Clinical trial NCT03894124
Conditions: Human Immunodeficiency Virus
Sponsor: Chelsea and Westminster NHS Foundation Trust
Start date: 2019-06-12; Completion date: 2019-08-06
Enrollment: 24 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Study to assess the pharmacokinetics of plasma doravirine once daily over 72 hours following drug intake cessation at steady-state in healthy volunteers

Detailed description:
The administration of combination antiretroviral therapy (cART) to HIV-infected patients has been associated with a dramatic reduction in AIDS-related morbidity and mortality. The key to successful HIV drug treatment is adhering to the prescribed combination every day. The approval of single tablet combinations (STRs) provides HIV care providers with a "one tablet once a day" therapy, making adherence much easier for patients. However, in HIV therapy, successful adherence also means attention to intervals between doses or dietary restrictions. Ideally, to guarantee long-term virological response, HIV-infected patients should take their cART every day at the same time. However, cART is for life and doses can be forgotten or delayed. For this study 14 healthy volunteers will receive Pifeltro® (doravirine 100mg tablets) daily for 7 days to reach steady state. Following the last dose samples will be taken for pharmacokinetic testing over 72 hours.

The incidence of adverse events between enrolment to the study (day 1) and last visit (day 20-23) will be recorded.

Blood, urine and faecal samples from study subjects will be taken for use in planned exploratory research and for use in future research:

Analyses looking at genes which affect drug disposition (pharmacogenomics); the impact of doravirine intake on platelet function and markers of platelet and endothelial cell activation; metabolic changes associated with doravirine.

Arms: arm 1: Pifeltro® (doravirine 100mg) daily dose for 7 days
Interventions: intervention 1: Doravirine
Intervention descriptions: intervention 1: Non-nucleoside reverse transcriptase inhibitor. Administered as film coated tablet.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
 
Pharmacokinetics of plasma doravirine once daily over 72 hours following 
drug intake cessation in healthy volunteers 
 
 
 
 
Protocol Number: 
 
CRF001 
 
Version and Date: 
 
 
Version 1.6 dated 06 June 2019 
 
EudraCT: 
 
 
 
2019-000978-33  
 
IRAS number:                       
 
261913 
 
Principal Chief Investigator:   
Dr Marta Boffito 
St. Stephen’s Centre 
Chelsea and Westminster Hospital 
369 Fulham Road, London 
SW10 9NH 
 
 
Sponsor:  
Chelsea and Westminster Hospital NHS Foundation Trust 
369 Fulham Road 
London SW10 9NH  
 
 
 
 
 
Protocol Approval:  
 
_________________________ ___________ 
  
 
 
 
Dr Marta Boffito  
 
Date 
 
 
 
GCP Compliance Statement: 
This trial will be conducted in compliance with the protocol, the principles that have their 
origin in the Declaration of Helsinki and all applicable regulatory requirements 


Protocol CRF001 
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                                          Page 2 of 37 
Synopsis 
 
Study title 
Pharmacokinetics of plasma doravirine once daily over 72 
hours following drug intake cessation in healthy volunteers. 
Phase of study  
 
 
Phase I 
Protocol Number 
CRF001 
EudraCT 
2019-000978-33  
Name of active ingredients 
Doravirine 
Name of Investigational Product 
Pifeltro® 
Objectives 
The objectives of this study are: 
Primary 
-To assess the pharmacokinetics of plasma doravirine once 
daily over 72 hours following drug intake cessation at steady-
state in healthy volunteers 
Secondary 
-To investigate the safety and tolerability of doravirine 
-To investigate the association between genetic 
polymorphisms in drug disposition genes and drug exposure 
Exploratory 
-To investigate the impact of doravirine intake on platelet 
function and markers of platelet and endothelial cell activation 
-To investigate of the metabolic changes associated with 
short term doravirine intake in healthy volunteers 
Study design 
10 days (excluding screening and follow up), open label, 
pharmacokinetic study 
Indication 
Not applicable 
Methodology 
Measurements of steady state plasma pharmacokinetic profile 
and pharmacokinetic forgiveness of doravirine 
Planned sample size 
Up to 24 healthy volunteers may be enrolled at baseline in 
order to achieve 14 completing the study  
Summary of eligibility criteria 
Healthy participants as determined by medical history, 
physical examination, 12-lead electrocardiogram, and clinical 


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laboratory evaluations will be eligible to participate in the 
study. Women of childbearing potential must not be nursing or 
pregnant. Women of childbearing potential must have a 
negative pregnancy test at screening 
Number of study centres 
One 
Duration of treatment 
10 days (excluding screening and follow up visits) 
Dose and route of administration  
All participants will be administered Pifeltro® 100 mg once 
daily for 7 days 
Criteria for evaluation 
Pharmacokinetic parameters of doravirine will be evaluated 
on blood drawn on day 7 (at 0 (pre-dose), 2, 4, 8, 12 hours 
post last dose), and on days 8 to 10 at 24, 30, 36, 48, 54, 60, 
and 72 hours post last dose 
Safety and tolerability of the study medication will also be 
assessed by questions, physical examination and laboratory 
parameters. These will be performed at regular intervals 
during the drug study 
Primary endpoint 
Steady state plasma concentrations of doravirine after drug 
intake cessation up to 72 hours post-dose 
Secondary end points                       
Safety and tolerability of the studied drug  
Relationship between genetic polymorphisms and exposure to 
the studied drugs 
Exploratory end points 
Effect of short term doravirine intake upon platelet function 
and markers  
Investigation of the metabolic changes associated with short 
term doravirine intake in healthy volunteers. 
 


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General Study Information 
 
Name of sponsor: 
Chelsea and Westminster Hospital NHS Foundation Trust 
369 Fulham Road 
LondonSW10 9NH 
Chief investigator: 
Dr Marta Boffito  
Chelsea and Westminster Hospital 
369 Fulham Road,  
London SW10 9NH 
Phone 0208 846 6507 
Laboratory facilities:  
Biochemistry & Haematology  
 
 
 
 
Imperial College NHS Foundation Trust 
Pathology Laboratory 
Chelsea and Westminster Hospital 
369 Fulham Road 
London SW10 9NH 
Virology & Hepatitis 
Imperial College NHS Foundation Trust  
Dept. of Infection & Immunity 
9th Floor Laboratory Block 
Charing Cross Hospital 
Fulham Palace Road 
London W6 8RF 
Pharmacokinetics and 
metabolomics 
 
 
 
 
Jefferies Research Trust Laboratories 
Wright-Fleming Institute 
Imperial College London 
Dept. of Medicine, St Mary’s Campus 
Norfolk Place 
London W2 1PG 
Pharmacogenetics 
 
 
 
 
 
Pharmacology Research Laboratories 
University of Liverpool 
Block H – First floor 
70 Pembroke Place 
Liverpool L69 3GF 
Platelet/endothelium 
Dr Mike Emerson 
National Heart and Lung Institute 


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Sir Alexander Fleming Building 
South Kensington Campus 
Imperial College London 
Exhibition Road 
London SW7 2AZ 
Processing and Shipping PK & PG 
samples: 
 
HIV/GUM Laboratory 
St Stephen’s Centre 
Chelsea and Westminster Hospital 
369 Fulham Road 
London SW10 9NH 
Medical expertise: 
Dr Marta Boffito  
St Stephens Centre 
Chelsea and Westminster Hospital 
369 Fulham Road  
London SW10 9NH 
Phone 0208 846 6507 
Data management and Statistics: 
Research and Development Office 
Chelsea and Westminster Hospital NHS Foundation Trust 
Unit G2, Harbour Yard 
Chelsea Harbour 
London SW10 0XD  
Monitor:  
Research and Development Office 
Chelsea and Westminster Hospital NHS Foundation Trust 
Unit G2, Harbour Yard 
Chelsea Harbour 
London SW10 0XD  
 
Phone 020 3315 6825 
Email research.development@chelwest.nhs.uk  
 


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List of abbreviations and definitions of terms 
 
ACTG 
AIDS Clinical Trial Group 
AE 
Adverse event 
AIDS 
Acquired Immune Deficiency Syndrome 
AUC 
Area Under the concentration-time Curve 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BID 
Twice daily 
BMI 
Body Mass Index 
Cmax 
Maximum concentration 
CM 
Concomitant Medication 
CRF 
Case Report Form 
Ctrough 
Trough concentration 
CYP450  
Cytochrome P450 
DAIDS 
Division of AIDS 
ECG 
Electrocardiogram 
FBC 
Full blood count 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human Immunodeficiency Virus 
ICH-GCP 
International conference of harmonization good clinical practice 
IMP 
Investigational Medicinal Product 
LFT 
Liver function test 
MHRA 
Medicines and Healthcare products Regulatory Agency 
NRTI 
Nucleoside reverse transcriptase inhibitor 
NNRTI 
Non-nucleoside reverse transcriptase inhibitor 
OD 
Once daily 
PG 
Pharmacogenetic 
PI 
Protease inhibitors 
PK 
Pharmacokinetic 
PLWH 
People living with HIV 
SAE 
Serious Adverse Event 
SmPC 
Summary of product characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TOPS 
The over-volunteering prevention scheme 
T1/2 
Half-life 
UK 
United Kingdom 
U&E 
Urea and Electrolytes 
WOCBP 
Women of Child Bearing Potential 


