING AND STORAGE 
Doravirine will be supplied by MSD on its marketed format. 
 
Doravirine will be sent to the study staff of each participating site, where reception, units, batch 
number and expiration date will be confirmed. The labeling will be performed by the sponsor 
 
Drug conditioning is not required. 
 
All study medication will be stored in a safe place during the study. Storage shall be in accordance 
with the conditions defined conservation in the summary of products characteristics. Being marketed 
medication, specific temperature control for the study will not be performed, but the usual procedures 
of the custody and traceability of medication will be done by study staff of each participating sites. 
 
 
6.3 
DOSE, INTERVAL, ROUTE AND METHOD OF ADMINISTRATION 
After enrolment, doravirine 100mg once daily will be added to participant’s stable cART for 5 days. 
 
Participants will be told to take one tablet of doravirine (Pifeltro, MDS) once daily, with or without food, 
approximately at the day time that they usually finish the hemodialysis sessions. The rest of their 
antiretroviral regimen and concomitant medications will remain unchanged. 
 
 
6.4 
DRUG ACCOUNTABILITY 
The drug accountability will be performed on day 6. Participant will return the study medication to 
study staff, who will check the numbers of tablets taken.   
 
 
6.5 
ARM DESCRIPTION 
This a single-arm study. All participants will receive doravirine 100 mg once daily during the study (5 
days). 
 

 
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Participants will be instructed to take doravirine orally once a day, with or without food, plus their 
antiretroviral treatment and concomitant medications. 
 
6.6 
MODIFICATION OF THE TREATMENT REGIMEN 
No changes in treatment regimens are foreseen during the study period.  
 
In case of adverse reactions, the investigator will consider the interruption of the related medication 
and the subject will withdraw the study. 
 
 
6.7 
CONCOMITANT TREATMENTS 
All other treatments apart from antiretroviral medication administered during the study period will be 
considered concomitant treatments and should be documented in the CRF. 
 
Participants who participate in the study will be remembered that they should not start any new or 
continue any concomitant treatment without the knowledge and permission of the investigator.  
 
In the SmPC of experimental drug (appendix  II), detail on pharmacological interacions and dose 
recomendations with other drugs are specified. 
 
Concomitant use of the following therapies is disallowed during the study and within 4 weeks before 
inclusion: 
- 
Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin 
- 
Androgen receptor inhibitor: enzalutamide 
- 
Antimycobacterials: rifampin, rifapentine 
- 
Cytotoxic agent: mitotane 
- 
St. John’s wort (Hypericum perforatum) 
 
Participants will be told to avoid intake of products containing grapefruit or Seville orange from 48 
hour before inclusion to day 6.  
 
 
6.8 
COMPLIANCE 
Study drug accountability will be performed on day 6, when the participants will return the study 
medication to study staff.  
Pill count will be performed to assess compliance.  

 
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7 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 
INCLUSION CRITERIA 
1. Males and females* aging ≥ 18 years. 
2. Documented HIV infection). 
3. Stable antiretroviral treatment for at least 2 weeks prior to enrolment. 
4. Optimal adherence to antiretroviral treatment, defined as less than 2 missed doses within the 
previous week. 
5. End-stage renal disease in renal replacement therapy with periodic hemodialysis. 
6. Agree with the study procedures and signature of the informed consent. 
 
* 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. Condom use is considered as an additional method of 
contraception only and cannot be the only method of contraception used as not been considered an effective 
method by the Clinical Trial Facilitation Group (CTFG) guidelines. 
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. 
 
7.2 
EXCLUSION CRITERIA 
1. Evidence or clinical suspicion that the patient will not be able to comply with the study 
protocol. 
2. Hypersensitivity to doravirine  
3. Concomitant therapy within the previous 4 weeks with any of the following drugs: 
- 
Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin 
- 
Androgen receptor inhibitor: enzalutamide 
- 
Antimycobacterials: rifampin, rifapentine 
- 
Cytotoxic agent: mitotane 
- 
St. John’s wort (Hypericum perforatum) 
4. Females who are pregnant or breastfeeding.      
5. ALT and/ or AST ≥ 4 times the upper limit of normal (ULN) at screening. 

