Clinical trial NCT02336074
Conditions: HIV
Keywords: HIV Vaccine Cure Early Intervention Infection Primary infection Reservoir Vorinostat HDAC
Sponsor: Imperial College London
Start date: 2015-11-27; Completion date: 2023-03-31
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will be a two-arm prospective 1:1 randomised controlled trial comparing:

Arm A: cART preferably including raltegravir (combination ART cART - control) Arm B: cART preferably including raltegravir (cART) plus ChAdV63.HIVconsv (ChAd) prime and MVA.HIVconsv (MVA) boost vaccines; followed by a 28-day course of vorinostat (10 doses in total).

We hypothesise that this intervention in primary HIV infection will confer a significant reduction in the latent HIV reservoir when compared with cART alone.

.

Detailed description:
The study design is a two-arm, open label randomised study. Eligible participants are recruited from two participant cohorts (Cohort I - Recently diagnosed or Cohort II - Previously diagnosed with HIV). All participants receive combination ART (cART) for the duration of the intervention phase of the study (Cohort I: 42 weeks, Cohort II: 18 weeks). In patients meeting the criteria for randomisation (eligibility assessed at week 22/screening), participants will either continue cART or receive an intervention consisting of two anti-HIV vaccines separated by 8 weeks followed by 10 doses of the HDACi, vorinostat, in addition to cART. We hypothesise that the prime-boost vaccination will result in the generation of vaccine induced HIV specific CTLs that will recognise HDACi-activated cells of the HIV reservoir and destroy them. The net effect will be a greater reduction in the HIV reservoir defined as HIV total DNA in CD4+ T-cells in the cART+vaccine+HDACi compared to the cART alone. Our strategy is entirely different from previous therapeutic vaccination approaches which have been largely unsuccessful. Immunological priming to conserved HIV proteins will drive CD8+ T-lymphocyte recognition of latently-infected cells rendered immunogenic by HDACi. We anticipate that the viral antigens expressed by latently-infected cells will be unable to adapt to, or escape from, the immune response as they will be expressed directly from chromosomal DNA, avoiding the steps of the viral life-cycle that facilitate immune-driven adaptation. We have chosen a prime-boost immunisation strategy with recombinant replication-defective chimpanzee adenovirus and modified vaccinia Ankara vectors, bearing conserved HIV antigens; these products have been shown to induce high titres of HIV-specific CD8+ T-cells. In addition, these vaccines will drive immune responses against conserved regions of the virus that may be well preserved in individuals with PHI.

Primary HIV Infection (PHI) is a unique period when HIV proviral reservoir is smaller than in chronic disease, is likely to be more homogeneous than in later stage disease and hence is more susceptible to immunological elimination. This provides an opportunity to use a vaccine to re-direct HIV-specific immune responses towards genetically fragile regions in the viral proteome. Immunisation in PHI should result in potent immune responses because ART initiated in PHI preserves CD4 function and early ART-mediated viral suppression limits viral diversification, reducing the chance of immune escape. The other key reason for conducting this trial in patients treated in PHI is that, in some patients, an early sustained course of ART started very early in infection may induce a state of viral remission in which therapy can be stopped without any rebound viraemia. This has been most notably reported in the VISCONTI cohort in which 'post-treatment control' was identified in 15.6% of selected individuals.

Data from our group and others has shown that whilst there is a rapid decline in measures of total HIV DNA following ART initiation up to 6 months after seroconversion this then plateaus out to approximately 2 years after diagnosis of acute infection. Hence randomisation of individuals starting immediate ART in acute infection have comparable levels of HIV reservoirs to those who have started treatment within a similar timeframe, but have remained on suppressive therapy for up to 2 years after initiation. Furthermore, since the primary endpoint of the RIVER study design compares total HIV DNA between the two arms from randomisation to post-randomisation weeks 16 \& 18 Cohorts I and II will be comparable.

We hypothesise that the combination of HDACi with immunisation in cART-suppressed PHI will significantly impact the HIV reservoir.

1. Patients in Cohort I - Recently diagnosed will receive combination antiretroviral therapy designed to reduce the plasma viral load as quickly as possible, hence the rationale for the preferred inclusion of raltegravir, an integrase inhibitor. Both cohorts will have been treated in PHI, which may restrict the size of the reservoir compared with people initiating ART in later stages of HIV infection. Cohort II - Previously diagnosed participants are screened the same as Cohort I and are maintained on ART throughout the study. The ART regimen is preferably a combination that includes raltegravir, as hypothetically, if vorinostat induced viral transcription an integrase inhibitor may protect uninfected cells. However, there is no evidence to support this hypothesis and the key inclusion criteria must be the continuation of a virally suppressive ART regimen throughout the study.
2. The prime-boost vaccination is designed to enhance the killing capacity of the cytotoxic T cells. This must be given before the HDACi in order to prime and boost a maximal HIV-specific T-cell response to recognise activated viral antigen expression on reservoir cells.
3. The HDACi is designed to cause viral transcription from latently infected cells; activate the reservoir, and in the presence of the enhanced killing capacity of the CD8+ T cells, results in killing of the cells previously harbouring latent virus, leading to further reductions in the reservoir.

This exact combined approach in treated PHI has never previously been used, we hypothesise there will be a 50% reduction in the proviral DNA (the 'reservoir'), in this 'proof-of-concept' study, in those randomised to the vaccine-HDACi intervention compared to those receiving antiretroviral therapy alone.

Arms: arm 1: Combination Antiretroviral Therapy (cART) preferably including raltegravir prescribed at week 0 for the duration of the study up to post-randomisation week 18 (42 weeks in total) arm 2: Combination Antiretroviral Therapy (cART) preferably including raltegravir prescribed at week 0 for the duration of the study up to post-randomisation week 18 (42 weeks in total) Plus ChAdV63.HIVconsv prime (post-randomisation week 00) and MVA.HIVconsv boost (post randomisation week 08 day 1) vaccines; followed by a 28-day course of vorinostat (10 doses in total).
Interventions: intervention 1: Combination Antiretroviral Therapy (cART) intervention 2: Raltegravir intervention 3: Vorinostat intervention 4: ChAdV63.HIVconsv (ChAd) intervention 5: MVA.HIVconsv (MVA)
Intervention descriptions: intervention 1: Likely consisting of an Nucleoside reverse-transcriptase inhibitor (NRTI) backbone i.e. Truvada plus a ritonavir-boosted protease inhibitor (PI) e.g. Darunavir + ritonavir. Prescribed at week 0 for the duration of the study. intervention 2: All participants will be dispensed sufficient supplies of Raltegravir to ensure they have sufficient medication to last to the next study visit. Raltegravir is supplied in marketed pack with 30 tablets per bottle. intervention 3: Vorinostat (suberoylanilide hydroxamic acid abbreviated to SAHA) inhibits the histone deacetylases HDAC1, HDAC2, HDAC3 (Class I) and HDAC6 (Class II).

Vorinostat is supplied as capsules containing 100mg vorinostat and the following inactive ingredients: microcrystalline cellulose, sodium croscarmellose and magnesium stearate. intervention 4: Dosage: 5x1010vp .This dose is obtained by injecting 0.37ml of the vaccine at 1.35x1011vp/ml without dilution. This prime vaccination is administered intramuscularly (IM) into the deltoid muscle of the non-dominant arm at post-randomisation week 00. intervention 5: Dosage: 2x108pfu Administration: This dose is obtained by injecting 0.23 ml of the vaccine IM at 8.6x108pfu/ml without dilution. This boost vaccination is administered intramuscularly (IM) into the deltoid muscle of the non-dominant arm at post-randomisation week 08 Day 1 (2 prior to start of vorinostat)

Protocol documents:
Prot_000.pdf: 


 
 
RIVER Protocol 
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MRC |CTU 
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GENERAL INFORMATION 
This document was constructed using the MRC CTU Protocol Template Version 3.0. The MRC CTU 
endorses the Standard Protocol Items: Recommendations For Interventional Trials (SPIRIT) initiative. 
It describes the RIVER trial, co-ordinated by the Medical Research Council (MRC) Clinical Trials Unit 
at UCL (herein referred to as MRC CTU), and provides information about procedures for entering 
participants into it. The protocol should not be used as an aide-memoire or guide for the treatment 
of other participants. Every care has been taken in drafting this protocol, but corrections or 
amendments may be necessary. These will be circulated to the registered investigators in the trial, 
but sites entering participants for the first time are advised to contact RIVER Co-ordinating Centre at, 
MRC CTU, to confirm they have the most up-to-date version. 
COMPLIANCE 
The trial will be conducted in compliance with the approved protocol, the Declaration of Helsinki 
1996, the principles of Good Clinical Practice (GCP), Commission Directive 2005/28/EC with the 
implementation in national legislation in the UK by Statutory Instrument 2004/1031 and subsequent 
amendments, the UK Data Protection Act (DPA number: Z6364106), and the National Health Service 
(NHS) Research Governance Framework for Health and Social Care (RGF).  
SPONSOR 
Imperial College London is the trial sponsor and has delegated responsibility for the overall 
management of the RIVER trial to the MRC CTU (RIVER Co-ordinating Centre). Queries relating to 
Imperial sponsorship of this trial should be addressed to the chief investigator via the Imperial Joint 
Research Compliance Office.  
FUNDING 
This study is funded by the Medical Research Council in collaboration with support from industry 
partners. 
AUTHORISATIONS AND APPROVALS 
The following persons are authorised to sign the final protocol and protocol amendments for the 
sponsor: Professor Sarah Fidler (Chief Investigator) and Professor Abdel Babiker (Trial Statistician). 
TRIAL REGISTRATION 
This trial has been registered with EUDRACT Clinical Trials Register, ISRCTN and clinicaltrials.gov.  
 
 
 


 
 
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TRIAL ADMINISTRATION 
 
Please direct all queries to the Trial Manager at the RIVER Co-ordinating Centre in the first instance; 
clinical queries will be passed to the Trial Physician via the Trial Manager. 
 
CHIEF INVESTIGATOR 
      Professor Sarah Fidler
Imperial College London 
HIV Clinical Trials Unit 
Winston Churchill Wing 
St Marys Hospital 
London 
W2 1NY 
Tel: 
0203 312 6972 
Email: 
s.fidler@imperial.ac.uk 
 
 
CO-ORDINATING CENTRE – MRC CLINICAL TRIAL UNIT 
RIVER Trial Co-ordinating Centre 
MRC Clinical Trials Unit at UCL 
Institute of Clinical Trials & Methodology 
4th Floor Aviation House 
125 Kingsway 
London WC2B 6NH 
Switchboard: 
020 7670 4700 
Fax: 
020 7670 4817 
Email: 
mrcctu.river@ucl.ac.uk 
Project Leader, Statistician & 
Co-applicant 
Professor Abdel Babiker
All members of the team can be 
contacted by email 
mrcctu.river@ucl.ac.uk 
Trial Physician:
Dr Sarah L. Pett
Trial Statistician
Dr Wolfgang Stöhr
Clinical Project Manager
Michelle Gabriel 
Trial Manager
Rachel Bennett 
 


 
 
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CO-INVESTIGATORS 
Professor John Frater  
Co-Applicant and Laboratory Lead 
University of Oxford 
Dr Julie Fox  
Clinical Site Principal Investigator  
Guy's and St Thomas' NHS Foundation Trust, 
London 
Dr Sarah L. Pett 
Clinical Site Principal Investigator and Trial Physician 
Mortimer Market Centre, Central and North West 
London Foundation Trust and MRC CTU at UCL 
Professor Mark Nelson  
Clinical Site Principal Investigator and Co-applicant  
Chelsea and Westminster Hospital NHS 
Foundation Trust, London  
Dr Nneka Nkwolo  
Clinical Site Principal Investigator  
Chelsea and Westminster Hospital NHS 
Foundation Trust, London 
Professor Margaret Johnson 
Clinical Site Principal Investigator  
Royal Free London NHS Foundation Trust 
Dr Sabine Kinloch 
Clinical Site Investigator 
Royal Free London NHS Foundation Trust 
Dr Amanda Clarke  
Clinical Site Principal Investigator 
Brighton and Sussex University Hospitals NHS 
Trust 
Professor Andrew Lever  
Co-Principal investigator - Virology Laboratory Scientist 
University of Cambridge 
Professor Myra McClure  
Co-Investigator - Virology 
Imperial College London 
Dr Steve Kaye  
Co-Investigator - Virology 
Imperial College London 
ENROLMENTS 
To enrol a participant, fax or email password protected scanned CRF to the  
RIVER Co-ordinating Centre 
Monday to Friday 09:00 – 17:00 
Fax: +44 (0) 20 7670 4817 
mrcctu.river@ucl.ac.uk 
SAE REPORTING 
Within 24 hours of becoming aware of an SAE, please fax or email a password protected 
completed SAE form to the RIVER Co-ordinating Centre 
Fax: +44 (0) 20 7670 4817  
mrcctu.river@ucl.ac.uk 
RANDOMISATIONS
To randomise, fax or email password protected scanned CRF to the  
RIVER Co-ordinating Centre 
Monday to Friday 09:00 – 17:00 
Fax: +44 (0) 20 7670 4817 
mrcctu.river@ucl.ac.uk 


 
 
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Professor Tom Hanke  
Co-Investigator - Vaccine Development 
University of Oxford 
Professor Lucy Dorrell 
Co-Investigator - Immunology 
University of Oxford 
 


 
 
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SUMMARY OF TRIAL 
SUMMARY INFORMATION TYPE 
SUMMARY DETAILS 
ACRONYM (or Short Title of Trial) 
RIVER 
Long Title of Trial 
Research In Viral Eradication of HIV Reservoirs 
Version 
5.0   
Date 
20-Oct-2016  
ISRCTN # 
ISRCTN83717528 
NCT # 
NCT02336074 
EudraCT # 
2014-001425-32 
Study Design 
This study is a two-arm prospective 1:1 phase II randomised controlled 
trial. 
Participants 
The study aims to enrol 60 individuals across 6 UK collaborating clinical 
centres, from  two different cohorts: 
 
Cohort I: Recently diagnosed with primary HIV-1 infection. Participants, 
must be enrolled within 4 weeks of a confirmed diagnosis of primary HIV-
1 infection. Eligible participants are enrolled at week 0 when 
combination ART (cART) begins. Randomisation of participants occurs 
after assessment of eligibility at week 22.  
Cohort II: Previously diagnosed with primary HIV-1 infection. Confirmed 
diagnosis of primary HIV-1 infection must be within a maximum of 2 
years prior to randomisation. Participants must have started at least 3-
drug ART within 4 weeks of a confirmed diagnosis of primary HIV-1 
infection and remained on ART since starting. Randomisation of 
participants occurs within 2 weeks of the assessment of eligibility at 
screening.  
For both groups primary HIV-1 infection must be confirmed by one of the 
following criteria: 
a. Positive HIV-1 serology within a maximum of 12  weeks of a 
documented negative HIV-1 serology test result (can include 
point of care test (POCT) using blood for both tests) 
b. A positive p24 antigen result and a negative HIV antibody test  
c. 
Negative antibody test with either detectable HIV RNA or 
proviral DNA  
d. PHE RITA test algorithm reported as “Incident” confirming the 
HIV-1 antibody avidity is consistent with recent infection (within 
the preceding 16 weeks)  
e. Weakly reactive or equivocal 4th generation HIV antibody 
antigen test 
f. 
Equivocal or reactive antibody test with <4 bands on western 
blot 
 
Detailed inclusion/exclusion criteria can be found in Section 3. 