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Contents 
 
Synopsis .................................................................................................................................................. 2 
General Study Information ...................................................................................................................... 4 
List of abbreviations and definitions of terms .......................................................................................... 6 
1 
Background ...................................................................................................................................... 9 
1.1 
Introduction .............................................................................................................................. 9 
1.2 
Background and study rationale ............................................................................................. 9 
2 
Trial Objectives .............................................................................................................................. 10 
2.1 
Primary .................................................................................................................................. 10 
2.2 
Secondary ............................................................................................................................. 11 
2.3 
Exploratory ............................................................................................................................ 11 
3 
Trial Design .................................................................................................................................... 11 
3.1 
Endpoints .............................................................................................................................. 11 
3.2 
Study design.......................................................................................................................... 11 
3.3 
Randomisation and blinding .................................................................................................. 12 
4 
Participant population .................................................................................................................... 13 
4.1 
Number of participants and participant selection .................................................................. 13 
4.2 
Inclusion criteria .................................................................................................................... 13 
4.3 
Exclusion criteria ................................................................................................................... 14 
4.4 
Duration of involvement ........................................................................................................ 15 
4.5 
Withdrawal of patients and discontinuation criteria ............................................................... 15 
4.5.1 
Criteria for premature withdrawal ...................................................................................... 16 
4.6 
Follow-up of abnormal laboratory test values ....................................................................... 16 
5 
Definition of end of trial .................................................................................................................. 16 
6 
Treatment of participants ............................................................................................................... 16 
6.1 
Study treatment regimen ....................................................................................................... 16 
7 
Study IMP ...................................................................................................................................... 16 
8 
Pharmacokinetics and pharmacodynamics ................................................................................... 17 
8.1 
Pharmacokinetics .................................................................................................................. 17 
8.2 
Undesirable effects ............................................................................................................... 18 
8.3 
Treatment compliance ........................................................................................................... 20 
8.4 
Provision of treatment after the end of the trial ..................................................................... 20 
9 
Visit schedule and procedures ....................................................................................................... 20 
9.1 
Assessments at each visit ..................................................................................................... 20 
10 
Statistical analysis ..................................................................................................................... 23 
10.1 
Participant numbers .............................................................................................................. 23 
10.1.1 
Sample size ................................................................................................................... 23 
10.1.2 
Criteria for evaluation .................................................................................................... 23 
10.2 
Statistical methods ................................................................................................................ 23 


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10.2.1 
Safety parameters ......................................................................................................... 24 
10.2.2 
Pharmacokinetic parameters ........................................................................................ 24 
10.3 
Criteria for termination of the trial .......................................................................................... 24 
11 
Adverse Events ......................................................................................................................... 24 
11.1 
Definitions .............................................................................................................................. 24 
11.2 
Assessment of intensity ........................................................................................................ 25 
11.3 
Assessment of causality ........................................................................................................ 25 
11.4 
Collection and follow up of Adverse Events .......................................................................... 25 
11.4.1 
Serious Adverse Events (SAEs) ................................................................................... 26 
11.4.2 
Serious Adverse Event Collection and Reporting ......................................................... 26 
11.4.3 
Pregnancy ..................................................................................................................... 27 
11.4.4 
Other safety considerations .......................................................................................... 27 
12 
Data handling ............................................................................................................................ 27 
12.1 
Recording of data .................................................................................................................. 27 
12.2 
Source documentation and study records ............................................................................ 28 
12.3 
Data management ................................................................................................................. 28 
12.4 
Archiving and storage of data ............................................................................................... 28 
13 
Quality control and quality assurance ....................................................................................... 28 
13.1 
Monitoring arrangements ...................................................................................................... 28 
13.2 
Quality assurance ................................................................................................................. 29 
14 
Administrative procedures ......................................................................................................... 29 
14.1 
Ethics approval ...................................................................................................................... 29 
14.2 
Regulatory approval .............................................................................................................. 29 
14.3 
Insurance provisions ............................................................................................................. 29 
14.4 
Publication policy .................................................................................................................. 29 
14.5 
Drug accountability ................................................................................................................ 30 
14.6 
Sample shipment and processing ......................................................................................... 30 
14.6.1 
Safety analysis samples ................................................................................................ 30 
14.6.2 
Pharmacokinetics analysis ............................................................................................ 31 
14.6.3 
Pharmacogenetics analysis .......................................................................................... 31 
14.6.4 
Platelets/endothelium .................................................................................................... 31 
14.6.5 
Metabolomics ................................................................................................................ 31 
15 
References ................................................................................................................................ 32 
16 
Appendices................................................................................................................................ 33 
Appendix 1: 
Study flowchart .......................................................................................................... 33 
Appendix 2: 
DAIDS grading scale ................................................................................................. 34 
Appendix 3: 
Collecting, processing, shipping and storing of blood, plasma,urine and faeces ..... 34 
Appendix 4: 
Highly Effective Methods for Avoiding Pregnancy in FOCBP ................................... 36 
 
 
 


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Background 
1.1 
Introduction 
The administration of combination antiretroviral therapy (cART) to HIV-infected patients has been 
associated with a dramatic reduction in AIDS-related morbidity and mortality [1-3]. 
The key to successful HIV drug treatment is adhering to the prescribed combination every day [2]. 
The approval of single tablet combinations (STRs) provides HIV care providers with a “one tablet once 
a day” therapy, making adherence much easier for patients. 
However, in HIV therapy, successful adherence also means attention to intervals between doses or 
dietary restrictions. Ideally, to guarantee long-term virological response, HIV-infected patients should 
take their cART every day at the same time. However, cART is for life and doses can be forgotten or 
delayed. 
1.2 
Background and study rationale 
A drug’s persistence in plasma or in cells depends on its half-life. Long half-life antiretroviral agents 
may allow for missed or delayed doses, if concentrations are maintained at therapeutic levels until the 
next dose is taken. However, data on drug persistence are limited and whether drug doses can be 
omitted and dosing delayed is unknown [1]. 
Knowledge of the length of time the drugs last would increase the confidence of doctors in this 
combination [1]. Therefore a study investigating the pharmacokinetic “forgiveness” of the new non 
nucleoside reverse transcriptase inhibitor doravirine would provide information on how to advise HIV 
infected patients on delayed and missed doses. Doravirine has been recently approved to treat HIV 
infection and it is available as a single agent (Pifeltro®) and as a fixed dose combination with tenofovir 
disoproxil fumarate (TDF) and lamivudine (3TC) (Delstrigo) [2]. The tail pharmacokinetics of tenofovir 
and lamivudine has been extensively characterised. 
Therefore in this study we will investigate the persistence of doravirine only, thus minimising the 
exposure of participants to medicinal agents. 
Rationale for pharmacogenetic analysis 
Pharmacogenetics holds promise in HIV treatment because of the complexity and potential toxicity of 
multi antiretroviral drug therapies that are prescribed for long periods. Thus far, few candidate genes 
have been examined for a limited number of allelic variants, but a number of confirmed associations 
have already emerged. 
From a public health perspective, as antiretroviral medications become increasingly available to 
racially and ethnically diverse populations worldwide, understanding the genetic structures of each 
population may allow us to anticipate the impact of adverse responses, even in groups that were not 
represented in drug registration trials. 
The existing literature on pharmacogenetic determinants of antiretroviral drug exposure, drug toxicity, 
as well as genetic markers associated with the rate of disease progression underline the recent 
advances which occurred in the past few years.  However, it is expected that larger-scale 
comprehensive genome approaches will profoundly change the landscape of knowledge in the future. 
Additional studies are needed to assess the implications for long-term responses to antiretroviral 
agents. 
 


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For this reason we plan to collect a single blood sample from each participant in our intensive 
pharmacokinetic studies, such as this one, in order to be able to investigate the association between 
genetic polymorphisms in drug disposition genes (such as those encoding for cytochrome P450 
isoenzymes or transmembrane transporters) and drug exposure. A candidate gene approach will be 
utilised to examine loci of interest. This procedure will provide potentially important information on 
genetic influences on plasma drug concentrations and give insight into how to improve the 
management of HIV-infected patients by individualising therapy.  These studies will not be powered 
for genetic associations but will enable us to build a data base of genotype-phenotype.  Prospective 
genetic studies would need to be planned based on these preliminary data. 
Rationale for exploratory endpoints: 
Platelet and endothelial function 
Cardiovascular risks, specifically platelet-driven events such as myocardial infarction, are more 
prevalent in people living with HIV. The causes of increased risk are unclear but a number of studies 
have shown risk to be associated with antiretroviral therapy. There is also evidence that some drug 
regimens impact the cardiovascular system to a greater extent than others. Understanding the 
cardiovascular risk profile of antiretrovirals delivers information on their tolerability that could ultimately 
reduce multi-morbidity in PLWH. The current study provides an opportunity to investigate acute 
changes in platelet and endothelial cell function that occur during doravirine administration. We shall 
isolate platelets and plasma from blood and conduct light transmission aggregometry assays as well 
as flow cytometric assays to measure markers of platelet and endothelial activation. These studies 
are intended to be preliminary and are intended to generate data to justify subsequent studies in older 
PLWH and patients with cardiovascular conditions in order to better understand the impact of 
doravirine-containing therapies relative to alternative antiretroviral regimens in relevant, at-risk 
populations.  
Metabolomics 
Metabolomics can be used to profile the maximum number of metabolites found within an organism 
tissue, cell or biofluids, enabling detailed mapping of perturbed pathways involved in ART drug 
response. This approach has the potential to unravel on- and off-target effects of ART and further our 
understanding of mechanisms of action, metabolism and toxicities. With new safer antiretrovirals 
becoming available, it is important to understand what the drug effect could be on certain metabolic 
pathways, especially in view of people living with HIV ageing and needing access to such safer drugs. 
We therefore aim to carry out liquid chromatography mass spectrometry (LC-MS) based 
metabolomics analysis on plasma and urine samples from the healthy volunteers enrolled in the study 
before drug intake and when the drug has reached steady-state to investigate the metabolic changes 
associated with short term doravirine intake.  The twelve plasma samples obtained primarily for PK 
samples may also be used for these analyses. 
These studies will not be powered for drug/metabolomics changes associations but will enable us to 
build a data base on drug/metabolomics changes.  Prospective studies would need to be planned 
based on these preliminary data. 
 
