Study on PhArmacokinetics of First liNe Antiretrovirals in Healthy Breastfeeding Volunteers
Phase: PHASE4
Conditions: Hiv
Sponsor: Radboud University Medical Center

NL 83180.091.22 / UMCN-AKF-22.04 
 
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Study on PhArmacokiNetics of first liNe 
Antiretrovirals in healthy Breastfeeding 
volunteers or women living with HIV and 
already on antiretrovirals 
 (PANNA-B PK) 
(27th of March 2025) 
 
 
Protocol changes 
 
Date 
Changes 
03-01-2023 
7.5 Limit added to number of dropouts 
05-01-2023 
7.3.3. Screening for eligibility added  
05-01-2023 
7.3.5. Description added on screening for 
AE and the handling screening and safety 
of repeating participant 
26-01-2023 
 Removed possibility for participants to 
participate multiple times 
25-04-2023 
Added possibility to participate and sustain 
from feeding infant breastmilk during 4 days 
after ingestion of study medication 

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13-06-2023 
Adapted language: ‘sustain’ from 
breastfeeding has been changed to ‘abstain’ 
from breastfeeding 
 
Added that the treatments will be applied in 
a sequential order (second arm will start 
when first arm is fully recruited), see chapter 
3 
02-01-2024 
Adjusted the timing of the safety visit.  
15-02-2024 
Added phone call 7 days after study visit to 
check for adverse events 
07-03-2024 
Added possibility to participate if already 
using an antiretroviral regimen  
Added measurement of breastmilk pH 
27-03-2025 
Removal of raltegravir as study-arm 
Adjustment of sample size for doravirine 
study-arm 

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PROTOCOL TITLE: Study on pharmacokinetics of first line antiretrovirals in healthy 
breastfeeding volunteers or women living with HIV and already taking antiretrovirals 
 
Protocol ID 
UMCN-AKF-22.04 
Short title 
PANNA-B PK 
EU CT Number  
2023-510221-36-00 
Version 
8 
Date 
27th of March 2025 
Project leader 
 
 
Principal investigator(s)  
 
 
Co-investigators 
 
 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
Radboudumc, Nijmegen 
Subsidising party 
ZonMW 
Independent expert (s) 
 
Laboratory sites 
Dept. of pharmacy 
Radboudumc, Nijmegen 
Pharmacy 
Dept. of pharmacy 
Radboudumc, Nijmegen 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Head Department of Pharmacy: 
 
 
 
Project leader / PI: 
 
 
 
 
 

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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .............................................................................10 
2. 
OBJECTIVES ................................................................................................................13 
3. 
STUDY DESIGN ...........................................................................................................13 
4. 
STUDY POPULATION ..................................................................................................15 
4.1 
Population ..............................................................................................................15 
4.2 
Inclusion criteria .....................................................................................................15 
4.3 
Exclusion criteria ....................................................................................................15 
4.4 
Sample size calculation ..........................................................................................16 
5. 
TREATMENT OF PARTICIPANTS ................................................................................18 
5.1 
Investigational product/treatment ............................................................................18 
5.2 
Use of co-intervention ............................................................................................18 
5.3 
Escape medication .................................................................................................19 
6. 
INVESTIGATIONAL PRODUCT ....................................................................................19 
6.1 
Name and description of investigational  products ..................................................19 
6.2 
Summary of findings from non-clinical studies ........................................................19 
6.3 
Summary of findings from clinical studies ...............................................................19 
Efficacy data is summarized in chapter 5.1 of the SmPC. .................................................19 
6.4 
Summary of known and potential risks and benefits ...............................................19 
6.5 
Description and justification of route of administration and dosage .........................19 
6.6 
Dosages, dosage modifications and method of administration ...............................19 
6.7 
Preparation and labelling of Investigational Medicinal Product ...............................20 
6.8 
Drug accountability .................................................................................................20 
7. 
METHODS ....................................................................................................................21 
7.1 
Study parameters/endpoints ...................................................................................21 
7.1.1 
Main study parameter/endpoint .......................................................................21 
7.1.2 
Secondary study parameters/endpoints ..........................................................21 
7.1.3 
Other study parameters ...................................................................................21 
7.2 
Randomisation, blinding and treatment allocation ..................................................22 
7.3 
Study procedures ...................................................................................................22 
7.3.1 
Screening for eligibility ....................................................................................22 
7.3.2 
Preparation and maintenance for blood drawl .................................................22 
7.3.3 
PK analysis of blood ........................................................................................22 
7.3.4 
PK analysis of breast milk ...............................................................................22 
7.3.5 
Other procedures for safety assessment .........................................................23 
7.4 
Withdrawal of individual participants .......................................................................23 
7.5 
Replacement of individual participants after withdrawal ..........................................23 
7.6 
Follow-up of participants withdrawn from treatment ................................................23 
8. 
SAFETY REPORTING ..................................................................................................24 
8.1 
Temporary halt for reasons of subject safety ..........................................................24 
8.2 
AEs, SAEs and SUSARs ........................................................................................24 
8.2.1 
Adverse events (AEs) ......................................................................................24 