 
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6. Hemoglobin < 7,5 g/dL at screening. 
 
7.3 
SUBJECT WITHDRAWAL CRITERIA 
 
7.3.1 
Early subject withdrawal 
 
Participants will complete the clinical study before the stipulated time in the following circumstances: 
 
▪ 
Interruption of treatment due to adverse events, intolerance or poor adherence during the 
study. 
 
▪ 
Concurrent process or illness which in the opinion of the investigator requires the withdrawal 
of the patient. 
 
▪ 
Protocol deviation which in the opinion of the sponsor requires the withdrawal of the patient. 
 
▪ 
The patient does not wish to continue in the study. 
 
▪ 
Other 
  
 
7.3.2 Medical approach to withdrawal 
 
In all cases, a ‘end of study form’ needs to be filled. Detailed information will be given about the date 
and reasons of the discontinuation to the sponsor. The investigator will facilitate the necessary 
medical support.   
 
7.3.3 Follow-up alter early withdrawal 
 
As a general rule, participants who discontinue treatment prematurely will undergo a clinical 
examination and all tests specified in the visit.  
 
In case early withdrawal happens while subject is participating in the present study a follow-up 
performs, in case of safety or until resolution of adverse events.  
 
7.3.4 Replacement of participants 
 
Participants withdrawn by protocol deviation will be replaced by new participants, if additional 
candidates are identified, until the expected number of participants will be met. Participants withdrawn 
by other reasons will not be replaced. 
 
 

 
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7.4 
PRE-RANDOMIZATION / PRE-BASELINE LOSSES  
 
Participants that do not meet the selection criteria after completing the screening visit will be 
considered screening failures. The reason for not inclusion of participant will be recorded in the CRF.  
Data from participants that do not meet the selection criteria will be recorded in the screening log 
form. 
 

 
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8 
TRIAL CONDUCTION AND RESPONSE EVALUATION 
8.1 
CRITERIA FOR RESPONSE EVALUATION  
 
8.1.1 
Primary parameter 
 
• 
Doravirine hemodialysis extraction ratio 
 
8.1.2 
Secondary parameters 
 
• 
Adverse events grade 3-4 related to doravirine 
• 
Doravirine concentrations in plasma at the beginning and at the end of a dialysis session 
 
8.2 
TRIAL DEVELOPMENT 
 
After accepting the participation and meeting selection criteria, participants would be assessed the 
screening visit. Study visits would be at screening visit and on days 1, 6 and 20.  All visit are 
mandatory.  
 
For each visit, the procedures indicated in the schedule will be followed. 
 
 
8.3 
STUDY VISITS 
 
8.3.1 
Screening visit (day -14 to 0) 
• 
Signed informed consent will be obtained from each participant. 
• 
Review of inclusion/exclusion criteria. 
• 
Record of demographic and clinical variables including gender, age, significant medical 
conditions, last HIV viral load in plasma, last CD4+ T lymphocytes count.  
• 
Physical exam, including vital signs, body weight and height 
• 
Blood test, including blood cell count and biochemistry. (This determination may be avoided if 
results within 2 weeks before the screening visit are available)  
• 
Evaluation of Adverse events and concomitant therapy review (the participant will be asked 
about all medication, antiretroviral or not). 
• 
Women of childbearing potential must have a pregnancy test. 

 
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8.3.2 
Day 1  
• 
Medical interview and a physical exam  
• 
The investigator will provide each participant with one bottle containing 30 tablets of Pifeltro 
(doravirine 100 mg). Participant will be instructed to take one pill once-daily for 5 days, 
approximately at the same day-time when they usually finish the dialysis sessions.   
• 
Blood test, a complete biochemistry and hematology (This determination may be avoided if 
results within 2 weeks before the Day 1 visit are available)  
• 
Evaluation of adverse events and concomitant therapy review (the participant will be asked 
about all medication, antiretroviral or not). 
 