 
 
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SUMMARY INFORMATION TYPE 
SUMMARY DETAILS 
Interventions to be Compared 
This study is a two-arm prospective 1:1 randomised controlled trial 
comparing: 
Arm A: Combination ART (cART) preferably including raltegravir (control)*
Arm B: Combination ART (cART) preferably including raltegravir* plus 
ChAdV63.HIVconsv (ChAd) prime and MVA.HIVconsv (MVA) boost 
vaccines; followed by a 28-day course of vorinostat (10 doses in total). 
Study Hypothesis 
In primary HIV infection, a combination of immediate cART, 
immunisation and latency reactivation using the HDACi vorinostat will 
confer a significant reduction in the HIV reservoir when compared with 
cART alone. 
Primary Outcome Measure(s) 
The primary study outcome measure is HIV ‘total’ DNA from CD4 T-cells. 
Secondary Outcome Measure(s) 
Secondary outcome measure include: 
 Clinical and laboratory adverse events, all grades, including SAE 
 Further assessment of the HIV reservoir e.g. HIV integrated 
DNA; HIV cell associated RNA; plasma HIV RNA measured with 
an ultra-low copy assay i.e. with a threshold of <1 copy/ml, viral 
outgrowth assays 
 Studies of immune function including measuring the latently-
infected resting memory T-cells and cytotoxic immune 
responses 
 Changes in inflammatory biomarkers 
Randomisation 
Participants will be randomised to either arm of the study in a 1:1 ratio 
once all inclusion criteria are met.  
Duration 
Planned duration 2.5 years. Participants will be followed for a  minimum 
of 18 weeks after randomisation.  
Sponsor 
Imperial College London 
Funder 
Medical Research Council & industry partners  
Legal Representative in Europe 
Imperial College London  
Chief Investigator 
Professor Sarah Fidler  
MRC CTU Project Leader 
Professor Abdel Babiker  
 
 
 
                                                             
* Preferred regimen prior to randomisation should contain raltegravir. However, where the use of raltegravir is 
contraindicated this can be substituted with another agent preferably in the same class. For some participants 
where this may require a switch prior to joining the study, the participant’s regimen should be switched at least 6 
weeks prior to randomisation.  Any switch made specifically for entry into the study should be conducted after the 
participant has consented to join the study. 


 
 
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TRIAL SCHEMA  
Figure 1 Trial Entry, Randomisation and Treatment – Cohort I - Recently diagnosed  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Figure 2 Trial Entry, Randomisation and Treatment – Cohort II - Previously diagnosed  
 
 


 
 
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TRIAL ASSESSMENT SCHEDULE & VISIT CODES  
Table 1 Trial Assessment Schedule – Cohort I - Recently diagnosed  
 
Schedule Notes: 
 
a) Results for these tests should already be available. If they are not these samples need to be taken as part of screening.  
b) If Viral Load is detectable at week 22 bloods, this may be repeated until the viral load falls below the level of detectability (<50copies/mL or <200copies/mL for the Taqman Roche 2.0 assay). All eligibility criteria must be assessed and met within 14 days prior to randomisation, and may 
need to be repeated. 
c) The timing of the randomisation visit will be determined by the capacity of the vaccination centre 
d) The first vaccination visit, PR00 , must take place within 1 week of randomisation  
e) Time between the two vaccines is 8 weeks (+/- 7 days) 
f) PR08-1 visit ideally takes place on a Monday but can be moved by up to 2 days, whilst still allowing all subsequent visits to fall on weekdays. 
 
 
 
 
Approx. Study Timeline (Weeks)
0
4
12
22
-
Rand
24
40
42
The length of the study period if randomisation takes place 24 weeks after 
enrolment.
STUDY VISITS
Screening
 (-4 to 0)
Enrolment
Week 0
Week 4
Week 12
Week 
22
Repeat 
Viral Load b
Randomisation c
PR Week 00 d
PR Week 
16 
PR Week 
18
DAY IN WEEK
1f
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
Mon
Tue
Wed
Thu
Fri
Sat
Sun
Mon
Tue
Wed
Thu
Fri
Sat
Sun
Mon
Tue
Wed
Thu
Fri
Sat
Sun
Mon
Tue
Wed
Thu
Fri
Sat
Sun
Mon
Tue
Visit Number
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Where 
necessary
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
Visit 12
Visit
13
Visit 14
Visit 15
Combination ART (cART) preferably including raltegravir*
(Both Arms)




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ChAd 
MVA 
Dose 1 
Dose 2
Dose 3
Dose 4
Dose 5
Dose 6
Dose 7
Dose 8
Dose 9
Dose 10
Day 
1 
Day
 2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Day 
8
Day 
9
Day 
10
Day 
11
Day 
12
Day 
13
Day 
14
Day 
15
Day 
16
Day 
17
Day 
18
Day 
19
Day 
20
Day 
21
Day 
22
Day 
23
Day 
24
Day
25
Day 
26
Day 
27
Day 
28
Resting 12-lead ECG






EQ-5D-5L QOL Questionnaire




Hepatitis B & C serology (Results up to 2 months old can be used) 
a

Resistance test a

HCV PCR a


Routine Study Bloods 
(34/27/25/14/7ml)
27
25
25
34
7
27
14
25
14
14
14
14
25
Full Blood Count 
(haemoglobin, haematocrit, white blood cell count (WBC) with 
differential and platelets)


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Biochemistry
(ALT, AST, alkaline phosphatase, total bilirubin and albumin; 
eGFR, creatine kinase)

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
Biochemistry electrolytes i.e. Mg, Ca, K


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
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


HbA1C (only Diabetics)

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Glucose


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

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Lipids 
(Total cholesterol, LDL, HDL, triglycerides)



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Viral Load

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T-Cell Counts

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Urinalysis
(uPCR)

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




Proviral DNA (total), Proviral DNA (integrated), Cell associated 
RNA , Genomics, Low Copy VL, p24 (18/60/80 ml)
Oxford
80
80
60
18
80
80
80
Replication competence and IUPM (250ml) Cambridge
250
250
Immunology (32/40ml)
Oxford
32
32
32
40
32
Vorinostat related virology - Arm B only
Cell associated RNA, HDAC Assay  (20ml pre Vorinostat, 20ml 
2hrs post  (40ml)
Oxford 
40
40
40
Total Blood Draw (mL)
27
112
25
25
34
7
389
0
14
125
86
14
32
174
387
80
TOTAL
1531
PR Week 11
PR Week 12
PR Week 08
Quarter 1
189
LONG-TERM ANNUAL FOLLOW-UP OUT TO 5 YEARS
Vorinostat  (Arm B only)
Vaccine (Arm B only)
Quarterly Blood Draw Totals (ml)
Quarter 2
Quarter 3
430
445
8 Weekse
36
Quarter 4
467
PR Week 09
PR Week 10
POST-RANDOMISATION (PR)
ENDPOINT
32
34
35
33


 
 
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Table 2 Trial Assessment Schedule – Cohort II - Previously diagnosed  
 
Schedule Notes: 
* Preferred regimen prior to randomisation should contain raltegravir. However, where the use of raltegravir is contraindicated this can be substituted with another agent preferably in the same class. For some participants where this may require a switch prior to joining the study, the 
participant’s regimen should be switched at least 6 weeks prior to randomisation.   Any switch made specifically for entry into the study should be conducted after the participant has consented to join the study. 
 
 
 
 
 
 
 
 
a) Screening must take place within the 2 weeks prior to randomisation. All results must be available before randomisation.  
 
 
 
 
 
 
 
 
 
 
 
b) The timing of the randomisation visit will be determined by the capacity of the vaccination centre 
 
 
 
 
 
 
 
 
 
 
 
c) The first vaccination visit, PR00 , must take place within 1 week of randomisation.  
 
 
 
 
 
 
 
 
 
 
 
d) Time between the two vaccines is 8 weeks (+/- 7 days)  
e) PR08-1 visit ideally takes place on a Monday but can be moved by up to 2 days, whilst still allowing all subsequent visits to fall on weekdays 
 
 
 
 
 
 
 
 
 
 
Approx. Study Timeline (Weeks)
0
1
16
18
STUDY VISITS
Screening a
 (-2 to 0)
Randomisation b
PR Week 00c
PR Week 
16 
PR Week 
18
DAY IN WEEK
1e
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
Mon
Tue
Wed
Thu
Fri
Sat
Sun
Mon
Tue
Wed
Thu
Fri
Sat
Sun
Mon
Tue
Wed
Thu
Fri
Sat
Sun
Mon
Tue
Wed
Thu
Fri
Sat
Sun
Mon
Tue
Visit number 
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 10
Visit 11
Combination ART (cART) preferably including raltegravir*
(Both Arms)






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ChAd 
MVA 
Dose 1 
Dose 2
Dose 3
Dose 4
Dose 5
Dose 6
Dose 7
Dose 8
Dose 9
Dose 10
Day 
1 
Day
 2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Day 
8
Day 
9
Day 
10
Day 
11
Day 
12
Day 
13
Day 
14
Day 
15
Day 
16
Day 
17
Day 
18
Day 
19
Day 
20
Day 
21
Day 
22
Day 
23
Day 
24
Day
25
Day 
26
Day 
27
Day 
28
Resting 12-lead ECG

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


EQ-5D-5L QOL Questionnaire



Hepatitis B serology & C serology (Results up to 2 months old can 
be used) a

Resistance test a

HCV PCR/Antigen a

Routine Study Bloods 
(34/27/25/14ml)
34
27
14
25
14
14
14
14
25
Full Blood Count 
(haemoglobin, haematocrit, white blood cell count (WBC) with 
differential and platelets)









Biochemistry
(ALT, AST, alkaline phosphatase, total bilirubin and albumin; 
eGFR, creatine kinase)









Biochemistry electrolytes i.e. Mg, Ca, K








HbA1C (only Diabetics)


Glucose









Lipids 
(Total cholesterol, LDL, HDL, triglycerides)



Viral Load




T-Cell Counts




Urinalysis
(uPCR)









Proviral DNA (total), Proviral DNA (integrated), Cell associated 
RNA , Genomics, Low Copy VL, p24 (18/60/80 ml)
Oxford
80
60
18
80
80
80
Replication competence and IUPM (250ml) Cambridge
250
250
Immunology (32/40ml)
Oxford
32
32
40
32
Vorinostat related virology - Arm B only
Cell associated RNA, HDAC Assay  (20ml pre Vorinostat, 20ml 2hrs 
post  (40ml)
Oxford 
40
40
40
Total Blood Draw (ml)
34
389
0
14
125
86
14
32
174
387
80
Quarterly Blood Draw Totals (ml)
Total 
1335
ENDPOINT
LONG-TERM ANNUAL FOLLOW-UP OUT TO 5 YEARS
8 Weeksd
PR Week 08
PR Week 09
PR Week 10
PR Week 11
PR Week 12
8
Vorinostat  (Arm B only)
Vaccine (Arm B only)
9
POST-RANDOMISATION (PR)
10
11
12
467
Quarter 1
423
Quarter 2 
Quarter 3 
445


 
 
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Table 3 Visit names and codes – Cohort I - Recently diagnosed  
 
 
 
 
 
 
 
 
 
Study visit name  
Visit 
number  
Visit schedule  
Visit code 
Pre – Randomisation 
Screening  
Visit 1 
Eligibility for enrolment assessed  
Screening  
Enrolment 
Visit 2 
Participant is enrolled and commences  
combination ART (cART) preferably 
including raltegravir  
Week 0 
Follow up week 04 
Visit 3 
Follow up visit 
Week 04 
Follow up week 12 
Visit 4 
Follow up visit 
Week 12 
Follow up week 22 
Visit 5 
Eligibility for randomisation assessed  
Week 22 
Randomisation 
Visit 6 
Participant is randomised  
Randomisation  
 
Arm A (control) 
Combination 
ART (cART) 
preferably 
including 
raltegravir  
Arm B  
Combination  ART 
(cART)  preferably 
including raltegravir 
+ Vaccines + 
vorinostat 
 
Post – Randomisation  
Post-randomisation week 00 
Visit 7 
Follow up visit 
Administration of 
ChAd vaccine 
PR00 
Post-randomisation week 08 Day 1 
Visit 8 
Follow up visit 
Administration of 
MVA vaccine  
PR08-1 
Post-randomisation week 08 Day 3 
Visit 9 
Follow up visit 
First dose of 
vorinostat  (then 
taken every 3rd day) 
PR08-3 
Post-randomisation week 09 Day 2 
Visit 10 
Follow up visit 
Vorinostat dosing 
continued 
PR09-2 
Post-randomisation week 10 Day 1 
Visit 11 
Follow up visit 
Vorinostat dosing  
continued 
PR10-1 
Post-randomisation week 11 Day 1 
Visit 12 
Follow up visit 
Vorinostat dosing  
continued 
PR11-1 
Post-randomisation week 12 Day 2 
Visit 13 
Follow up visit 
Last dose of 
vorinostat  
PR12-2 
Post-randomisation week 16 
Visit 14 
Follow up visit 
Follow up visit 
PR16 
Post-randomisation week 18 
Visit 15 
Final follow up 
visit 
Final follow up visit 
PR18 


 
 
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Table 4 Visit names and codes – Cohort II – Previously diagnosed  
 
 
Study visit name  
Visit 
number  
Visit schedule  
Visit code 
Pre-randomisation 
Screening  
Visit 1 
Eligibility for randomisation assessed  
Screening  
Randomisation 
Visit 2 
Participant is randomised  
Randomisation  
 
Arm A (control) 
Combination 
ART (cART) 
preferably 
including 
raltegravir 
Arm B  
Combination ART 
(cART) preferably 
including raltegravir 
+ Vaccines + 
vorinostat 
 
Post – Randomisation  
Post-randomisation week 00 
Visit 3 
Follow up visit 
Administration of 
ChAd vaccine 
PR00 
Post-randomisation week 08 Day 1 
Visit 4 
Follow up visit 
Administration of 
MVA vaccine  
PR08-1 
Post-randomisation week 08 Day 3 
Visit 5 
Follow up visit 
First dose of 
vorinostat  (then 
taken every 3rd day) 
PR08-3 
Post-randomisation week 09 Day 2 
Visit 6 
Follow up visit 
Vorinostat dosing 
continued 
PR09-2 
Post-randomisation week 10 Day 1 
Visit 7 
Follow up visit 
Vorinostat dosing  
continued 
PR10-1 
Post-randomisation week 11 Day 1 
Visit 8 
Follow up visit 
Vorinostat dosing  
continued 
PR11-1 
Post-randomisation week 12 Day 2 
Visit 9 
Follow up visit 
Last dose of 
vorinostat  
PR12-2 
Post-randomisation week 16 
Visit 10 
Follow up visit 
Follow up visit 
PR16 
Post-randomisation week 18 
Visit 11 
Final follow up 
visit 
Final follow up visit 
PR18 


 
 
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CONTENTS 
GENERAL INFORMATION .............................................................................................. I 
SUMMARY OF TRIAL................................................................................................... V 
TRIAL SCHEMA.......................................................................................................... VII 
TRIAL ASSESSMENT SCHEDULE & VISIT CODES ......................................................... IX 
CONTENTS ................................................................................................................. 13 
ABBREVIATIONS ........................................................................................................ 17 
1 
BACKGROUND ................................................................................................ 19 
 
RESEARCH TREATMENT: HISTONE DEACETYLASE INHIBITORS (HDACI)................................................ 20 
1.1
 
Pre-clinical safety data .......................................................................................................... 20 
1.1.1
 
Rationale and Clinical Experience with the HDACi in HIV-infection ........................................ 22 
1.1.2
 
RESEARCH TREATMENT: HIV VACCINES ........................................................................................ 23 
1.2
 
The Development of Unique HIV-1 Immunogens .................................................................. 23 
1.2.1
 
Development of Highly Immunogenic Replication-Defective Simian Adenoviral Vectors ....... 23 
1.2.2
 
Modified Vaccinia Virus Ankara (MVA) as a Viral Vector ....................................................... 24 
1.2.3
 
Pre-clinical data .................................................................................................................... 24 
1.2.4
 
Clinical data .......................................................................................................................... 25 
1.2.5
 
STUDY DESIGN AND HYPOTHESIS ................................................................................................. 26 
1.3
2 
SELECTION OF SITES/CLINICIANS .................................................................... 29 
 
SITE/INVESTIGATOR INCLUSION CRITERIA...................................................................................... 29 
2.1
 
Principal Investigator's Qualifications & Agreements ............................................................ 29 
2.1.1
 
Adequate Resources ............................................................................................................. 29 
2.1.2
 
APPROVAL AND ACTIVATION ...................................................................................................... 30 
2.2
 
RIVER TRIAL CENTRES .............................................................................................................. 30 
2.3
3 
SELECTION OF PARTICIPANTS ......................................................................... 31 
 
NUMBER OF PARTICIPANTS......................................................................................................... 31 
3.1
 
CONSENT PROCESS ................................................................................................................... 31 
3.2
 
COHORT I – RECENTLY DIAGNOSED PARTICIPANTS ........................................................................... 32 
3.3
 
Enrolment Inclusion Criteria ................................................................................................. 32 
3.3.1
 