2 
Trial Objectives 
2.1 
Primary 
 
To assess the pharmacokinetics of plasma doravirine once daily over 72 hours following drug 
intake cessation at steady-state in healthy volunteers. 


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2.2 
Secondary 
 
To investigate the safety and tolerability of doravirine. 
 
To investigate the association between genetic polymorphisms in drug disposition genes and 
drug exposure. 
2.3 
Exploratory 
 
To investigate the impact of doravirine intake on platelet function and markers of platelet and 
endothelial cell activation. 
 
To investigate of the metabolic changes associated with short term doravirine intake in 
healthy volunteers. 
 
3 
Trial Design 
3.1 
Endpoints 
Primary endpoint 
 
Steady state plasma concentrations of doravirine after drug intake cessation up to 72 hours 
post-dose. 
Secondary endpoints 
 
Safety and tolerability of the studied drug. 
 
Relationship between genetic polymorphisms and exposure to the studied drugs. 
Exploratory endpoints 
 
Impact of doravirine intake on platelet function and markers of platelet and endothelial cell 
activation. 
 
Investigation of the metabolic changes associated with short term doravirine intake in healthy 
volunteers. 
3.2 
Study design 
This study is a 10 day (excluding screening and follow up), open label, pharmacokinetic study. 
Table 1: Study design 
Study Visit 
Day 
Study procedures 
Screening 
Day -28 to 0 
Written informed consent, demographics, medical  
history and co-medications (CMs) review.   
 
Physical examination, height, weight, vital signs 
(including temperature, blood pressure, heart rate 
and respiratory rate), ECG, urinalysis (macro-


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analysis, drug screen and pregnancy test for 
WOCBP), HIV/HBV/HCV testing, safety bloods 
(see appendix 1) and registration of TOPS 
database.  Fulfil all inclusion criteria. 
Baseline 
 
Start doravirine 100 mg  
Day 1 (morning) 
Vital signs, safety bloods, urinalysis (macro-
analysis, drug screen and pregnancy test for 
WOCBP) 
 
First drug dose in a fasted state (one tablet once 
daily), witnessed drug intake, concomitant 
medication check and adverse events (AE 
review). 
PG blood sample collection 
(can be collected any visit after Day 1) 
 
Platelet and metabolomics (plasma, urine and 
faeces) pre-dose sampling 
Day 2-6 Drug  self-
administration 
Day 2-6  
All participants will be instructed to take their 
doravirine dose at home in the morning (fasting) 
Day 7-10 PK Phase 
 
 
Day 7 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 8 
Day 9 
Day 10 
All participants will be dosed in the unit fasting, 
witnessed drug intake, vital signs, safety bloods, 
urinalysis (macro-analysis, drug screen and 
pregnancy test for WOCBP), review of CM and 
AE. 
 
Cannulas will be placed when possible/preferred. 
 
Platelet and metabolomics (plasma, urine and 
faeces) post-dose sampling. 
 
Blood for PK assessment will be drawn pre-dose 
and 2,4,8,12 hrs post dose 
AND 
24, 30, 36 hours post dose 
48, 54, 60 hours post dose 
72 hours post dose 
These PK samples may also be used for 
metabolomics analyses. 
Follow up visit  
(10-13 days after last PK 
blood sample) 
Day 20 to 23 
Safety bloods, vital signs, review of CM and AEs 
 
Platelet and metabolomics (plasma, urine and 
faeces) post-dose sampling 
 
3.3 
Randomisation and blinding 
Not applicable. 


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4 
Participant population 
4.1 
Number of participants and participant selection 
Healthy male and female volunteers as determined by medical history, physical examination, 12-lead 
electrocardiogram, and clinical laboratory evaluations will be eligible to participate in the study. 
Women of childbearing potential must not be nursing or pregnant.  
No formal size calculation was performed.  Fourteen (14) participants completed are considered 
sufficient to allow for relevant conclusions to be drawn, given experience from similar studies 
conducted previously.  Up to 24 participants will be enrolled to achieve this. 
4.2 
Inclusion criteria 
Participants must meet all of the following inclusion criteria within 28 days prior to the baseline visit: 
1. The ability to understand and sign a written informed consent form, prior to participation in any 
screening procedures and must be willing to comply with all study requirements 
2. Male or non-pregnant, non-lactating females. 
3. Between 18 to 65 years, inclusive 
4. Body Mass Index (BMI) of 18 to 35 kg/m2, inclusive 
5. ALT, alkaline phosphatase and bilirubin ≤ 1.5xULN (isolated bilirubin >1.5xULN is acceptable if 
bilirubin is fractionated and direct bilirubin <35%). A single repeat is allowed for eligibility 
determination. 
6. Women of childbearing potential (WOCBP – definition in Appendix 4) must be using an adequate 
method of contraception to avoid pregnancy throughout the study and for a period of at least 4 
weeks after the study.     
A female may be eligible to enter and participate in the study if she: 
a. is of non-child-bearing potential defined as either post-menopausal (12 months of spontaneous 
amenorrhea and ≥ 45 years of age) or physically incapable of becoming pregnant with 
documented tubal ligation, hysterectomy or bilateral oophorectomy or, 
b. is of child-bearing potential with a negative pregnancy test at both Screening and day 1 and 
agrees to use one of the following methods of contraception to avoid pregnancy: 
i. 
Complete abstinence from penile-vaginal intercourse from 2 weeks prior to 
administration of IP, throughout the study, and for at least 4 weeks after discontinuation 
of all study medications.  Abstinence is acceptable only as true abstinence when this is 
in line with the preferred and usual lifestyle of the patient; 
ii. 
Double barrier method (male condom/spermicide, male condom/diaphragm, 
diaphragm/spermicide); 
iii. Any intrauterine device (IUD) with published data showing that the expected failure rate 
is <1% per year (not all IUDs meet this criterion, see protocol appendix 4 for an 
example listing of approved IUDs); 


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iv. Male partner sterilisation confirmed prior to the female subject’s entry into the study, 
and this male is the sole partner for that subject; 
v. Approved hormonal contraception (see protocol appendix 4 for a listing of examples of 
approved hormonal contraception) plus male condom; 
vi. Any other method with published data showing that the expected failure rate is <1% 
per year. 
Any contraception method must be used consistently, in accordance with the approved product 
label and for at least 4 weeks after discontinuation of IP. 
7. Men who have partners who are women of childbearing potential (WOCBP – definition in Appendix 
4) must be using an adequate method of contraception to avoid pregnancy in their partner 
throughout the study and for a period of at least 4 weeks after the study (see inclusion criteria 6);   
a. Complete abstinence from penile-vaginal intercourse.  Abstinence is acceptable only as true 
abstinence when this is in line with the preferred and usual lifestyle of the patient; 
b. Double barrier method (male condom/spermicide, male condom/diaphragm, 
diaphragm/spermicide); 
c. Any intrauterine device (IUD) with published data showing that the expected failure rate is <1% 
per year (not all IUDs meet this criterion, see Appendix 4 for an example listing of approved 
IUDs); 
d. Sterilisation confirmed prior to the subject’s entry into the study 
e. Approved hormonal contraception used by female partner (see protocol appendix 4 for a listing 
of examples of approved hormonal contraception) plus male condom; 
f. 
Any other method with published data showing that the expected failure rate is <1% per year 
and not containing hormones. 
Any contraception method must be used consistently, in accordance with the approved product label 
and for at least four weeks after discontinuation of IMP. 
8. Willing to consent to their personal details being entered onto the TOPS database 
9. Willing to provide proof of identity by photographic ID at screen and any subsequent visit 
10. Registered with a GP in the UK 
4.3 
Exclusion criteria 
Participants who meet any of the following exclusion criteria are not to be enrolled in this study; 
1. Any clinically significant acute or chronic medical illness 
2. Evidence of organ dysfunction or any clinically significant deviation from normal in physical 
examination, vital signs, ECG or clinical laboratory determinations 
3. Positive blood screen for hepatitis B surface antigen or C antibody 
4. Positive blood screen for HIV-1 or 2 by antibody/antigen assay 


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5. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the 
exception of Gilbert's syndrome or asymptomatic gallstones) 
6. History or presence of allergy to the study drugs and their components 
7. Current or recent (within three months) gastrointestinal disease 
8. Known intolerance of lactose monohydrate, sunset yellow aluminium lake (E110), and patients 
with galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption  
9. Clinically relevant alcohol or drug use (positive urine drug screen) or history of alcohol or drug use 
considered by the Investigator to be sufficient to hinder compliance with treatment, follow-up 
procedures or evaluation of adverse events.  Smoking is permitted, but tobacco intake should 
remain consistent throughout the study 
10. Exposure to any investigational drug (or placebo) or participation in a clinical study involving the 
donation of blood samples within three months of first dose of study drug 
11. Use of any other drugs (unless approved by the Investigator), including over-the-counter 
medications and herbal preparations, within two weeks prior to first dose of study drug, unless 
approved/prescribed by the Principal Investigator as known not to interact with study drugs. 
12. Females of childbearing potential without the use of effective non-hormonal birth control methods, 
or not willing to continue practising these birth control methods for at least four weeks after the 
end of the treatment period 
4.4 
Duration of involvement 
Total duration of involvement in the study is 10 days plus a screening visit within 28 days prior to 
commencement at day 1 and follow-up visit between study days 20 and 23 (approximately 14 days 
after the last blood test). 
During this time participants will be instructed in the information leaflet to refrain from certain activities, 
which can potentially affect the rate of drug metabolism: 
 
Strenuous exercise, contact sports and sunbathing 
 
Drinking alcohol-containing beverages for two days prior to Days 7 and during Days 7-10.  
Alcohol is prohibited whilst a participant is in the unit 
 
Drinking or eating any grapefruit, Seville oranges or grapefruit and Seville orange containing 
products for two days prior to Day 7 and during Days 7-10. 
 
