Conditions: Hiv
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 38
Healthy volunteers: yes

Brief summary:
This study evaluates whether a 7-day course of Raltegravir 400mg bd or Raltegravir 400mg/lamivudine 150mg bd can prevent HIV from infecting genital tissue and will relate the level of drug in the blood to the level of drug in genital tissue and to the ability to of HIV to infect genital tissue. As well as determining whether these regimes can provide ex vivo protection against HIV, this study will also determine speed to provision of protection and a 48 hour PK/PD decay profile of Raltegravir following drug cessation after attaining steady state concentrations. The results will also inform all future HIV pre-exposure prophylaxis studies of Raltegravir and form the basis for large scale clinical trials without the need for tissue sampling. To date, efficacy studies assessing PrEP regimens have utilized HIV-acquisition endpoints with the consequence being such studies are required to be large in subject number in order to power observations. In addition the study will provide for the first time data on HIV protection rather than just Raltegravir drug levels in tissue, and allow assessment of the possibility of Raltegravir being used as an intermittent dosing regimen in PrEP.

Detailed description:
This is a multi-site, open-label, randomised, pharmacokinetic (PK) and pharmacodynamic (PD) trial whereby 36 individuals (18 women and 18 men) will be randomised according to gender 1:1:1:1:1:1 to one of 6 arms (A 1 A 2 A 3 B 1 B 2 B 3). The result being 3 women and 3 men will be in each arm. The letter dictates the ART regimen order and the number dictates the time points that tissue sampling will occur on and off ART. Two ART regimes will be investigated and all individuals will receive both regimes separated by a one month wash out.

Arm A (A 1 A 2 A 3): will start with 7 days Raltegravir 400mg bd and then have a one month wash out before then starting 7 days Raltegravir 400mg /lamivudine 150mg bd.

Arm B (B 1 B 2 B 3): will start with 7 days Raltegravir 400mg /lamivudine 150mg bd and then have a one month wash out before then starting 7 days Raltegravir 400mg bd. This will remove sequential selection bias. All individuals will receive tissue sampling at baseline for ex vivo analysis to ensure biopsies are infectable on challenge assays. Sampling from women will avoid menstruation and if possible focus on the luteal phase of the menstrual cycle. Individuals will receive another set of tissue sampling during and after ART in phase 1, have a 4 week wash out period and then have another set of sampling during and after ART in phase 2. Individuals will therefore have 5 sets of sampling during the trial.

Arms:
arm 1: 7 days Raltegravir 400mg bd followed by minimum 4 weeks wash out and then 7 days Raltegravir 400mg/lamivudine 150mg (oral tablets) bd. arm 2: Raltegravir 400mg + Lamivudine 150mg tablet, taken twice a day for 7days followed by a minimum of 4 weeks wash out and then 7 days Raltegravir 400mg bd.

Interventions: intervention 1: Raltegravir 400Mg Tab intervention 2: Lamivudine 150Mg Tablet
Intervention descriptions: intervention 1: bd for 7 days intervention 2: \+ Raltegravir 400Mg tablet bd for 7 days

Protocol document:
Prot_SAP_000.pdf: 
PROTOCOL IDENTIFICATION NUMBER: JF-007  
EudraCT Number: 2016-000437-43 
 
R-PrEP V1.3 23/11/2018   
 
IRAS Project ID: 202316 
 
 
 
 
 
Page 1 of 39 
PROTOCOL FULL TITLE: 
 
The time to protection and adherence requirements of Raltegravir with or without 
lamivudine in protection from HIV infection 
 
Protocol Short Title/Acronym  
R-PrEP 
Trial Identifiers: 
EudraCT Number –  
REC Number – 
2016-000437-43 
17/LO/0094 
 
 
Sponsor 
Name: Guy’s and St Thomas’ NHS Foundation Trust 
Address: King’s Health Partners Clinical Trials Office, F16 Tower Wing Guys 
Hospital, Great Maze Pond, London SE1 9RT 
Telephone: 020 7188 5732 
Fax: 020 7188 8330 
Email: R&D@gstt.nhs.uk 
 
Chief Investigator  
Name: Julie Fox 
Address: Harrison Wing, 2nd Floor Lambeth Wing, St Thomas’ Hospital 
Westminster Bridge Road, London SE1 7EH 


PROTOCOL IDENTIFICATION NUMBER: JF-007  
EudraCT Number: 2016-000437-43 
 
R-PrEP V1.3 23/11/2018   
 
IRAS Project ID: 202316 
 
 
 
 
 
Page 2 of 39 
Telephone: 020 7188 2643 
Fax: 020 7188 2646 
Email: Julie.Fox@kcl.ac.uk 
 
Co-Investigator(s), Statistician, Laboratories  
 
Name: Professor Robin Shattock (pharmacodynamics) 
Address: Department of Medicine, St Mary’s Campus, Imperial College London 
Telephone: 020 7594 2510 
Fax: 020 7504 2699 
Email: r.shattock@imperial.ac.uk 
 
Name: Dr Carolina Herrera, (pharmacodynamics) 
Address: Imperial College, St Mary’s Campus, Imperial College London 
Telephone: 020 7594 2545 
Fax: 020 7504 2699 
Email: c.herrera@ic.ac.uk 
Name: Dr Laura Else (pharmacokinetics) 
Address: Pharmacology Research Laboratories, Block H – First floor, 70 Pembroke 
Place, Liverpool, L69 3GF 
Phone: 0151 794 5553 
Fax: 0151 794 5656 
Email: l.else@liv.ac.uk 
 
 
Name: Professor Saye Khoo (pharmacokinetics) 
Address: Pharmacology Research Laboratories, Block H – First floor, 70 Pembroke Place, 
Liverpool, L69 3GF 


PROTOCOL IDENTIFICATION NUMBER: JF-007  
EudraCT Number: 2016-000437-43 
 
R-PrEP V1.3 23/11/2018   
 
IRAS Project ID: 202316 
 
 
 
 
 
Page 3 of 39 
Phone: 0151 794 5547 
Fax: 0151 794 5656 
Email: s.khoo@liv.ac.uk 
 
 
Name: Vanessa Tierney (Statistics) 
 
Address: Biometrics Lead, St Stephen’s Clinical Research 
St Stephen's AIDS Trust, 369 Fulham Road, London SW10 9NH 
 
Phone:  
Fax:  
  Email: vanessa.tierney@ststcr.com 
 
1. Study Synopsis 
 
Title of clinical trial The time to protection and adherence requirements of 
Raltegravir with or without lamivudine in protection from HIV 
infection 
Protocol Short Title/Acronym R-PrEP 
 
Study Phase  
 
Phase IV 
Sponsor name Guy’s and St Thomas’ NHS Foundation Trust 
Chief Investigator Julie Fox 
Eudract number 2016-000437-43 
REC number  
Medical condition under 
investigation 
HIV 
Purpose of clinical trial To investigate the role of Raltegravir +/- lamivudine in HIV 
prevention 


PROTOCOL IDENTIFICATION NUMBER: JF-007  
EudraCT Number: 2016-000437-43 
 
R-PrEP V1.3 23/11/2018   
 
IRAS Project ID: 202316 
 
 
 
 
 
Page 4 of 39 
Aims 
 
For each regimen (Raltegravir versus Raltegravir/lamivudine) we 
have the following aims: 
 
1. To determine the level of drug required in the plasma, 
vagina and rectum for mucosal ex vivo protection from HIV 
2. To determine the time from first dose of drug to mucosal ex 
vivo protection from HIV infection 
3. To determine the time to cessation of mucosal ex vivo 
protection from HIV after stopping ART at steady state.  
4. To determine the safety and tolerability of Raltegravir based 
PrEP in HIV negative individuals 
 
Trial Design  Phase IV, open-label, randomised controlled trial (RCT) 
Endpoints 
 
Primary endpoints 
The level of Raltegravir alone or Raltegravir /lamivudine  required 
in the plasma, vagina and rectum for 100% ex vivo protection 
from HIV 
 