Enrolment Exclusion Criteria ................................................................................................. 33 
3.3.2
 
Criteria for Randomisation.................................................................................................... 34 
3.3.3
 
COHORT II – PREVIOUSLY DIAGNOSED PARTICIPANTS ...................................................................... 35 
3.4
 
Randomisation Inclusion Criteria .......................................................................................... 35 
3.4.1
 
Randomisation Exclusion Criteria .......................................................................................... 36 
3.4.2
4 
ENROLMENT & RANDOMISATION .................................................................. 38 
 
ENROLMENT PRACTICALITIES ...................................................................................................... 38 
4.1
 
RANDOMISATION PRACTICALITIES ............................................................................................... 38 
4.2


 
 
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CO-ENROLMENT GUIDELINES ...................................................................................................... 39 
4.3
5 
TREATMENT OF PARTICIPANTS ...................................................................... 40 
 
IMP MANAGEMENT ................................................................................................................. 40 
5.1
 
PRE-RANDOMISATION TREATMENT ............................................................................................. 40 
5.2
 
Use of an Integrase inhibitor................................................................................................. 40 
5.2.1
 
Use of ART prior to Enrolment – Cohort I – Recently diagnosed ............................................ 41 
5.2.2
 
Use of ART prior to Enrolment – Cohort II – Previously diagnosed......................................... 41 
5.2.3
 
TREATMENT AT ENROLMENT/RANDOMISATION .............................................................................. 41 
5.3
 
POST-RANDOMISATION (PR) TREATMENT .................................................................................... 42 
5.4
 
CRITERIA FOR STARTING VORINOSTAT .......................................................................................... 45 
5.5
 
DISPENSING AND HANDLING ...................................................................................................... 45 
5.6
 
Combination ART (cART) ....................................................................................................... 45 
5.6.1
 
Raltegravir ............................................................................................................................ 45 
5.6.2
 
Vaccines ............................................................................................................................... 46 
5.6.3
 
Vorinostat ............................................................................................................................ 46 
5.6.4
 
STOPPING DRUG EARLY ............................................................................................................. 46 
5.7
 
Combination ART .................................................................................................................. 46 
5.7.1
 
Raltegravir ............................................................................................................................ 47 
5.7.2
 
Vaccines ............................................................................................................................... 47 
5.7.3
 
Vorinostat ............................................................................................................................ 47 
5.7.4
 
DOSE MODIFICATIONS, INTERRUPTIONS & DISCONTINUATIONS ........................................................ 48 
5.8
 
Vorinostat toxicity management ........................................................................................... 48 
5.8.1
 
OVERDOSE OF TRIAL MEDICATION ............................................................................................... 49 
5.9
 
PROTOCOL TREATMENT DISCONTINUATION ................................................................................... 50 
5.10
 
ACCOUNTABILITY & UNUSED DRUGS ........................................................................................... 50 
5.11
 
COMPLIANCE & ADHERENCE ...................................................................................................... 51 
5.12
 
TREATMENT DATA COLLECTION .................................................................................................. 51 
5.13
 
CONCOMITANT MEDICATIONS .................................................................................................... 51 
5.14
 Medications Permitted ......................................................................................................... 51 
5.14.1
 Medications Not Permitted .................................................................................................. 51 
5.14.2
 Medications to be Used With Caution .................................................................................. 51 
5.14.3
6 
ASSESSMENTS & FOLLOW-UP ......................................................................... 52 
 
TRIAL ASSESSMENT SCHEDULE .................................................................................................... 52 
6.1
 
Screening ............................................................................................................................. 52 
6.1.1
 
PROCEDURES FOR ASSESSING EFFICACY ........................................................................................ 53 
6.2
 
PROCEDURES FOR ASSESSING SAFETY ........................................................................................... 53 
6.3
 
PROCEDURES FOR ASSESSING QUALITY OF LIFE .............................................................................. 54 
6.4
 
EARLY STOPPING OF FOLLOW-UP................................................................................................. 54 
6.5
 
PARTICIPANT TRANSFERS ........................................................................................................... 54 
6.6
 
LOSS TO FOLLOW-UP................................................................................................................. 54 
6.7
 
ASSESSMENTS AT TRIAL CLOSURE ................................................................................................ 55 
6.8
 
LONG-TERM FOLLOW-UP ........................................................................................................... 55 
6.9
7 
SAFETY REPORTING ........................................................................................ 56 
 
DEFINITIONS............................................................................................................................ 56 
7.1
 
Medicinal Products ............................................................................................................... 57 
7.1.1
 
Adverse Events ..................................................................................................................... 57 
7.1.2


 
 
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Disease-related Events ......................................................................................................... 57 
7.1.3
 
OTHER STUDY-SPECIFIC REQUIREMENTS & EXPLORATORY OUTCOMES ................................................ 57 
7.2
 
Large volume blood draw ..................................................................................................... 57 
7.2.1
 
Exploratory outcomes – Human endogenous retroviruses .................................................... 58 
7.2.2
 
OTHER NOTABLE EVENTS ........................................................................................................... 58 
7.3
 
Vaccine related events ......................................................................................................... 58 
7.3.1
 
Cancers ................................................................................................................................ 58 
7.3.2
 
Pregnancy ............................................................................................................................ 59 
7.3.3
 
INVESTIGATOR RESPONSIBILITIES ................................................................................................. 59 
7.4
 
Investigator Assessment ....................................................................................................... 59 
7.4.1
 
Notification Procedure ......................................................................................................... 61 
7.4.2
 
RIVER CO-ORDINATING CENTRE RESPONSIBILITIES ......................................................................... 61 
7.5
8 
QUALITY ASSURANCE & CONTROL ................................................................. 63 
 
RISK ASSESSMENT .................................................................................................................... 63 
8.1
 
CENTRAL MONITORING AT THE RIVER CO-ORDINATING CENTRE ....................................................... 63 
8.2
 
ON-SITE MONITORING .............................................................................................................. 63 
8.3
 
Direct Access to Participant Records ..................................................................................... 64 
8.3.1
 
Confidentiality ...................................................................................................................... 64 
8.3.2
9 
STATISTICAL CONSIDERATIONS ...................................................................... 65 
 
METHOD OF RANDOMISATION.................................................................................................... 65 
9.1
 
OUTCOME MEASURES ............................................................................................................... 65 
9.2
 
Primary Outcome Measure ................................................................................................... 65 
9.2.1
 
Secondary Outcome Measures ............................................................................................. 65 
9.2.2
 
SAMPLE SIZE ........................................................................................................................... 65 
9.3
 
INTERIM MONITORING & ANALYSES ............................................................................................ 66 
9.4
 
ANALYSIS PLAN (BRIEF) ............................................................................................................. 66 
9.5
10 
PARTICIPANT AND PUBLIC INVOLVEMENT ..................................................... 67 
11 
REGULATORY & ETHICAL ISSUES..................................................................... 68 
 
COMPLIANCE ........................................................................................................................... 68 
11.1
 Regulatory Compliance ......................................................................................................... 68 
11.1.1
 Site Compliance .................................................................................................................... 68 
11.1.2
 Data Collection & Retention ................................................................................................. 68 
11.1.3
 
ETHICAL CONDUCT OF THE STUDY ................................................................................................ 68 
11.2
 Ethical Considerations .......................................................................................................... 69 
11.2.1
 Ethical Approvals .................................................................................................................. 69 
11.2.2
 
COMPETENT AUTHORITY APPROVALS ........................................................................................... 69 
11.3
 
OTHER APPROVALS .................................................................................................................. 70 
11.4
12 
INDEMNITY ..................................................................................................... 71 
13 
FINANCE .......................................................................................................... 72 
14 
OVERSIGHT & TRIAL COMMITTEES ................................................................. 73 
 
TRIAL MANAGEMENT TEAM (TMT) ............................................................................................. 73 
14.1
 
PROJECT MANAGEMENT GROUP (PMG) ...................................................................................... 73 
14.2


 
 
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TRIAL STEERING COMMITTEE (TSC) ............................................................................................. 74 
14.3
 
INDEPENDENT DATA MONITORING COMMITTEE (IDMC) ................................................................. 74 
14.4
 
ROLE OF STUDY SPONSOR .......................................................................................................... 74 
14.5
15 
PUBLICATION .................................................................................................. 75 
16 
PROTOCOL AMENDMENTS ............................................................................. 76 
17 
REFERENCES .................................................................................................... 79 


 
 
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ABBREVIATIONS 
ABBREVIATION DEFINITION 
ABBREVIATION 
DEFINITION 
ADI 
AIDS-defining illness 
GMFA 
Gay Men Fight AIDS 
AE 
Adverse Event 
GMO 
Genetically modified organism 
AHSC 
Academic Health Science Centre 
GMP 
Good Manufacturing Practice 
ANCOVA 
Analysis of covariance 
GSK 
GlaxoSmithKline 
AR 
Adverse Reaction 
HCV 
Hepatitis C virus (HCV) 
ART 
Antiretroviral therapy 
HDACi 
Histone deacetylase inhibitors 
AUC 
Area under the curve 
HIV-1 
Human Immunodeficiency Virus Type 1 (HIV-1) 
BHIVA 
British HIV Association 
HTLV-1 
Human T Cell Lymphotropic Virus-1 
BID 
Twice a day 
IB 
Investigator Brochure 
CAB 
Community Advisory Board 
IDMC 
Independent Data Monitoring Committee  
cART 
Combination Antiretroviral Therapy 
IL-7 
Interleukin 7 
CBF 
Clinical BioManufacturing Facility 
IM 
 
Intra-muscularly 
CHERUB 
Collaborative HIV Eradication of viral 
Reservoirs 
INSTI 
Integrase Strand Transfer Inhibitors 
CHO 
Chinese Hamster Ovary 
ITT 
Intention to Treat 
CNS 
Central Nervous System 
IVIG 
Intravenous immunoglobulin 
CRF 
Case Report Form 
LFT 
Liver Function Tests 
CTA 
Clinical Trials Authorisation  
LPLV 
Last participant last visit 
CTCL 
Cutaneous T cell lymphoma  
MHRA 
Medicines and Healthcare Products Regulatory 
Agency 
CTU 
Clinical Trials Unit 
MSD 
Merck Sharp and Dohme 
CYP 
Cytochromes P450  
MRC 
Medical Research Council 
DDI 
Drug-to-drug interaction 
MRC CTU 
Medical Research Council Clinical Trials Unit at 
UCL 
DNA 
Deoxyribonucleic acid 
NGO 
Non-governmental organisation  
DPA 
Data Protection Act 
NHS 
National Health Service 
DSUR 
Development Safety Update Report 
NNRTI 
Non-nucleoside reverse transcriptase 
inhibitors 
EBV 
Estimation of blood volume 
NRTI 
Nucleoside/nucleotide reverse transcriptase 
inhibitors 
ECG 
Electrocardiography 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
eGFR 
Estimated Glomerular Filtration Rate 
OD 
Once a day 
EU 
European Union 
PBMC 
Peripheral blood mononucleated cell 
FBC 
Full Blood Count 
PEP 
Post-Exposure Prophylaxis  
GCP 
Good Clinical Practice 
PHE 
Public Health England 


 
 
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ABBREVIATION DEFINITION 
ABBREVIATION 
DEFINITION 
PHI 
Primary HIV-1 infection 
SAHA 
Suberoylanilide hydroxamic acid 
PI 
Protease Inhibitor 
SAE 
Serious Adverse Event 
PIL 
Patient Information Leaflet 
SAP 
Statistical Analysis Plan 
PIM 
Protocol Instruction Manual 
SAR 
Serious Adverse Reaction 
PI/r 
Ritonavir-boosted PI 
SIV 
Simian immunodeficiency virus 
PK 
Pharmacokinetics 
SmPC 
Summary of product characteristics 
PMG 
Project Management Group 
SNA 
Serious Non-AIDS Event 
POCT 
Point-of-care testing 
SUSAR 
Suspected Unexpected Serious Adverse 
Reaction 
PR 
Post-Randomisation  
THT 
Terrance Higgins Trust 
PrEP 
Pre-Exposure Prophylaxis  
TMF 
Trial Master File 
QA/QC 
Quality Assurance/Quality Control 
TSC 
Trial Steering Committee  
QD 
Quaque die (one a day) 
UAR 
Unexpected Adverse Reaction 
R&D 
Research and Development 
UK BRC 
UK Biomedical Research Centres 
REC 
Research Ethics Committee 
UK DPA 
UK Data Protection Act 
RGF 
Research Governance Framework 
uPCR 
Urine protein to creatinine ratio 
RITA 
Recent Infection Testing Algorithm 
ULN 
Upper Limit of Normal 
RIVER 
Research In Viral Eradication of HIV 
Reservoirs 
VL 
HIV viral load 
RNA 
Ribonucleic acid  
 
 


 
 
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1 
BACKGROUND  
Although antiretroviral therapy (ART) has significantly improved long-term survival for people living 
with HIV by controlling viral replication, it alone cannot ‘cure’ infection. This is because ART alone is 
not capable of eradicating virus from all infected cells, and so in chronic stages of HIV disease, for 
the majority of individuals cessation of ART leads to immediate recrudescence of viraemia1.  
 
There is broad consensus that following HIV transmission (acute infection or HIV seroconversion), 
the first viraemia of HIV infection leads to the seeding of the HIV genome as integrated proviral DNA 
in all CD4-bearing permissive cells, predominantly resting memory CD4+ T-cells and other long-lived 
cells, such as macrophages2-4. After the initial viraemia has settled, many of these provirally-infected 
cells will revert to a resting state where they become non-activated and non-replicating and where 
the viral genome is transcriptionally silent (viral latency). These infected cells are termed the HIV 
reservoir or latently-infected pool, and it is the failure to eradicate these cells that means ART is 
unable to cure infection. As these latently-infected cells do not express any viral antigens they 
cannot be recognised or eliminated by T cell surveillance and ART does not affect them. As many 
latently-infected cells may be long-lived, there is lifelong persistence of HIV in the face of 
suppressive ART.  
 
Latently infected cells will randomly become activated over time and viral particles may be 
produced, although with continued ART viral progeny will not be able to propagate. However, the 
observation that viral recrudescence is almost universal on cessation of ART1 suggests that the 
half-life of these latently-infected cells must be very long.  
 
Maintenance of viral latency is a complex process where several factors restrict completion of viral 
replication. Latency is maintained in part by the activity of histone deacetylase (HDAC)5, an enzyme 
that removes acetyl groups from DNA-bound histone proteins and, in so doing, affects gene 
expression.  
 
The only way to ‘cure’ HIV infection, defined as the absence of any detectable infected cells off ART, 
has been to use a complex intervention including bone marrow transplantation, total body 
irradiation and systemic chemotherapy6 which is not feasible or scaleable but provides a fascinating 
proof of concept. The much cited ‘Mississippi baby’ case gave some hope that starting immediate 
ART within hours of estimated vertical transmission might prevent the establishment of HIV 
infection. Unfortunately, HIV has now rebounded in this child, and subsequently one other similar 
case indicating that despite very early antiretroviral therapy and no initial rebound of virus off 
treatment, that this child is truly HIV infected7. Alternative strategies more amenable to 
generalizable use are the strategic use of ART as near to the defined time of viral acquisition8. In one 
cohort of patients (VISCONTI) treated with ART during primary infection, 15.6% had no rebound of 
virus following treatment interruption, however, in the majority, virus rebounded and became 
detectable on stopping ART. It appears therefore that for the majority of individuals a further 
intervention in addition to ART maybe required to confer viral control off therapy, even for those 
starting as close to the time of viral transmission as possible. Elimination of the HIV reservoir is likely 
to require more than one intervention: 1) suppression of viral replication through ART; 
2) re-activation of HIV transcription from latently-infected cells and 3) elimination of these 
reactivated cells; the ‘shock and kill’ strategy9,10. 
 


 
 
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Re-activation of latently-infected cells results in viral transcription and hence is likely to lead to 
expression of viral antigens. One approach currently being explored to eliminate latently-infected 
CD4+ T-cells is to activate viral production from these cells in the presence of ART. The rationale for 
this approach is that production of virus should kill the infected cells and subsequent rounds of 
infection would be inhibited by the presence of ART. Based upon this principle, initial proof of 
concept studies have explored the role of adding novel agents capable of inducing viral transcription 
to ART; including anti-PD-1, IL-7, intravenous immunoglobulin (IVIG), gene therapy, prostratin and 
histone deacetylase inhibitors (HDACi)4,10-12. 
 