Drinking caffeine-containing beverages for two days prior to Day 7 and during Days 7-10. 
Smoking whilst residing at the clinical facility is not allowed. 
4.5 
Withdrawal of patients and discontinuation criteria 
Participants may be asked whether they are interested in taking part into the study while all study 
participants have already been identified. This would make the participant a reserve and they will be 
contacted to take part into the whole study only if a study participant withdraws from the study and the 
number of subjects completing the study is considered insufficient. This means that they may only 
attend the screening visit and be remunerated only for their limited attendance. Details on this will be 
further explained to the participant by study staff in these circumstances. 


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4.5.1 Criteria for premature withdrawal 
Participants have the right to withdraw from the study at any time for any reason. The investigator 
may also withdraw participants from the study or decide to discontinue medication dosing in the event 
of inter-current illness, AEs, protocol violations, administrative reasons or other reasons. An excessive 
rate of withdrawals can render the study impossible to interpret; therefore unnecessary withdrawal of 
participants should be avoided.  
In all cases, the date and reasons for withdrawal or discontinuation of medication will be clearly stated 
on the participant’s CRF. If the reason for removal of a participant from the study is an AE or an 
abnormal laboratory test result, the principal specific event or test will be recorded on the CRF.  
Withdrawn participants may be replaced at the discretion of the Investigator. 
4.6 
Follow-up of abnormal laboratory test values 
In the event of unexplained abnormal laboratory test values, the tests should be repeated and 
followed up as per medical need, until they have returned to the normal range and/or an adequate 
explanation of the abnormality is found. If a clear explanation is established it should be recorded on 
the CRF. 
 
5 
Definition of end of trial 
 
The end of the trial is defined as the date of the last visit of the last participant undergoing the trial. 
 
6 
Treatment of participants 
6.1 
Study treatment regimen 
Participants will be administered: 
Pifeltro® (doravirine 100 mg) once daily for 7 days 
All IMPs will be labelled for clinical trial use using MHRA approved annex 13 compliant labels. 
 
7 
Study IMP 
 
Refer to current version of Pifeltro® summary of product characteristics for full IMP information and 
administration instructions. 
 
 
 


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8 
Pharmacokinetics and pharmacodynamics 
8.1 
Pharmacokinetics 
Absorption 
The pharmacokinetics of doravirine was studied in healthy subjects and HIV-1-infected subjects. 
Doravirine pharmacokinetics is similar in healthy subjects and HIV-1-infected subjects. Steady state 
was generally achieved by Day 2 of once-daily dosing, with accumulation ratios of 1.2 to 1.4 for AUC0-
24, Cmax, and C24. Doravirine steady state pharmacokinetics following administration of 100 mg once 
daily to HIV-1 infected subjects, based on a population pharmacokinetics analysis, are provided 
below. 
 
Following oral dosing, peak plasma concentrations are achieved 2 hours after dosing. Doravirine has 
an estimated absolute bioavailability of approximately 64% for the 100 mg tablet. 
Effect of food on oral absorption 
The administration of a single doravirine tablet with a high-fat meal to healthy subjects resulted in a 
16% and 36% increase in doravirine AUC and C24, respectively, while Cmax was not significantly 
affected. 
Distribution 
Based on administration of an IV microdose, the volume of distribution of doravirine is 60.5 L. 
Doravirine is approximately 76% bound to plasma proteins. 
Biotransformation 
Based on in vitro data, doravirine is primarily metabolized by CYP3A. 
Elimination 
Doravirine has a terminal half-life (t1/2) of approximately 15 hours. Doravirine is primarily eliminated via 
oxidative metabolism mediated by CYP3A4. Biliary excretion of unchanged medicinal product may 
contribute to the elimination of doravirine, but this elimination route is not expected to be significant. 
Excretion of unchanged medicinal product via urinary excretion is minor. 
Renal impairment 
Renal excretion of doravirine is minor. In a study comparing 8 subjects with severe renal impairment 
to 8 subjects without renal impairment, the single dose exposure of doravirine was 31% higher in 
subjects with severe renal impairment. In a population pharmacokinetic analysis, which included 
subjects with CrCl between 17 and 317 mL/min, renal function did not have a clinically relevant effect 
on doravirine pharmacokinetics. No dose adjustment is required in patients with mild, moderate or 


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severe renal impairment. Doravirine has not been studied in patients with end-stage renal disease or 
in patients undergoing dialysis (see section 4.2). 
Hepatic impairment 
Doravirine is primarily metabolized and eliminated by the liver. There was no clinically relevant 
difference in the pharmacokinetics of doravirine in a study comparing 8 subjects with moderate 
hepatic impairment (classified as Child-Pugh score B primarily due to increased encephalopathy and 
ascites scores) to 8 subjects without hepatic impairment. No dose adjustment is required in patients 
with mild or moderate hepatic impairment. Doravirine has not been studied in subjects with severe 
hepatic impairment (Child-Pugh score C) (see section 4.2). 
Elderly 
Although a limited number of subjects aged 65 years and over has been included (n=36), no clinically 
relevant differences in the pharmacokinetics of doravirine have been identified in subjects at least 65 
years of age compared to subjects less than 65 years of age in a Phase 1 trial or in a population 
pharmacokinetic analysis. No dose adjustment is required. 
Gender 
No clinically relevant pharmacokinetic differences have been identified between men and women for 
doravirine. 
Race 
No clinically relevant racial differences in the pharmacokinetics of doravirine have been identified 
based on a population pharmacokinetic analysis of doravirine in healthy and HIV-1-infected subjects. 
8.2 
Undesirable effects 
Summary of the safety profile: The most frequently reported adverse reactions considered possibly or 
probably related to doravirine were nausea (4%) and headache (3%). 
Tabulated summary of adverse reactions: The adverse reactions with suspected (at least possible) 
relationship to treatment are listed below by body system organ class and frequency. Within each 
frequency grouping, undesirable effects are presented in order of decreasing seriousness. 
Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 
1/1,000 to < 1/100) or rare (≥ 1/10,000 to < 1/1,000). 
Tabulated summary of adverse reactions associated with doravirine used in combination with other 
antiretrovirals: 
Frequency  
Adverse reactions  
Infections and infestations  
Rare 
rash pustular 
Metabolism and nutrition disorders  
Uncommon 
hypophosphataemia,  
Rare 
hypomagnesaemia 
Psychiatric disorders  
Common 
abnormal dreams, insomnia1 
Uncommon 
nightmare, depression2, anxiety3, irritability,  
confusional state, suicidal ideation 


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Rare 
aggression, hallucination, adjustment 
disorder, mood altered, somnambulism 
Nervous system disorders  
Common 
headache, dizziness, somnolence 
Uncommon 
disturbance in attention, memory impairment, 
paraesthesia, hypertonia, poor quality sleep 
Vascular disorders  
Uncommon 
hypertension 
Respiratory, thoracic and mediastinal disorders  
Rare 
dyspnoea, tonsillar hypertrophy 
Gastrointestinal disorders  
Common 
nausea, diarrhoea, flatulence, abdominal 
pain4, vomiting 
Uncommon 
constipation, abdominal discomfort5, 
abdominal distension, dyspepsia, faeces soft6, 
gastrointestinal motility disorder7 
Rare 
rectal tenesmus 
Skin and subcutaneous tissue disorders  
Common 
rash8 
Uncommon 
pruritus 
Rare 
dermatitis allergic, rosacea 
Musculoskeletal and connective tissue disorders  
Uncommon 
myalgia, arthralgia 
Rare 
musculoskeletal pain 
Renal and urinary disorders  
Rare 
acute kidney injury, renal disorder, calculus 
urinary, nephrolithiasis  
General disorders and administration site conditions  
Common 
fatigue  
Uncommon 
asthenia, malaise 
Rare 
chest pain, chills, pain, thirst 
Investigations  
Common 
alanine aminotransferase increased9 
Uncommon 
lipase increased, aspartate aminotransferase 
increased, amylase increased, haemoglobin 
decreased 
Rare 
blood creatine phosphokinase increased 
1insomnia includes: insomnia, initial insomnia and sleep disorder 
2depression includes: depression, depressed mood, major depression, and persistent 
depressive disorder 
3anxiety includes: anxiety and generalized anxiety disorder 
4abdominal pain includes: abdominal pain, and abdominal pain upper 
5abdominal discomfort includes: abdominal discomfort, and epigastric discomfort 
6faeces soft includes: faeces soft and abnormal faeces 
7gastrointestinal motility disorder includes: gastrointestinal motility disorder, and frequent 
bowel movements 
8rash includes: rash, rash macular, rash erythematous, rash generalized, rash maculo-
papular, rash papular, and urticarial 
9 alanine aminotransferase increased includes: alanine aminotransferase increased and 
hepatocellular injury 


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For full specifications on Pifeltro® please refer to the updated SmPCs [3]. 
 