Secondary endpoints 
1. The time from first dose of drug to mucosal ex vivo 
protection from HIV infection 
2. The time to cessation of mucosal ex vivo protection from 
HIV after stopping ART at steady state.  
3. The safety and tolerability of Raltegravir based PrEP in 
HIV negative individuals 
 
Sample Size 
 
36 
Summary of eligibility criteria 
 
Inclusion Criteria 
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 trial 


PROTOCOL IDENTIFICATION NUMBER: JF-007  
EudraCT Number: 2016-000437-43 
 
R-PrEP V1.3 23/11/2018   
 
IRAS Project ID: 202316 
 
 
 
 
 
Page 5 of 39 
requirements. 
2. Male or non-pregnant, non-lactating females 
3. Age between 18 to 60 years, inclusive. 
4. Body Mass Index (BMI) of 16 to 35 kg/m2, inclusive. 
5. Negative antibody/antigen combined test for HIV. 
6. Absence of any significant health problems (in the opinion 
of the investigator) on the basis of the screening 
procedures; including medical history, physical 
examination, vital signs. 
7. Women participating in sexual intercourse that could 
result in pregnancy must use an adequate form of 
contraception throughout the study and for two weeks 
after the study. This includes intrauterine device, 
condoms, anatomical sterility in self or partner.  Oral 
hormonal methods and implant contraceptives are 
allowed but only in combination with the additional 
protection of a barrier method. 
 
8. Female participants may not use any vaginal products or 
objects or have vaginal sex for 48 hours before and after 
the collection of vaginal fluid and vaginal biopsies. This 
list includes tampons, female condoms, cotton wool, rags, 
diaphragms, cervical caps (or any other vaginal barrier 
method),douches, lubricants, vibrators/dildos, and drying 
agents. 
 
9. Males participating in sexual intercourse that could result 
in pregnancy must use condoms during the duration of 
the study.  
 
10. Men and women cannot use anal products or objects 
including but not exclusive to douches, lubricants and 
vibrators/dildos, butt plugs or urethral sounds or have 


PROTOCOL IDENTIFICATION NUMBER: JF-007  
EudraCT Number: 2016-000437-43 
 
R-PrEP V1.3 23/11/2018   
 
IRAS Project ID: 202316 
 
 
 
 
 
Page 6 of 39 
receptive anal intercourse for 48 hours before and after 
the collection of rectal biopsies.   
 
11. Willing to abstain from St. John’s Wort, multivitamins and 
antacids for the study duration. 
 
 
 
 
 
Exclusion Criteria 
1. 
Any significant acute or chronic medical illness as 
determined by the investigator. 
2. 
Evidence of organ dysfunction or any clinically significant 
deviation from normal in physical examination, vital 
signs or clinical laboratory determinations. 
3. 
Positive blood screen for hepatitis B (HBs Ag) and/or C 
antibodies. 
4. 
Positive blood screen for HIV antibody/antigen by 4th 
generation assay. 
5. 
Positive screen for sexually transmitted infections at 
screening visit  
6. 
High-risk behaviour for HIV infection, which is defined as 
having one of the following within three months before 
trial day 0 (first dose): 
i. had unprotected vaginal or anal sex with a known 
HIV infected person or a casual partner. 
ii. engaged in sex work for money or drugs. 
iii. acquired a bacterial sexually transmitted disease. 
iv. having a known HIV positive partner either currently 
or in the previous six months  
7. 
Females who are pregnant or breast-feeding. 


PROTOCOL IDENTIFICATION NUMBER: JF-007  
EudraCT Number: 2016-000437-43 
 
R-PrEP V1.3 23/11/2018   
 
IRAS Project ID: 202316 
 
 
 
 
 
Page 7 of 39 
8. 
Clinically significant laboratory abnormalities  
9. Ingestion of H2 receptor antagonists or proton pump 
inhibitor drugs in the preceding 14 days 
10.  Current of planned use of anti-epileptics 
 
IMP, dosage and route of 
administration 
Oral Raltegravir 400mg bd alone or Raltegravir 
400mg/lamivudine 150mg bd for 7 days 
Active comparator product(s) None 
Maximum duration of 
treatment of a 
subject 
7 days Raltegravir 400mg bd followed by minimum 4 weeks 
wash out and then 7 days Raltegravir 400mg/lamivudine 150mg 
(oral tablets) bd. Or vice versa. 
Version and date of final 
protocol 
V1.2 03/04/17 
Version and date of protocol 
amendments  
V1.3 23/11/18 
 
 
 
 
 
 


PROTOCOL IDENTIFICATION NUMBER: JF-007  
EudraCT Number: 2016-000437-43 
 
R-PrEP V1.3 23/11/2018   
 
IRAS Project ID: 202316 
 
 
 
 
 
Page 8 of 39 
2. Glossary of Terms 
AE – adverse event 
AIDS - acquired immunodeficiency syndrome 
ART – antiretroviral therapy 
BMI – body mass index 
CNST – clinical negligence scheme for trusts 
CRF – case report/record form 
CVF – cervico-vaginal fluid 
DSUR – development safety update report 
EDTA - ethylenediaminetetraacetic acid 
FBC – full blood count 
FDA – US food & drug administration 
GCP – good clinical practice 
Hb - haemoglobin 
HIV - human immunodeficiency virus 
IMP – investigational medicinal product          
KCL – King’s College London 
KHP CTO – King’s Health Partners Clinical Trials Office 
LFTs – liver function tests 
MHRA – medicines & healthcare products regulatory agency 
MSM – men who have sex with men 
PBMC – peripheral blood mononuclear cell 
PD – pharmacodynamics 
PK – pharmacokinetics 
PrEP – pre-exposure prophylaxis 
RCT – randomised controlled trial 
REC – research ethics committee 
SAE – serious adverse event 
SAR – serious adverse reaction 
SmPC – summary of product characteristics 
SOP – standard operating procedure 
SUSAR – suspected unexpected serious adverse reaction 


PROTOCOL IDENTIFICATION NUMBER: JF-007  
EudraCT Number: 2016-000437-43 
 
R-PrEP V1.3 23/11/2018   
 
IRAS Project ID: 202316 
 
 
 
 
 
Page 9 of 39 
TMG – trial management group 
U&Es – urea & electrolytes 
WCC – white cell count 
 
 
 
 


PROTOCOL IDENTIFICATION NUMBER: JF-007  
EudraCT Number: 2016-000437-43 
 
R-PrEP V1.3 23/11/2018   
 
IRAS Project ID: 202316 
 
 
 
 
 
Page 10 of 39 
CONTENTS 
1. Study Synopsis 
2. Glossary of Terms  
3. Background & Rationale ................................................................................... 10 
4. Trial Objectives and Design .............................................................................. 12 
4.1. Trial Objectives ................................................................................................. 12 
4.1.1 Primary Endpoints……………………………………………………………………12 
4.1.2 Secondary Endpoints……………………………………………………………......12 
4.1.3 Experimental Endpoints……………………………………………………………..12 
4.2 Trial Design ....................................................................................................... 12 
4.3 Trial Flowchart ................................................................................................... 14 
5 Trial Medication .................................................................................................. 16 
5.1 Investigational Medicinal Product ...................................................................... 16 
5.2 Dosing Regimen ................................................................................................ 16 
5.3 IMP Risks………………………………………………………………………………..16 
5.4 Drug Accountability ............................................................................................ 16 
5.5 Storage of IMP………………………………………………………………………….16 
5.6 Subject Compliance. .......................................................................................... 16 
5.7 Concomitant Medication .................................................................................... 17 
6 Selection and Withdrawal of Subjects .............................................................. 17 
6.1 Inclusion Criteria ................................................................................................ 17 
6.2 Exclusion Criteria ............................................................................................... 17 
6.3 Selection of Participants .................................................................................... 18 
6.4 Randomisation Procedure / Code Break ............................................................ 18 
6.5 Withdrawal of Subjects ...................................................................................... 18 
6.6 Expected Duration of Trial. ................................................................................ 19 
7  Trial Procedures ................................................................................................ 19 
7.1 By Visit ............................................................................................................... 19 
7.2 Laboratory Tests ................................................................................................ 23 
8 Assessment of Efficacy ..................................................................................... 27 
8.1.1 Primary Efficacy Parameters .......................................................................... 27 