8.3.3 
Day 6 
• 
Medical interview and physical exam  
• 
Adverse events 
• 
Concomitant treatments 
• 
Adherence 
• 
Dialysis parameters (type of dialysis, dialyzer, membrane, blood flux, begging and end of the 
session) 
• 
Blood samples from the pre-dialyzer line (‘in’) will be collected from each participant at the 
beginning (‘Cpre’) and at the end (‘Cpost’) of a dialysis session. Additionally, paired samples 
of blood entering (‘Cin’) and leaving (‘Cout’) the dialyzer and resulting dialysate fluid will be 
collected during the dialysis session, approximately one hour after the start of the session. 
 

 
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8.3.4 
Day 20 (+/- 4 days): Safety follow-up / End-of-study visit (Remote visit is 
accepted) 
• 
Adverse events follow-up 
 
8.4 
STUDY ASSESMENTS 
 
8.4.1 
Clinical record and physical exam 
 
Demographic and clinical variables will be recorded at screening visit. 
 
Participants will be asked for all medications taken within the 4 weeks prior to the screening visit and 
during the study, antiretroviral or not, with special emphasis in prohibited medications (see section 
6.7). 
 
A complete physical examination will be performed at the screening visit. In the follow-up, a symptom-
directed physical exam will be performed. 
 
 
 
 
 

 
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8.4.2 
Laboratory tests 
 
A blood test will be performed, in the points specified in the flow chart of the study (section 8.5). The 
following parameters will be quantified, as needed: 
 
▪ 
Hematology: 
Hematocrit 
Red blood cell count 
Hemoglobin 
Leucocytes 
Lymphocyte  
Platelet count 
 
▪ 
Blood biochemistry:  
Glucose 
Urea  
Creatinine 
Ionogramme: sodium, potassium 
Total protein 
Albumin 
Liver enzymes: aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
  
 
▪ 
Pregnancy test in women (urine test strip or blood test in anuric women) 
 
 
Note: Before the beginning of the study, all labs will facilitate to the sponsor and to the 
investigator a list of the reference normal values of the parameters assessed. 
 
▪ 
Specific Lab Procedures:  
 
o 
Doravirine concentrations in plasma: 
Blood samples for the determination of the plasma concentration of doravirine shall be 
collected in 5 ml EDTA tubes. The plasma will be separated by centrifugation (3,200 g during 
15 minutes), and stored at -80ºC until analysis. The concentration of total doravirine in plasma 
will be determined by liquid chromatography with mass spectrometry (LC-MS/MS), according 
to a validated method. 
 
 
 
 
 
 
 
 
 

 
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8.5 
ASSESSMENTS FLOW-CHART 
 
Parameter 
SCR 
Day 1 
Day 6 
End-of-visit  
Day 20  
 
Window 
Day -14 to 0 
 
 
+/- 4 days 
Inclusion/ exclusion  criteria 
 
 
 
 
Informed consent 
 
 
 
 
Pregnancy test a 
 
 
 
 
Clinical visit 
 
 
 
 
First dose of doravirine 
 
 
 
 
 
 
 
 
 
Cell count and chemistry 
b 
b 
c 
 
Adverse Events 
 
 
 
 
Concomitant medication 
 
 
 
 
Plasma sample (PK)  
 
 
 
 
B Women of childbearing potential, within 10 days prior to inclusion 
b Cell count, glucose, urea, creatinine, Na, K, AST, ALT. Parameters performed within 2 weeks will be accepted. 
c Total protein and albumin will be determined in Cin and Cout samples 
 
 

 
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9 
ADVERSE EVENTS 
9.1 
DEFINITION 
Adverse event (AE): Medical event presented by a patient or clinical research subject administered a 
pharmaceutical product, and which does not necessarily have a causal relation to the treatment. 
  
Serious adverse event (SAE): Medical event classified as such and which, regardless of the dose 
involved: 
 
▪ 
Causes patient death. 
▪ 
Produces a life-threatening situation for the patient. 
▪ 
Requires or prolongs in hospital admission. 
▪ 
Produces important or persistent incapacitation/handicap or constitutes a congenital defect or 
anomaly. 
▪ 
Needs action to prevent any of above situations. 
▪ 
Is considered medically significant (examples of such events are intensive care in an 
Emergency Service or at home in a patient with allergic bronchospasm; blood dyscrasias or 
seizures not giving rise to hospital admission, or the development of drug dependency or 
abuse).  
 