Prior and Concomitant Therapy 
All illegal drugs are forbidden 
No concomitant medications (prescription, over-the-counter or herbal) are to be administered during 
the study unless they are approved / prescribed by the Investigator for treatment of specific clinical 
events. Any concomitant therapies must be recorded on the CRF. 
8.3 
Treatment compliance 
Participants will be requested to return to site any unused Pifeltro® tablets on day 7.  Site staff will 
count the IMP and this will be recorded in the source. 
Furthermore, adherence to study drugs will be evaluated on Day 7 and ETV (if required), by study 
staff – by direct questioning of dosing schedules, missed and late doses. This will be documented in 
the participant’s source document and CRF. 
8.4 
Provision of treatment after the end of the trial 
All study participants are healthy volunteers, and no medication will be provided after the final dose of 
study drugs. Post study follow up will occur between days 20 and 23 for monitoring of vital signs, 
haematology with a differential and clotting screen, chemistry panel, concomitant medications, and an 
adverse event check. 
 
9 
Visit schedule and procedures 
9.1 
Assessments at each visit 
The schedule of assessments is summarised in the study flow chart in Appendix 1. Visits may take 
place up to 48 hours from that specified at the discretion of the investigator. 
Screening 
Each participant must sign an Informed Consent Form prior to the conduct of any screening 
procedures. They will sign three informed consent forms and keep one.  As part of the consent 
procedure participants will also be asked to consent to their personal details being entered onto 
TOPS.   Participants will be given the opportunity to ask any questions regarding the trial at this stage.  
Screening evaluations will be used to determine the eligibility of each candidate for study enrolment. 
The screening visit will evaluate: 
 Demographic details, including age, gender and ethnic background.  
 Full medical, drug and social history 
 
Physical examination including weight, height, and vital signs (temperature, blood pressure, 
heart rate, and respiratory rate) 
 ECG 


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 Chemistry panel (see Appendix 1) 
 Haematology with a differential and clotting screen (Appendix 1) 
 HIV antibody testing 
 Hepatitis B and C screening 
 Urinalysis (including macro analysis) 
 Drug screen (urine) 
 Pregnancy test for WOCBP (urine) 
 Registration of TOPS database 
 Concomitant medications 
GP verification of medical history  
A medical history questionnaire should be sent to all participants’ GPs for verification of medical 
history. This information is reviewed by the Investigator as part of the medical history evaluation. If the 
completed questionnaire is not received from the GP, then the available information regarding the 
participant should be reviewed by the Principal Investigator. The Principal Investigator will assess this 
information and decide whether they are sufficiently confident that the inclusion and exclusion criteria 
are met and whether the participant may be enrolled into the research trial. This decision must be 
documented in writing BEFORE the participant is dosed. Copies of sent GP letters and returned 
confirmation of medical history must be filed in each participant’s source documentation. 
Randomisation 
Not applicable 
Baseline visit, Day 1 
Participants will attend the unit in the morning. They will be asked to fast for 8 hours overnight prior to 
attending.  
The following evaluations will be performed in the morning of Day 1, before study medication dosing: 
 
Vital signs (temperature, blood pressure, heart rate, and respiratory rate) 
 
Haematology with a differential and clotting screen (Appendix 1)  
 
Chemistry panel (Appendix 1) 
 
Urinalysis (including macro analysis) 
 
Pregnancy test for WOCBP (urine) 
 
Drug screen (urine) 
 
Concomitant medications 
 
Review of AEs 
 
Witnessed dosing 
Blood collection (one 4mL EDTA bottle) for the pharmacogenetic analysis will occur on Day 1 (or on 
any subsequent study day) only for enrolled participants who signed the pharmacogenetic analysis 
informed consent. 
Pre-dose: Platelet/endothelium sample: see Appendix 3 for details 
Pre-dose: Metabolomics: plasma, urine and faeces: see Appendix 3 for details 
A Pifeltro® tablet will be administered in a fasting state (no food for at least 2 hours before dosing, only 
water is allowed), along with 240 mL of water. This will set the nominal time of dosing. Subjects will be 
instructed to administer Pifeltro®  at home in the morning on all other days (5 days in total) in the same 
way. 


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Day 7 
Participants will attend the Unit in the morning. They will be asked to fast for 8 hours overnight prior to 
attending.  
The following evaluations will also be performed in the morning of Day 7, before study medication 
dosing: 
 
Vital signs (temperature, blood pressure, heart rate, and respiratory rate) 
 
Haematology with a differential and clotting screen (Appendix 1) 
 
Chemistry panel (Appendix 1) 
 
Urinalysis (including macro analysis) 
 
Pregnancy test for WOCBP (urine) 
 
Drug screen (urine) 
 
Concomitant medications 
 
Review of AEs 
 
Witnessed dosing 
A Pifeltro® tablet will be administered in a fasting state, along with 240 ml of water. This will set the 
nominal time of dosing.  
 
Intensive Pharmacokinetic Visits (Days 7 to 10) 
Participants will be admitted to the unit in the morning on days 7, 8, 9 and 10. 
On day 7, they will remain in the unit for approximately 14 hours and they will be asked to fast for 8 
hours overnight prior to attending on day 7. 
Serial blood specimens will be obtained from each subject for determining plasma drug 
concentrations at the following time points: pre-dose and 2, 4, 8, 12 hours post dose. All plus/minus 
10 minutes. 
From two hours after administration of study drug, subjects may resume water intake. A standardised 
lunch will be served at least four hours after dosing. After lunch, subjects may resume their usual diet. 
The start time of lunch served will be recorded on the CRF. 
The exact time of intake of study medication will be recorded on the CRF. Subjects should remain in a 
semi-recumbent position until four hours post dose. 
Post-dose: Platelet/endothelium sample: see Appendix 3 for details 
Post-dose: Metabolomics: plasma, urine and faeces: see Appendix 3 for details 
Patients will be able to leave the unit after the 12-hour sample to return the following morning.  
On days 8, 9, and 10 they will undergo blood sampling at the following time-points: 
24, 30, 36, 48, 54, 60, 72 hours post dose. All plus/minus 10 minutes. 
And the following will take place: 
 
Review of AEs 
 
Concomitant medication check 
Follow up visit (day 20 to 23)  


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Participants will return to the unit on one occasion between days 20 to 23 inclusive, they will be asked 
to fast for 8 hours overnight prior to attending and the following evaluations will be performed: 
 
Vital signs (temperature, blood pressure, heart rate, and respiratory rate) 
 
Haematology with a differential and clotting screen (Appendix 1) 
 
Chemistry panel (Appendix 1). 
 
Concomitant medications 
 
Review of AEs 
Follow-up: Platelet/endothelium sample: see Appendix 3 for details 
Follow-up: Metabolomics: plasma, urine and faeces: see Appendix 3 for details  
Early termination visit 
In case of early termination, participants should attend the unit for an early termination visit within one 
week (or otherwise as the investigator believes appropriate).  Participants will be asked to fast for 8 
hours overnight prior to attending, when possible.  
During these visits the following evaluations will be performed: 
 
Vital signs (temperature, blood pressure, heart rate, and respiratory rate) 
 
Haematology with a differential and clotting screen (Appendix 1) 
 
Chemistry panel (Appendix 1). 
 
Concomitant medications  
 
Review of AEs and adverse event check 
 
Pregnancy test 
 
ECG 
 
Adherence questioning (if required) 
The reason for the early termination of the participant should be clearly documented on the 
participant’s CRF. The participant will not then be required to attend for a follow up visit unless 
deemed necessary in the opinion of the investigator (e.g. due to adverse event follow up). 
 
10 Statistical analysis 
10.1 Participant numbers 
10.1.1 Sample size 
This is an exploratory study and, as such, no formal sample size calculation was performed.  Fourteen 
(14) participants completing the study will allow for relevant conclusions. 
10.1.2 Criteria for evaluation 
All eligible participants who complete the pharmacokinetic assessment will be included in the final 
data analysis and all baselined participants will be included in the safety analysis.  
10.2 Statistical methods 
Statistical analysis will be descriptive. 


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10.2.1 Safety parameters 
All patients, whether withdrawn prematurely or not, will be included in the safety analysis.  
All safety data and adverse events will be summarised. 
10.2.2 Pharmacokinetic parameters 
Summary statistics will be provided for all pharmacokinetic parameters calculated. 
The pharmacokinetic parameters calculated for doravirine will be trough concentration (Ctrough), 
defined as the concentration at 24 hours after the observed drug dose, the maximum observed 
plasma concentration (Cmax), elimination half-life (t1/2 – to last measurable time-point), time point at 
Cmax (Tmax), and total drug exposure, expressed as the area under the plasma concentration–time 
curve from 0–24 hours after dosing (AUC0–24h) and 0-72 hours (AUC0-72h). 
Coefficient of variation (CV=mean/SD*100) will be calculated at all time-points and for the measured 
parameters. 
All pharmacokinetic parameters will be calculated using non-compartmental modelling techniques 
(WinNonlin®). All statistical calculations will be performed an analysed using SAS (version 9.1). 
10.3 Criteria for termination of the trial 
The sponsor or investigator may terminate either part of, or the entire study for safety or 
administrative reasons. A written statement fully documenting the reasons for such a termination will 
be provided to the Ethics Committee and the Regulatory Authority as appropriate. 
 