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8.2.2 
Serious adverse events (SAEs) .......................................................................24 
8.2.3 
Suspected unexpected serious adverse reactions (SUSARs) .........................25 
8.3 
Annual safety report ...............................................................................................25 
8.4 
Follow-up of adverse events ...................................................................................26 
8.5 
Data Safety Monitoring Board (DSMB) / Safety Committee ....................................26 
9. 
DATA ANALYSIS ..........................................................................................................26 
9.1 
Bioanalysis .............................................................................................................26 
9.2 
Assay validation .....................................................................................................26 
9.3 
Statistical analysis ..................................................................................................27 
9.4 
Pharmacokinetic analysis .......................................................................................27 
10. 
ETHICAL CONSIDERATIONS ...................................................................................27 
10.1 
Regulation statement .............................................................................................27 
10.2 
Recruitment and consent........................................................................................27 
10.3 
Benefits and risks assessment, group relatedness .................................................27 
10.4 
Compensation for injury .........................................................................................28 
10.5 
Incentives ...............................................................................................................28 
11. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .........................29 
11.1 
Handling and storage of data and documents ........................................................29 
11.2 
Monitoring and Quality Assurance ..........................................................................29 
11.3 
Amendments ..........................................................................................................29 
11.4 
Annual progress report ...........................................................................................30 
11.5 
Temporary halt and (prematurely) end of study report ............................................30 
11.6 
Public disclosure and publication policy ..................................................................30 
11.7 
Sample destruction after study completion .............................................................31 
12. 
STRUCTURED RISK ANALYSIS...............................................................................31 
13. 
REFERENCES ..........................................................................................................32 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ABR 
General Assessment and Registration form (ABR form), the 
application form that is required for submission to the accredited 
Ethics Committee; in Dutch: Algemeen Beoordelings- en 
Registratieformulier (ABR-formulier) 
AE 
Adverse Event 
AR 
Adverse Reaction 
ARV 
Antiretrovirals 
BIC/FTC/TAF Bictegravir/emtricitabine/tenofovir alafinamide 
CA 
Competent Authority 
cART 
Combination anti-retroviral therapy 
CCMO 
Central Committee on Research Involving Human Participants; in 
Dutch: Centrale Commissie Mensgebonden Onderzoek 
CV 
Curriculum Vitae 
CV% 
Coefficient of variation 
CRF 
Case Report form  
DOR 
Doravirine 
DSMB 
Data Safety Monitoring Board 
EU 
European Union 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation; in Dutch: Algemene Verordening 
Gegevensbescherming (AVG) 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
IMP 
Investigational Medicinal Product  
IMPD 
Investigational Medicinal Product Dossier  
METC  
Medical research ethics committee (MREC); in Dutch: medisch-
ethische toetsingscommissie (METC) 
PK 
Pharmacokinetic(s) 
PLWH 
People living with HIV 
(S)AE 
(Serious) Adverse Event  
SPC 
Summary of Product Characteristics; in Dutch: officiële 
productinformatie IB1-tekst 
Sponsor 
The sponsor is the party that commissions the organisation or 
performance of the research, for example a pharmaceutical 

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company, academic hospital, scientific organisation or investigator. 
A party that provides funding for a study but does not commission it 
is not regarded as the sponsor, but referred to as a subsidising 
party. 
SUSAR  
Suspected Unexpected Serious Adverse Reaction 
UAVG 
Dutch Act on Implementation of the General Data Protection 
Regulation; in Dutch: Uitvoeringswet AVG 
WMO 
Medical Research Involving Human Participants Act; in Dutch: Wet 
Medisch-wetenschappelijk Onderzoek met Mensen 
 
 

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SUMMARY 
 
Rationale: Although current guidelines advise against breastfeeding while using antiretrovirals in 
people living with HIV, some women choose to breastfeed  because advantages of breastfeeding may 
exceed the possible risk of HIV transmission to the newborn. However, no sound recommendation can 
be made on which antiretrovirals are most suitable during breastfeeding, because no to little data on 
penetration of these drugs in breastmilk exist. Too high concentrations may lead to infant toxicity and 
too low concentrations may lead to development of resistance in case the infant inadvertently 
becomes infected with the virus.  
Objective: to determine the concentration of currently often used ARV (doravirine, and bictegravir, 
tenofovir alafenamide, emtricitabine) in breast milk after administration of a single dose 
Study design: This is a single centre, single dose, open label, pharmacokinetic study in healthy 
volunteers and women living with HIV and using antiretroviral drugs.  
Study population: Adult, healthy breastfeeding volunteers willing to end or abstain from 
breastfeeding during study. Also, breastfeeding women living with HIV and already using antiretroviral 
drugs will be recruited to examine their current regimen, or to add on a single dose of study drug if no 
interactions are to be expected.  
Intervention: Administration of one dose of either doravirine (DOR) 100mg, or a combination of 
tenofovir alafenamide 25mg, emtricitabine 200mg and bictegravir 50mg (BIC/FTC/TAF).  
Main study parameters/endpoints: Area under the plasma and milk concentration curve are used to 
calculate milk to plasma ratio.  
Nature and extent of the burden and risks associated with participation, benefit and group 
relatedness: Participants will not directly benefit from this study, but will contribute to knowledge on 
breastmilk transfer of ARV and possibly enable people living with HIV to make an informed decision on 
breastfeeding while using these medications.  
No harm is expected from participation in this study, but possible side effects should be anticipated. 
Known side effects of DOR are nausea (4%) and headache (3%), abnormal dreams and insomnia (1-
10%), dizziness and somnolence and fatigue (1-10%). BIC/FTC/TAFs known side effects are: 
headache (5%), diarrhea (5%) and nausea (4%), depression and abnormal dreams and fatigue (1-
10%), suicidal ideation (0,1-1%), angio-edema (0,1-1%) and Steven Johnson syndrome (0,01-0,1%) 
and osteonecrosis (0,01-0,1%).  Due to the fact that only one dose of the drugs will be ingested, the 
risk of development of one or more of these side effects is considered to be low.  
Participation of women living with HIV and already taking antiretroviral drugs and taking an extra dose 
of DOR for study purposes, are not expected to experience any, or at least minimal adverse events, as 
only a single dose is to be administered. As their infants are already exposed to antiretroviral drugs 
through breastmilk, the extra exposure of a single dose of study drug is deemed to be futile.  
Participation in this study requires participants to be admitted for 12 hours, a visit the next morning and 
a return visit 7 days later. During the sampling day an intravenous indwelling catheter is installed for 
collection of blood samples. A total volume of 25-50ml of blood, 2 urine samples and 6 breastmilk 
samples (expressed using a personal electronic pump) are collected. No harm is to be expected from 
these sample collection procedures. 
 

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1. INTRODUCTION AND RATIONALE 
 