Unexpected adverse event (UAE): AE related to the product in investigation the nature or intensity 
of which does not coincide with the information available on the product administered (IB or SmPC). 
 
Serious Unexpected Adverse Reaction (SUSAR): SAE related to the product in investigation the 
nature or intensity of which does not coincide with the information available on the product 
administered (IB or SmPC). 
 
 
9.2 
DESCRIPTION OF THE IMPUTABILITY CRITERIA  
The causal relation will be established according to the algorithm of the Spanish Pharmacovigilance 
System, which contemplates the following categories: 
 
Definitive: 
▪ 
A plausible time sequence exists in relation to administration of the drug or its plasma or 
tissue concentrations. 
▪ 
The observed manifestation coincides with the known adverse reactions profile of the 
implicated drug. 
▪ 
The event cannot be explained by the concurrent disease or by other drugs or chemical 
substances. 
▪ 
Response to withdrawal must be clinically plausible, i.e., the condition improves on 
discontinuing administration of the drug. 
▪ 
A positive response to repeat exposure is observed. 
 

 
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Probable: 
▪ 
A reasonable time sequence exists in relation to administration of the drug. 
▪ 
The observed manifestation coincides with the known adverse reactions profile of the 
implicated drug. 
▪ 
The event is unlikely to be explained by the concurrent disease or by other drugs or chemical 
substances. 
▪ 
Response to withdrawal is clinically plausible, i.e., the condition improves on discontinuing 
administration of the drug. 
▪ 
No repeat exposure is required to complete this definition. 
 
Possible: 
▪ 
A reasonable time sequence exists in relation to administration of the drug. 
▪ 
The observed manifestation coincides with the known adverse reactions profile of the 
implicated drug. 
▪ 
The event might be attributable to the clinical condition of the patient or to other concomitantly 
administered drugs or chemical substances. 
▪ 
Information concerning drug withdrawal may be unavailable or confusing. 
 
Improbable:  
▪ 
A clinical event, including anomalous laboratory test findings, with a time relation to 
administration of the drug which makes a causal association unlikely, and where other drugs, 
chemical substances or intercurrent disease afford plausible explanations for the observed 
event. 
  
Unrelated: 
▪ 
None of the above criteria are met. 
 
9.3 
ADVERSE EVENTS GRADING 
Grading will be performed using the Division of AIDS (DAIDS) Table for Grading the Severity of Adult 
and Pediatric Adverse Events, Version 2.1. [March 2017]. 
 
Citation: U.S. Department of Health and Human Services, National Institutes of Health, National 
Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1. [March 2017]. Available 
from: 
https://rsc.tech-res.com/docs/default-source/safety/daids-ae-grading-table-mar2017.pdf 
 
In case of events or laboratory abnormalities not included in the table, the following scale will be used: 
 
Grade 1 (mild):  
Symptoms causing no or minimal interference with usual social & functional  
activities 
 
Grade 2 (moderate): 
Symptoms causing greater than minimal interference with usual social  
  
 
 
and functional activities 

 
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Grade 3 (severe):  
Symptoms causing inability to perform usual social & functional activities 
 
Grade 4 (potentially 
life-threatening): 
Symptoms causing inability to perform basic self-care functions or Medical or 
operative intervention indicated to prevent permanent impairment, persistent 
disability, or death 
 
Grade 5 (death): 
Any AE where the outcome is death. 
 
 
9.4 
PROCEDURE FOR  REPORTING ADVERSE EVENTS  
 
9.4.1 
Investigator 
 
The investigator will immediately notify the study sponsor of any serious and/or unexpected adverse 
events. 
 
The report will be realized during the first 24 hours since the start of the serious adverse event. 
Notification will be made by means of the adverse events reporting form contained in Appendix V of 
this protocol.  
 
Contact details for Sponsor 
Fundació Lluita contra la SIDA 
e-mail: safety@fls-rs.com 
Fax. +34 93 465 76 02 
 
All adverse events will be recorded, regardless of the imputability (i.e., causal) relationship involved, in 
the corresponding adverse events description form. The latter is found in the CRF of each participant 
in the study (see Appendix I). 
 