11 Adverse Events 
11.1 Definitions 
An adverse event is any untoward medical occurrence (any new untoward medical occurrence or 
worsening of a pre-existing medical condition) in a clinical investigation subject administered a study 
drug and which does not necessarily have a causal relationship with the study treatments. An adverse 
event (AE) can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporarily associated with the use of a medicinal (investigational) 
product, whether or not considered related to the medicinal (investigational) product. 
Adverse events observed by the Investigator, or reported by the participant, and any remedial action 
taken, will be recorded in the participant’s CRF and should be verifiable in the participant’s notes 
throughout the study.  The nature of each event, time of onset after drug administration, duration and 
severity will be documented together with the Investigator’s opinion of the causal relationship to the 
treatment (unrelated, unlikely, possible, probable, and definite). 
All participants experiencing adverse events, whether considered associated with the use of the study 
medication or not, must be monitored until the symptoms subside and any clinically relevant changes 
in laboratory values have returned to baseline, or until there is a satisfactory explanation for the 
changes observed. 
Procedures such as surgery should not be reported as adverse events.  However, the medical 
condition for which the procedure was performed should be reported if it meets the definition of an 


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adverse event.  For example, an acute appendicitis that begins during the adverse event reporting 
period should be reported as the adverse event and the resulting appendectomy noted on the CRF. 
Planned procedures such as surgery (planned prior to the participant’s enrolment into the study) need 
not be reported as adverse events if these are documented as planned at the screening visit. 
Clinically significant changes in physical examination and blood safety profiles should also be 
recorded as adverse events. 
11.2 Assessment of intensity 
Severity should be recorded and graded according to the DAIDS Clinical Trial Group (ACTG) Grading 
Scale (Appendix 2). 
Note: There is a distinction between the gravity and the intensity of an adverse event. Severe is a 
measure of intensity; thus, a severe reaction is not necessarily a serious adverse event. For example, 
a headache may be severe in intensity but would not be classified as serious unless it met one of the 
criteria for serious events. 
11.3 Assessment of causality 
The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE). The causal relationship can be one of the following (Related means there is a 
reasonable causal relationship between study drug administration and the AE. The term "reasonable 
causal relationship" means there is evidence to suggest a causal relationship): 
DEFINITE: distinct temporal relationship with drug treatment. Known reaction to agent or 
chemical group, or predicted by known pharmacology. Event cannot be explained by 
participant’s clinical state or other factors. 
PROBABLE: reasonable temporal relationship with drug treatment. Likely to be known reaction 
to agent or chemical group, or predicted by known pharmacology. Event cannot easily be 
explained by participant’s clinical state or other factors. 
POSSIBLE: reasonable temporal relationship with drug treatment. Event could be explained by 
participant’s clinical state or other factors. 
UNLIKELY: poor temporal relationship with drug treatment. Event easily explained by 
participant’s clinical state or other factors. 
UNRELATED: the event occurs prior to dosing. Event or intercurrent illness is due wholly to 
factors other than drug treatment. There is not a reasonable causal relationship between study 
drug administration and the AE. 
11.4 Collection and follow up of Adverse Events  
All adverse events, however minor, will be documented in the CRF whether or not the Investigator 
concludes the event to be related to drug treatment. 
The adverse event-reporting period will be from participant consent until the participants final study 
visit.  In addition, any untoward event that may occur subsequent to the reporting period that the 
Investigator assesses as possibly, probably or definitely related to the study drug medication should 
also be reported as an Adverse Event. 


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Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.) 
All adverse events should be followed up until they are resolved or the participant’s participation in the 
study ends (i.e. until the final CRF is completed for that participant).  In addition, all serious and non-
serious adverse events assessed by the Investigator as possibly related to the investigational 
medication should continue to be followed even after the volunteer’s participation in the study is over.  
Such events should be followed until resolution, or until no further change can reasonably be 
expected.  Deaths occurring more than 30 days after the final dose, which are considered to be 
unrelated to the study medication, should not be reported as a Serious Adverse Event. 
11.4.1 Serious Adverse Events (SAEs) 
A serious adverse event is any untoward medical occurrence that at any dose: 
i) 
Results in death 
ii) 
Is life threatening 
iii) 
Requires in-patient hospitalisation or prolongation of existing hospitalisation 
iv) 
Results in persistent or significant disability/ incapacity 
v) 
Is a congenital anomaly/ birth defect 
OR 
vi) 
Is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above). Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See below for the definition of potential DILI). 
 
Although pregnancy and potential drug induced liver injury (DILI) are not always serious by regulatory 
definition, these events must be handled as SAEs (See pregnancy section below for reporting 
pregnancies). 
Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported as 
SAE. 
11.4.2 Serious Adverse Event Collection and Reporting 
Section 4.8 in the Summary of Product Characteristics (SmPC) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. Following 
the subject’s written consent to participate in the study, all SAEs, whether related or not related to 
study drug, must be collected, including those thought to be associated with protocol-specified 
procedures. All SAEs must be collected that occur during the screening period and up to 28 days after 
discontinuation of the study drugs. If applicable, SAEs must be collected that relate to any later 
protocol-specified procedure (eg, a follow-up skin biopsy). The investigator should report any SAE 
that occurs after these time periods and that is believed to be related to study drug or protocol-
specified procedure.  


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The SAE should be reported immediately to the Principal Investigator (within 24 hours of a member of 
the study team becoming aware of the event). A study SAE form should be completed, and an 
assessment of whether the SAE is a Suspected Unexpected Serious Adverse Reaction (SUSAR) 
conducted. The Principal Investigator is responsible for determining whether the SAE is a SUSAR and 
for reporting this in accordance with Good Clinical Practice (GCP) and applicable regulatory 
requirements. Copies of both SAEs and SUSARs should also be sent to MSD within 24 hours of 
becoming aware of the event.  
An SAE report should be completed for any event where doubt exists regarding its seriousness. If the 
investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form. 
SAEs, and SUSARS whether related or not related to study drug, and pregnancies must be reported 
to the nominated person at the sponsor research and development office as set by the sponsor 
standard operating procedures (SOPs) within 24 hours of awareness of the event. Suspected 
Unexpected Serious Adverse Reactions (SUSARs) should also be notified to the marketing 
authorisation holder.   
The assessment of expectedness should be made against the current version of the reference safety 
information. 
11.4.3 Pregnancy 
Any pregnancy, including pregnancies of partners of male participants, that occurs during study 
participation must be reported using the SAE form.  To ensure subject safety, each pregnancy must 
be reported to the sponsor (see section 11.4.2) within 24 hours of learning of its occurrence.  The 
pregnancy must be followed up to determine outcome (including premature termination) and status of 
mother and child, which must also be reported to the sponsor, using the SAE form.  Pregnancy 
complications and elective terminations for medical reasons must be reported as an AE or SAE.  
Spontaneous abortions must be reported as an SAE. 
Any SAE occurring in association with a pregnancy brought to the investigator’s attention after the 
subject has completed the study and considered by the investigator as possibly related to the 
investigational product, must be promptly reported to the sponsor (see section 11.4.2) where female 
study participants have been exposed to the IMP. 
11.4.4 Other safety considerations 
Any significant worsening noted during interim or final physical examinations, electrocardiogram, x-ray 
filming, any other potential safety assessment required or not required by protocol should also be 
recorded as a non-serious or serious AE, as appropriate, and reported accordingly. 
 
12 Data handling 
12.1 Recording of data 
The data collected during the study will be recorded in an individual, participant specific Case Report 
Form (CRF). In order to maintain confidentiality, the participant will be identified only by participant 
codes on the CRF.  


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Any paper CRFs should be completed legibly in black ink by an appropriate member of the study 
team who must be identified and authorised in writing by the Principal Investigator before they 
conduct any study related tasks. A delegation of responsibility signature log identifying personnel who 
can enter data and/or sign off a CRF will be maintained by the Principal Investigator.  
Corrections to the data on paper CRFs will only be made by drawing a single line through the 
incorrect data (so as not to obscure the original entry) and inserting the correct data next to the 
original entry. The incorrect data must never be obliterated using correction fluid (e.g. Snopake® or 
Tippex®).  Each correction will be initialled and dated by the person making the correction. 
CRFs should be kept current to allow review and validation of data as required by the monitoring plan. 
CRFs will be completed, reviewed and signed off by the Investigator within two weeks of the last 
participant visit. 
12.2 Source documentation and study records 
The participant’s number and date of entry into the study, along with a study identifier, should be 
recorded in the participant’s study records.  The following should also be recorded in the study 
records; confirmation of written and oral consent, the participant’s clinical status, date of every study 
visit, date study medication was started and stopped, concomitant medications, copies of all relevant 
reports and laboratory tests, comments on results and reference to any adverse events and all study 
procedures at each visit. 
12.3 Data management 
Data will be entered into case report forms which may be paper or electronic.  These will be used to 
generate the study database for analysis. The database will be kept in a secure location and access 
will be given to authorised personnel only, a log of which will be stored in the Trial Master File. 
Any data anomalies or values found to be outside normal ranges will be checked with the Investigator. 
When corrections are required these will be made on CRF and the study database will be amended. 
12.4 Archiving and storage of data 
Following completion of the study, participant records, CRF and other study documentation will be 
retained by the Investigator in accordance with Good Clinical Practice (GCP) and applicable 
regulatory requirements. 
 