Worldwide, 19,7 million women are living with HIV (1). An estimated 1,3 million of them become 
pregnant each year (2). The risk of transmitting the virus to their infants is drastically reduced by the 
implementation of guidelines on use of antiretroviral therapy (ART) in pregnancy(3, 4), but a slight risk 
remains, especially during delivery and in smaller extent trough breastfeeding.  
Data on HIV transmission trough breastfeeding mainly originates from African countries and range 
from 0-12% (5-7). No cases of mother-to-child transmission (MTCT) have been reported in Europe, 
but these cohorts might have been too small to detect these events(8-10).  
So unclarity on the actual risk on MTCT trough breastfeeding in Western countries remains. Therefore, 
European and American guidelines recommend against breastfeeding for HIV-1 infected women(11, 
12). However, many benefits from breastfeeding might outweigh this potential risk. Breastfeeding is 
associated with a reduced risk of childhood infections and development of obesity and diabetes 
mellitus and it positively influences cognitive development. Also mothers benefit from breastfeeding 
their infants, because it reduces the risk of breast- and ovarian cancer and type 2 diabetes(13). Many 
sociocultural and psychological factors should be considered as well. Mother-child bonding, forming of 
a maternal identity, self-image and acceptance by social environment influence a mothers choice on 
ways to feed her child(14-16). The exact amount of HIV-1 infected mothers who rather breastfeed, is 
not established. A survey among 93 health care providers in the US showed that 75% of these 
caregivers cared for women who asked whether they could breastfeed and 29% eventually cared for 
women who – despite recommendations – actually chose to breastfeed(17).   
To make a well thought-out decision on child-feeding, the HIV-infected mother and her treating 
physician should have access to data on which ART suits the needs of mother- and child best. 
Detectable concentrations of ART might lead to infant toxicities or – in the case MTCT has occurred – 
development of a resistant virus(18, 19). Despite rules on labeling drugs with information on 
pregnancy and lactation(20), clinically relevant information on drug labels of newly approved drugs is 
still lacking(21). It can take up to six year for such information to become available form post marketing 
studies (22). Only for a few antiretrovirals (ARV) such information exists (see table 1).   
Therefore, the purpose of this study is to establish the concentrations of currently often used ARV 
(doravirine, and bictegravir with emtricitabine and tenofovir alafenamide) in breast milk. Due to ethical 
reasons, healthy volunteers who are willing to stop breastfeeding (temporarily) during the study will be 
recruited. The maximum elimination half life of the study drugs is 18hours, so interruption of 
breastfeeding for four days (5 times the elimination half life) will ensure the blood – and therefore – 
breastmilk concentrations will expected to be zero. In this way the risk of exposure of infants to 
antiretroviral drugs is minimized.  
 

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Table 1: Summary of available lactation studies 
Treatmen
t 
Milk/maternal plasma 
ratio 
Infant plasma/milk ratio 
RID 
(dosing) 
Data amount + REF 
 
Mea
n 
CI 
I2 
Mean 
CI 
I2 
ISTIs 
DTG 
0.04
; 
0.03
;  
0.02 
0,03-0,05 
N
A 
Median 
IDD = 
0,02 
0,01-
0,02 
- 
0,78-1,33 
BM/MP = Two studies + 
case report (23-25)  
RALA 
0.46
; 
0.55
; 
0.39 
0.39-0.42 
N
A 
Median 
IDD = 
0.25 
0.15-
0.32 
- 
0.12 
BM/MP = Case report 
(26) and single study 
(n=14) (25) 
BIC  
0.01  
0,01-0,01 
N
A 
Median 
IDD = 
0.01 
0.01-
0.01 
 
NA 
BM/MP + IDD + RID = 
Single study (n=3) (25) 
PIs 
ATZB 
0.08
; 
0.06 
NG 
N
A 
- 
- 
- 
- 
BM/MP = Two studies 
(27) 
DRVB 
0.12 
0.10-0.14 
N
A 
Median 
IDD = 
0.05 
0.04-
0.05 
- 
0.11-0.12 
BM/MP + IDD + RID = 
Single study (n=4) (25) 
RTV 
0.17 
0.15-0.19 
94
% 
0.19 
NG 
NA 
0.42% 
(100mg 
BID) 
BM/MP = Pooled (27) 
IP/BM = Single study(27) 
RID (27) 
NRTIs 
ABC 
0.85
; 
1.03 
0.78-1.66 
N
A 
Median 
IDD = 
0.01 
0.01-
0.02 
NA 
0.1 - 0.88% 
(300mg 
BID); 0.17-
0.46%  
BM/MP = Two studies 
(25, 27) 
IP/BM = Single study (27) 
IDD (25) 
RID (25, 28) 
FTC 
3.01
; 
3,92 
2.06-3.38; 
2,34-5,55 
N
A 
Median 
IDD = 
0.12 
0.07-
0.17 
- 
0.93 – 
3.57% 
(400mg 
once, to 
200mg/d); 
2.38-5.59% 
RID = single study (25)  
BM/MP = two studies (25, 
29) 
TAF 
4.09 
3.38-4.92 
N
A 
Median 
IDD = 
0.007  
0.006-
0.008 
- 
NA 
Single study (n=5) (25) 

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TDF 
0.08 
0.06-0.10 
N
A 
IP=ND 
in most 
cases, 
Median 
IDD = 
0.001 
0.0001-
0.002 
NA 
0.02 – 
0.03% 
(600mg 
once, to 
300mg/d); 
0.01-0.02% 
IP/BM = Multiple studies 
(30) 
BM/MP = single study 
(n=24) (25) 
RID  (28) 
3TC 
0.93
; 
3.74 
0.88-0.98; 
2.77-4.73 
98
%; 
N
A 
0.02; 
median 
IDD = 
0.20 
0.01-
0.02; 
0.12-
0.24 
88
% 
0.49-6.4% 
(150mg 
BID); 2.95-
6.10%  
BM/MP = Pooled (27) and 
later published (n=11) 
(25) 
IP/BM = Pooled (27) 
IDD (25) 
RID  (25, 28) 
NNRTIs 
EFV 
0.86 
0,70-1,11 
- 
Median 
IDD = 
0.41 
0.32-
0.48 
- 
1.07-1.61% 
BM/MP + IDD + RID = 
Single study (n=3) (25) 
NVP 
0.70 
0.68-0.75 
- 
Median 
IDD = 
0.41  
0.29-
0.42 
- 
2.38-3.51% 
BM/MP + IDD + RID = 
Single study (n=5) (25) 
RPV 
1.08 
1.1-1.1 
- 
Median 
IDD = 
0.02 
0.02-
0.02 
 
NA 
BM/MP + IDD + RID = 
Single study (n=2) (25) 
A. 
First value calculated at 4 months postpartum, second value at 8 months postpartum 
B. 
These regimens are given with RTV, a pharmacologic enhancer. RTV is not prescribed alone. 
ABC = Abacavir; ATZ = Atazanavir; BM = Breastmilk concentration; DNV = Darunavir; DTG = Dolutegravir; EFV = Efavirenz, 
FTC =  Emtricitabine; IDD = infant daily dose (mg/kg),  IP = Infant plasma concentration; ISTI = Integrase Strand Transfer 
Inhibitors; NA = not applicable; ND = Not detectable; NG = not given; NRTI = nucleoside/nucleotide transcriptase inhibitor; 
NNRTI= non- nucleoside/nucleotide transcriptase inhibitor, NVP = neviraprine, PI = Protease Inhibitor; RAL= Raltegravir; 
REF = reference; RID = Relative infant dose; RTV = Ritonavir; TAF =  Tenofovir alafenamide; TDF =  Tenofovir disoproxil 
fumarate; 3TC = Lamivudine. 