RESEARCH TREATMENT: HISTONE DEACETYLASE INHIBITORS (HDACI) 
1.1
HDACi are a new class of anti-neoplastic agents, which have undergone rapid development in several 
phase I/II studies. Vorinostat (suberoylanilide 
hydroxamic acid abbreviated to SAHA) inhibits the 
histone deacetylases HDAC1, HDAC2, HDAC3 (Class I) 
and HDAC6 (Class II).  
 
Vorinostat (Zolinza) is supplied as capsules 
containing 100mg vorinostat and the following 
inactive ingredients: microcrystalline cellulose, 
sodium croscarmellose and magnesium stearate. 
The capsule shell excipients are titanium 
dioxide, gelatin and sodium lauryl sulphate. 
Figure 3 Vorinostat Structure  
 
PRE-CLINICAL SAFETY DATA  
1.1.1
Vorinostat was mutagenic in vitro in the bacterial reverse mutation assays (Ames test), caused 
chromosomal aberrations in vitro in Chinese hamster ovary (CHO) cells and increased the incidence 
of micro-nucleated erythrocytes when administered to mice (mouse micronucleus assay). Effects on 
the female reproductive system were identified in the oral fertility study when females were dosed 
for 14 days prior to mating through gestational day 7. Doses of 15, 50 and 150mg/kg/day to rats 
resulted in approximate exposures of 0.15, 0.36 and 0.70 times the expected clinical exposure based 
on AUC. Dose dependent increases in corpora lutea were noted at ≥15mg/kg/day and increased 
peri-implantation losses were noted at ≥50mg/kg/day. At 150mg/kg/day, there were increases in the 
incidences of dead foetuses and in resorptions. No effects on reproductive performance observed in 
male rats dosed (20, 50, 150mg/kg/day; approximate exposures of 0.15, 0.36 and 0.70 times the 
expected clinical exposure based on AUC), for 70 days prior to mating with untreated females. 
 
1.1.1.A 
 PHARMACOKINETICS (PK) 
Vorinostat is absorbed orally and absorption is increased (33%) by co-absorption of dietary fat. 
Administration of vorinostat with food achieves maximum concentration at a median of 
4 (0.5-14) hours. Vorinostat is ≈71% bound to human plasma proteins; mean terminal half-life (t½) is 
~2.0 hours. Elimination is predominantly through metabolism to two inactive metabolites by 
glucuronidation and hydrolysis followed by ß-oxidation. While vorinostat has not been evaluated in 
patients with hepatic or renal insufficiency, renal excretion does not play a role in the elimination of 
vorinostat. Based upon an exploratory analysis of limited data, gender, race and age do not appear 
to have meaningful effects on the PK; vorinostat has not been evaluated in patients <18 years of age. 
Vorinostat is not eliminated via the CYP pathways, neither is it an inhibitor of CYP drug metabolising 
enzymes in human liver microsomes at steady state. Some suppression of CYP2C9 and CYP3A4 
activity was detected at concentrations higher (≥10μM) than pharmacologically relevant. It is not 
anticipated that vorinostat will be subject to drug-drug interactions (DDI) when co-administered 
with drugs that are known CYP inhibitors or inducers. However, no formal DDI clinical studies have 


 
 
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been conducted to evaluate drug interactions with vorinostat. In vitro studies indicate that 
vorinostat is not a substrate of human P-glycoprotein (P-gp). In addition, vorinostat has no inhibitory 
effect on human P-gp mediated transport of vinblastine (a marker P-gp substrate) at concentrations 
of ≤100μM. Thus, vorinostat is not likely to inhibit P-gp at pharmacologically relevant serum 
concentrations of 2μM (Cmax) in humans. There does, however, appear to be an interaction with 
warfarin (coumarin) with prolongation of INR (international normalized ratio).  
 
1.1.1.B PHARMACOKINETIC/PHARMACODYNAMIC – EFFECTS ON QTC 
The “normal” range for QTc interval from the general population, as measured by 12-lead ECG, is 
generally considered to be between 350 and 440ms13,14. In addition the actual clinical relationship 
between drug-induced QTc interval prolongation and Torsades de Pointes is likely only with very 
long intervals (> 500ms) and is less defined with smaller interval changes13. The Division of AIDS 
toxicity grading table (see Appendix III) defines abnormal QTc interval as: 
 
Grade 1 - 0.45 – 0.47 sec OR increase interval < 0.03 sec above baseline 
 
Grade 2 - 0.48 – 0.49 sec OR increase in interval 0.03 - 0.05 sec above baseline  
 
Grade 3 - ≥0.50 sec OR increase in interval ≥ 0.06sec above baseline  
 
Grade 4 - Life threatening consequences e.g. Torsade de pointes or other associated 
ventricular dysrhythmia. 
 
Data on vorinostat and QTc prolongation is largely derived from patients taking this drug for the 
treatment of cutaneous T cell lymphoma (CTCL). In 25 healthy volunteers given a single 
supratherapeutic dose of vorinostat 800mg, no patient had a significant change in QTc over 24 hours 
of ECG monitoring. In other studies 3 of 86 (3.4%) CTCL patients exposed to 400mg QD had Grade 
1-2 QTc prolongation. In a retrospective analysis of 5 studies (3 Phase I trials and 2 Phase II trials), 4 
of 116 (3.4%) evaluable patients had grade 2 QTc prolongation, and 1/116 (0.8%) had grade 3 QTc 
prolongation. Of 49 non-CTCL patients from 3 clinical trials, 1 had grade 2 prolongation and 2 had 
grade 3 QTc prolongation15. 
 
The first study to use multiple doses of vorinostat in HIV-positive individuals excluded individuals 
from enrolment with a QTc value >450msec. In the Lewin study, vorinostat was administered as 14 
continuous 400mg daily oral doses15. There were no Serious AEs related to QTc prolongation in this 
study. 
 
1.1.1.C CLINICAL EXPERIENCE WITH HDACI IN OTHER DISEASE AREAS 
HDACi have shown efficacy in relapsed/refractory myelodysplasia (MDS), acute myeloid leukaemia 
Hodgkin lymphoma (HL) and in particular the T cell lymphomas16. In the US vorinostat is licensed 
(since 2006) for the treatment of cutaneous manifestation of CTCL in those who have progressive, 
persistent or recurrent disease on or following two systemic therapies. It has also been granted 
orphan drug status for the treatment of refractory multiple myeloma in the US (October 2013). In 
the EMEA, vorinostat was granted orphan designation for use in malignant mesothelioma in 
September 2010; but this was withdrawn at the Sponsor (MSD) in February 2013. Other HDACi such 
as romidepsin (depsipeptide), panobinostat and MGCD-0103 have also demonstrated activity in 
various haematological malignancies. Further information on the toxicity profile of vorinostat is 
provided in Appendix II but in summary – in the cancer setting, the most common drug-related 
adverse reactions can be classified into four symptom complexes. 
 
1. Gastrointestinal symptoms - Anorexia, nausea, vomiting, diarrhoea, weight loss and 
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2. Constitutional symptoms - Fatigue has been reported commonly with use of vorinostat and 
occurred more commonly at doses of vorinostat >400mg per day. Chills and fever have also 
been reported. 
3. Abnormalities - Dose-related anaemia and thrombocytopaenia can occur with vorinostat and 
are more common at doses of >400mg per day. Neutropaenia is uncommon, but has been 
reported. Monitoring of blood cell counts should be performed every 2 weeks during the 
first 2 months of therapy and monthly thereafter. If platelet counts and/or haemoglobin are 
reduced during treatment with vorinostat, the dose should be modified or therapy 
discontinued. 
4. Taste disorders - Dysgeusia and dry mouth have been reported. 
 
The most common serious adverse events (SAE), regardless of causality, in the 86 CTCL patients in 
two clinical studies were pulmonary embolism reported in 4.7% (4/86) of patients, squamous cell 
carcinoma reported in 3.5% (3/86) of patients and anaemia reported in 2.3% (2/86) of patients. 
Patients on vorinostat should therefore be monitored for pertinent signs or symptoms of deep vein 
thrombosis or pulmonary embolism. 
 
1.1.1.D DISCONTINUATION DUE TO ADVERSE EVENTS IN CTCL PATIENTS WHO RECEIVED THE 400MG QD DOSE 
9.3% (8/86) discontinued vorinostat due to AE and 10.5% (9/86) required a dose modification due to 
AE. The median time to the first AE resulting in dose reduction was 42 days (range 17 to 263 days). 
Laboratory abnormalities were reported in the 86 patients who received the 400-mg dose and one 
patient who received a 350-mg dose. Increased serum glucose was detected by laboratory safety 
tests in 69% (60/86) of CTCL patients, but was severe (Grade 3) in only 5 of these. Hyperglycaemia 
was reported as a drug-related adverse event in in 4.7% (4/86) of CTCL patients receiving 400mg QD. 
Transient increases in serum creatinine were detected in 47.1% (41/87) of CTCL patients; in most 
cases these increases were non-severe, however, Grade 3 AEs have been observed. Based on reports 
of dehydration as a serious drug-related adverse experience in clinical trials, patients were 
instructed to drink at least 2L/day of fluids for adequate hydration. After these precautions were 
implemented, the incidence of dehydration decreased. Proteinuria was detected as a laboratory 
abnormality (51.4%) in 38 of 74 patients tested. The clinical significance of this finding is unknown. 
 
 
RATIONALE AND CLINICAL EXPERIENCE WITH THE HDACI IN HIV-INFECTION 
1.1.2
Although some (HDACi) can induce mutations (in vitro), they may reverse latency5,11. Initial studies 
using HDACis such as sodium valproate with ART in HIV failed to limit the reservoir size, or confer 
clinical advantage17. Vorinostat better targets the specific histones associated with HIV repression 
and reactivates HIV from latently-infected T cell lines and primary T-cells infected in vitro and 
in vivo18,19. Transient hyperacetylation of histones in peripheral blood mononuclear cells (PBMC) and 
tumour cells occurred two hours after in vivo administration and returned to baseline levels eight 
hours post treatment20 . A single dose proof-of-concept trial in chronically HIV infected individuals, 
showed that vorinostat with ART resulted in a 5-fold increase in viral transcription from the 
reservoir21. More recently, a 14 day dosing schedule of vorinostat in chronically HIV infected 
individuals on ART induced a 2.5-fold increase in viral transcription22. Recent data from Margolis et 
al23 has shown that for some individuals there is a refractory period after dosing with vorinostat 
during which there is no measureable increase in histone deacetylation inhibition. In addition, in 
vitro cell culture models have similarly demonstrated a potential refractory period after vorinostat 
dosing of between 24-28 hours. Whilst daily oral dosing was used in the Lewin 14 day course with 
some but limited effect on histone deacetylation inhibition, we have altered our dosing schedule to 
every 3 days to try and accommodate this potential refractory period. Furthermore, we anticipate 
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proof-of-concept for HDACi as a potential therapeutic class in HIV to activate latent HIV infection in 
humans. Vorinostat is currently not licensed for the treatment for HIV.  
 
From the two clinical studies employing vorinostat with ART, there is evidence that vorinostat 
stimulated viral transcription from latently-infected cells. However, there was no evidence of 
alteration in replication competent viral expression or total proviral DNA, suggesting that 
reactivation of viral transcription was not accompanied by cell death9. An in vitro model of viral 
latency using infected resting CD4+ T-cells from HIV positive individuals on ART showed that reversal 
of latency using vorinostat failed to lead to cell death, even in the presence of autologous cytolytic 
T lymphocytes (CTLs) isolated from patients on ART. However, addition of autologous 
antigen-specific stimulation of HIV positive patients’ CTLs to the in vitro latency model after 
activation with HDACi led to efficient killing of infected cells. These results demonstrate that 
stimulating HIV-1-specific CTLs prior to reactivating latent HIV-1 may be essential for successful 
eradication efforts24. It is for this reason that we propose a unique immunisation strategy as an 
adjunct to HDACi administration in vivo.  
 
More information on the tolerability of 14 days of daily dosing in chronically infected HIV-infected 
patients on combination antiretroviral therapy (cART) can be found in Appendix II. 
 
RESEARCH TREATMENT: HIV VACCINES 
1.2
 
THE DEVELOPMENT OF UNIQUE HIV-1 IMMUNOGENS 
1.2.1
The selection of viral sequences for inclusion in an HIV-1 immunogen in the setting of a therapeutic 
“viral activation”  is challenging since an immune correlate of viral reservoir expression as well as 
protection is lacking and the immunodominant responses detected in HIV+ patients in chronic 
infection may have little impact on virus control in ART treated seroconverters. The extreme 
variability of HIV-1 enables rapid escape from cell-mediated and humoral immunity, and is thus a 
major obstacle to the development of an effective vaccine. To overcome this challenge, a unique 
‘universal’ T cell immunogen (HIVconsv) has been developed at the University of Oxford that is 
comprised of the 14 most highly conserved regions of the HIV-1 proteome assembled into a single 
chimaeric protein25. HIVconsv is encoded by a 2.4kbp gene as a fusion protein and contains 
approximately 25% of the known HIV-1 CD8+ T cell epitopes, of which 70% are identical between the 
major clades. Each segment is a consensus sequence from one of the four major HIV-1 clades, A, B, C 
and D, which alternate to ensure equal clade coverage. Epitopes recognised by rhesus macaque and 
mouse CD8+ T-cells were added to the C-terminus to facilitate pre-clinical development. The gene 
coding for HIVconsv was inserted into the three most studied vaccine vectors, plasmid DNA, human 
Ad5 and MVA, and tested for immunogenicity in Balb/c and HLA-A2 transgenic (HHD) mice. A 
regimen comprising the DNA, Ad5, MVA (DAM) sequence of vaccinations induced CD8+ T cell 
responses >2000 spot-forming units (SFU)/million PBMCs in IFN-ɣ ELISpot assays and was superior to 
other combinations of these vaccines25. Peptides based on HIVconsv stimulated strong and broad 
responses in IFN-ɣ ELISpot assays with PBMC from HIV-1-infected individuals, indicating that human 
T-cells which have been primed by HIV-1 can recognise HIVconsv-derived epitopes. 
 
 
DEVELOPMENT OF HIGHLY IMMUNOGENIC REPLICATION-DEFECTIVE SIMIAN ADENOVIRAL VECTORS 
1.2.2
Replication-defective adenoviruses are currently the most potent vectors for induction of human 
T cell responses to encoded antigens. They are easily propagated in cell culture to high titres, are 
relatively inexpensive to manufacture and have an excellent safety profile26. However, the use of 
human Ad vectors is limited by pre-existing humoral anti-vector immunity, with 60% and 90% 


 
 
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anti-Ad5 seroprevalence rates in Europe and sub-Saharan Africa, respectively27. The prevalence of 
immunity to human Ad has prompted the consideration of simian adenoviruses as vectors as these 
have low or no seroprevalence in the human population (less than 5% in humans residing in the 
USA28). In addition, Simian adenoviruses are not known to cause disease in humans. To identify 
novel vaccine carriers suitable for vaccine delivery in humans, Okairos Srl isolated and sequenced 
over a thousand Adenovirus strains from chimpanzees (ChAd or AdCh)29. Replication-defective 
vectors were generated and screened for neutralisation by human sera and for ability to grow in 
human cell lines that were approved for clinical studies. The vectors studied varied up to a thousand-
fold in potency for CD8+ T cell induction in mice. The most potent ChAd vectors were selected for 
Phase I clinical studies at the University of Oxford, where it was shown that ChAd-vectored vaccines 
for malaria, HCV and HIV-1 infections are safe and highly immunogenic30-32  
 
 
MODIFIED VACCINIA VIRUS ANKARA (MVA) AS A VIRAL VECTOR 
1.2.3
Modified vaccinia virus Ankara (MVA) is a vaccinia virus strain which was attenuated by serial 
passage in chick embryo fibroblasts (CEF). It has lost 15% of the parental genome, including cytokine 
receptor genes. It replicates well in CEF and baby hamster cells but poorly in most mammalian 
cells33,34. It was used as a smallpox vaccine in the early 1970s, towards the end of the eradication 
campaign, in 120,000 people without any serious adverse event. Its safety in humans is therefore 
well established. 
 