PROTOCOL IDENTIFICATION NUMBER: JF-007  
EudraCT Number: 2016-000437-43 
 
R-PrEP V1.3 23/11/2018   
 
IRAS Project ID: 202316 
 
 
 
 
 
Page 11 of 39 
8.1.2 Secondary Efficacy Parameters ...................................................................... 27 
8.2 Procedures for Assessing Efficacy Parameters ................................................. 27 
9 Assessment of Safety ........................................................................................ 28 
9.1 Specification, Timing and Recording of Safety Parameters. .............................. 28 
9.2 Management of Potential Adverse Outcomes after proctoscopy                                      28 
9.3 Procedures for Recording and Reporting Adverse Events ................................. 28 
9.3.1 Adverse events that do not require reporting .................................................. 36 
9.3 Treatment Stopping Rules ................................................................................. 36 
10 Statistics ............................................................................................................ 36 
10.1 Sample Size .................................................................................................... 36 
10.2 Randomisation ................................................................................................. 36 
10.3 Analysis ........................................................................................................... 31 
11. Trial Steering Committee ................................................................................ 31 
12. Data Monitoring Committee ............................................................................ 32 
13 Direct Access to Source Data and Documents .............................................. 32 
14 Ethics & Regulatory Approvals ....................................................................... 32 
15 Quality Assurance ............................................................................................ 32 
16 Data Handling ................................................................................................... 32 
17 Data Management ............................................................................................. 33 
18 Publication Policy ............................................................................................. 33 
19 Insurance & Indemnity ..................................................................................... 33 
20 Financial Aspects ............................................................................................. 33 
21 Signatures ......................................................................................................... 33 
References………………………………………………………………………………….34 
Appendices…………………………………………………………………………………35 
 


PROTOCOL IDENTIFICATION NUMBER: JF-007  
EudraCT Number: 2016-000437-43 
 
R-PrEP V1.3 08/08/2018  
 
IRAS Project ID: 202316 
 
Page 12 of 39 
3. Background & Rationale 
Pre-exposure prophylaxis (PrEP) is a rapidly emerging prevention strategy that could 
help reduce HIV incidence globally (iPrEx, Grant  2010; Partners PrEP, Baeten 2012; 
TDF2, Thigpen 2012; FEM-PrEP Van Damme 2012). The use of daily oral Truvada for 
PrEP has demonstrated efficacy and is licenced in the USA (FDA 2012).  
 
Raltegravir is promising as a PrEP agent, particularly for men who have sex with men- It 
is well tolerated, has few drug-drug interactions and has good penetration into rectal 
tissue- plateau levels are 1.5-7x higher in gut associated lymphoid tissue compared to 
plasma (Patterson PK Workshop 2012).  However, it is not known whether tissue 
penetration is equal between men and women or whether Raltegravir on its own or in 
combination with lamivudine can provide ex vivo protection from HIV.   
 
Raltegravir may provide tissue penetration through absorption into the circulation. In 
addition there are 2 further ways in which Raltegravir may access the rectum: firstly, 
directly as unabsorbed drug carried in faeces or secondly that it is excreted in a 
conjugated form by the bile duct and de-conjugates in the large bowel back to 
Raltegravir.   
 
The efficacy of Raltegravir in the female genital tract and in the rectum can be evaluated 
by ex vivo challenge of mucosal tissue explants. This model has become essential for 
microbicide pre-clinical evaluation (Herrera 2014), for measurement of drug combination 
activity (Herrera 2009, Herrera 2011) and for HIV transmission studies (Shaw 2012). 
Importantly, several studies have shown its capacity to evaluate in vivo efficacy not only 
in non-human primates (Cranage et al. 2008, Wallace et al.2009, Ouattara et al. 2014) 
but also in clinical trials (Richardson-Harman et al. 2012), and is currently used as a 
routine technique in microbicide trials performed by the Microbicide Trial Network. 
Despite the variety of models, it has been shown that consistent results can be obtained 
among different laboratories through protocol standardization (Richardson-Harman et al. 
2009). The ex vivo challenge approach is currently being used to assess efficacy, proof 
of concept and insight into adherence requirements for other oral PrEP agents 
(HPTN069 and UK PrEP group). The information collected provides milestone data 
before embarking on large scale efficacy studies, informs on the possibility of event 
driven versus daily PrEP and can provide useful licensing data should efficacy be 
shown.   


PROTOCOL IDENTIFICATION NUMBER: JF-007  
EudraCT Number: 2016-000437-43 
 
R-PrEP V1.3 08/08/2018  
 
IRAS Project ID: 202316 
 
Page 13 of 39 
 
A number of key issues in the use of Raltegravir for PrEP are unknown: 
 
1. The concentration of Raltegravir in either plasma or genital tract required for 
100% ex vivo protection from HIV in PrEP 
2. The pharmacokinetic (PK) profile of different Raltegravir containing regimens 
given orally in HIV negative individuals both in the plasma and genital tract ( 
vagina, rectum)   
3. The frequency of Raltegravir dosing required for ex vivo protection from HIV 
4. The correlation between plasma and genital tract Raltegravir drug levels and ex 
vivo protection from HIV infection 
 
 
This study evaluates whether a 7-day course of Raltegravir 400mg bd or Raltegravir 
400mg/lamivudine 150mg bd can prevent HIV from infecting genital tissue and will relate 
the level of drug in the blood to the level of drug in genital tissue and to the ability to of 
HIV to infect genital tissue. As well as determining whether these regimes can provide 
ex vivo protection against HIV, this study will also determine speed to provision of 
protection and  a 48 hour PK/PD decay profile of Raltegravir following drug cessation 
after attaining steady state concentrations.  The results will also inform all future HIV pre-
exposure prophylaxis studies of Raltegravir and form the basis for large scale clinical 
trials without the need for tissue sampling.  To date, efficacy studies assessing PrEP 
regimens have utilized HIV-acquisition endpoints with the consequence being such 
studies are required to be large in subject number in order to power observations. In 
addition the study will provide for the first time data on HIV protection rather than just 
Raltegravir drug levels in tissue, and allow assessment of the possibility of Raltegravir 
being used as an intermittent dosing regimen in PrEP. 
 
By recruiting men and women, data on plasma pharmacokinetics and the relative 
distribution kinetics in the female genital tract and male rectal compartment will be 
generated which will support expanded safety studies and a large global efficacy trial. 
This pharmacodynamic model is the optimal and only practical way to address the 
clinical question of duration of protection given the uncertainty regarding the time of 
transmission under real-life conditions. As each phase will be scheduled to avoid 
menstruation and sampling of women will occur at similar stages of the menstrual cycle. 


PROTOCOL IDENTIFICATION NUMBER: JF-007  
EudraCT Number: 2016-000437-43 
 
R-PrEP V1.3 08/08/2018  
 
IRAS Project ID: 202316 
 
Page 14 of 39 
 
 
The team: 
The applicants are highly experienced in carrying out such studies and collaborating 
together. Dr Fox is Chief Investigator on similar PrEP studies and is highly experienced 
in running clinical trials. Professor Shattock and Dr Herrera are world renown for their 
pioneering work in HIV prevention and pioneered the use of explant models to quantify 
HIV infectivity. Professor Khoo and Dr Boffito are world renown for their pharmacokinetic 
work in novel drugs and HIV prevention. The volunteers for similar studies remain in 
touch with the unit via newsletters and patient representatives are involved with study 
design and protocol development.  
 