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2. OBJECTIVES 
 
Primary Objective: to determine the concentrations of currently often used ARV (doravirine, and  
bictegravir, tenofovir alafenamide, emtricitabine) in breast milk after administration of a single dose 
 
Secondary Objective: 
- 
to determine pharmacokinetics (e.g. half life, clearance, volume of distribution; see chapter 
7.1.2.) of abovementioned ARV in breast milk 
- 
to estimate absolute and relative infant dosage trough breastmilk 
 
3. STUDY DESIGN 
 
This is a single centre, single dose, open label, pharmacokinetic study in healthy volunteers and 
breastfeeding women living with HIV and using antiretroviral drugs.  
Participants will be screened for inclusion using the in- and exclusion criteria. Once included, they will 
be admitted at the study centre for a duration of 12hours and return for sample collection 24hours after 
ingestion of study medication.  During this sampling day, plasma will be collected at t=0 (pre-dose), 1, 
2, 3, 4, 5, 6, 8, 10, 12, 24 hours post ingestion of a single dose of doravirine 100mg or a single dose of 
the combination tablet containing 50mg bictegravir, 200mg emtricitabine and 25mg tenofovir 
alafenamide. Treatments will be tested in a sequential order.Breastmilk expression is planned at 0, 2, 
4, 6, 12, 24h after dosing. At the 24h sampling time point, a safety assessment will be performed. 7 
days after the study visit the participants will be contacted by telephone to inquire for any adverse 
events.  
 
 
 
 

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Figure 1: overview of study design 
 
 

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4. STUDY POPULATION 
4.1 Population   
Three types of participants are eligible for inclusion: 
• 
Healthy volunteers → in- and exclusion criteria 4.2.1 and 4.3.1. 
• 
Women living with HIV and using antiretroviral therapy currently under investigation 
(DOR, or BIC/FTC/TAF) → in- and exclusion criteria 4.2.2 and 4.3.2. 
• 
Women living with HIV and using antiretroviral therapy and willing to ingest a single 
dose of DOR  on top of their own regimen → in- and exclusion criteria 4.2.3 and 4.3.3. 
 
Women living with HIV and using antiretroviral drugs using either  DOR or BIC/FTC/TAF may choose 
to participate in study using their own regimen, or to ingest one of the drugs under investigation on top 
of their regular regimen.  
 
4.2 Inclusion criteria 
4.2.1. Healthy volunteers 
In order to be eligible to participate in this study, a subject must meet all of the following criteria: 
• 
At least 18 years of age at the moment of screening 
• 
At least 10 days post partum 
• 
At the end of breastfeeding period; subject is able to produce breastmilk at least two times 
a day and is no longer feeding infant at start of study or willing and able to abstain from 
breastfeeding during four days after ingestion of study medication 
• 
Able and willing to sign an informed consent 
 
4.2.2. Women living with HIV using either DOR or BIC/FTC/TAF 
In order to be eligible to participate in this study, a subject must meet all of the following criteria: 
• 
At least 18 years of age at the moment of screening 
• 
At least 10 days post partum 
• 
Able and willing to sign an informed consent 
 
4.2.3. Women living with HIV using antiretroviral drugs and able to ingest a single dose of 
DOR 
In order to be eligible to participate in this study, a subject must meet all of the following criteria: 
• 
At least 18 years of age at the moment of screening 
• 
At least 10 days post partum 
• 
Able and willing to sign an informed consent 
 
4.3 Exclusion criteria 
4.3.1. Healthy volunteers 
A potential subject who meets any of the following criteria will be excluded from participation in this 
study:  

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• 
Relevant co-medication or comorbidity that might interfere with drug absorption, 
distribution, metabolism or excretion 
• 
Inability to take drugs according to the instructions (i.e. with food) 
• 
Presence of positive HIV screening or HIV RNA 
• 
Presence of HBsAg or HBcAg without anti-HBs 
• 
Presence of grade III/IV anaemia (i.e. Hb <4.6 mmol/L or <7.4 g/dL). 
• 
Presence of hereditary forms of severe galactose intolerance, total lactase deficiency or 
glucose-galactose malabsorption 
4.3.2. Women living with HIV and taking either DOR or BIC/FTC/TAF 
A potential subject who meets any of the following criteria will be excluded from participation in this 
study:  
• 
Relevant co-medication or comorbidity that might interfere with drug absorption, 
distribution, metabolism or excretion, especially the use of ritonavir/cobicistat boosted 
protease inhibitors are expected to interfere with study drugs and are therefor excluded.  
• 
Inability to take drugs according to the instructions (i.e. with food) 
• 
Presence of grade III/IV anaemia (i.e. Hb <4.6 mmol/L or <7.4 g/dL). 
• 
Presence of hereditary forms of severe galactose intolerance, total lactase deficiency or 
glucose-galactose malabsorption 
 
4.3.3. Women living with HIV using antiretroviral drugs and able to ingest a single dose of 
DOR  
• 
Relevant co-medication or comorbidity that might interfere with drug absorption, 
distribution, metabolism or excretion; especially participants whose regular ARV regimen 
contains ritonavir or cobicistat 
• 
Inability to take drugs according to the instructions (i.e. with food) 
• 
Presence of grade III/IV anaemia (i.e. Hb <4.6 mmol/L or <7.4 g/dL). 
• 
Presence of hereditary forms of severe galactose intolerance, total lactase deficiency or 
glucose-galactose malabsorption 
 
Participation to other studies is not an exclusion criterion per se, when other in- and exclusion 
criteria are met and the other study does not interfere with the outcomes of the current study. 
 
4.4 Sample size calculation 
No formal statistical comparison will be performed, as the main objective of this study is to 
determine concentrations in breastmilk transfer of the aforementioned drugs,  
Considering a coefficient of variation (CV%) of 30%, 12 participants are estamted to be required to 
reliably establish the pharmacokinetic (PK) parameters for BIC/FTC/TAF in breastmilk. For 
doravirine a sample size of 8 is deemed sufficient, because interim analysis of data collected so far 
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pharmacokinetic model was developed in which doravirine transfer into breastmilk was simulated. 
Results from this study are similar to those seen in the samples collected thus far in current study, 
The combination of these two data sources creates a reliable determination of dorvarine 
pharmacokinetics in breastmilk. 
Women are recruited from the child consultation clinics, infant day care facilities, through lactation 
specialists and midwives in the Nijmegen area. Also, approved promotion material is shared 
through the research platform of Radboudumc and nearby hospitals as well as social media 
(Instagram en Linkedin).  
 