MVA has been shown to be effective as a vaccine vector; in particular, recombinant MVA is capable 
of inducing potent CD8+ T cell responses to passenger proteins, particularly when used as a booster 
in prime-boost regimens. The immunogenicity of MVA has been attributed in part to loss of cytokine 
and chemokine receptor genes35. MVA-vectored vaccines expressing SIV (simian immunodeficiency 
virus) genes have been evaluated in the macaque model, either as a single vaccine modality or in 
prime-boost regiments. Vaccination followed by a pathogenic SIV challenge rarely gave complete 
protection against infection but strong virus-specific CD8+ T cell responses were observed36. In some 
monkeys, containment of infection, indicated by significantly lower virus set points compared with 
sham-vaccinated animals, were observed after infection with the challenge virus37,38. 
 
 
PRE-CLINICAL DATA  
1.2.4
The Investigator Brochures for the vaccines detail the pre-clinical and clinical experience to date with 
the vaccine proposed for use in RIVER. Please refer to the respective Investigator’s Brochure for 
detailed information.  
 
Available pre-clinical data for each vaccine candidate is summarised below. 
 
1.2.4.A CHADV63.HIVCONSV 
In pre-clinical studies in mice and rhesus macaques, the ChAdV63.HIVconsv vaccine was found to be 
safe and immunogenic. In a dose escalation experiment in mice (105 to 109 virus particles per dose), 
the frequencies of HIV-1-specific T-cells increased in a dose-dependent manner. In macaques, the 
ChAdV63.HIVconsv vaccine significantly boosted transgene-specific T-cells in optimally-primed 
animals. 
 
A pre-clinical GLP toxicology study carried out by Huntingdon Life Sciences, study UNO0012, 
assessed in groups of 10 male and 10 female BALB/c mice the systemic toxic potential following 
administration of 50µg dose of the DNA vaccine pSG2.HIVconsv (‘D’) by intramuscular injection on 
days 1, 15 and 29, followed by an intramuscular injection of 5x109 viral particles (vp) 
ChAdV63.HIVconsv (‘C’) on day 43 (the ‘DDDC’ regimen). Vaccinations were not found to be 


 
 
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associated with any systemic toxicological changes and all the observed lymph node changes were 
consistent with response to vaccine administration.  
 
1.2.4.B MVA.HIVCONSV 
Study UNO011 was performed by Huntingdon Life Sciences to assess the systemic toxic potential of 
2 x 107 pfu/dose of MVA.HIVconsv, administered by intramuscular injection to groups of 10 male and 
10 female BALB/c mice on days 1, 15 and 29 (the mMM regimen). Vaccinations were not found to be 
associated with any systemic toxicological changes. The findings of increased cellularity of the 
draining lymph nodes, high plasma gamma globulin, concentration and aspartate aminotransferase 
activity and inflammatory changes at the dose sites were considered to be consistent with a 
predicted response to vaccine administration. These results supported the MHRA approval for 
clinical trial HIV-CORE 001. 
 
 
CLINICAL DATA 
1.2.5
1.2.5.A CHADV63.HIVCONSV 
In trial HIV-CORE 002, conducted at the University of Oxford, the safety and immunogenicity of three 
HIVconsv vaccine regimens, with and without DNA priming, was investigated in healthy volunteers. 
The three vaccines administered during the study were as follows: pSG2.HIVconsv DNA (D), 
ChAdV63.HIVconsv (C) and MVA.HIVconsv (M). Two volunteers received a single dose of 
ChAdV63.HIVconsv (5x109 vp) in an initial safety evaluation of the ChAdV63 vector. Thirty volunteers 
were then recruited and assigned sequentially in groups of 10 to one of three vaccination regimens: 
CM (weeks 0 and 8), DDDCM (weeks 0, 4, 8, 12 and 20) or DDDMC (weeks 0, 4, 8, 12 and 16). Within 
each group, subjects were randomised to receive vaccine or placebo in a 4:1 ratio. Vaccine doses 
were: ChAdV63.HIVconsv 5x1010 vp, MVA.HIVconsv 2x108 pfu, pSG2.HIVconsv DNA 4mg. All vaccines 
were given via the intramuscular route and each dose divided between two arms. 28/30 subjects 
completed the vaccination schedule; two subjects withdrew after receiving one vaccination, for 
reasons unrelated to safety or tolerability. 
 
Overall, safety and tolerability profiles were excellent39. There were no suspected unexpected 
serious adverse reactions (SUSARs) and the majority of local and systemic vaccination reactions were 
grade 1 and lasted less than 48 hours (erythema/pain at the injection site, myalgia, ‘flu-like’ 
symptoms, headache). One volunteer experienced fever >38.5oC and there was one SAE that was 
unrelated to any of the investigational vaccines (appendicitis occurring after enrolment and before 
receipt of any vaccine). Additionally, a further trial has received approval to test pSG2.HIVconsv DNA 
(D) and ChAdV63.HIVconsv (C) in the format DDDC (HIV-CORE 003). This is a randomised 
double-blind placebo-controlled phase I/IIa trial to investigate the effect of depletion of serum 
amyloid P component (SAP) on the immune response to DNA vaccination in healthy male volunteers.  
 
1.2.5.B MVA.HIVCONSV 
MVA.HIVconsv has been evaluated in two phase I studies conducted at the University of Oxford. 
HIV-CORE 001 tested the safety and immunogenicity of three MVA.HIVconsv immunisations, 
administered by intramuscular injection to 19 HIV-1 seropositive patients on highly active 
anti-retroviral therapy (HAART)40. Ten volunteers were randomised to receive either MVA.HIVconsv 
(5x107 pfu) or placebo in a 4:1 ratio. A further 9 volunteers were randomised to receive either 
MVA.HIVconsv (2x108 pfu) or placebo in a 4:1 ratio. All 19 patients received at least two doses of 
MVA.HIVconsv and 17 patients completed their allocated vaccine regimen. The vaccine was well 
tolerated and there have been no SARs or SUSARs to date. There have been four SAEs in three 
volunteers, none considered related to the vaccine (pneumonia, pulmonary abscess, pyelonephritis 
and Hodgkin’s lymphoma). A blinded analysis of the data indicates that CD8+ T cell responses to 


 
 
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highly conserved HIV-1 epitopes, which were primed by natural infection, were both boosted and 
broadened, with epitopes across the entire immunogen being targeted.  
 
1.2.5.C USE OF CHADV63.HIVCONSV AND MVA.HIVCONSV IN HIV INFECTION  
In the trial BCN01, which was conducted at the Irsicaixa AIDS Research Institute-HIVACAT, Barcelona, 
the safety and immunogenicity of ChAdV63.HIVconsv prime followed by MVA.HIVconsv boost 
vaccinations was assessed in early ART-treated HIV-1-positive individuals (NCT01712425)41. 24 
individuals with recent HIV infection were treated immediately (median 91 days since HIV 
acquisition) with Tenofovir / Emtricitabine / Raltegravir for 6 months and then allocated to receive 
ChAdV63.HIVconsv (5x1010vp) followed by MVA.HIVconsv (2x108pfu) after either a 24-week (n = 12) 
or 8-week (n = 12) interval. Both vaccinations were given by intramuscular injection. Participants 
remained on ART throughout follow-up. Local and systemic events were recorded for a minimum of 
7 days following each immunisation and were observed in 22/24 subjects. The majority were grade 1 
or 2. One individual experienced grade 3 pain after each immunisation; grade 3 systemic symptoms 
were observed in one subject after ChAdV63.HIVconsv and 3 subjects after MVA.HIVconsv. Pain was 
more frequent after MVA.HIVconsv than after ChAdV63.HIVconsv, which was consistent with 
previous trials. There have been no SUSARs or vaccine-related SARs. There were no significant 
differences observed in peak immunogenicity between the short and long prime/boost regimen42. 
 
STUDY DESIGN AND HYPOTHESIS 
1.3
The study design is a two-arm, open label randomised study. Eligible participants will either be: 
 
Cohort I: Recently diagnosed with primary HIV-1 infection. Participants must be enrolled and 
start ART within 4 weeks of a confirmed diagnosis of primary HIV-1 infection 
 
Cohort II: Previously diagnosed with primary HIV-1 infection. Confirmed diagnosis of primary 
HIV-1 infection and start of at least 3-drug ART must be within a maximum of 2 years prior to 
randomisation. Participants must have started at least 3-drug ART within 4 weeks of a 
confirmed diagnosis of primary HIV-1 infection and remained on ART since starting. 
 
Participants should receive combination ART (cART) preferably including raltegravir for the duration 
of the interventional phase of the study (unless they experience intolerance Section 5.7).  
 
In patients meeting the criteria for randomisation (eligibility assessed at either week 22 for Cohort I, 
or at screening for Cohort II), participants will either continue cART alone or receive an intervention 
consisting of two anti-HIV vaccines separated by 8 weeks followed by 10 doses of the HDACi, 
vorinostat, in addition to cART.  
 
We hypothesise that the prime-boost vaccination will result in the generation of vaccine induced HIV 
specific CTLs that will recognise HDACi-activated cells of the HIV reservoir and destroy them. The net 
effect will be a greater reduction in the HIV reservoir defined as HIV total DNA in CD4+ T-cells in the 
cART+vaccine+HDACi compared to the cART alone. Our strategy is entirely different from previous 
therapeutic vaccination approaches which have been largely unsuccessful43,44. Immunological 
priming to conserved HIV proteins will drive CD8+ T-lymphocyte recognition of latently-infected cells 
rendered immunogenic by HDACi. We anticipate that the viral antigens expressed by 
latently-infected cells will be unable to adapt to, or escape from, the immune response as they will 
be expressed directly from chromosomal DNA, avoiding the steps of the viral life-cycle that facilitate 
immune-driven adaptation. We have chosen a prime-boost immunisation strategy with recombinant 
replication-defective chimpanzee adenovirus and modified vaccinia Ankara vectors, bearing 
conserved HIV antigens; these products have been shown to induce high titres of HIV-specific CD8+ 


 
 
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T-cells32,45. In addition, these vaccines will drive immune responses against conserved regions of the 
virus that may be well preserved in individuals with PHI. 
 
Primary HIV Infection (PHI) is a unique period when HIV proviral reservoir is smaller than in chronic 
disease, is likely to be more homogeneous than in later stage disease and hence is more susceptible 
to immunological elimination. This provides an opportunity to use a vaccine to re-direct HIV-specific 
immune responses towards genetically fragile regions in the viral proteome. Immunisation in PHI 
should result in potent immune responses because ART initiated in PHI preserves CD4 function46 and 
early ART-mediated viral suppression limits viral diversification, reducing the chance of immune 
escape47. The other key reason for conducting this trial in patients treated in PHI is that, in some 
patients, an early sustained course of ART started very early in infection may induce a state of viral 
remission in which therapy can be stopped without any rebound viraemia. This has been most 
notably reported in the VISCONTI cohort48 in which ‘post-treatment control’ was identified in 15.6% 
of selected individuals. 
 
Data from our group and others has shown that whilst there is a rapid decline in measures of total 
HIV DNA following ART initiation up to 6 months after seroconversion this then plateaus out to 
approximately 2 years after diagnosis of acute infection49-52. Hence randomisation of individuals 
starting immediate ART in acute infection have comparable levels of HIV reservoirs to those who 
have started treatment within a similar timeframe, but have remained on suppressive therapy for up 
to 2 years after initiation. Furthermore, since the primary endpoint of the RIVER study design 
compares total HIV DNA between the two arms from randomisation to post-randomisation weeks 16 
& 18 Cohorts I and II will be comparable.  
 
Figure 4 Pathway to an HIV cure. The triple combination of cART, immunisation and latency 
reversal should lead to T cell-induced killing of the HIV reservoir. 
 
 


 
 
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We hypothesise that the combination of HDACi with immunisation in cART-suppressed PHI will 
significantly impact the HIV reservoir. 
 
Figure 4 illustrates the rationale for the interventions in the study. 
1) Patients in Cohort I – Recently diagnosed  will receive combination antiretroviral therapy 
designed to reduce the plasma viral load as quickly as possible, hence the rationale for the 
preferred inclusion of raltegravir, an integrase inhibitor53,54. Both cohorts will have been 
treated in PHI, which may restrict the size of the reservoir compared with people initiating 
ART in later stages of HIV infection. Cohort II – Previously diagnosed participants are 
screened the same as Cohort I and are maintained on ART throughout the study. The ART 
regimen is preferably a combination that includes raltegravir, as hypothetically, if vorinostat 
induced viral transcription an integrase inhibitor may protect uninfected cells. However, 
there is no evidence to support this hypothesis and the key inclusion criteria must be the 
continuation of a virally suppressive ART regimen throughout the study. 
2) The prime-boost vaccination is designed to enhance the killing capacity of the cytotoxic 
T-cells. This must be given before the HDACi in order to prime and boost a maximal 
HIV-specific T-cell response to recognise activated viral antigen expression on reservoir cells. 
3) The HDACi is designed to cause viral transcription from latently infected cells; activate the 
reservoir, and in the presence of the enhanced killing capacity of the CD8+ T-cells, results in 
killing of the cells previously harbouring latent virus, leading to further reductions in the 
reservoir.  
 
This exact combined approach in treated PHI has never previously been used, and we hypothesise 
there will be a 50% reduction in the proviral DNA (the ‘reservoir’), in this ‘proof-of-concept’ study, in 
those randomised to the vaccine-HDACi intervention compared to those receiving antiretroviral 
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2 
SELECTION OF SITES/CLINICIANS 
The trial sponsor (Imperial College London) has overall responsibility for site and investigator 
selection. 
 
SITE/INVESTIGATOR INCLUSION CRITERIA 
2.1
To participate in the RIVER trial, investigators and clinical trial sites have fulfilled a set of basic 
criteria that have been agreed by the RIVER Project Management Group (PMG) and are defined 
below. 
 
The clinical sites included in this protocol have previously been part of a successful collaborative 
effort to enrol individuals presenting with acute HIV infection55. The CHERUB collaboration 
(Collaborative HIV Eradication of viral Reservoirs: UK BRC) is a unique collective effort between the 5 
key Academic Health Science Centres (AHSC) in the UK who have been working together for the past 
3 years to develop laboratory and clinical expertise in the field of HIV cure research56.  
 
 
PRINCIPAL INVESTIGATOR'S QUALIFICATIONS & AGREEMENTS 
2.1.1
1. The investigator should be qualified by education, training, and experience to assume 
responsibility for the proper conduct of the trial at their site and should provide evidence of 
such qualifications through an up-to-date curriculum vitae and/or other relevant 
documentation requested by the Sponsor, the REC, and/or the regulatory authority. 
2. The investigator should be thoroughly familiar with the appropriate use of the 
investigational product, as described in the protocol, in the current Investigator Brochure, in 
the product information and in other information sources provided by the Sponsor. 
3. The investigator should be aware of, and should comply with, the principles of GCP and the 
applicable regulatory requirements. A record of GCP training should be accessible for all 
investigators. 
4. The investigator/site should permit monitoring and auditing by the Sponsor, and inspection 
by the appropriate regulatory authority  
5. The investigator should maintain a delegation log of appropriately-qualified persons to 
whom the investigator has delegated significant trial-related duties. 
6. The investigator should sign an investigator statement, which verifies that the site is willing 
and able to comply with the requirements of the trial. 
 
 
ADEQUATE RESOURCES 
2.1.2
1. The investigator should be able to demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period (that is, the investigator 
regularly treats the target population). 
2. The investigator should have sufficient time to properly conduct and complete the trial 
within the agreed trial period. 
3. The investigator should have available an adequate number of qualified staff and adequate 
facilities for the foreseen duration of the trial to conduct the trial properly and safely. 


 
 
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4. The investigator should ensure that all persons assisting with the trial are adequately 
informed about the protocol, the investigational product(s), and their trial-related duties 
and functions. 
5. The site should have sufficient processes in place to manage the use of a genetically 
modified organism containing IMP at the site.  
6. The site should have sufficient data management resources to allow prompt data return to 
the MRC CTU. Sites that have previously participated in MRC CTU-co-ordinated trials should 
have a proven track record of good data return. 
 