Hypothesis 
We hypothesize that a 7- day course of Raltegravir given either with or without 
lamivudine will produce adequate drug levels of Raltegravir in genital tissue to provide 
ex vivo protection from HIV infection. 
 
 
4 Trial Objectives and Design 
4.1. Trial Objectives 
For each drug (Raltegravir and lamivudine) we have the following aims: 
 
1. To determine the level of drug required in the plasma, vagina and rectum for mucosal ex 
vivo protection from HIV 
2. To determine the time from first dose of drug to mucosal ex vivo protection from HIV 
infection 
3. To determine the time to cessation of mucosal ex vivo protection from HIV after stopping 
ART at steady state.  
4. To determine the safety and tolerability of Raltegravir based PreP in HIV negative 
individuals 
 


PROTOCOL IDENTIFICATION NUMBER: JF-007  
EudraCT Number: 2016-000437-43 
 
R-PrEP V1.3 08/08/2018  
 
IRAS Project ID: 202316 
 
Page 15 of 39 
4.1.1 Primary endpoints 
The level of Raltegravir alone or Raltegravir /lamivudine  required in the plasma, 
vagina and rectum  for 100% ex vivo protection from HIV 
 
 
4.1.2 Secondary endpoints 
1. The time from first dose of drug to mucosal ex vivo protection from HIV 
infection 
2. The time to cessation of mucosal ex vivo protection from HIV after stopping 
ART at steady state.  
3. The safety and tolerability of Raltegravir based PrEP in HIV negative 
individuals 
 
 
4.2 Trial Design  
This 
is 
a 
multi-site, 
open-label, 
randomised, 
pharmacokinetic 
(PK) 
and 
pharmacodynamic (PD) trial whereby 36 individuals (18 women and 18 men) will be 
randomised according to gender 1:1:1:1:1:1 to one of 6 arms (A 1   A 2   A 3   B 1   B 2 B 3). 
The result being 3 women and 3 men will be in each arm.  The letter dictates the ART 
regimen order and the number dictates the time points that tissue sampling will occur on 
and off ART. 
 
Regimes  
Two ART regimes will be investigated and all individuals will receive both regimes 
separated by a minimum of 4 week wash out.  
 
Arm A (A 1    A 2   A 3): will start with 7 days Raltegravir 400mg bd and then have a 
minimum 4 week wash out before then starting 7 days Raltegravir 400mg /lamivudine 
150mg bd.  
 
Arm B (B 1   B 2   B 3): will start with 7 days Raltegravir 400mg /lamivudine 150mg bd and 


PROTOCOL IDENTIFICATION NUMBER: JF-007  
EudraCT Number: 2016-000437-43 
 
R-PrEP V1.3 08/08/2018  
 
IRAS Project ID: 202316 
 
Page 16 of 39 
then have a minimum 4 week wash out before then starting 7 days Raltegravir 400mg 
bd. This will remove sequential selection bias. 
 
For each phase (part 1 & 2): 
A 1  &  B 1   will have sampling visits on day 2 and 8 post first dose 
A 2  & B 2   will have sampling visits on day 4 and 10 post first dose 
A3  & B 3    will have sampling visits on day 6 and 12 post first dose 
 
 
All individuals will receive tissue sampling at baseline for ex vivo analysis to ensure biopsies are 
infectable on challenge assays. Sampling from women will avoid menstruation and if possible 
focus on the luteal phase of the menstrual cycle. Individuals will receive another set of tissue 
sampling during and after ART in phase 1, have a minimum 4 week wash out period and then 
have another set of sampling during and after ART in phase 2.  Individuals will therefore have 5 
sets of sampling during the trial.  
 
 
Substudy: To determine the decay kinetics of Raltegravir following cessation at steady 
state. 
All participants will be offered the chance to participate in the sub study, but their participation is 
optional. Participants who consent to the optional sub study will be required to provide paired 
plasma, urine & saliva samples which will be collected on day 8,9,10 from ARM B and day 
42,43,44 from ARM A. If Sub study sampling days fall on main study visit days, sampling can be 
obtained the same time. Should sub study visits fall over a weekend, visits can be postponed 
accordingly. Date and time of sampling will be recorded and sent with samples for analysis. 
 
 
 
Recruitment: 
Recruitment will take place at Guys and St Thomas’ NHS Trust Hospital. .  Recognizing that 
anal sex is a route of transmission for heterosexuals, women will undertake vaginal and rectal 
sampling. The Site has carried out many similar tissue sampling studies.  
 


PROTOCOL IDENTIFICATION NUMBER: JF-007  
EudraCT Number: 2016-000437-43 
 
R-PrEP V1.3 08/08/2018  
 
IRAS Project ID: 202316 
 
Page 17 of 39 
4.3 Trial Flowchart 
 
Figure 1: Flow chart to summarize the visit schedule 
 
 
 
 
 
 
 
 
 
 
 
 


PROTOCOL IDENTIFICATION NUMBER: JF-007  
EudraCT Number: 2016-000437-43 
 
R-PrEP V1.3 08/08/2018  
 
IRAS Project ID: 202316 
 
Page 18 of 39 
 Table 1: visit schedule 
 
*fasted 
**genital swabs: vaginal (women only), rectal (women and men) 
Women may need to attend for baseline biopsies on a separate day from ART initiation due to menstrual cycle factors (ie biopsies should not be taken around menstruation and the 
luteal phase should be targeted where possible). 
***PD sample only
day 
Screen 
0 
 
 
 
 
 
 
WASH OUT PERIOD 
 
 
 
 
 
 
 
 
visit number 
1 
2 
3 
3 
3 
4 
4 
4 
5 
6 
6 
6 
7 
7 
7 
8 
  
  
on 
ART 
  
  
  
  
Off 
ART 
  
on 
ART 
  
  
  
  
off ART 
  
  
Eligibility 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Informed consent 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Demographics 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV test & Syphillis RPR 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Randomisation 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP Dispensing 
  
x 
  
  
  
  
  
  
x 
  
  
  
  
  
  
  
Directed physical exam  
x 
x 
one time point 
one time point 
x 
one time point 
one time point 
x 
Asymptomatic STI screen 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
-Hep C Ab 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
-HepBsAg 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
FBC, U&E, ALT 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
drug levels (vaginal/rectal/oral) 
 
  
one time point 
one time point 
  
one time point 
one time point 
  
Plasma Drug levels (PK)* 
 
 
one time point 
one time point 
 
one time point 
one time point 
 
Rectal/vaginal biopsy (PK/PD) 
  
X*** 
one time point 
 
one time point 
 
  
one time point 
 
one time point 
 
  
Pregnancy Test 
x 
X 
 
 
X 
 
x 
 
progesterone (women only) 
  
x 
one time point 
one time point 
 
  
one time point 
one time point 
  
Conmed Reporting 
 x 
x 
x 
  
  
x 
  
  
x 
  
x 
  
  
 x 
  
x 
Adverse Event Reporting 
 
x 
x 
 
 
x 
 
 
 
x 
 
x 
 
 
x 
 
x 


PROTOCOL IDENTIFICATION NUMBER: JF-007  
EudraCT Number: 2016-000437-43 
 
R-PrEP V1.3 08/08/2018  
 
IRAS Project ID: 202316 
 
Page 19 of 39 
 
Women may need to attend for baseline sampling on a separate day from Baseline visit due to menstrual cycle factors (ie 
biopsies should not be taken around menstruation and the luteal phase should be targeted where possible).  
Once randomisation has occurred and study drug dispensed, participants will be informed when to take their first dose to 
ensure timelines between first dose and sampling are adhered to, based on their randomisation group. 
 