 
 

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5. TREATMENT OF PARTICIPANTS 
5.1 Investigational product/treatment 
 
 
Participants will either receive one administration of DOR 100mg, or a single tablet containing a 
combination of bictegravir 50mg, tenofovir alafenamide 25mg and emtricitabine 200mg 
(BIC/FTC/TAF).   
If a participant is already using an antiretroviral regimen containing one of the study drugs, the 
participant may choose to ingest one extra study drug on top of her existing regimen. However, 
participants who use DOR on a daily basis, will not receive additional BIC/FTC/TAF, to prevent 
additional exposure to the NRTIs FTC/TAF, because their regimen most likely already contains two 
NRTIs.  
For participants using DOR or BIC/FTC/TAF or other ART on a daily basis, with or without add on 
study drugs, observed intake of the daily regimen will take place at the study centre.   
DOR is a non-nucleoside reverse transcriptase inhibitor (NNRTI) and – in combination with other 
ARV – indicated for treatment of HIV-1 infection without evidence for NNRTI class resistance. 
Bictegravir is an integrase inhibitor and tenofovir alafenamide and emtricitabine belong to the class 
of nucleoside reverse transcriptase inhibitors. In combination, these drugs are indicated for the 
treatment of a HIV-1 infection.  
 
5.2 Use of co-intervention 
 
Co-ingestion of (medicinal) products that have the capacity to induce or inhibit CYP3A is prohibited 
up till 7 days before participation in the study. Simultaneous ingestion of study medication and 
certain supplements may influence absorption and is therefore avoided. Examples of such products 
are summarized in table 1. Co-medication will be judged during screening.  
 
Table 1: Examples of prohibited co-medication and products 
Examples of prohibited co-medication and products 
Ritonavir or cobicistat 
Carbamazepin, oxcarbazepine, phenobarbital, phenytoin 
Rifampicin, rifapentine, rifabutin 
Mitotane 
Grape fruit or Seville oranges 
Saint John’s wort 
Ketoconazole, fluconazole, itraconazole, posaconazole and voriconazole 
Diltiazam, verapamil 
Anti-acids containing aluminium or magnesium 
Oral iron and calcium supplements 
 

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Standardized meals, drinks and snacks will be provided to the subject during sampling day.  
 
In the case participants already use ART, but are accustomed to ingest their drugs at night, a 
scheme will be provided to switch to daily intake during 3-5 days prior to the sampling day. Also a 
scheme to return back to their normal routine will be provided.  
 
5.3 Escape medication  
 
Not applicable 
 
 
6. INVESTIGATIONAL PRODUCT  
 
6.1 Name and description of investigational  products 
- 
Doravirine (DOR) 
- 
Bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) 
 
6.2 Summary of findings from non-clinical studies 
In chapter 5.1 of the Summary of Product Characteristics (SmPC) results of in vitro studies on 
antiviral activity and resistance are listed under subsection “antiviral activity” and “resistance” 
respectively. Chapter 5.3 of the SPC summarizes preclinical safety data.  
 
6.3 Summary of findings from clinical studies 
Efficacy data is summarized in chapter 5.1 of the SmPC. 
 
6.4 Summary of known and potential risks and benefits 
Chapter 5.3 of the SmPC summarizes preclinical safety data. Chapter 4.8 of the SmPC outlines al 
known undesirable effects. Findings regarding fertility, pregnancy and lactation are listed in chapter 
4.6 of the SmPC.  
 
6.5 Description and justification of route of administration and dosage 
 
Route of administration and dosages in this study are in line with manufacturers advice (SmPC).  
  
6.6 Dosages, dosage modifications and method of administration 
- 
Doravirine 100mg, 1 tablet, single dose, administered orally with water 
- 
Bictegravir 50mg/emtricitabine 200mg/tenofovir alafenamide 25mg, 1 tablet, single dose, 
administered orally with water  
 

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6.7 Preparation and labelling of Investigational Medicinal Product 
 
Study medication will be procured by the clinical trial unit (CTU) and stored at the Pharmacy of the 
Radboudumc. Packing of the medication on an individual level will be done by the Hospital 
Pharmacy’s Clinical Trial Unit (CTU).  
For the (licenced) medication preparation, we use the European Clinical Trial Regulation No 
536/2014, item (57): ‘Where the investigational or auxiliary medicinal product have already been 
placed on the market as an authorised medicinal product in accordance with Directive 2001/83/EC 
and Regulation (EC) No 726/2004 of the European Parliament and of the Council, as a general rule 
no additional labelling should be required for clinical trials that do not involve the blinding of the 
label.’  
This means that labelling in accordance with GMP annex 13 is not necessary for the study 
medication in this study, and that the KNMP’s guideline ‘ter handstellen’ in this case applies. 
All drugs will only be administered at the study site on the sampling day(s). Doravirine will be taken 
directly from the commercial package and is then stored at the CTU. The date at which the 
package is first opened and the subsequent expiration date (30 days after opening according to 
information provided by the manufacturer) is noted on the package itself. Biktarvy comes in a 
blisterpackage. The drug is taken directly from the commercial package and then stored at the 
CTU. Batch numbers, expiry dates and logs of deliveries of all drugs are recorded. As soon as the 
expiration date is reached, the drugs will be disposed 
The CTU of the Pharmacy will be in charge of drug accountability of the study medication on a 
Pharmacy level (i.e. overview of the purchased and dispensed packages). Drug accountability on a 
participant’s level will be performed at the study site In case of a participant already using DOR or 
BIC/FTC/TAF and who will not be using add on drugs for study purposes, the drugs already 
prescribed and in possession of participant will be ingested..  
 
 
6.8 Drug accountability 
Shipment, disposition, return and eventual destruction of investigational medicinal products will be 
carried out according ICH guidelines for Good Clinical Practice (GCP). 

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7. METHODS 
7.1 Study parameters/endpoints 
7.1.1 Main study parameter/endpoint 
 
Area under the plasma and milk concentration curve are used to calculate milk to plasma ratio.  
7.1.2 Secondary study parameters/endpoints  
 
The following pharmacokinetic parameters of ARV in plasma and/or breastmilk will be described: 
o 
AUC0-tau (AUC over a dosing interval) estimated using the trapezoidal 
method. 
o 
Peak plasma concentration (Cmax) 
o 
Time to Cmax 
o 
Concentration at end of dosing interval (Ctrough) 
o 
Apparent clearance 
o 
Apparent volume of distribution 
o 
Half life 
o 
Parameter estimation trough compartmental modelling 
7.1.3 Other study parameters 
- 
Body weight and height at moment of participation in study and reported weight 
pre-pregnancy 
- 
Use of co-medication, herbal or dietary supplements, tobacco, alcohol or illicit 
drugs two weeks prior to study participation 
- 
Time post partum, gestational age at delivery 
- 
Serum glucose 
- 
Glomerular filtration rate calculated using CKD-EPI (31) 
- 
Complete blood count (hemoglobin, leukocytes, thrombocytes) 
- 
Liver panel (alanine transferase, aspartate aminotransferase, bilirubine, gamma 
glutamyl transferase, alkalic phosphatase) 
- 
Albumin and α-1-acid glycoprotein 
- 
Urineanalysis (glucose, protein, blood, leukocytes, and nitrite. If positive, 
microscopic examination will be performed) 
- 
Adverse effects reported by participants 
- 
Concentrations found in breastmilk will be extrapolated to infant dosages 
- 
pH of breastmilk 
- 
If participants are living with HIV extra parameters will be noted: 
- 
 