13 Quality control and quality assurance 
13.1 Monitoring arrangements 
The purpose of monitoring is to verify the rights and wellbeing of human participants are protected; 
that trial data is accurate, complete and verifiable with source data; that the trial is conducted in 
compliance with the protocol, GCP and the applicable regulatory requirements. 
A monitor will conduct site visits for the purpose of monitoring various aspects of the study. The 
Investigator must agree to allow the study monitor to inspect all CRF and corresponding source 
documents, e.g. original medical records, participant records and laboratory raw data, access to the 
clinical supplies, dispensing and storage areas and agree to assist with their activities if requested.  
The Investigator should provide adequate time and space for monitoring visits. 


Protocol CRF001 
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The monitor will query any missing or spurious data with the Investigator, which should be resolved in 
a timely manner.  A monitoring log will be maintained recording each visit, the reason for the visit, the 
monitor’s signature and Investigator’s or designee’s confirmation signature. 
A monitoring plan will be in place for this study in line with the relevant standard operating procedures 
of the sponsor. 
13.2 Quality assurance 
For the purpose of compliance with GCP and regulatory agency guidelines, it may be necessary for 
sponsor authorised Quality Assurance personnel and/or authorised personnel from an external 
regulatory agency to conduct an audit/inspection of an Investigational Site.  The purpose of an audit is 
to assess the quality of data with regard to accuracy, adequacy and consistency, and to assure that 
studies are in accordance with Good Clinical Practices, and Regulatory Agency guidelines.  Having 
the highest quality data from studies is an essential aspect of drug development. 
The Investigator will be given sufficient notice to prepare for such visits, which may be conducted at 
any stage during the study.  The audit will involve the review of all study related documentation, which 
is required by GCP to be maintained by each site, review of drug storage, dispensing and return, 
review of all study related supplies and review of source documents against the CRF to assure the 
adequacy and accuracy of the information which has been recorded, including the verification of any 
AE which have occurred. 
 
14 Administrative procedures 
14.1 Ethics approval 
The study protocol, participant information and consent form, the Investigator Brochure, available 
safety information, participant recruitment procedures (e.g. advertisements), information about 
payments and compensation available to the participants and documentation evidencing the 
Investigator’s qualifications should be submitted to the Ethics Committee for ethical review and 
approval according to local regulations, prior to the study start. Any changes, which may need to be 
made, will be submitted in the form of numbered and dated protocol amendments in accordance with 
local regulations.  
14.2 Regulatory approval 
As required by local regulations, approval of the appropriate regulatory bodies will be obtained, prior 
to study initiation. 
14.3 Insurance provisions 
The Sponsor will take out appropriate insurance cover for this trial. 
14.4 Publication policy 
A whole or part of the study results will be communicated, orally presented, and/or published in 
appropriate scientific journals. Full anonymity of participant’s details will be maintained throughout. 
Participants wanting to see the results of the trial can request a copy of the article from the 
investigators once it has been published. 


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14.5 Drug accountability 
The investigator will ensure that the investigational product will only be used in accordance with the 
protocol.  
Pifeltro® supplies will be kept in the hospital pharmacy in a secure, limited access storage area under 
the recommended storage conditions.   
The investigator will ensure that records are maintained showing the receipt and disposition of all 
study supplies. A drug accountability log will be kept with the investigational supplies for reconciliation 
purposes. This should be used to record the identification of the participant to whom the 
investigational product was dispensed, the date, the quantity, batch number and expiry date of the 
investigational product dispensed and the quantity of the investigational product unused/returned by 
the participant. These will be made available for review by the monitor as set out in the study 
monitoring plan and standard operating procedures. 
Partially used or empty containers may be destroyed by pharmacy after completion of inventory and 
notification of and acknowledgement by sponsor research and development office.  Due to the nature 
of the study and the need to dose participants outside of normal working hours, pharmacy may need 
to prepare and dispense investigational medicinal product to the unit in advance of Day 1. A process 
is in place to retrieve investigational medicinal product for those participants who are withdrawn after 
medication has been dispensed to the unit and prior to dosing.  The dispensing may include additional 
contingency supply for Day 7 doses in case participants fail to bring back their Day 7 doses to the 
visit. 
Due to the nature of the study and intensive pharmacokinetic days occurring outside normal working 
hour’s pharmacy will dispense investigational medicinal product (IMP) to the unit. It is the 
responsibility of the investigator to release the IMP and to ensure that pharmacy is informed in order 
to document which participants received the IMP.  Any IMP not required will be returned to pharmacy 
when no longer required for use in the study. 
14.6 Sample shipment and processing 
14.6.1 Safety analysis samples 
All urinalysis will take place within the clinical research facility, samples may also be sent to one of the 
below labs in the event of a positive/abnormal result. 
Biochemistry, haematology and virology samples will be analysed by the local hospital laboratories 
according to the local procedures. 
Biochemistry & Haematology 
Pathology Laboratory 
Imperial College NHS Foundation Trust 
Chelsea & Westminster Hospital 
369 Fulham Road 
London SW10 9TH 
 
Virology & Hepatitis 
Dept. of Infection & Immunity 
9th Floor Laboratory Block 
Charing Cross Hospital 
Fulham Palace Road 
London W6 8RF 


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14.6.2 Pharmacokinetics analysis 
PK samples will be processed by the HIV/GUM research laboratory and couriered to the following 
address for measurement of doravirine plasma concentrations: 
Jefferies Research Trust Laboratories 
Wright-Fleming Institute 
Imperial College London 
Dept. of Medicine, St Mary’s Campus 
Norfolk Place 
London W2 1PG 
14.6.3 Pharmacogenetics analysis 
EDTA blood samples will be shipped to Liverpool with a coded label only, in dry ice, to the following 
address: 
Professor Andrew Owen 
Pharmacology Research Laboratories 
Block H – First floor 
70 Pembroke Place 
Liverpool L69 3GF 
Tel +44 (0) 151 794 5553 
Fax +44 (0) 151 794 5656 
Email: aowen@liv.ac.uk 
14.6.4 Platelets/endothelium 
Samples will be collected by a member of the specialised laboratory from the clinical research facility. 
Dr Mike Emerson 
Cardio-respiratory Interface Section 
National Heart and Lung Institute 
Imperial College London 
SAF Building 
London SW7 2AZ 
Tel: +44 (0) 207 5941877 
Email: m.emerson@imperial.ac.uk 
14.6.5 Metabolomics 
Plasma, urine and faecal samples will be processed as described in appendix 3 and stored at -80°C.  
Appropriate arrangements will be made for transport to laboratory for analysis. 
 
Jefferies Research Trust Laboratories 
Wright-Fleming Institute 
Imperial College London 
Dept. of Medicine, St Mary’s Campus 
Norfolk Place 
London W2 1PG 
 


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15 References 
 
1. 
Elliot ER, Cerrone M, Else L, Amara A, Bisdomini E, Khoo S, Owen A, Boffito M. 
Pharmacokinetics of dolutegravir with and without darunavir/cobicistat in healthy volunteers. J 
Antimicrob Chemother. 2019;74:149-156. 
2. 
Wilby KJ, Eissa NA. Clinical Pharmacokinetics and Drug Interactions of Doravirine. Eur J 
Drug Metab Pharmacokinet. 2018;43:637-644. 
3. 
https://www.medicines.org.uk/emc/product/9693/smpc 
 
 


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16 Appendices 
 
Appendix 1:  
Study Flowchart 
Appendix 2: 
DAIDS Grading Scale 
Appendix 3: 
Collection, processing, shipping and storage of blood and plasma for pharmacokinetic 
analysis 
Appendix 4: 
Highly effective methods for avoiding pregnancy in females of child bearing potential 
 
Appendix 1: Study flowchart 
 
1 
Patients will be admitted to the morning of the PK assessment days and will spend approximately 
12 hours in the Unit. 
 