Depending on the nature of the condition, each adverse event is to be classified as: 
 
▪ 
serious / not serious 
▪ 
unexpected / expected 
 
The recording of adverse events is the responsibility of the trial investigator team, which should 
indicate the time of appearance of the event (expressed in the shortest time unit possible), its serious 
/ not serious status, and in case it is considered related to investigational products, whether it was 
expected or unexpected. The intensity of the event (grade 1 to 5) is to be specified, along with the 
measures adopted (none, treatment, temporal or permanent discontinuation of investigational 
product), course (complete remission, partial remission, persistence) and imputability based on the 
criteria indicated in section 9.2. 
 

 
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9.4.2 
Sponsor 
 
The sponsor will inform the Spanish Drug Agency (Ministry of Health), the competent authorities of the 
autonomous region and the Ethics Committees implicated in the clinical trial about any important 
information of security of the investigational medicinal product. 
 
The sponsor will inform the Spanish Drug Agency (Ministry of Health) of any SUSAR which may be 
related to the study treatment. 
 
The sponsor will inform competent authorities of the implicated autonomous region of any SUSAR 
which may be related to the study treatment, and that have been happened in participants in its 
autonomous region. 
 
The deadlines to notify suspect adverse reaction are, from the moment the SUSAR is known by the 
Sponsor: 
▪ 
15 days 
▪ 
7 days if the SUSAR has resolved in death or has been life-threatening. The information will 
be completed in 8 further days. 
 
If the notification is sent in electronic form, it is not necessary to notify the competent authorities of the 
autonomous region. 
 
The sponsor will keep a detailed register of all the adverse events notified by the investigators. 
 
All adverse events will be notified in table form in the final report of the clinical trial. 
 
9.5 
HOSPITALIZATION AND FORESEEN PROCEDURES 
If a subject has to be hospitalized or undergone a procedure (i.e, Elective surgery) scheduled before 
he/she was included in the trial (i.e, before the subject [or representative Legal thereof] signed 
informed consent) for any event / pre-trial disease, the hospitalization is considered a therapeutic 
intervention and not the result of a SAE. However, if the event / disease worsens during the test 
should be reported as an AE (SAE or if the event / disease ends in a serious situation such as 
hospitalization). 
 
9.6 
ABNORMAL LABORATORY PARAMETERS  
An abnormal laboratory parameter shall be considered an AE if the abnormality: 
 
• 
results in withdrawal from the study 
 
• 
requires treatment, dose modification or investigational drug interruption or any other 
therapeutically intervention 
 

 
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• 
is considered clinically important 
 
Regardless of their severity, only laboratory abnormalities that meet criteria of seriousness should be 
recorded as SAE. 
 
If the laboratory abnormality is part of a diagnosis or syndrome, only the syndrome or diagnosis will be 
included as AE or SAE. If the laboratory abnormality is not part of a diagnosis or syndrome, it shall be 
recorded as AE or SAE. 
 
Clinically significant changes in safety parameters that are associated with the disease under study 
will not be rated as AE or SAE unless the investigator judges that are more severe than expected 
given the patient's condition. 
 
9.7 
DOCUMENTATION RELATED TO AE AND SAE 
Each AE and SAE to take place during the study should be documented in the medical records of the 
patient in accordance with standard clinical practice of the investigator, and in the CRF. For each 
SAE, an independent set of SAE form will be used independently. Only if there are multiple SAE at 
the time of the initial report and these are temporary and / or clinically interrelated can be registered 
on the same set of SAE form. 
 
 
The investigator should try to make a diagnosis of the event based on the signs, symptoms and / or 
other clinical information. An AE diagnosis has to be recorded per line or a sign/symptom if the 
diagnosis is not available. If a diagnosis subsequently becomes available, this then should be entered 
and the sign/symptom crossed out, initialed and dated by the investigator.  
 
SAE pages found in the investigator’s file shall be completed as precisely as possible, printed and 
shall be signed by the investigator before being sent to the sponsor. It is very important that the initial 
page SAE investigator provide its opinion in regard to the relationship of the event to the 
investigational product. 
 
9.8 
SAE FOLLOW-UP 
The investigator must record all AE occurring from the moment the patient signs the informed consent 
until the last study visit. 
 
AE will be followed-up until last visit or resolution. 
 