Table 1a: Substudy Visit schedule 
 
ARM B 
ARM A 
Day* 
8 
9 
10 
42 
43 
44 
Plasma 
x 
x 
x 
x 
x 
X 
Urine 
x 
x 
x 
x 
x 
X 
Saliva 
x 
x 
x 
x 
x 
x 
.* Should any sub study days coincide with a weekend, visits can be postponed accordingly.  
5 Trial Medication 
5.1 Investigational Medicinal Products 
Raltegravir  (Isentress®)400 mg tablets in a 60 tablet pack. 
Lamivudine 150mg film-coated tablets, 60 tablet, blister pack 
 
Raltegravir is being supplied by Merck to the sponsor site.  The sponsor site will 
distribute the raltegravir to the other recruiting sites. 
Lamivudine will be supplied from hospital commercial stock at each site.  
All drugs will be dispensed by the pharmacy department of the participating centres 
against a Trial Specific Prescription. A R-Prep prescription will be supplied by the 
sponsor but sites may wish to use their own prescription template (a copy of which 
should be provided to the sponsor).  
 
The medication will be packed down into the required quantities and a trial-specific, 
Annex 13 compliant label attached at the point of dispensing.  
 
5.2 Dosing Regimen 
Raltegravir 400mg tablet bd for 7 days 
Raltegravir 400mg  + lamivudine 150mg bd for 7 days 
 
Both regimes are taken twice a day. Participants will be advised to take tablets at 11am 
and 11pm.  


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Page 20 of 39 
  
 
 
5.3 IMP Risks  
The SmPC for Isentress® and Lamivudine will act as the reference documents. We do not 
anticipate any interaction concerns.  
5.4 Drug Accountability 
Each local pharmacy must maintain accurate accountability records of the IMP, including 
but not limited to the quantity received, the quantity dispensed to which subject, batch 
number, expiry date, study drug returns and the date of each transaction. Participants 
will be asked to return empty packaging to the pharmacy for accountability. Study drug 
returns must be verified by the study monitor prior to disposal. 
 
R-Prep Accountability Log will be provided by the sponsor, but sites may wish to use in 
house logs (a copy of which should be provided to the sponsor). 
5.5 Storage of IMP 
Raltegravir (Isentress®) does not require any special storage conditions (as per SmPC) 
Lamivudine – store < 30°C  
5.6 Subject Compliance 
The administration of ART will be planned between the participant and study nurse. The 
participant will take the morning dose at 11am and the evening dose at 11pm. The 
sampling must occur fasted and prior to that day’s morning dose of study drug. 
 
5.7 Concomitant Medication 
All concomitant medication will be recorded. Concomitant therapies will be managed in 
line with the Summary of Product Characteristics guidance for Isentress® 400mg tablets 
and Lamivudine 150mg tablets. 
 


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Page 21 of 39 
6 Selection and Withdrawal of Subjects 
6.1 Inclusion Criteria 
Participants must satisfy all of the following criteria 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 trial 
requirements. 
2. Male or non-pregnant, non-lactating females 
3. Age between 18 to 60 years, inclusive. 
4. Body Mass Index (BMI) of 16 to 35 kg/m2, inclusive. 
5. Negative antibody/antigen combined test for HIV. 
6. Absence of any significant health problems (in the opinion of the investigator) on the 
basis of the screening procedures; including medical history, physical examination, 
vital signs. 
7. Women participating in sexual intercourse that could result in pregnancy -must use 
an adequate form of contraception throughout the study and for two weeks after the 
study. This includes intrauterine device, condoms, anatomical sterility in self or 
partner.  Oral hormonal methods and implant contraceptives are allowed but only in 
combination with the additional protection of a barrier method. 
 
8. Female participants may not use any vaginal products or objects or have vaginal sex 
for 48 hours before and after the collection of vaginal fluid and vaginal biopsies. This 
list includes tampons, female condoms, cotton wool, rags, diaphragms, cervical caps 
(or any other vaginal barrier method),douches, lubricants, vibrators/dildos, and drying 
agents. 
 
9. Males participating in sexual intercourse that could result in pregnancy must use 
condoms during the duration of the study.  
 
10. Men and women cannot use anal products or objects including but not exclusive to 
douches, lubricants and vibrators/dildos, butt plugs or urethral sounds or have 
receptive anal intercourse for 48 hours before and after the collection of rectal 
biopsies.   


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Page 22 of 39 
 
11. Willing to abstain from multivitamins and antacids for the study duration. 
 
 
 
 
 
6.2 Exclusion Criteria 
1. 
Any significant acute or chronic medical illness. 
2. 
Evidence of organ dysfunction or any clinically significant deviation from normal in 
physical examination, vital signs or clinical laboratory determinations. 
3. 
Positive blood screen for syphilis, hepatitis B (HBs Ag) and/or C antibodies. 
4. 
Positive blood screen for HIV antibodies. 
5. 
Positive screen for sexually transmitted infections at screening visit  
6. 
High-risk behaviour for HIV infection which is defined as having one of the following 
within three months before trial day 0 (first dose): had unprotected vaginal or anal sex 
with a known HIV infected person or a casual partner. engaged in sex work for money 
or drugs. acquired a bacterial sexually transmitted disease in the past 3 months. having 
a known HIV positive partner either currently or in the previous six months Females 
who are pregnant or breast-feeding. 
7. 
Clinically significant laboratory abnormalities (according to normal range as defined by 
central laboratory). 
8. 
Participation in a clinical trial of an Investigational product within 1 month of planned 
baseline enrolment in this study. 
9. 
Ingestion of H2 receptor antagonists or proton pump inhibitor drugs in the preceding 14 
days 
10. Current of planned use of anti-epileptics 
 
 
6.3 Selection of Participants 
Healthy adult volunteers will be recruited through information presented in community 
organisations, hospitals, colleges, other institutions and/or advertisements, including email 
responses to expressed interest. The content of these advertisements will be included in the 


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R-PrEP V1.3 08/08/2018  
 
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Page 23 of 39 
submission to the Research Ethics Service, for approval. This information will contain contact 
details for the units conducting the study. 
During the recruitment process, interested volunteers will be provided with a participant 
information sheet, detailing the trial, its procedures and medication to be investigated and given 
time to consider their participation prior to arranging an appointment for a screening visit. 
Potential participants will be given a minimum of one day to review the information sheet and 
ask questions relating to trial participation, but can have as long as the trial remains open for 
recruitment. At the screening visit, before undertaking any screening procedures, volunteers will 
be able to discuss the trial to ensure they have enough information to confirm their written 
informed consent. An important part of the screening history will involve assessment of HIV risk, 
and all trial staff will be experienced healthcare practitioners, trained in the conduct of clinical 
research and capable of conducting such a discussion. 
 
6.4 Randomisation Procedure / Code Break 
 
Individuals will be randomized according to gender into one of 6 groups 1:1:1:1:1:1 
randomisation and within, with randomisation/allocation to study arm being determined 
using the MedSciNet eCRF randomisation function.   This is not a blinded study 
therefore patients and research team will know what medications the patient is receiving.  
6.5 Withdrawal of Subjects 
Participants have the right to withdraw from the trial at any time for any reason. The investigator 
may also withdraw participants from the trial in the event of inter-current illness, adverse events, 
protocol violations, administrative reasons or other reasons. An excessive rate of withdrawals 
can render the trial impossible to interpret; therefore unnecessary withdrawal of participants 
should be avoided. Those withdrawing prior to the second phase will be replaced and new 
participants will be allocated to the same treatment arm as the individual who withdrew from the 
study. These new participants will start from baseline. Participants withdrawing from the trial will 
be asked to attend for a withdrawal visit. 
 
 


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In all cases the date and reasons for withdrawal or withholding the dose of medication will be 
clearly stated on the participant’s CRF. If the reason for removal of a participant from the trial is 
an adverse event or an abnormal laboratory test result, the principal specific event or test will be 
recorded on the CRF. 
 