Year of HIV diagnosis 
- 
 
CD4 cells 
- 
 
HIV-1 or HIV-2  
- 
 
Recent (<3 months) HIV viral load 
 

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7.2 Randomisation, blinding and treatment allocation 
This is a non-randomised, open label trial. Participants will be allocated to DOR, or BIC/FTC/TAF in a 
consecutive manner. First 8 participants will receive DOR, followed by administration ofBIC/FTC/TAF 
is administered in 12 other participants.  
 
 
7.3 Study procedures 
7.3.1 
Screening for eligibility 
The participants will be screened for eligibility for inclusion within 4 weeks and 3 days prior to 
study participation. The following procedures will be performed and documented:  
 
- 
Medical history and demographics (with a focus on co-medication, drug, alcohol- 
and tobacco use) 
- 
Haematological and biochemical analysis of blood (complete blood count, kidney 
function, livertests, albumin) 
- 
Urinalysis  
- 
Serologic tests (HIV and hepatitis B screening) in case of healthy volunteers 
 
When a subject is found eligible the study day and safety visit will be planned as soon as 
possible.  
 
7.3.2 
Preparation and maintenance for blood drawl  
At the start of the study day an indwelling intravenous canula will be installed by a certified 
nurse for repeated collection of blood samples. After every sample collection, the cannula will 
be flushed with a 0.9% NaCl solution in order to maintain patency. Prior to each blood sample 
collection, approximately 1 mL blood will be discarded. 
7.3.3 
PK analysis of blood 
 
A total of 11 samples will be collected for PK analysis. After the first sample (pre-dose, t=0) is 
drawn, DORor BIC/FTC/TAF is administered. Hereafter, a new sample is collected using the 
intravenous canula after 1, 2, 3, 4, 5, 6, 8, 10, 12, 24 hours post ingestion. Each sample 
contains a minimum of 2ml of blood collected in a EDTA tube. After collection, the samples are 
centrifugated during 5 minutes at room temperature at 1900g and transferred to a 
polypropylene tube and stored at freezers with a temperature of -40ºC.  
7.3.4 
PK analysis of breast milk 
 
For pharmacokinetic analysis of milk, samples of whole, mature (at least 10 days post-partum) 
breast milk will be collected from both breasts with the use of a personal electric pump.  

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After the milk is collected, it is gently mixed and the necessary aliquots (a minimum of 1ml) for 
assay will be saved using proper storage methods. Expression of breastmilk is planned at 0, 2, 
4, 6, 12, 24h after dosing. The timing of sampling relative to dose and the total volume of the 
sample will be reported in the case report form (CRF). 
7.3.5 
Other procedures for safety assessment  
During the 24h post-dosing sampling time point, 2 samples (one in EDTA, one in lithium 
heparin; each filled with a minimum of 2ml) will be collected for haematological and 
biochemical analysis. An urine sample will be collected as well, using a plastic, sterile cup 
provided by the study team.  
The participants will be asked if they experienced any adverse events at the 24h sampling 
time point and 7 days after intake of study medication. Any spontaneously reported by subject 
or observed by investigator will be documented. 
 
7.4 Withdrawal of individual participants 
Participants can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for urgent 
medical reasons. Other reasons for termination of participation are: protocol violation, difficulty in 
collecting blood-, or breastmilk samples or in the case of a serious adverse event.  
 
7.5 Replacement of individual participants after withdrawal 
 
The following definitions apply: 
Screening failure: subject that does not comply with the in- and exclusion criteria at some point 
before the first samples for pharmacokinetic analysis are collected.  
 
Entered/included: first pharmacokinetic sample taken. 
Dropout: subject withdrawn from the study after collection of at least one pharmacokinetic blood 
sample. 
 
 
Replacement occurs as follows: 
 
Screening failures: are replaced with a new subject. 
Dropout: in general, included participants (for example withdrawn from the study by the Investigator 
on ground of adverse events) will be replaced.  
 
7.6 Follow-up of participants withdrawn from treatment 
Participants will only receive one dose of study drugs. If participants are withdrawn – defined as a 
dropout in section 7.5 – the subject will still be invited for the 7day post-dose safety follow up visit. 
In the case of an adverse event, procedures mentioned in chapter 8 section 4 of this protocol will 
be followed.  
 

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8. SAFETY REPORTING 
8.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study if there 
is sufficient ground that continuation of the study will jeopardise subject health or safety.  The 
sponsor will notify the accredited METC without undue delay of a temporary halt including the 
reason for such an action. The study will be suspended pending a further positive decision by the 
accredited METC. The investigator will take care that all participants are kept informed.  
 
8.2 AEs, SAEs and SUSARs 
8.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject during the 
study, whether or not considered related to DOR or BIC/FTC/TAF. All adverse events reported 
spontaneously by the subject or observed by the investigator or his staff will be recorded. 
 
8.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; or 
- 
any other important medical event that did not result in any of the outcomes listed above 
due to medical or surgical intervention but could have been based upon appropriate 
judgement by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
 
The investigator will report all SAEs to the sponsor without undue delay after obtaining 
knowledge of the events.  
 
The sponsor will report the SAEs through the web portal ToetsingOnline to the accredited 
METC that approved the protocol, within 7 days of first knowledge for SAEs that result in death 
or are life threatening followed by a period of maximum of 8 days to complete the initial 
preliminary report. All other SAEs will be reported within a period of maximum 15 days after 
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8.2.3 Suspected unexpected serious adverse reactions (SUSARs) 
Adverse reactions are all untoward and unintended responses to an investigational product 
related to any dose administered. 
 
Unexpected adverse reactions are SUSARs if the following three conditions are met: 
1. the event must be serious (see chapter 8.2.2); 
2. there must be a certain degree of probability that the event is a harmful and an 
undesirable reaction to the medicinal product under investigation, regardless of the 
administered dose; 
3. the adverse reaction must be unexpected, that is to say, the nature and severity of the 
adverse reaction are not in agreement with the product information as recorded in the 
SPC.  
 