APPROVAL AND ACTIVATION 
2.2
Each selected clinical trial site must apply for their local R&D approval. The Principal investigator will 
be required to sign an Investigator Statement which verifies that the site is willing, and able to 
comply with the requirements of the trial. In addition and in compliance with the principles of GCP, 
all site staff participating in the trial must complete the Signature and Delegation of Responsibilities 
Log and forward this to the RIVER Co-ordinating Centre. The RIVER Co-ordinating Centre must be 
notified of any changes to trial personnel and/or their responsibilities. An up-to-date copy of this log 
must be stored in the Trial Master File (TMF) at the site and also at the RIVER Co-ordinating Centre. 
A clinical trial agreement will also be signed by the NHS Trust or Board. Local laboratory normal 
ranges must also be provided. 
 
On receipt of all necessary approvals, written confirmation will be sent to the principal investigator. 
The site’s pharmacist will also be informed of the site’s activation and an initial drug order will be 
placed by the named pharmacist. 
 
1. The site should conduct the trial in compliance with the protocol as agreed by the Sponsor, 
by the regulatory authority, and the REC. 
2. The principal investigator or delegate should document and explain any deviation from the 
approved protocol, and communicate this with the trial team at the RIVER Co-ordinating 
Centre. 
 
RIVER TRIAL CENTRES 
2.3
 
St Mary’s Hospital, Imperial College London 
 
Guy's and St Thomas' NHS Foundation Trust, London 
 
Chelsea and Westminster Hospital NHS Foundation Trust, London 
 
Royal Free London NHS Foundation Trust 
 
Brighton and Sussex University Hospitals NHS Trust 
 
Mortimer Market Centre, Central and North West London Foundation Trust 


 
 
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3 
SELECTION OF PARTICIPANTS 
RIVER aims to recruit participants from 2 different cohorts: 
 
 
Cohort I – Recently diagnosed 
Recently diagnosed with primary HIV-1 infection. Participants must be enrolled within 4 
weeks of a confirmed diagnosis of primary HIV-1 infection. Participants are first screened 
and if eligible are enrolled at week 0 when combination ART preferably including raltegravir 
begins. Randomisation occurs after assessment of eligibility at week 22 (see Section 3.3) 
 
 
Cohort II - Previously diagnosed 
Previously diagnosed with primary HIV-1 infection.  Confirmed diagnosis of primary HIV-1 
infection must be within a maximum of 2 years prior to randomisation. Participants must 
have started at least 3-drug ART within 4 weeks of a confirmed diagnosis and remained on 
ART since starting. Participants are first screened and if eligible are randomised (see Section 
3.4 for full randomisation criteria) 
 
The criteria for primary HIV-1 infection are the same across both cohorts.  
 
The eligibility criteria are the standards used to ensure that only medically appropriate participants 
are considered for this study. Participants not meeting the criteria should not join the study. For the 
safety of the participants, as well as to ensure that the results of this study can be useful for making 
treatment decisions regarding other participants with similar diseases, it is important that no 
exceptions be made to these criteria for enrolment and randomisation to the study.  
 
NUMBER OF PARTICIPANTS  
3.1
The study aims to enrol  60 individuals overall from 6 UK centres (both cohorts combined).  
 
Where participants withdraw consent for participation, or are deemed lost to follow-up after 
randomisation, they will not be replaced.  Cohort I participants who do not have an undetectable 
HIV RNA viral load (<50copies/mL or <200copies/mL for the Taqman Roche 2.0 assay) at week 22 
bloods (even after repeat testing) will not be randomised. In such cases, participants will discontinue 
participation in RIVER. Study participants enrolled into Cohort I that are subsequently ineligible for 
randomisation or those from either cohort who withdraw consent will be managed as per standard 
of care (SOC) and no further data will be collected for the study. If study supplied raltegravir is being 
used, this will no longer be supplied to such patients, although the drug might be continued as part 
of SOC at the discretion of the treating clinician.  
 
CONSENT PROCESS  
3.2
Eligible individuals will be flagged by a clinical pathway at each clinical site. This is to incorporate one 
or more of the following:  
 
Direct referral from participants following recent diagnosis of HIV 
 
The study will be advertised through NGO, advocacy partners such as THT, HIV ibase, GMFA 
and through the CHERUB website 
 
Virology laboratories where recent infection is identified will notify lead clinical principal 
investigators to follow up with potentially eligible study participants.  


 
 
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 
Clinical referrals pathways will be made from colleagues and from other sites where 
enrolment is not currently planned - through BHIVA, MRC CTU website and clinical 
networks 
 
For Cohort II several of the clinical sites participating in RIVER have been recruiting individuals into a 
separate observational cohort study called HEATHER (funded through NIHR BRC and MRC senior 
fellowship). The HEATHER (REC reference: 14/WM/1104) study has enrolled individuals with 
confirmed PHI according to similar criteria to those that define PHI for the RIVER study, all of whom 
commenced and remained on combination ART from the time of PHI. Individuals who enrol into 
RIVER Cohort II will cease blood draws and clinical follow up through HEATHER for the time they are 
in the RIVER protocol. They may return to the HEATHER study after completion of the RIVER 
protocol.  
 
Written informed consent to enter into the study and be randomised must be obtained from 
participants after explanation of the aims, methods, benefits and potential hazards of the study and 
BEFORE any study-specific procedures are performed or any blood is taken for the study (sample 
participant information leaflet is available in Appendix VII). Separate Participant Information Leaflets 
and consent forms have been developed for each cohort.  
 
It must be made completely and unambiguously clear to the participant that they are free to refuse 
to participate in all or any aspect of the study, at any time and for any reason, without incurring any 
penalty or affecting their treatment.  
 
Signed consent forms must be kept by the investigator and documented in the case report form and 
copies given to the participant and the RIVER Co-ordinating Centre. With consent, a letter should be 
sent to the general practitioner informing him/her of the study and the participant's involvement in 
it; unless the participant expresses on the consent form that they do not wish their GP to be 
informed (sample GP letter is available in Appendix VI). 
 
COHORT I – RECENTLY DIAGNOSED PARTICIPANTS  
3.3
Recently diagnosed participants will be considered eligible for enrolment in this trial if they fulfil all 
the inclusion criteria and none of the exclusion criteria as defined below. Eligible participants are 
enrolled at week 0.  
 
 
ENROLMENT INCLUSION CRITERIA 
3.3.1
1. Aged ≥18 to ≤60 years old 
2. Able to give informed written consent including consent to long-term follow-up 
3. Should be enrolled within a maximum of 4 weeks of diagnosis of primary HIV-1 infection 
confirmed by one of the following criteria: 
a. Positive HIV-1 serology within a maximum of 12  weeks of a documented negative 
HIV-1 serology test result (can include point of care test (POCT)) 
b. A positive p24 antigen result and a negative HIV antibody test  
c. Negative antibody test with either detectable HIV RNA or proviral DNA  


 
 
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d. PHE RITA test algorithm† reported as “Incident” confirming the HIV-1 antibody 
avidity is consistent with recent infection (within the preceding 16 weeks) 
e. Weakly reactive or equivocal 4th generation HIV antibody antigen test 
f. Equivocal or reactive antibody test with <4 bands on western blot 
4. Adequate haemoglobin (Hb≥12g/dL for males, ≥11g/dL for females) 
5. Weight ≥50kg‡  
6. Willing to be treated with cART (preferably including raltegravir) and be randomised to 
continue cART alone or cART plus intervention (HIV vaccines plus HDACi)  
7. Willing and able to comply with visit schedule and provide blood sampling. 
 
 
ENROLMENT EXCLUSION CRITERIA 
3.3.2
1. Women of child bearing potential (WCBP)§  
2. In women with intact ovaries and no uterus, any planned egg donation anytime in the future 
to a surrogate 
3. Intention to donate sperm or father a child within 6 months of the intervention 
4. Co-infection with hepatitis B (surface antigen positive or detectable HBV DNA levels in 
blood) or hepatitis C (HCV RNA positive or HCV antigen positive) 
5. Any current or past history of malignancy 
6. Concurrent opportunistic infection or other comorbidity or comorbidity likely to occur 
during the trial e.g. past history of ischaemic or other significant heart disease, 
malabsorption syndromes, autoimmune disease 
7. Any contraindication to receipt of BHIVA recommended combination antiretrovirals 
8. HIV-2 infection 
9. Known HTLV-1 co-infection 
10. Prior immunisation with any experimental HIV Immunogens (including any component of 
the vaccines used in the RIVER protocol; simian or human adenoviral vaccine; other 
experimental HIV vaccines)  
11. Current or planned systemic immunosuppressive therapy (inhaled corticosteroids are 
allowed) 
12. Any history of proven thromboembolism (pulmonary embolism or deep vein thrombosis) 
                                                             
† using current cut-offs for optical density as defined by PHE 
‡ females aged <20 years of age, and weighing <65kg and <168cm in height will need to have an estimation of blood 
volume (EBV) >3500mL prior to enrolment . This circumstance is unlikely to arise as most women between the ages of 18 
to 20 years would be of child-bearing potential (CBP) and excluded on that basis. 
§ defined as any female who has experienced menarche and who has not undergone successful surgical sterilisation 
(hysterectomy or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhoea ≥ 12 consecutive months; 
or women on hormone replacement therapy (HRT) with documented serum follicle stimulating hormone (FSH) level > 
35mIU/mL); NB bilateral tubal ligation is reversible, a women with only tubal ligation who does not meet any of the other 
criteria is considered a WCBP 
 


 
 
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13. Any inherited or acquired bleeding diathesis including gastric or duodenal ulcers, varices 
14. Concurrent or planned use of any drugs contraindicated with vorinostat i.e. antiarrhythmics; 
any other drugs that prolong QTc; warfarin, aspirin, sodium valproate 
15. Prior intolerance of any of either the components of the vaccine or HDACi, 
16. Uncontrolled diabetes mellitus defined as an HBA1C>7% 
17. Any congenital or acquired prolongation of the QTc interval, with normal defined as 0.44s 
(≤440ms) 
18. Participation in any other clinical trial of an experimental agent or any non-interventional 
study where additional blood draws are required; participation in an observational study is 
permitted 
19. Allergy to egg 
20. History of anaphylaxis or severe adverse reaction to vaccines 
21. Planned receipt of vaccines within 2 weeks of the first trial vaccination administered at 
PR week 00 (including vaccines such as yellow fever; hepatitis B, influenza)  
22. Abnormal blood test results at screening including 
a. Moderate to severe hepatic impairment as defined by Child-Pugh classification 
b. ALT >5xULN 
c. Platelets <150x109/L 
d. eGFR <60** 
e. uPCR >30 mg/mmol 
23. Physical and laboratory test findings: Evidence of organ dysfunction or any clinically 
significant deviation from normal in physical examination and/or vital signs that the 
investigator believes is a preclusion from enrolment into the study 
24. Active alcohol or substance use that, in the Investigator’s opinion, will prevent adequate 
adherence with study requirements 
25. Insufficient venous access that will allow scheduled blood draws as per protocol 
 
 
CRITERIA FOR RANDOMISATION  
3.3.3
Blood samples will be taken at week 22 to assess whether the participant can proceed to 
randomisation. Eligibility must be assessed within 14 days prior to randomisation. If necessary it is 
permitted for the week 22 visit to be repeated, however it is likely that most participants will meet 
all eligibility criteria and be randomised around week 23. Randomisation will take place once the 
participant meets the following eligibility criteria:  
 
1. Participant is willing to continue on combination antiretroviral therapy 
2. HCV RNA or HCV antigen negative 
                                                             
**eGFR is calculated using CKD-EPI. Units ml/min/1.73m2. 


 
 
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3. Undetectable plasma HIV RNA (<50copies/mL or <200copies/mL for the Taqman Roche 2.0 
assay). 
Participants who do not have undetectable plasma HIV RNA at week 22 can have this 
repeated until the HIV RNA falls below the specified threshold. The time period between and 
the number of repeat tests performed will be at the clinician’s discretion and up until 
virological failure in accordance with standard BHIVA guidelines. If it takes more than 14 
days (after week 22) to become undetectable it would be necessary to repeat the whole 
week 22 visit prior to randomisation. 
4. Laboratory parameters†† 
 
Platelet count ≥150x109/L 
 
eGFR ≥60** 
 
Adequate haemoglobin (Hb≥12g/dL for males, ≥11g/dL for females) 
 
ALT <5xULN 
 
uPCR ≤30mg/mmol 
 
In diabetics, HbA1C <7% 
5. QTc interval normal, with normal defined as 0.44s (440ms) 
6. Physical examination: No evidence of organ dysfunction or any clinically significant deviation 
from normal in physical examination and/or vital signs that in the opinion of the investigator 
would be a contraindication to randomisation 
 
COHORT II – PREVIOUSLY DIAGNOSED PARTICIPANTS  
3.4
Previously diagnosed participants will be considered eligible for randomisation in this trial if they 
fulfil all the inclusion criteria and none of the exclusion criteria as defined below. Blood samples will 
be taken at screening to assess whether the participant is eligible for randomisation. Eligibility must 
be assessed within 14 days prior to randomisation. 
 
 
RANDOMISATION INCLUSION CRITERIA  
3.4.1
1. Aged ≥18 to ≤60 years old  
2. Able to give informed written consent including consent to long-term follow-up 
3. Weight ≥50kg‡‡  
4. Confirmed date of diagnosis of primary HIV-1 infection  ≤2 years prior to randomisation  
5. Started at least 3-drug ART within a maximum of 4 weeks of diagnosis of the primary HIV-1 
infection confirmed by one of the following criteria: 
                                                             
†† Results from lab parameters should be within 14 days of randomisation. Repeat tests must be within the ranges as listed 
above.  
‡‡ females aged <20 years of age, and weighing <65kg and <168cm in height will need to have an estimation of blood 
volume (EBV) >3500mL prior to enrolment . This circumstance is unlikely to arise as most women between the ages of 18 
to 20 years would be of child-bearing potential (CBP) and excluded on that basis. 
 


 
 
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a. Positive HIV-1 serology within a maximum of 12  weeks of a documented negative 
HIV-1 serology test result (can include point of care test (POCT)) 
b. A positive p24 antigen result and a negative HIV antibody test  
c. Negative antibody test with either detectable HIV RNA or proviral DNA  
d. PHE RITA test algorithm§§ reported as “Incident” confirming the HIV-1 antibody 
avidity is consistent with recent infection (within the preceding 16 weeks) 
e. Weakly reactive or equivocal 4th generation HIV antibody antigen test 
f. Equivocal or reactive antibody test with <4 bands on western blot 
6. Currently taking at least 3-drug ART (preferably including raltegravir) and has been on 
treatment for ≥22 weeks  
7. Undetectable plasma HIV RNA (<50copies/mL or <200copies/mL for the Taqman Roche 2.0 
assay) 
8. Reached an undetectable plasma HIV RNA (<50copies/mL or <200copies/mL for the Taqman 
Roche 2.0 assay) within 9 months of starting ART and has had no evidence of virological 
failure as defined by current BHIVA guidelines 
9. Adequate haemoglobin (Hb≥12g/dL for males, ≥11g/dL for females) 
10. Total blood volume taken in 3 months prior to screening does not exceed 40mL  
11. Willing to be randomised to continue cART alone or cART plus intervention (HIV vaccines 
plus HDACi)  
12. Willing and able to comply with visit schedule and provide blood sampling 
 
 
RANDOMISATION EXCLUSION CRITERIA  
3.4.2
1. Women of child bearing potential (WCBP)***  
2. In women with intact ovaries and no uterus, any planned egg donation anytime in the future 
to a surrogate 
3. Intention to donate sperm or father a child within 6 months of the intervention 
4. Co-infection with hepatitis B (surface antigen positive or detectable HBV DNA levels in 
blood) or hepatitis C (HCV RNA positive or HCV antigen positive) 
5. Any current or past history of malignancy 
6. Concurrent opportunistic infection or other comorbidity or comorbidity likely to occur 
during the trial e.g. past history of ischaemic or other significant heart disease, 
malabsorption syndromes, autoimmune disease 
                                                             
§§ using current cut-offs for optical density as defined by PHE 
*** defined as any female who has experienced menarche and who has not undergone successful surgical sterilisation 
(hysterectomy or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhoea ≥ 12 consecutive 
months; or women on hormone replacement therapy (HRT) with documented serum follicle stimulating hormone 
(FSH) level > 35mIU/mL); NB bilateral tubal ligation is reversible, a women with only tubal ligation who does not 
meet any of the other criteria is considered a WCBP 
 


 
 
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7. HIV-2 infection 
8. Known HTLV-1 co-infection 
9. Prior immunisation with any experimental HIV Immunogens (including any component of 
the vaccines used in the RIVER protocol; simian or human adenoviral vaccine; other 
experimental HIV vaccines)  
10. Current or planned systemic immunosuppressive therapy (inhaled corticosteroids are 
allowed) 
11. Any history of proven thromboembolism (pulmonary embolism or deep vein thrombosis) 
12. Any inherited or acquired bleeding diathesis including gastric or duodenal ulcers, varices 
13. Concurrent or planned use of any drugs contraindicated with vorinostat i.e. antiarrhythmics; 
any other drugs that prolong QTc; warfarin, aspirin, sodium valproate 
14. Prior intolerance of any of either the components of the vaccine or HDACi, 
15. Uncontrolled diabetes mellitus defined as an HBA1C>7% 
16. Any congenital or acquired prolongation of the QTc interval, with normal defined as 0.44s 
(≤440ms) 
17. Participation in any other clinical trial of an experimental agent; participation in an 
observational study is permitted 
18. Allergy to egg 
19. History of anaphylaxis or severe adverse reaction to vaccines 
20. Planned receipt of vaccines within 2 weeks of the first trial vaccination administered at 
PR week 00 (including vaccines such as yellow fever; hepatitis B, influenza)  
21. Abnormal blood test results at screening including 
a. Moderate to severe hepatic impairment as defined by Child-Pugh classification 
b. ALT >5xULN 
c. Platelets <150x109/L 
d. eGFR <60††† 
e. uPCR >30 mg/mmol 
22. Physical and laboratory test findings: Evidence of organ dysfunction or any clinically 
significant deviation from normal in physical examination and/or vital signs that the 
investigator believes is a preclusion from enrolment into the study 
23. Active alcohol or substance use that, in the Investigator’s opinion, will prevent adequate 
adherence with study requirements 
24. Insufficient venous access that will allow scheduled blood draws as per protocol 
                                                             
†††eGFR is calculated using CKD-EPI. Units ml/min/1.73m2. 