6.6 Expected Duration of Trial 
The trial is expected to last 7 months. Starting from first patient first visit and the end of 
the trial will be considered the last patient’s last visit. 
As the visit windows are generous, the total duration of involvement will vary for each patient. 
From signing consent to completing the trial, patients will be involved for approximately 8 
weeks.  
 
 
7 Trial Procedures 
7.1 By Visit 
Individuals attend for 8 visits. Once screened the remaining 7 visits will take place over 
approximately an 8 week period. 
 
Assessments at each visit 
The schedule of assessments is summarised in the trial flow chart.  
During the study, participants will be instructed to refrain from certain activities: 
• strenuous exercise or marked increases in current exercise activity 
• sexual intercourse as per inclusion criteria and anal and vaginal products and 
preparations as per inclusion criteria for 48 hours prior to and post each scheduled 
sample/biopsy collection. 
• donating blood  
• engaging in high-risk behaviour for HIV infection as per inclusion criteria  
• taking part in another drug trial for the duration of the study  
 
 
Visit 1: Screening Visit 


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Page 25 of 39 
 
Prior to the screening visit participants will be provided with written information about the trial in 
the form of a participant information sheet and will be allowed adequate time for questions and 
to consider the trial before agreeing to participate. It will be the responsibility of the investigator 
or co-investigator to obtain written informed consent prior to undertaking any procedures 
detailed in the protocol. 
 
The investigator or designee must provide adequate explanation of the aims, methods, 
objectives and potential hazards of the trial. It must also be explained to the participant that they 
are free to refuse or withdraw from the trial for any reason without detriment to their future care 
or treatment. 
 
Possible eligible and interested participants will be asked to volunteer their participation in this 
trial. Willing participants will be required to read, sign and date an informed consent document 
prior to any trial related procedures being performed. 
 
Participants will be given the opportunity to ask any questions regarding the trial at this stage 
and throughout the whole trial period. 
 
If the volunteer agrees to participate, site personnel will perform an HIV risk assessment (see 
exclusion criteria number 6) and an HIV blood test. Any volunteers found to be infected with HIV 
at screening will be managed as described in section 7.2. 
 
Screening evaluations will be used to determine the eligibility of each candidate for trial 
enrolment. Following informed consent, the screening visit will evaluate: 
 
• HIV risk assessment (as per inclusion / exclusion criteria)  
• Demographic details (age, gender, ethnic origin) 
• Full medical, drug and social history 
• Directed Physical examination including examination of skin, weight, height, and vital 
signs (temperature, blood pressure, heart rate and respiratory rate) 
• Brief external genitalia examination 
• Blood tests:  
− HIV antibody testing and discussion 


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Page 26 of 39 
− Hepatitis B (surface antigen), Hepatitis C (antibody) 
− Syphilis Screening 
− Biochemistry (U&E, ALT) and haematology  
• 
Urine ßhCG for women- for females of childbearing potential 
 
• Urine and self-administered rectal swab for Chlamydia and gonorrhoea testing for men 
• Self-administered vaginal and rectal swab for Chlamydia and gonorrhoea testing for 
women 
• Concomitant medications 
• Women will be asked at enrolment if they have any vaginal discharge and men if they 
have any rectal or urethral discharge.  If they do they will be asked to attend a sexual 
health clinic.  If their symptoms are not caused by a sexually transmitted infection and 
have resolved by the time of visit 2, they will be able to proceed with the study.  Patients 
will be asked to attend a sexual health clinic if they have vaginal, rectal or urethral 
symptoms at any further point during the study and to report this to the study co-
ordinator.  
 
For women, the baseline visit will be scheduled for a time that avoids menstruation. If a female 
is menstruating the visit will be delayed until after menstruation has completed and around the 
luteal phase where possible.  
 
Individuals will be informed that the tissue pharmacodynamics analysis can only be performed 
on fresh tissue and therefore biopsies at the baseline visit and any subsequent ones must be 
taken in the morning. 
 
Randomisation will take place once screening evaluations have confirmed eligibility, and it has 
been confirmed that individuals are still willing to take part in the study.  This will occur prior to 
any baseline procedures.  
 
Visit 2: Baseline (3-42 days from screening): 
Women may need to attend for baseline sampling  on a separate day from Baseline visit due to 
menstrual cycle factors (ie biopsies should not be taken around menstruation and the luteal 
phase should be targeted where possible). The on ART and off ART biopsies visits must not 
occur during menstruation. The maximum time between baseline visit and sampling is 6 weeks.  


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Page 27 of 39 
 
Participants will be instructed to attend the research unit at a specified time. 
The following evaluations will be performed in the morning of Day 0, before trial medication 
dosing and tissue sampling: 
 
• 
Randomisation 
• 
Physical / genital exam if clinically indicated  
• 
Vital signs (temperature, blood pressure, heart rate, and respiratory rate) 
• 
Concomitant medications review 
• 
Urine ßhCG - for females of childbearing potential 
• 
Progesterone (women only) 
 
Tissue samples  (pharmacodynamics only):  
Men: Rectal tissue biopsy  
Women: vaginal and rectal tissue biopsies 
 
Visit 2: ART initiation (post sampling) 
This may occur on the same day as visit 2. For women, this is  providing that the estimated date 
of menstruation will not impact subsequent biopsy visits. If this occurs, the day of ART initiation 
should be soon after menstruation has finished.  
 
Visit 3,4,6,7: Sample collection. Fasting trough levels to be taken prior to that day’s 
morning dose 
 
The following evaluations will take place prior to sampling: 
• 
Confirmation of time that participant administered Raltegravir 400mg +/-lamivudine  
• 
Physical / genital exam if clinically indicated  
• 
Vital signs (temperature, blood pressure, heart rate, and respiratory rate) 
• 
Concomitant medications review 
• 
Adverse event review. If significant adverse events have been reported, these will be 
clinically followed in accordance to the instruction of the study physician. 
• 
Blood and tissues samples for routine safety analysis and research purposes will be 
taken as follows: 
 


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Page 28 of 39 
PK samples: 
- 
Plasma will be extracted from 6mls of blood for drug level analysis 
- 
2 x saliva sample for men and women 
- 
2 x Vaginal swab for women 
- 
2 x rectal swab for men and women 
- 
5-6 x Rectal tissue for men and women 
- 
5-6 x Vaginal tissue for women 
 
• 
Progesterone (women only) 
• 
Urine ßhCG - for females of childbearing potential (visit 7 only) 
 
 
 Visit 5:  
For women, this visit will occur soon after menstruation has finished so that subsequent tissue 
sampling visits will avoid menstruation.  
The following evaluations will take place prior to sampling: 
• 
Directed Physical / genital exam if clinically indicated  
• 
Vital signs (temperature, blood pressure, heart rate, and respiratory rate) 
• 
Concomitant medications review 
• 
Adverse event review. If significant adverse events have been reported, these will be 
clinically followed in accordance to the instruction of the study physician. 
• 
Urine ßhCG - for females of childbearing potential 
 
ART will be prescribed. 
 
Visit 8: Follow-up visit/withdrawal visit (3 days to 14 days after visit 7) 
Participants will attend for: 
• 
Concomitant medications review 
• 
Adverse event review 
• 
Genital and physical examination if clinically indicated 
 
 
Substudy (Optional) 
Participants consenting to the Substudy will need to attend for the following: 


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• 
Upon discontinuation of Raltegravir + lamivudine, 3 consecutive days of sampling: 
• 
Arm B: Days 8, 9 & 10 
• 
Arm A: Days 42, 43 & 44. 
PK samples to be obtained: 
-  plasma (6mls),  
- urine (10mLs) 
- saliva (3mLs)  
 
If any of the substudy sampling days fall on main study visit days, sampling can be done 
at the same time. 
 
 
7.2 Laboratory Tests 
Safety analysis samples 
At screening, blood will be drawn for chemistry, haematology & viral serology together with urine 
(dipstick for pregnancy) samples. Samples will be analysed locally.  
 