SAE will be followed preferably until: 
▪ 
Resolution of the event; 
▪ 
Stabilization of the event; or 
▪ 
Resetting the baseline situation of the event, in case baseline situation is available. 
 
Otherwise, they will continue until: 
▪ 
The event can be attributed to products other than the investigational product or factors 
unrelated to the study; or 

 
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▪ 
It is unlikely to obtain further information. 
 
The investigator should ensure that follow-up reports include any additional information to enable a 
full assessment of the nature and/or the cause/effect of SAE, including any other laboratory test, 
pathology report and examination by a specialist. 
 
9.9 
PREGNANCY 
The cases of pregnancy shall be recorded as AE and should only be considered as SAE only if they 
meet any seriousness criteria. Pregnancy is also a protocol deviation requiring premature termination 
of the patient. The investigator will provide medical support to the pregnant patient.   
 
The Investigator will follow the female subject until completion of the pregnancy and must notify to the 
Sponsor immediately about the outcome of the pregnancy (either normal or abnormal outcome). 
 
If the outcome of the pregnancy was abnormal (i.e., spontaneous, or therapeutic abortion), the 
investigator should report the abnormal outcome as an AE.  If the abnormal outcome meets any of the 
serious criteria, it must be reported as an SAE within 24 hours of the Investigator’s knowledge of the 
event using the SAE Report Form, or approved equivalent form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to causality, 
as SAEs.  In addition, any infant death after 28 days that the Investigator suspects is related to the in 
utero exposure to the IP should also be reported within 24 hours of the Investigator’s knowledge of 
the event using the SAE Report Form, or approved equivalent form. 
 
9.9.1 
Male subjects 
 
If a female partner of a male subject taking investigational product becomes pregnant, the male 
subject taking IP should notify the Investigator, and the pregnant female partner should be advised to 
call their healthcare provider immediately.    
 

 
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10 
STATISTICS 
Statistical analysis will be conducted by the study investigators in collaboration the CRO FLS-
Research. A computerized database for the study will be created, which will be used for data analysis. 
 
Descriptive statistics (number of participants, proportions, median and range) will be performed.  
 
The hemodialysis extraction ratio (ER) for doravirine will be calculated as: 
( )
100
%

−
=
in
out
in
C
C
C
ER
 
where Cin is predialyzer doravirine concentration in plasma (i.e., blood entering the dialyzer), and Cout 
is postdialyzer doravirine concentration in plasma (i.e., blood leaving the dialyzer). 
 
Doravirine postdialyzer concentrations (Cout) will be corrected for hemoconcentration by a factor F 
based on total protein (TP) concentration pre- and postdialyzer: 
out
in
TP
TP
F =
 
 
Doravirine concentrations in plasma after the dialysis session (Cpost) will be numerically compared 
with those before entering the dialysis session (Cpre) as well as with doravirine trough concentrations 
in plasma in HIV-infected patients with normal renal function (KL Yee, A Ouerdani, A Claussen, R 
Greef, L Wenning. Population Pharmacokinetics of Doravirine and Exposure-Response Analysis in 
Individuals with HIV-. Antimicrob Agents Chemother. 2019 Mar 27;63(4):e02502-18).  No formal 
statistical comparisons are envisioned. 
The number/proportion of participants with doravirine concentrations at the end of a dialysis session 
above the protein binding-adjusted EC50 (>238 ng/mL) will be assessed.  
 
Adverse events related to doravirine will be listed and graded according to DAIDS grading scale. 
 
 
10.1 SAMPLE SIZE DESCRIPTION 
Inclusion of 8 participants will allow detecting differences in doravirine concentrations in plasma (Cin 
vs Cout) of at least 30%, with an alpha risk of 0.05 and a beta risk of 0.2 in a one-sided comparison. 
Smaller changes in doravirine concentrations are not deemed as clinically significant. 
 
10.2 DEVIATION OF STATISTICAL PLAN 
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11 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
Investigators and institutions will allow the monitoring, and audits by the Health Authorities or the 
Sponsor giving direct access to data and original source documents. 
 