 
 
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RANDOMISATIONS 
To randomise, fax or email password protected scanned CRF to the  
RIVER Co-ordinating Centre 
Monday to Friday 09:00 – 17:00 
Fax: +44 (0) 20 7670 4817 
mrcctu.river@ucl.ac.uk 
4 
ENROLMENT & RANDOMISATION 
Eligibility for enrolment and randomisation will be confirmed by a web-based program. At 
randomisation eligible participants will be randomised to two parallel groups in a 1:1 ratio (see 
Figure 1 and Figure 2). Randomisation lists will be computer-generated based on random permuted 
blocks and will be performed by the RIVER Co-ordinating Centre staff on receipt of a completed 
randomisation CRF. Randomisation will be stratified by Cohort I and Cohort II.  
 
ENROLMENT PRACTICALITIES  
4.1
Participants in Cohort I – Recently diagnosed must be enrolled into the study within 4 weeks of a 
confirmed diagnosis of primary HIV-1 infection. A screening visit will be conducted prior to 
enrolment where laboratory tests will be conducted in order to determine participant eligibility for 
enrolment at week 0 (see Section 6.1.1).  
 
 
 
RANDOMISATION PRACTICALITIES 
4.2
Screening for randomisation:  
 
For participants in Cohort I – Recently diagnosed  
Blood samples will be taken at week 22 (or later if repeat bloods are required) to assess 
whether the participant can proceed to randomisation.  
 
For participants in Cohort II – Previously diagnosed  
Blood samples will be taken at screening to assess whether the participant can proceed 
to randomisation.   
 
As soon as results from the week 22 or screening visits are known and eligibility for randomisation 
can be determined, a completed CRF should be submitted to the RIVER Co-ordinating Centre. The 
result of the randomisation will determine where the participant’s first visit post-randomisation will 
take place (at Royal Free Hospital or at recruiting site).  
 
Further details on the process of randomisation can be found in Section 9.1. 
 
 
 
 
 
 
 
A manual randomisation process will be set up to cover any instances when the main electronic 
system is unavailable. This will be detailed in the study working instructions. 
ENROLMENTS 
To enrol a participant, fax or email password protected scanned CRFs to the  
RIVER Co-ordinating Centre 
Monday to Friday 09:00 – 17:00 
Fax: +44 (0) 20 7670 4817 
mrcctu.river@ucl.ac.uk 


 
 
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CO-ENROLMENT GUIDELINES 
4.3
Participants will not be permitted to co-enrol into other interventional studies for the duration of 
this study. However, there is an expectation that participants will be asked to co-enrol into other 
observational studies run by the CHERUB network, this participation is allowable.  


 
 
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5 
TREATMENT OF PARTICIPANTS 
 
IMP MANAGEMENT 
5.1
All IMPs for the study will be stored and managed by a central pharmacy based at the Royal Free 
Hospital. They will be responsible for the storage and distribution of IMP to the clinical sites. 
Raltegravir has been donated by industry partners for use in the study and will be pre-shipped to 
clinical site pharmacies from where it will be dispensed to participants recruited. Dispensation of 
vaccines and vorinostat will take place at the Royal Free Hospital, when participants in Arm B attend 
for vaccination visits.  
 
Raltegravir will be provided as a marketed product so MHRA-approved clinical trial labelling will be 
applied at the central pharmacy. Both the vaccines and vorinostat are unlicensed products so 
MHRA-approved clinical trial labelling will be applied by the manufacturer prior to shipping to RIVER 
central pharmacy. 
 
Clinical trial IMP will be allocated to a participant on receipt of a completed prescription from the 
participant’s clinician. On no account should any drug assigned to a participant be used by anyone 
else. Unused drug must be returned to the site pharmacy if a participant withdraws from treatment. 
The date that each participant started study treatment should be documented in the participant’s 
clinical notes and added to the appropriate CRF. 
 
All drug dispensed at and returned to the site pharmacy should be documented on a site 
accountability log, maintained by a named person (study pharmacist or research nurse). The 
designated study pharmacist/nurse will, on receipt of supplies prior to the commencement of the 
study, conduct an inventory and complete a receipt. Inventories will be conducted on an ongoing 
basis. Procedures for drug shipping, labelling, accountability and destruction will be detailed in the 
RIVER working practice documents. The RIVER Co-ordinating Centre will monitor drug accountability 
at site visits. 
 
PRE-RANDOMISATION TREATMENT 
5.2
 
USE OF AN INTEGRASE INHIBITOR  
5.2.1
Participants recently diagnosed (Cohort I) will receive combination antiretroviral therapy designed to 
reduce the plasma viral load as quickly as possible, hence the rationale for the preferred inclusion of 
raltegravir, an integrase inhibitor53,54.  Also, there is a hypothetical benefit for individuals receiving 
the latency reversing agent vorinostat that leads to viral transcription from the latent HIV reservoir, 
that the presence of an integrase inhibitor agent may better protect infection of uninfected CD4+ T-
cells. However, there is no in vivo data to support this hypothesis. We therefore would prefer to 
include raltegravir as part of the combination antiretroviral therapy for all individuals at the time of 
randomisation.   
 
However, in the absence of clear data individual participant preferences, viral genotype and co-
morbidity, concomitant medication and clinical judgement can be used to ensure optimal viral 
suppression.   
 
 
 


 
 
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USE OF ART PRIOR TO ENROLMENT – COHORT I – RECENTLY DIAGNOSED  
5.2.2
Participants who have taken Post-Exposure Prophylaxis (PEP) or Pre-Exposure Prophylaxis (PrEP) for 
prevention and prior to confirmation of primary HIV-1 infection are eligible for inclusion on the 
RIVER study. Participants in Cohort I – Recently diagnosed will either be ART naïve, have recently 
started an ART regimen after PHI diagnosis or have previously taken ART for prevention.  
 
 
USE OF ART PRIOR TO ENROLMENT – COHORT II – PREVIOUSLY DIAGNOSED  
5.2.3
For previously diagnosed participants who have already started on ART (Cohort II) only those that 
started at least 3 drug ART at PHI diagnosis, have been on at least 3-drug ART for ≥ 22 weeks and ≤ 2 
years and are still on ART at screening will be eligible for randomisation.   
 
If a participant is already on combination ART regimen that includes raltegravir this participant can 
proceed straight to screening and randomisation.  
 
The preferred regimen prior to randomisation should contain raltegravir. For those participants that 
are not on raltegravir, and are willing to switch regimen, we recommend that once consent for the 
study has been taken, their combination ART be changed 6 weeks prior to randomisation to include 
raltegravir. During these 6 weeks, any toxicities associated with this switch in regimen should be 
monitored as per routine clinical guidelines. If the new regimen is well tolerated and the participant 
is compliant with their new regimen they can proceed to screening and randomisation. The 
participant should then continue on raltegravir the duration of the study.   
 
However, where the use of raltegravir is contraindicated this can be substituted with ideally another 
integrase inhibitor.  If however it is not possible to substitute this and the participant is eligible for 
randomisation they can join the study on their current ART regimen.   
 
TREATMENT AT ENROLMENT/RANDOMISATION  
5.3
Once eligibility for the study has been confirmed by the RIVER Co-ordinating Centre all participants 
will initiate or continue on appropriate combination ART (cART) preferably including raltegravir.   
 
For ART naïve participants that start ART at enrolment the choice of the exact components of this 
will be based on HIV genotype, potential drug toxicities and interactions with any other concomitant 
medication and baseline HIV viral load. Usually at the time of acute HIV seroconversion with high 
viral load and high rates of skin rash and CNS symptoms, Truvada™ with a boosted Protease Inhibitor 
(PI) or an integrase inhibitor is the preferred regimen (Cohort I – Recently diagnosed).  
 
For this study any BHIVA recognised appropriate ART is acceptable and will be individual participant-
clinician choice. Preferably this will include the integrase inhibitor (INSTI), raltegravir (BID). Industry 
partners have donated this for the duration of the study with the plan to simplify treatment at the 
end of the study to standard therapy. 
 
Patients who meet the eligibility criteria for randomisation (bloods taken at week 22 or at repeat 
visits for Cohort I Section 3.3 and at screening for Cohort II Section 3.4) and have confirmed they are 
happy to proceed, will be randomised. At the randomisation visit, patients will be randomised to one 
of the two arms i.e. Arm A cART alone or Arm B to receive prime-boost vaccine and HDACi in 
addition to cART. Participants randomised to Arm B will have their post-randomisation week 00 and 
week 08 day 1 (PR00 and PR08-1) vaccine visits conducted at the Royal Free Hospital. 
 
 


 
 
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POST-RANDOMISATION (PR) TREATMENT 
5.4
Once a participant has been randomised to the study the participant allocation will be confirmed by 
the RIVER Co-ordinating Centre. Participants in Arm B will be scheduled for their first vaccination at 
Royal Free Hospital as per treatment schedule see Figure 5.  
ARM 
COMPONENT 
DETAIL 
Arm A:  
cART preferably 
including raltegravir 
Combination 
ART 
(cART) 
 
Likely consisting of an Nucleoside reverse-transcriptase inhibitor 
(NRTI) backbone i.e. Truvada and raltegravir. cART is prescribed 
at enrolment/randomisation for the duration of the study   
Raltegravir dosage: oral 400mg tablet twice per day (BID).  
SmPC: Current version as posted to www.medicines.org.uk  
Marketing Authorisation Holder: Merck Sharp & Dohme Ltd 
Arm B:  
cART preferably 
including raltegravir 
+ Vaccines  
+ vorinostat 
Combination 
ART 
(cART) 
 
Likely consisting of an Nucleoside reverse-transcriptase inhibitor 
(NRTI) backbone i.e. Truvada and raltegravir. cART is prescribed 
at enrolment/randomisation for the duration of the study  
Raltegravir dosage: oral 400mg tablet twice per day (BID).  
SmPC: Current version as posted to www.medicines.org.uk  
Marketing Authorisation Holder: Merck Sharp & Dohme Ltd 
ChAdV63.HIVconsv
(ChAd)  
Dosage: 5x1010vp  
Administration: This dose is obtained by injecting 0.37ml of the 
vaccine at 1.35x1011vp/ml without dilution. This prime vaccination 
is administered intramuscularly (IM) into the deltoid muscle of the 
non-dominant arm within 1 week of randomisation at visit 
post-randomisation week 00 (PR00).  
Manufacturer: Clinical BioManufacturing Facility (CBF), Oxford, UK
Storage: Vials are stored at between -70 and -90°C 
MVA.HIVconsv 
(MVA) 
Dosage: 2x108pfu  
Administration: This dose is obtained by injecting 0.23 ml of the 
vaccine IM at 8.6x108pfu/ml without dilution. This boost 
vaccination is administered intramuscularly (IM) into the deltoid 
muscle of the non-dominant arm at post-randomisation week 8 
Day 1 (PR08-1), 2 days prior to start of vorinostat. 
Manufacturer: Impfstoffwerk Dessau-Tornau (IDT) Biologika 
GmbH, Germany 
Storage: Vials are stored at between -70 and -90°C 
Vorinostat
Dosage: oral 400mg every third day from post-randomisation 
week 8 day 3 (PR08-3) to week 12 day 2 (PR12-2) inclusive. 10 
doses in total.  
Administration: Vorinostat is administered orally with food. 
Participants should drink at least 2L fluid/day (on drug dosing 
days) to prevent dehydration and must report any excessive 
vomiting or diarrhoea; signs or symptoms of deep vein thrombosis 
(swelling and pain in a limb, shortness of breath, cough, pleuritic 
chest pain); unusual bleeding and seek medical attention. 
Manufacturer: Merck Sharp & Dohme Ltd 
Storage: at 20-25oC, excursions permitted between 15-30oC 


 
 
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Figure 5 RIVER Treatment Schedule – Cohort I – Recently diagnosed  
 
 
 
 
 
 
 


 
 
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Figure 6 RIVER Treatment Schedule – Cohort II – Previously diagnosed  
 
 


 
 
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CRITERIA FOR STARTING VORINOSTAT 
5.5
Safety assessments will be undertaken to ensure it is safe for participants randomised to Arm B to 
receive vorinostat at post-randomisation week 08 day 3 (PR08-3). Only participants who meet these 
criteria will proceed to receive dosing with vorinostat. 
 
Arm B participants must meet the following criteria at post-randomisation week 08 day 1 (PR08-1) in 
order to commence vorinostat 2 days later at post-randomisation week 08 day 3 (PR08-3): 
 
1. Participant is willing to continue on combination antiretroviral therapy 
2. Platelet count ≥150x109/L 
3. eGFR ≥60** 
4. Adequate haemoglobin (Hb≥12g/dL for males, ≥11g/dL for females) 
5. ALT <5xULN 
6. QTc interval normal, with normal defined as 0.44s (440ms)  
Any out-of-range results from the above indicate that the participant must not receive vorinostat. 
Participants in Arm B will then be followed for the rest of the study as per study visit schedule. 
Analysis of their data will be included as part of the intention to treat analysis of the primary study 
end point (see Section 9.5) 
 
DISPENSING AND HANDLING 
5.6
 
 COMBINATION ART (CART) 
5.6.1
All participants will be dispensed sufficient supplies of cART to ensure they have sufficient 
medication to last to the next study visit. Storage of ART is in accordance with the current SmPC for 
each agent. For Cohort I – Recently diagnosed suggested dispensing schedules are as follows (but 
may depend on time taken to meet eligibility criteria for randomisation):  
 
One-month supply at enrolment (week 0) 
 
Two-month supply at week 4, and 
 
Three-month supplies at week 12, randomisation visit and post-randomisation week 12.  
 
For Cohort II – Previously diagnosed suggested dispensing schedules are as follows: 
 
Three month supplies at randomisation visit and post-randomisation week 12 
 
 
RALTEGRAVIR  
5.6.2
All participants will preferably be on a regimen than contains raltegravir at enrolment. All 
participants enrolled/randomised will be dispensed sufficient supplies to ensure they have sufficient 
medication to last to the next study visit. Raltegravir is supplied in marketed packs with 60 tablets 
per bottle. Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F).  
 
Dispensing and handing procedures for raltegravir is as above for cART. Suggested dispensing 
schedule for both cohorts is as above for cART.   
 