All results will be in written in the source and eCRF. The investigator must review, sign and date 
the laboratory results/reports, comment whether any abnormal values are clinically significant 
and record any clinically relevant changes occurring during the study in the adverse event 
section of the CRF. 
 
STI screening: The Gen-Probe Aptima test (for chlamydia and gonorrhoea) will be used on first 
void urine and self-collected rectal swab in men and self-collected vaginal and rectal swab for 
women. Samples will be analysed locally. 
 
HIV risk assessment, HIV testing/discussion, and treatment in case of a positive HIV test 
Site personnel will assess volunteers for past and current risk of HIV infection. Additionally, site 
personnel will perform pre-HIV test counselling (prior to collecting blood for an HIV test) and 
post-HIV test counselling (when HIV test results are available). Samples will be analysed locally. 
In the event of a volunteer being diagnosed HIV positive at screening they will immediately be 
referred to the HIV clinic for further counselling and engagement into HIV services. 


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Page 30 of 39 
Research samples 
Research PK  samples are taken at visit 3,4,6,7.  
o 
9mls blood will be drawn: 25μL of whole blood will be used for dry blood spot. 
Plasma will be extracted from the remainder of the 9mls and transported to 
Liverpool University for PK analysis with dry blood spot card. 
o 
Oral fluid sample – saliva will be extracted from 2 x Salivette samples and 
transported to Liverpool University for PK analysis 
  
• 
Genital tract sampling: 
o 
For men: 2 rectal swabs using a WEKs sponge followed by 5-6x 1mm3 rectal 
biopsies taken from the wall of the rectum 
o 
For women: 2x cervico-vaginal swabs, 2 rectal swabs, followed by 5-6 x 1mm3 
vaginal biopsies taken from the wall of the vagina and 5-6x 1mm3 rectal biopsies 
taken from the wall of the rectum 
 
Sample analysis: 
• 
Raltegravir and lamivudine drug levels will be measured at Liverpool University 
• 
Quantification of protection from HIV infection: will be carried out by Professor Shattock’s 
laboratory at Imperial College London. Biopsy tissue will be exposed to different 
concentrations of HIV virus (BAL R5), washed and cultured for 15 days. Cultures wil be 
fed at days 3, 7, 11 and 15 when culture supernatant will be harvested and frozen prior 
to addition of fresh media. HIV p24 Ag ELISA measurements will be carried out for 
detection of antigen in culture supernatants though out the 15 days of culture. Evaluation 
of the viral replication kinetics during culture (p24 at days 3, 7, 11 and 15) and level of 
p24 at day 15 will allow us to assess if the initial ex vivo inoculum has been able to 
replicate in the tissue following in vivo dosing. 
 
Safety blood tests, STI tests, research sampling and processing: 
- 
Harrison Wing, 2nd floor Southwark Wing, Guy’s Hospital, Great Maze Pond, London, 
SE1 9RT 
 
Pharmacokinetics (drug levels) 


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Pharmacology Research Laboratories, Block H – First floor, 70 Pembroke Place, Liverpool, L69 
3GF 
 
Pharmacodynamic analysis (vaginal and rectal tissue)  
Professor Robin Shattock, 4th floor Medical School, Imperial College- St Mary’s Hospital 
1 Norfolk Place, London, W2 1PG 
 
 
8 Assessment of Efficacy 
8.1.1 Primary Efficacy Parameters  
The level of Raltegravir alone or Raltegravir /lamivudine required in the plasma, vagina and 
rectum for 100% ex vivo protection from HIV. 
8.1.2 Secondary Efficacy Parameters 
1. Time from first dose of drug to mucosal ex vivo protection from HIV infection 
2. Time to cessation of mucosal ex vivo protection from HIV after stopping ART at steady state 
3. Safety and tolerability of Raltegravir based PreP in HIV negative individuals 
 
9 Assessment of Safety 
9.1 Specification, Timing and Recording of Safety Parameters. 
Subject safety will be determined by physical examination, blood tests and adverse event 
reporting. FBC, U&E and LFTs will be carried out at baseline and thereafter as symptom 
directed.  
9.2 Management of potential adverse outcomes after tissue 
biopsies 
Study participants will be given information regarding which symptoms should alert them 
to the possibility of perforation or major bleed following their biopsies. In the event of 
these symptoms they will be advised to attend their local Accident & Emergency 
Department directly and to take with them their Patient Information Card and/or inform 


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R-PrEP V1.3 08/08/2018  
 
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Page 32 of 39 
the medical staff that they are participating in a study at the Harrison Wing research unit 
or SSAT involving rectal biopsies and that the research unit needs to be informed of their 
admission.    
 
9.3 Procedures for Recording and Reporting Adverse Events 
 
The Medicines for Human Use (Clinical Trials) Regulations 2004 and Amended 
Regulations 2006 gives the following definitions: 
 
Adverse Event (AE): Any untoward medical occurrence in a subject to whom a 
medicinal product has been administered including occurrences which are not 
necessarily caused by or related to that product. 
Adverse Reaction (AR): Any untoward and unintended response in a subject to an 
investigational medicinal product which is related to any dose administered to that 
subject. 
Unexpected Adverse Reaction (UAR): An adverse reaction the nature and severity of 
which is not consistent with the information about the medicinal product in question set 
out in: 
The summary of product characteristics  (SmPC) for that product (for products 
with a marketing authorisation) 
 
Serious adverse Event (SAE), Serious Adverse Reaction (SAR) or Unexpected 
Serious Adverse Reaction (USAR): Any adverse event, adverse  reaction or 
unexpected adverse reaction, respectively, that 
 
Results in death; 
 
Is life-threatening; 
 
Required hospitalisation or prolongation of  existing hospitalisation; 
 
Results in persistent or significant disability or incapacity; 
 
Consists of a congenital anomaly or birth defect. 
 
Although not a serious adverse event, any unplanned pregnancy should be reported via 


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Page 33 of 39 
the SAE reporting system as stated below. 
Reporting Responsibilities 
Guy’s & St. Thomas’ NHS Foundation Trust have delegated the delivery of the 
Sponsor’s responsibility for Pharmacovigilance (as defined in Regulation 5 of the 
Medicines for Human Use (Clinical Trials) Regulations 2004 to the King’s Health 
Partners Clinical Trials Office (KHP CTO).  
 
All SAEs, SARs and SUSARs (excepting those specified in this protocol as not requiring 
reporting) will be reported immediately (and certainly no later than 24 hours) by the 
Principal Investigator to the Chief Investigator who will review and report to the KHP-
CTO in accordance with the current Pharmacovigilance Policy. 
 
The KHP CTO will report SUSARs to the regulatory authorities (MHRA, competent 
authorities of other EEA (European Economic Area) states in which the trial is taking 
place. 
The Chief Investigator will report to the relevant ethics committee. Reporting timelines 
are as follows: 
− 
SUSARs which are fatal or life-threatening must be reported not later than 7 days 
after the sponsor is first aware of the reaction. Any additional relevant information 
must be reported within a further 8 days. 
− 
SUSARs that are not fatal or life-threatening must be reported within 15 days of the 
sponsor first becoming aware of the reaction.   
− The Chief Investigator and KHP CTO (on behalf of the sponsor), will submit a 
Development Safety Update Report (DSUR) relating to this trial IMP, to the MHRA 
and REC annually. 
 
9.3.1 Adverse events that do not require reporting 
Raltegravir and lamivudine are licenced drugs in HIV infected individuals. However as 
this study concerns HIV negative individuals all events or reactions will be reported from 
randomisation until the final visit. 


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9.4 Treatment Stopping Rules 
The trial may be prematurely discontinued by the Sponsor, Chief Investigator, ethics 
committee concerned or Regulatory Authority on the basis of new safety information. 
 