The sponsor will report expedited the following SUSARs through the web portal 
ToetsingOnline  to the METC : 
− 
SUSARs that have arisen in the clinical trial that was assessed by the METC; 
− 
SUSARs that have arisen in other clinical trials of the same sponsor and with the same 
medicinal product, and that could have consequences for the safety of the participants 
involved in the clinical trial that was assessed by the METC. 
 
The remaining SUSARs are recorded in an overview list (line-listing) that will be submitted 
once every half year to the METC. This line-listing provides an overview of all SUSARs from 
the study medicine, accompanied by a brief report highlighting the main points of concern.  
The expedited reporting of SUSARs through the web portal Eudravigilance or 
ToetsingOnline is sufficient as notification to the competent authority. 
 
The sponsor will report expedited all SUSARs to the competent authorities in other Member 
States, according to the requirements of the Member States.  
 
The expedited reporting will occur not later than 15 days after the sponsor has first 
knowledge of the adverse reactions. For fatal or life threatening cases the term will be 
maximal 7 days for a preliminary report with another 8 days for completion of the report.  
8.3 Annual safety report 
 
In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year throughout 
the clinical trial, a safety report to the accredited METC, competent authority, and competent 
authorities of the concerned Member States. 
This safety report consists of: 

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− 
a list of all suspected (unexpected or expected) serious adverse reactions, along with an 
aggregated summary table of all reported serious adverse reactions, ordered by organ system, 
per study; 
− 
a report concerning the safety of the participants, consisting of a complete safety analysis and 
an evaluation of the balance between the efficacy and the harmfulness of the medicine under 
investigation. 
 
8.4 Follow-up of adverse events 
 
All AEs will be followed until they have abated, or until a stable situation has been reached. 
Depending on the event, follow up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the protocol. 
 
8.5 Data Safety Monitoring Board (DSMB) / Safety Committee 
 
This study takes place in healthy, adult volunteers and consists of the intake of a single dose of a 
drug that is well studied and not associated with severe drug reactions. Therefore, the installation 
of a data safety monitoring board or safety committee is not needed.  
 
9. DATA ANALYSIS 
9.1 Bioanalysis 
 
RadboudUMC has established or will establish high pressure liquid chromatography (HPLC)/ ultra 
pressure liquid chromatography (UPLC)/ liquid chromatography with tandem mass spectrometry 
(LC-MS/MS)  assays for ARV (32).   
 
9.2 Assay validation 
 
The plasma assays will be externally validated by the International Interlaboratory Program for the 
Quality Control of Therapeutic Drug Monitoring in HIV Treatment (33, 34). The breastmilk assay 
are internally validated according EMA guidelines(35). Acceptable accuracy is defined as a 
performance within 80-120% of the nominal concentrations for te lower limit of quantification 
(LLOQ) and 85-115% for low-, middle-, high- and highest level of quantification in a run of 5 
samples. Acceptable precision is defined as a coefficient variation (CV%) below 20% for the LLOQ 
and below 15% for the other levels of quantification. The carry over effect and matrix effect are also 
established and should be below 20% of LLOQ and CV% <15% respectively. Stability evaluation is 
carried out as well for long term stability and freeze and thaw stability. 
 

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9.3 Statistical analysis 
 
In general, all participants who completed the study will be included in the statistical evaluation for 
description of demographics and pharmacokinetics. No formal statistical comparisons will be 
performed.  
 
Descriptive statistics will be carried out using R software.  
 
9.4 Pharmacokinetic analysis 
 
For the calculation of pharmacokinetic parameters WinNonlin (Pharsight Corporation, CA, USA) will 
be used. Individual and mean plasma concentrations and area under the curve (AUCtau)  will be 
presented. AUCtau  will be calculated using the trapezoidal method. Inter-subject variability will be 
illustrated using overlay presentations.  
 
10. ETHICAL CONSIDERATIONS 
 
10.1 Regulation statement 
 
This study will be conducted according to the principles of the Declaration of Helsinki (8th version, 
2013), Declaration of Tapei (2016) and in accordance with the Medical Research Involving Human 
Participants Act (WMO).  
 
10.2 Recruitment and consent 
 
Participants will be recruited through the Dutch Breastmilk Bank and at child consultation clinics in 
Nijmegen area. The Dutch Breastmilk Bank has a continuous number of approximately 30 
individuals who donate milk in their database that can be approached. These individuals are 
interested in enabling others to breastfeed and may be willing to participate in this study. Normally, 
individuals donate for approximately 3 months and are then replaced by others; on a yearly basis 
the Breast Milk Bank has 120 individuals on file. 
The investigator will inform the subject and provide a patient information leaflet and be available 
for additional questions. Participants are given as much time as needed to consider participation in 
this study.  
 
10.3 Benefits and risks assessment, group relatedness 
 
Participants will not directly benefit from this study, but will contribute to knowledge on breastmilk 
transfer of ARV and possibly enable people living with HIV to make a better informed decision on 
breastfeeding while using these medications.  

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No harm is expected from participation in this study, but possible side effects should be 
anticipated. Known side effects of DOR are nausea (4%) and headache (3%), abnormal dreams 
and insomnia (1-10%), dizziness and somnolence and fatigue (1-10%). BIC/FTC/TAFs known side 
effects are: headache (5%), diarrhoea (5%) and nausea (4%), depression and abnormal dreams 
and fatigue (1-10%), suicidal ideation (0,1-1%), angio-edema (0,1-1%), Steven Johnson syndrome 
(0,01-0,1%).  Due to the fact that only one dose of the drugs will be ingested, the risk of 
development of one or more of these side effects is considered to be low. 
Participation in this study requires participants to be admitted during 24hours and will be contacted 
by telephone 7 days later. During the sampling day an intravenous indwelling catheter is installed 
for collection of blood samples. A total volume of 25-50ml of blood, 2 urine samples and 6 
breastmilk samples (expressed using a personal electronic pump) are collected. No harm is to be 
expected from these sample collection procedures.  
In participants who chose to abstain from breastfeeding for a minimum of four days, the risk of 
toxicity for their infants will be negligibly small. All study drugs are metabolized by first line kinetics, 
which means that after 4-5 times the elimination half-life of the drug, the plasma concentrations will 
be near to zero. Because breastmilk concentrations are mainly determined by passive diffusion 
from  plasma, the breastmilk concentrations will most likely be lower than the plasma 
concentrations. So, when a near to zero concentration in plasma has been reached after 4-5 
elimination half-life periods, the risk of getting exposed to toxic concentrations via breastmilk will 
be nihil. Therefore, participants who agree to feed their infants in an alternative way (formula, pre-
pumped milk form before ingestion of study drug, donor milk etc) will have to plan this alternative 
feeding in advance and might need to pump during this period to retain milk-production. This might 
be conceived as an inconvenience.  
In participants living with HIV no harm is to be expected if they ingest a single dose of DOR or 
BIC/FTC/TAF. Also, the exposure of their infants trough breastmilk resulting from an extra single 
dose is regarded futile.  
 