Screening 
visit 
Baseline 
visit 
Intensive 
PK visit1 
PK TAIL1 
FU/ETV 
Time (days) 
-28 to 0 
1 
7 
8-10 
20-23 
Informed consent 
X 
 
 
 
 
Demographic data 
X 
 
 
 
 
Medical history/ 
concomitant disease 
X 
 
 
 
 
Physical examination 
X 
 
X8 
 
 
Vital signs10 
X 
X 
X 
 
X 
ECG 
X 
 
 
 
X11 
Weight 
X 
 
 
 
 
Height 
X 
 
 
 
 
Urinalysis2 
X 
X 
X 
 
X12 
HIV testing 
X 
 
 
 
 
HBV & HCV testing 
X 
 
 
 
 
Haematology3 
X 
X 
X 
 
X 
Clinical chemistry4 
X 
X 
X 
 
X 
Pharmacokinetics5 
 
 
X 
 
 
24-72 hour 
Pharmacokinetics5 
 
 
 
X 
 
Pharmacogenetics6 
 
X6 
 
 
 
Metabolomics7 
 
X 
X 
 
X 
Platelet/endothelium blood 
sample 
 
X 
X 
 
X 
Adherence assessment9 
 
 
X 
 
X12 
Witnessed dosing 
 
X 
X 
 
 
Adverse events 
 
X 
X 
 
X 
Start new drug 
 
X 
 
 
 
Concomitant medication 
check 
X 
X 
X 
 
 


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2 
Urinalysis including macro-analysis, drug screen and pregnancy test (female subjects of child-
bearing potential) 
3 
FBC (Hb, WBC, platelets, RBC, MCV, MCH, MCHC, RDW, HCT/PCV and MPV) with a differential 
and clotting screen 
4 
Fasting (except for screening visit) for at least 8 hours and including U&Es (creatinine, urea, 
potassium, sodium, chloride, estimated GFR, bicarbonate), LFTs (bilirubin, ALT, alkaline 
phosphatase, albumin, AST, GGT), Bone Profile (calcium, calcium adjusted, phosphate, total protein, 
albumin, globulin), glucose, amylase, Lipids (total cholesterol, triglycerides, HDL, LDL) 
5 
Subjects will undergo 3 PK assessment days in total. Blood will be drawn over the full dosing 
interval at the following time-points: pre dose (within 10 minutes before dosing), 2, 4, 8, 12, 24, 30, 
36, 48, 54, 60, 72 hours post dose (+/- 10min). 
6 
This sample can be collected on Day 1 or any other study day for those subjects who consent 
7 
See appendix 3 for details of metabolomics samples 
8 
Only if clinically indicated 
9 
Including pill count on Day 7 
10 Temperature, Blood Pressure, Heart Rate and Respiratory Rate 
11 ECG at ETV visit only 
12 At ETV visit only if required 
 
ETV= Early termination visit (subjects will not be required to attend for follow up visit) FU= Follow Up 
visit (required for subjects that have completed all study visits) 
 
Appendix 2: DAIDS grading scale 
Please reference latest version of grading scale available at below location. 
https://rsc.tech-res.com/docs/default-source/safety/daids_ae_grading_table_v2_nov2014.pdf 
 
Appendix 3: Collecting, processing, shipping and storing of blood, plasma, urine and 
faeces for pharmacokinetics (PK), pharmacogenetics (PG), 
metabolomics and platelet/endothelium markers. 
A) Pharmacokinetic analysis 
At each scheduled blood draw, approximately 12 mL of whole blood will be collected from an in-
dwelling venous catheter or by direct venepuncture into two Vacutainer® blood collection tube (Lithium 
heparin).  If saline flushes are used to keep the peripheral catheter functional then a small volume of 
blood (1 mL) should be withdrawn from the catheter before sample collection and discarded.  
Immediately after collection, the blood tube will be inverted several times and kept on wet ice or 
refrigerated as well as protected from light until centrifugation.  Within 90 minutes of blood collection 
each blood sample will be centrifuged in a refrigerated clinical centrifuge for 10 minutes at 2000 g at 
4°C.  Plasma will then be transferred and aliquoted equally into three opaque polypropylene storage 
tubes with caps. 
Each tube must be appropriately labelled and stored at -20°C or lower.  One tube must be kept for 
back-up and two tubes will be transferred by courier to:  


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Jefferies Research Trust Laboratories 
Wright-Fleming Institute 
Imperial College London 
Dept. of Medicine, St Mary’s Campus 
Norfolk Place 
London W2 1PG 
 
B) Pharmacogenetic analysis 
Full blood will be collected in a 4 mL EDTA tube.  The label will report only a coded identification 
number.  The samples will be stored at -20°C until transferred by courier in dry ice to: 
Professor Andrew Owen 
Pharmacology Research Laboratories 
University of Liverpool 
Block H – First floor 
70 Pembroke Place 
Liverpool L69 3GF 
Tel. +44 (0) 151 794 5553 
Fax. +44 (0) 151 794 5656 
Email aowen@liv.ac.uk 
 
C) Platelet aggregation/endothelium markers sampling 
3 x 4.5mL citrate vials will be handed to a member of the specialised laboratory to be analysed in an 
aggregometer and flow cytometer. 
Samples will be collected: on Day 1 pre-dose; on Day 7 post-dose and at FU visit. 
Dr Michael Emerson 
National Heart and Lung Institute 
Sir Alexander Fleming Building 
Imperial College London 
London SW7 2AZ 
 
D) Metabolomics sampling 
Plasma samples 
At each scheduled blood draw, approximately 12 mL of whole blood will be collected from an in-
dwelling venous catheter or by direct venepuncture into two Vacutainer® blood collection tube 
(EDTA).  If saline flushes are used to keep the peripheral catheter functional then a small volume of 
blood (1 mL) should be withdrawn from the catheter before sample collection and discarded. 
Immediately after collection, the blood tube will be inverted several times and kept on wet ice or 
refrigerated as well as protected from light until centrifugation.  Within 90 minutes of blood collection 
each blood sample will be centrifuged in a refrigerated clinical centrifuge for 10 minutes at 2000 g at 
4°C.  Plasma will then be transferred and aliquoted (500 µL/aliquote) equally into six opaque 
polypropylene storage tubes with caps (Five for analysis and one for back-up). Each tube must be 
appropriately labelled and stored at -80°C.  


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Urine samples 
Midstream of urine (approximately 10 mL) will be collected using 50ml Falcon tube (FalcomTM) and 
kept on ice once patients hand over the samples. Within 30 minutes of urine collection, each urine 
sample will be centrifuged in a refrigerated clinical centrifuge for 10 minutes at 2000g at 4°C. 
Supernatant will then be transferred and aliquoted (500 µL/aliquote) into six opaque polypropylene 
storage tubes with caps (Five for analysis and one for back-up).  Care should be taken not to disturb 
the bottom of the tube whether there is a visible pellet or not. Samples and tubes will be kept on ice 
during processing. Each tube must be appropriately labelled and stored at -80°C.  
Faecal samples 
Participants will be given faeces containers (Sarstedt 101x16.5mm) with short special spoon to collect 
a defined faeces sample and stool sample collection device (HYSTOOL®). Participants will be 
instructed to sample three aliquots at distinct topographical locations of the faecal sample and place 
each aliquot into an individual faeces container. The subjects will be asked to place samples 
immediately in a home freezer and return to them to the unit in a provided cold pack and bag.  Each 
container should be labelled with time of collection. The faecal sample should be collected closest to 
the time of visits (less than 24 hours) and given to clinical staff at the time of visit. The containers will 
be stored at -80°C.  As an alternative to freezing samples the protocol allows tubes to be provided to 
participants with a 95% ethanol solution to preserve the sample.  It should be clearly recorded which 
option was used. 
Appropriate arrangements will be made for transport to laboratory for analysis: 
Jefferies Research Trust Laboratories 
Wright-Fleming Institute 
Imperial College London 
Dept. of Medicine, St Mary’s Campus 
Norfolk Place 
London W2 1PG 
Appendix 4: Highly Effective Methods for Avoiding Pregnancy in Females of Child 
Bearing Potential* 
The following is the all-inclusive list of the highly effective methods for avoiding pregnancy (i.e., have 
a failure rate of less than 1% per year when used consistently and  correctly and, when applicable, in 
accordance with the product label). 
The list does not apply to FCBP with same sex partners, when this is their preferred and usual 
lifestyle. 
• 
Abstinence from penile-vaginal intercourse, when this is the female’s preferred and usual 
lifestyle [Hatcher, 2007a]  
• 
Oral contraceptive, either combined or progestogen alone [Hatcher, 2007a] plus male 
condom 
• 
Injectable progestogen [Hatcher, 2007a] plus male condom 
• 
Implants of etonogestrel or levonorgestrel [Hatcher, 2007a] plus male condom 
• 
Estrogenic vaginal ring [Hatcher, 2007a] plus male condom 
• 
Percutaneous contraceptive patches [Hatcher, 2007a] plus male condom 
• 
Intrauterine device or intrauterine system that meets the effectiveness criteria as stated in the 
product label [Hatcher, 2007a] 


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• 
Hormone-free Intrauterine device that meets the effectiveness criteria as stated in the product 
label [Hatcher, 2007a] 
• 
Male partner sterilization prior to the female subject's entry into the study, and this male is the 
sole partner for that subject [Hatcher, 2007a]. The information on the male sterility can come 
from the site personnel’s: review of subject’s medical records; medical examination of the 
subject and/or semen analysis; or interview with the subject on his medical history. 
• 
Male condom combined with a female diaphragm, either with or without a vaginal spermicidea 
(foam, gel, film, cream, or suppository) [Hatcher, 2007b] 
a Nonoxynol-9 is the critical component in most spermicides, and is regarded as an acceptable 
spermicidal agent. Concern has been raised that nonoxynol-9 damages the epithelial lining of the 
vagina, and exposure may facilitate transmission of viruses, particularly HIV. The World Health 
Organization conducted a technical consultation in October 2001 and concluded that the increased 
risk for such transmission was low to minimal [WHO/CONRAD, 2003]. 
* A Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) 
and is not postmenopausal, females under the age of 55 years must have a serum follicle stimulating 
hormone, (FSH**) level > 40mIU/mL to confirm menopause. 
** Females treated with hormone replacement therapy, (HRT) are likely to have artificially suppressed 
FSH levels and may require a washout period in order to obtain a physiologic FSH level.