Access to personal patient information will be restricted to the Study physician / staff. To allow 
monitoring, audits and inspections, access to data to Health Authorities (Spanish Agency for 
Medicines and Health Products), the Ethics Committee and personnel authorized by the Sponsor, is 
guaranteed while maintaining the confidentiality thereof according to current legislation. 

 
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12 
QUALITY CONTROL AND QUALITY ASSURANCE 
12.1 STUDY MONITORING 
In accordance with applicable regulations and Good Clinical Practice (GCP), the monitor will visit or 
contact the center on a regular basis. The duration, nature and frequency of visits / contacts depend 
on the monitoring plan. 
 
During these contacts, the monitor shall: 
 
▪ 
monitor and evaluate the progress of the study; 
▪ 
examining the data collected; 
▪ 
carry out a verification of the source documents; 
▪ 
identify any problems and find solutions; 
 
The goal of the monitoring activity is to verify that: 
 
▪ 
the rights and welfare of subjects are respected; 
▪ 
survey data are accurate, complete and verifiable with the help of original documents; 
▪ 
the study is performed according to the protocol and any amendment adopted, GCPs and 
regulations. 
 
The investigator must agree to: 
 
▪ 
grant to monitor direct access to all relevant documentation; 
▪ 
devote part of his/her time and staff time to the monitor to discuss the results of the 
monitoring, as well as any other possible aspect. 
 
The monitor should also contact the center before starting the study with the aim to discuss with staff 
the Protocol and procedures for data collection. 
 
12.2 AUDITS AND INSPECTIONS 
Sponsor can carry out an audit of quality control at its sole discretion. In this case, the investigator 
should agree to grant the auditor direct access to all relevant documentation and devote part of 
his/her time and staff time to the auditor in order to discuss the results of the monitoring, as well as 
any other possible aspect. 
 
Moreover, regulatory authorities may also inspect the study. In this case, the investigator should 
agree to give the inspector direct access to all relevant documentation and devote part of his/her time 
and staff time to the inspector in order to discuss the results of the supervision, as well as any other 
possible aspect. 
 

 
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12.3 CASE REPORT FORM 
Data collection will be done through an electronic CRF with a system of access by username and 
password. The application includes track changes monitoring (recording the changes that have been 
made and details of the user that has made these changes). 
 
Accurate and reliable data collection is ensured by checking and cross checking the CRF front site 
records conducted by the study monitor (verification of source documents). The data collected will be 
added to a computer database which will be reviewed for possible inconsistencies to be resolved by 
the research team of the study in each site. 
 
Accurate and reliable data collection is ensured by checking and cross checking the eCRF front site 
records conducted by the study monitor (verification of source documents).  
 

 
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13 
ETHICS 
13.1 GENERAL CONSIDERATIONS 
The clinical trial will be conducted according to the principles of the Declaration of Helsinki, Fortaleza, 
Brazil, October 2013. 
 
This study will be conducted according to Spanish regulations regarding clinical trials (Royal Decree 
1090/2015) and biomedical investigations (Organic Law 14/2007 of biomedical investigation and the 
Royal Decree 1716/2011), which develop the Clinical Trial Regulation (Regulation EU No 536/2014). 
The required documentation prior to the start will be: 
 
▪ 
Protocol acceptance by the sponsor and the coordinating investigator  
▪ 
Protocol approval by the Ethics Committee. 
▪ 
Protocol authorization from the Spanish Drug Agency (Ministry of Health) 
 
All subjects will be guaranteed continued medical and nursing supervision throughout the duration of 
the study. 
 
This study will conform to the standards of GCP published by ICH (E6 R2), as required by Directive 
2001/20/EC. Confidentiality requirements will follow the required Data Protection legislation (see 
section 13).  
 
13.2 PATIENT INFORMATION SHEET AND INFORMED CONSENT 
Informed consent will be obtained before including the patient in the trial (Appendix III). The 
investigator is to inform the patient of the nature, duration and purpose of the study, as well as of all 
the obstacles and inconveniences which – within reason – may be expected from it. Furthermore, the 
patient is to receive information in writing. The participating subjects must be legally competent to give 
informed consent, with the possibility of taking decisions at his/her own free will. The patient has the 
right to leave the study at any time. 
 