10.4 Compensation for injury 
 
The sponsor/investigator has a liability insurance which is in accordance with article 7 of the WMO. 
  
The sponsor (also) has an insurance which is in accordance with the legal requirements in the 
Netherlands (Article 7 WMO). This insurance provides cover for damage to research participants 
through injury or death caused by the study. 
The insurance applies to the damage that becomes apparent during the study or within 4 years 
after the end of the study. 
 
10.5 Incentives  
 

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Participants will receive compensation for travel expenses and a compensation of €300,- . 
 
11. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
 
11.1 Handling and storage of data and documents 
 
All data obtained in the clinical study described in this protocol will be recorded on CRFs or study 
specific entry forms. Data will be partly collected as source data only, and it will be clearly documented 
in the Trial Master File which data will be collected as source data only. The database will be 
constructed by the Radboudumc in Castor (a validated data management system): it is ensured and 
documented that the electronic data processing system(s) conforms to the sponsor’s established 
requirements for completeness, accuracy, reliability, and consistent intended performance. 
The data management system will be compliant with GCP, as set out in Title 21 CRF Part 11. A data 
management plan will be written. 
 
Data from working copies of CRFs, obtained from the Investigator, will be directly entered into the 
database management system. 
 
The investigator must assure that subject’s anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Blood and milk samples for PK analysis will be 
identified by study name, patient number, date and time of sampling and sample code. CRFs do not 
contain identifiable information and will be coded with randomization numbers only. Information and 
study files that are necessary for the evaluation of the research are stored anonymously and the 
identification key will not be accessible by unauthorized parties.  
 
11.2 Monitoring and Quality Assurance  
 
The original CRF will be submitted to Data Management after a subject completed the study, including 
the data corrections (a copy of CRF pages used to collect source data will be provided). To eliminate 
entry errors and other inconsistencies between the data on the CRF and those in the database, Data 
Management will validate the data as follows: by entering numerical data twice into the database 
(double data entry), and by rereading comment fields, or by single data entry and at least 10% QC. 
Remaining queries will be solved on data clarification forms and updating of the database. These 
forms, signed by the Investigator, together with the original CRFs will complete the raw data set. 
 
11.3 Amendments  
 

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A ‘substantial amendment’ is defined as an amendment to the terms of the METC application, or 
to the protocol or any other supporting documentation, that is likely to affect to a significant 
degree: 
- the safety or physical or mental integrity of the participants of the trial; 
- the scientific value of the trial; 
- the conduct or management of the trial; or 
- the quality or safety of any intervention used in the trial. 
 
All substantial amendments will be notified to the METC and to the competent authority. 
 
Non-substantial amendments will not be notified to the accredited METC and the competent 
authority, but will be recorded and filed by the sponsor.  
 
11.4 Annual progress report 
 
The sponsor/investigator will submit a summary of the progress of the trial to the accredited METC 
once a year. Information will be provided on the date of inclusion of the first subject, numbers of 
participants included and numbers of participants that have completed the trial, serious adverse 
events/ serious adverse reactions, other problems, and amendments.  
 
11.5 Temporary halt and (prematurely) end of study report 
 
The sponsor will notify the accredited METC and the competent authority of the end of the study 
within a period of 90 days. The end of the study is defined as the last patient’s last visit.  
 
The sponsor will notify the METC immediately of a temporary halt of the study, including the 
reason of such an action. 
 
In case the study is ended prematurely, the sponsor will notify the accredited METC and the 
competent authority within 15 days, including the reasons for the premature termination. 
 
 Within one year after the end of the study, the investigator/sponsor will submit a final study report 
with the results of the study, including any publications/abstracts of the study, to the accredited 
METC and the Competent Authority.  
 
11.6 Public disclosure and publication policy 
 
The study will be registered to a publicly accessible registry and results database 
(ClinicalTrials.gov). The investigator will submit any proposed publication or presentation along with 

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the respective scientific journal or presentation forum at least 7 days prior to submission of the 
publication or presentation to all co-investigators.  
 
11.7 Sample destruction after study completion  
 
Any samples left over after analysis will be destroyed when the study is completed. Samples will be 
discarded in compliance with local biologic waste disposal requirements.  
 
12. STRUCTURED RISK ANALYSIS  
 
Participants will not directly benefit from this study, but will contribute to knowledge on breastmilk 
transfer of ARV and possibly enable people living with HIV to make an informed decision on 
breastfeeding while using these medications.  
Participants are entitled to reimbursement of travel expenses and will receive a compensation of 
€300,- for each completed sampling day.  
No harm is expected from participation in this study, but possible side effects should be anticipated. 
Known side effects of DOR are nausea (4%) and headache (3%), abnormal dreams and insomnia (1-
10%), dizziness and somnolence and fatigue (1-10%). BIC/FTC/TAFs known side effects are: 
headache (5%), diarrhoea (5%) and nausea (4%), depression and abnormal dreams and fatigue (1-
10%), suicidal ideation (0.1-1%), angio-edema (0,1-1%) and Steven Johnson syndrome (0.01-0.1%) 
and osteonecrosis (0.01-0.1%).  Due to the fact that only one dose of the drugs will be ingested, the 
risk of development of one or more of these side effects is considered to be low.  
Participation in this study requires participants to be admitted during 12hours and a return visit 
24hours after ingestion of the study drug and again 7 days later. During the sampling day an 
intravenous indwelling catheter is installed for collection of blood samples. A total volume of 25-50ml 
of blood, 2 urine samples and 6 breastmilk samples (expressed using a personal electronic pump) are 
collected. No harm is to be expected from these sample collection procedures.  
Lastly, no harm to infants of participants who temporarily stop breastfeeding is to be expected, 
because a stopping-period of four days is ensured, which is more than enough time for metabolization 
of the drugs to a nearly zero concentration. The need to plan alternative feeding options for subject’s 
infants and the possible need to pump to maintain milk production, are inconvenient implications of 
temporary breastfeeding stops.  
In participants living with HIV no harm is to be expected if they ingest a single dose of DOR or 
BIC/FTC/TAF. Also, the exposure of their infants trough breastmilk resulting from an extra single dose 
is regarded futile.  
 
 
 

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