If the study is prematurely discontinued, active participants will be informed and no 
further participant data will be collected. 
 
10 Statistics 
This randomised study contains a larger number of individuals per arm than most other 
HIV PK/PD studies. Therefore bias is significantly reduced to a minimum. Each patient is 
their own control hence bias is further reduced. There will be an equal number of men 
and women in each arm. 
 
10.1 Sample Size 
 
The number of subjects per gender in each group will be calculated taking into account previous 
results (Cranage et al. 2008), where the difference (d) observed between protected and non-
protected animals was at least of 0.9 log units, and the SD (s) was 0.5 log units. Using the 
equation: n = 1 + 2C(s/d)2, where C is a constant derived from the desired p<0.05 (α) and 
power of 0.8 (β), this gives a group size (n) of 5.8; hence, 6 men and 6 women will be used in 
each group for dosing.  
 
10.2 Randomisation 
Individuals will be randomized into one of 6 groups 1:1:1:1:1:1 
Analysis 


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All data will be inputted using a MedSciNet e-CRF and analysed at the end of the study. 
Data analysis of eCRF data will be carried out Vanessa Tierney at St. Stephen’s AIDS 
Trust. 
Results from Raltegravir and Raltegravir/lamivudine will be compared at study 
completion.  All eligible participants who receive at least two tissue biopsy visits will be 
included in the final data analysis. The analysis plan for estimating the 
pharmacodynamic dose-response curves will follow the methodology described in 
[O'Quigley Stats Med 2011]. In addition, the relationship between pharmacokinetic 
parameters (concentrations of Raltegravir and lamivudine in rectal tissue, vaginal tissue 
and plasma) and pharmacodynamic outcomes will be evaluated. All PK lab analysis will 
be conducted by the lab team at University of Liverpool and PD analysis will be 
conducted by the lab team at Imperial College London.  
Once analysis is complete, any residual samples will be transferred to the KCL 
Infectious Disease Biobank for use in future ethically approved studies. 
 
Demographic and Safety parameters 
All demographic (age, height, weight, BMI, ethnic origin, etc) and clinical (physical examination, 
medical history, concomitant diseases) characteristics will be tabulated and analysed 
descriptively. 
 
Pharmacokinetic parameters 
Summary statistics of drug levels will be presented with either means with SD indicating source 
of inter participant variability where data are found to be parametric, or medians with IQR where 
data are found to be non-parametric. 
 
Plots of the concentration time curves will be produced for plasma, genital tract and rectal 
compartments. Area under the concentration-time curve (AUC), maximum plasma concentration 
(Cmax), time to Cmax (Tmax), minimum plasma concentration (Cmin) and plasma half-life (t½) 
will be derived. All pharmacokinetic parameters will be presented using descriptive summary 
statistics including geometric mean, median, coefficient of variation and interquartile range. 
 


PROTOCOL IDENTIFICATION NUMBER: JF-007  
EudraCT Number: 2016-000437-43 
 
R-PrEP V1.3 08/08/2018  
 
IRAS Project ID: 202316 
 
Page 36 of 39 
Inter participant variability in plasma concentration following drug administration will be 
assessed by measuring the coefficient of variation (CV = SD/mean*100). 
 
Pharmacodynamic parameters 
Protection from HIV is defined as a descending viral replication curve during tissue culture 
resulting in complete protection from infection at day 15 following ex vivo HIV challenge. This 
pharmacodynamic model is the optimal and only practical way to address the clinical question of 
duration of protection given the uncertainty regarding the time of transmission under real-life 
conditions By using a pharmacodynamic model we will determine whether Raltegravir or 
Raltegravir/lamivudine may options for PrEP. 
 
Criteria for termination of the trial 
The Sponsor or Investigator may terminate either part of, or the entire trial 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 Trial Steering Committee (TSC) 
A trial steering committee is not required in view of the study protocol. Sponsors and 
investigators will meet on a regular basis to review recruitment and safety.  
 
12 Data Monitoring Committee 
There is not a data monitoring committee for this study. However the sponsor and investigators 
will meet on a regular basis to review recruitment and safety. 
 
13 Direct Access to Source Data and Documents 
The Investigator(s) will permit trial-related monitoring, audits, REC review, and 
regulatory inspections by providing the Sponsor(s), Regulators and REC direct access to 
source data and other documents (eg patients’ case sheets, blood test reports, X-ray 
reports, histology reports etc). 


PROTOCOL IDENTIFICATION NUMBER: JF-007  
EudraCT Number: 2016-000437-43 
 
R-PrEP V1.3 08/08/2018  
 
IRAS Project ID: 202316 
 
Page 37 of 39 
 
14 Ethics & Regulatory Approvals 
The trial will be conducted in compliance with the principles of the Declaration of Helsinki 
(1996), the principles of GCP and in accordance with all applicable regulatory 
requirements including but not limited to the Research Governance Framework and the 
Medicines for Human Use (Clinical Trial) Regulations 2004, as amended in 2006 and 
any subsequent amendments. 
 
This protocol and related documents will be submitted for review to the Medicines and 
Healthcare products Regulatory Agency (MHRA) for Clinical Trial Authorisation. 
 
The Chief Investigator will submit a final report at the conclusion of the trial to the KHP-
CTO (on behalf of the Sponsor), the REC and the MHRA within the timelines defined in 
the Regulations.  
15 Quality Assurance 
Monitoring of this trial will be to ensure compliance with Good Clinical Practice and 
scientific integrity will be managed and oversight retained, by the KHP Clinical Trials 
Office Quality Team.  
 
 
16 Data Handling 
The Chief Investigator will act as custodian for the trial data. The following guidelines will 
be strictly adhered to: 
 
Patient data will be anonymised 
All anonymised data will be stored on a password protected computer. All trial data will 
be stored in line with the Medicines for Human Use (Clinical Trials) Amended 
Regulations 2006 and the Data Protection Act and archived in line with the Medicines for 
Human Use (Clinical Trials) Amended Regulations 2006 as defined in the KHP Clinical 
Trials Office archiving SOP. 


PROTOCOL IDENTIFICATION NUMBER: JF-007  
EudraCT Number: 2016-000437-43 
 
R-PrEP V1.3 08/08/2018  
 
IRAS Project ID: 202316 
 
Page 38 of 39 
 
17 Data Management 
All trial data will be inputted using MedSciNet e-CRF and stored on a database to be analysed 
at the end of the study. All lab data will be generated, stored and analysed by University of 
Liverpool and Imperial University. 
18 Publication Policy  
A whole or part of this trial 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. 
19 Insurance / Indemnity 
Insurance for this trial will be undertaken by Guy’s &St. Thomas’ Hospital NHS Foundation Trust 
under the CNST (Clinical Negligence for Trusts) scheme. 
 
20 Financial Aspects 
Funding to conduct the trial is provided by Merck.  
21 Signatures 
 
 
 
 
 
______________________________________ 
 
 
_________________________ 
Chief Investigator 
 
 
 
 
 
Date 
Print name 
 
 
 
 


PROTOCOL IDENTIFICATION NUMBER: JF-007  
EudraCT Number: 2016-000437-43 
 
R-PrEP V1.3 08/08/2018  
 
IRAS Project ID: 202316 
 
Page 39 of 39 
 
References 
 
 
 
1 
FDA; http://www.gilead.com/pr_1660616 
2 
Grant, R.M. et al; http://www.ncbi.nlm.nih.gov/pubmed/21091279  
3 
Garcia-Lerma, J.G et al; http://www.ncbi.nlm.nih.gov/pubmed/18254653  
4 
Herrera, C. et al; http://www.ncbi.nlm.nih.gov/pubmed/21811139 
5 
Anton, P.A. et al; http://www.ncbi.nlm.nih.gov/pubmed/21969851 
6 
O'Quigley J and Zohar S. http://www.ncbi.nlm.nih.gov/pubmed/16434987  
7 
Cranage et al. 2008