 
12.3 PAYMENT TO RESEARCH PARTICIPANTS 
Participants will be reimbursed for their time, effort and time travels to study site due to study 
participation. Reimbursement amounts will be documented. 
A payment of €100 for meals, transfers and lost in productivity is foreseen. It will be paid after 
completing the follow-up visit (day 20). No payment will be offered in case of premature withdrawals 
before day 6 visit. 
 
 

 
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14 
DATA HANDLING AND RECORD KEEPING 
14.1 DATA HANDLING 
The processing of the data to be compiled by the study sponsor during the study will be subject to 
current legislation as regards data protection (LOPD, The Organic Law 3/2018 of 5 December on the 
Protection of Personal Data and the Guarantee of Digital Rights complementary to the Regulation 
(EU) 2016/679 of the European Parliament and of the Council of 27 April 2016, on the protection of 
natural persons with regard to the processing of personal data and on the free movement of such 
data). 
The participant will be identified in the records by the corresponding unique code number. The 
participant is to be guaranteed anonymity and is to be informed that all communication will take place 
between him/her and the investigator and not the sponsor of the study. 
 
It is not expected to transmit data to third parties. 
 
14.2 RECORD KEEPING 
 
14.2.1 
Investigator file and document retention 
 
The investigator must keep the investigator file with the proper and accurate records to enable the 
study to be fully documented and data subsequently verified. 
 
The Investigator's study file will contain the protocol and its amendments, CRFs, questionnaires’ 
forms, EC approval and authorization from the health authorities, samples of the participant 
information sheet and informed consent, staff curriculum, signatures’ delegation log and listing of 
subjects, as well as other appropriate documents and correspondence. 
 
Clinical source documents from subjects (usually predefined by the project to record key efficacy and 
safety parameters or documents that are not in the clinical record of the hospital) will be filed 
indicating the number of subject without personal data. 
 
The investigator should retain these documents at least twenty-five years, according to Royal Decree 
1090/2015, provided that the sponsor does not express another period. 
 
 
14.2.2 
Source documents and basic data  
 
Patient participation in the study will be included on medical records, including assigned code number 
and identification of the different study visits that will take place throughout the study. At the end of the 
study, a copy of the CRF will be placed on the site. 
 

 
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15 
FINANCING AND INSURANCE 
15.1 SOURCE OF FINANCING 
The funding source is the Lluita contra la SIDA Foundation. 
This study is partially funded through a research grant from Initiated studies Program by researcher 
Merck Sharp & Dohme Corp. 
 
15.2 INSURANCE POLICY 
In accordance with the Royal Decree 1090/2015, of 4th December, the trial sponsor has a policy of 
liability insurance with Zurich Insurance Company PLC Branch in Spain established in Barcelona. The 
sponsor shall extend this policy or another with equivalent coverage until the end of the trial. The 
policy will cover the damages to the people that could be set as a result of the trial by an insured 
amount of € 600.000,00 per subject tested to a maximum of € 6.000.000,00 per year and clinical trial. 
This policy also covers the responsibilities of the sponsor, the principal, and his/her collaborators, as 
well as the hospital or site where they carry out the clinical trial. 
 
The sponsor agrees to pay the premiums to cover the liability pertaining to the trial. It is presumed, 
unless proven otherwise, that damage affecting the health of the person subject to testing during 
implementation and in the following year the completion of treatment, have occurred as a result of the 
trial. However, once the year ended, the test subject is required to prove the link between the trial and 
damage. 
 
The site and the principal investigator undertake to inform the sponsor of any claim or legal, real or 
potential action if known, linkable to trial. 
 
 

 
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PUBLICATION POLICY 
The publication of the trial results shall meet the requirements set out in Article 42 of Royal Decree 
1090/2015. 
 

 
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APPENDIX I: CASE REPORT FORM (CRF) 

 
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APPENDIX II: INVESTIGATOR’S BROCHURE 

 
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APPENDIX III: PATIENT INFORMATION AND WRITTEN INFORMED CONSENT 

 
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APPENDIX IV: INSURANCE 

 
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APPENDIX V: SERIOUS ADVERSE EVENT REPORT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX VI: DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF ADULT AND 
PEDIATRIC ADVERSE EVENTS