 
 
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VACCINES 
5.6.3
Irrespective of clinical site of enrolment, all vaccine study visits for the Arm B participants will be 
undertaken at one centralised vaccine site (Royal Free Hospital). The reason for this is to ensure 
uniform temperature and GMO procedures for vaccine procurement, storage, thawing and 
administration. 
 
The first vaccination (ChAd) takes place at post-randomisation week 00 (PR00), within 1 week after 
randomisation, and the second vaccine (MVA), 8 weeks later, at PR week 08 day 1 (PR08-1). There is 
a visit window around the second vaccine of 7 days. On the days of vaccination, the vaccine will be 
allowed to thaw to room temperature and then administered within 1 hour of removal from the 
freezer. The vaccine will be administered intramuscularly (IM) over the deltoid region of the non-
dominant arm. The investigator or study nurse will wear gloves and eye protection. During 
administration of the vaccines, medicines and resuscitation equipment will be immediately available 
for the management of anaphylaxis. The participant will remain in clinic for ≥1 hour of observation 
following the receipt of each vaccine. The participant will be contacted by phone by designated 
study personnel within 72 hrs of receipt of both vaccines to review any AEs. Participants should 
complete a 3 day vaccine diary following each vaccination.  
 
In order to minimise dissemination of the recombinant vectored vaccine virus into the environment, 
the inoculation sites will be covered with a dressing after immunisation. This should absorb any virus 
that may leak out through the needle tracks. The dressings will be removed from the injection sites 
after 30 minutes and disposed of as genetically modified organism (GMO) waste by autoclave and 
then standard disposal, in accordance with current standard UK practice. 
 
 
VORINOSTAT 
5.6.4
Procedures for proper handling and disposal of vorinostat as cytotoxic drug should be employed. 
The drug should only be dispensed at Royal Free Hospital to those randomised to Arm B. Total 
number of doses is 10 x 400mg doses over 28 days with 4 x 100mg capsules taken every third day 
with food. Vorinostat will be dispensed to participants on PR week 08 day 1 (PR08-1) at the Royal 
Free Hospital at the participant’s second vaccination visit. Participants will be required to bring their 
vorinostat to their clinic visit (at recruiting site) at PR week 08 day 3 (PR08-3). Participants will be 
required to take their first vorinostat dose in clinic. Ideally, Day 1 of vorinostat dosing will occur on a 
Wednesday to avoid study blood draws over the weekend. Dosing should be undertaken at the same 
time each day. Vorinostat must be kept at room temperature, 15°-30°C (59°-86°F). Vorinostat 
capsules if damaged or broken should not be used. Vorinostat capsules must not be opened or 
crushed. If vorinostat powder (within the capsule) comes into contact with skin or mucous 
membranes, the area must be washed immediately with plain water; participants should notify the 
site.  
 
STOPPING DRUG EARLY 
5.7
 
COMBINATION ART 
5.7.1
Participants ceasing cART at any point on the study for toxicity or other reasons should be managed 
according to the BHIVA antiretroviral guidelines for adults. Participants choosing to stop cART cannot 
receive further vaccination or vorinostat if randomised to Arm B.  
 


 
 
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RALTEGRAVIR 
5.7.2
Participants that cease raltegravir at any point on the study for toxicity or other reasons should be 
managed according to the BHIVA antiretroviral guidelines for adults. Ideally, an intra-class 
substitution is preferred i.e. with another integrase inhibitor such as dolutegravir, provided there is 
no contraindication to use. If, however, it is not possible to substitute another drug to replace 
raltegravir, they can continue with vaccination and vorinostat as per protocol if randomised to Arm B 
provided their HIV RNA remains <50copies/mL. 
 
 
VACCINES 
5.7.3
In the event of a severe local or systemic reaction to the first vaccination (ChAd) the following must 
be considered in regards to administration of the second vaccination (MVA).  
1. The second vaccination must not be given if an anaphylactic reaction occurred after the first 
vaccine administration. 
2. In the event of a severe local reaction or non-anaphylactic systemic reaction, the site should 
discuss with the RIVER Co-ordinating Centre team in the first instance who will then discuss 
with the IDMC for the RIVER study. Advice will be given on whether the second vaccination 
should be given. 
 
If the participant does not receive the second vaccination for any reason, the participants should 
remain on cART and in follow-up for the study. Only participants who have received both doses of 
the vaccines (remain on cART and meet eligibility criteria see Section 5.4) can proceed to vorinostat 
dosing.  
 
 
VORINOSTAT 
5.7.4
In the event of a serious AE related to vorinostat the dosing will be terminated early. See below 
(Section 5.8) and in Appendix II for further guidance of toxicity management and dosing.  
 
 


 
 
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DOSE MODIFICATIONS, INTERRUPTIONS & DISCONTINUATIONS 
5.8
Toxicity will be managed in all randomised groups according to standard clinical practice. Blood tests 
additional to those described in the study schedule may be requested at any time for clinical 
management of the participant. 
 
 
VORINOSTAT TOXICITY MANAGEMENT 
5.8.1
In the event of any vorinostat toxicity Table 5 details actions that should be taken. 
Table 5 Toxicity management during vorinostat dosing 
Toxicity 
Grade 
Vorinostat Dosing Action 
Continuation 
Non-haematological toxicity  
Grade 1 or 2 
No change unless due to 
impairment of QoL at discretion 
of Investigator (consider dose 
reduction as detailed below for 
Grade 2 toxicity) 
Continue 
Non-haematological toxicity  
Grade 3 or 4 
Cease treatment 
Never 
Anaemia, neutropenia or 
thrombocytopenia  
Grade 1 
No change 
Continue 
Neutropenia  
Grade 2 
Withhold vorinostat until 
returns to Grade ≤1. 
If resolves to Grade ≤1, 
continue vorinostat at full 
dose. If on rechallenge 
recurs to Grade 2 or 
above, cease treatment. 
G-CSF is allowed at the 
clinician’s discretion 
Neutropenia  
Grade 3 or 4 
Cease treatment 
 
Febrile neutropenia  
Grade 3 or 4 
Cease treatment 
 
Anaemia or 
thrombocytopenia  
Grade 2 
Withhold vorinostat until 
returns to ≤Grade 1  
If resolves to ≤ Grade 1, 
continue vorinostat at full 
dose. If on rechallenge 
recurs to Grade 2 or 
above, cease treatment. 
Anaemia or 
thrombocytopenia  
Grade 3 or 4 
Cease treatment 
 
 
Specific toxicity management in the setting of vorinostat dosing is provided in Table 5 above. 
Grade 2 non-haematological toxicities, at the discretion of the treating clinician and with the 
agreement of the participant, can be managed with dose reduction of vorinostat to 300mg every 
third day. If the participant is intolerant of this reduced dose then the drug should be ceased all 
together, see Section 5.7. 
 
All attempts must be made to avoid treatment interruptions; especially those for non-medical 
reasons e.g. ‘drug holidays’ or lost prescriptions. Treatment interruptions for medical reasons e.g. 
unable to have oral intake for whatever reason, are unavoidable and are permissible under this 
protocol as a protocol deviation. Every attempt should be made to limit the duration of treatment 
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5.8.1.A SPECIFIC GUIDELINES FOR MANAGEMENT OF EXPECTED TOXICITIES: 
 
Diarrhoea – management with loperamide is strongly encouraged. 
 
Dehydration – encourage anti-emetics and anti-diarrhoeals as appropriate; encourage 
drinking of at least 2L fluid per day. Rehydration solutions are also encouraged as 
appropriate. 
 
Nausea and vomiting – aggressive management is encouraged.  
 
Hyperglycaemia – monitor blood glucose closely, treat with hypoglycaemic agents as 
appropriate. 
 
Electrolyte disturbance – replace potassium, calcium and magnesium as appropriate, as 
guided by regular blood electrolyte tests. 
 
Venous thromboembolism – monitor closely for signs and symptoms and investigate if 
there is suspicion of embolic event or venous thrombosis 
 
QTc prolongation – aggressively manage electrolyte disturbances. 
 
Hematologic toxicities: 
o Anaemia – transfuse as per institutional guidelines. Erythropoietin is allowed on-
study as per prescribing guidelines. 
o Neutropenia – G-CSF is allowed on-study at investigator discretion. 
o Thrombocytopaenia - Platelet transfusions should be administered in the following 
situations: 
- 
Platelets <10x109/L. 
- 
Platelets <20x109/L with fever ≥38.5oC due to infection or presumed 
infection (at discretion of treating clinician). 
- 
Platelets <20x109/L with clinically significant bleeding (at discretion of 
treating clinician). 
- 
Platelets <50x109/L in participants having invasive procedures (at discretion 
of treating clinician). 
 
If the participant is intolerant of the 300mg every third day dose, then the drug should be ceased all 
together, see Section 5.7. 
 
5.8.1.B VIROLOGICAL REBOUND 
If a significant increase in viral replication occurs at any time on study (while on or off vorinostat), 
the Trial Physician will be informed, the participant managed according to current guidelines and 
continuation in the trial will be managed on a case by case basis. Participants must have HIV RNA 
<50 copies/mL (<200 copies/mL Taqman Roche 2.0 assay) to be eligible for randomisation.  
 
OVERDOSE OF TRIAL MEDICATION 
5.9
All participants should be counselled about the importance of taking the medications as prescribed. 
It is particularly important that participants understand how many tablets of which type they are 
taking. Participants must be told to contact their clinic immediately if they take too many tablets. In 
the event of overdose of study medication, all appropriate medical care will be given and regular 
tests will be carried out to ensure safety. 


 
 
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 PROTOCOL TREATMENT DISCONTINUATION 
5.10
In consenting to the study, participants are consenting to study treatment, study follow-up and data 
collection. However, an individual participant may stop treatment early or be stopped early for any 
of the following reasons: 
 
 
Unacceptable toxicity or adverse event. 
 
Intercurrent illness that prevents further treatment. 
 
Development of malignancy. 
 
Any change in the participant’s condition that, in the opinion of the clinician, justifies 
treatment discontinuation. Clinicians should avoid interruption of a suppressive ART 
regimen unless this is unavoidable.  
 
Inadequate compliance with the protocol treatment in the judgement of the treating 
physician. 
 
Withdrawal of consent for study intervention medication by the participant. 
 
As the participant’s participation in the study is entirely voluntary, they may choose to discontinue 
the study treatment at any time without penalty or loss of benefits to which they are otherwise 
entitled. Although the participant is not required to give a reason for discontinuing their study 
treatment, a reasonable effort should be made to establish this reason while fully respecting the 
participant's rights. 
 
Participants should remain in the study for the purpose of follow-up and data analysis (unless the 
participant withdraws their consent from all stages of the study). If a participant is withdrawn from 
follow-up, refer to Section 6.5. 
 
Data will be kept and included for participants who stop follow-up early.  
 ACCOUNTABILITY & UNUSED DRUGS 
5.11
Investigational Medicinal Product (IMP) will be centrally packed and distributed as described in 
Section 5.1. Supplies of raltegravir will be sent to the hospital pharmacy at each of the participating 
sites. The hospital pharmacy will document receipt of supplies and destruction of any raltegravir 
returned by a participant. 
 
Supplies of raltegravir will be dispensed to a participant from the site at which they were recruited. 
Vaccines and vorinostat will be dispensed to participants in Arm B at their visits to Royal Free 
Hospital. Unused vaccine and/or vorinostat will be returned to the study pharmacy and entered onto 
the accountability log. Vorinostat will be handled and destroyed as per the requirements of a 
chemotherapy (anti-cancer) drug. Study vaccines will be disposed of as Genetically Modified 
Organism (GMO) waste by autoclaving and usual disposal, in accordance with current standard UK 
practice. 
 
IMP accountability will be maintained and monitored by site staff and RIVER Co-ordinating Centre 
respectively according to the RIVER working practices and pharmacies will be asked to maintain 
records of any returned IMP. At the end of the study all non-dispensed IMP will be checked against 
the inventory before disposal. Disposal of IMP should not be carried without approval of the RIVER 
Trial Manager and should be carried out according to local pharmacy guidelines and applicable 
regulations. Documentation of disposal will be provided to RIVER Co-ordinating Centre. 


 
 
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 COMPLIANCE & ADHERENCE 
5.12
Suitable participant information and fully informed consent procedures will ensure that participants 
understand the study requirements.  
 
The study vaccines will be given in hospital by clinic nurses intramuscularly therefore few problems 
with compliance or adherence are envisaged. Compliance and adherence to the cART and vorinostat 
treatment regimens will be assessed at clinic visits through interview with the participant. 
Participants will be interviewed about missed doses at study visits, and if they do occur these will be 
recorded in the CRF.  
 TREATMENT DATA COLLECTION 
5.13
Every drug prescribed, its dose, frequency, route of administration, and duration will be recorded in 
the study case report forms (CRF).  
 CONCOMITANT MEDICATIONS 
5.14
 MEDICATIONS PERMITTED 
5.14.1
Antibiotics to treat intercurrent infection, treatment for other co-morbidities not contraindicated for 
the study e.g. diabetic treatment, hypertension treatment, lipid lowering agents and inhaled 
corticosteroids are all permitted for concomitant use. 
 
 MEDICATIONS NOT PERMITTED 
5.14.2
The following medications are not permitted for concomitant use: 
 
Immunosuppressive drugs (inhaled corticosteroids are permitted). 
 
Chemotherapy drugs. 
 
Other HIV vaccines. 
 
All medication whose co-administration with ritonavir boosted protease inhibitor (e.g. 
darunavir), raltegravir and NRTI backbone (e.g. Truvada or Kivexa) is contraindicated. 
See details in the relevant SmPC.  
 
In Arm B drugs that have been associated with Torsades de Pointes and/or are associated 
with QT shortening (see Appendix I and reference www.torsades.org). 
 
In Arm B, other HDACi i.e. sodium valproate. 
 
 MEDICATIONS TO BE USED WITH CAUTION 
5.14.3
Intermittent use of non-steroidal anti-inflammatory drugs (NSAIDS), caution is only required if these 
are given within a week of or during receipt of vorinostat in Arm B participants. The reason for 
caution is that all NSAIDS can impair platelet function. One of the most common side-effects of 
vorinostat is thrombocytopenia, and this coupled with impaired platelet function might increase the 
risk of bleeding. 
 
Co-administration of raltegravir with aluminium and magnesium antacids results in reduced 
raltegravir plasma levels, separate doses by at least 2hrs to avoid chelation effects on raltegravir and 
reduced absorption. More information is also provided in Appendix I.  


 
 
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6 
ASSESSMENTS & FOLLOW-UP 
All randomised participants will be asked to attend follow-up visits until week 18 after 
randomisation (PR18) in order to assess primary outcome measures. Participants will also be invited 
to an annual follow-up visit at the site for 5 years following the end of the interventional part of the 
study. 
 
Staff recording clinical data will be identified by each site Principal Investigator, receive appropriate 
training and sign a delegation Log. Clinical data will be obtained through consultation with the 
participant, their medical team, or their medical records. Laboratory measures will be extracted 
from participant notes/electronic records; study nurses will administer the QOL questionnaires to 
participants. All data will be recorded on paper CRFs submitted to the RIVER Co-ordinating Centre 
for processing within 7 days of the study visit.  
 
Any additional visits or diagnostic/laboratory tests needed for participant management should occur 
as required at the discretion of the treating physician. 
 
TRIAL ASSESSMENT SCHEDULE 
6.1
Procedures planned at study visits follow the schedules outlined in Table 1 (Cohort I - Previously 
diagnosed) and Table 2 (Cohort II - Recently diagnosed). Participants will be provided with a 
summary of what to expect at study visits prior to providing consent, to ensure they are fully 
informed of the commitment required as part of the RIVER study. Details of logistics surrounding 
study visits will be included in study specific working practices and training for study staff will be 
provided.  
 
 SCREENING  
6.1.1
For Cohort I – Recently diagnosed, one of the eligibility criteria for enrolment in to the RIVER study is 
a confirmed HIV diagnosis within 4 weeks of enrolment. Therefore, potentially eligible individuals 
must undergo all tests required for assessment of eligibility in the 4 weeks following diagnosis. All 
results from this screening must be available for enrolment (Week 0). 
 
For Cohort II – Previously diagnosed, group potentially eligible individuals must undergo all tests 
required for assessment of eligibility in the 2 weeks prior to randomisation. All results from this 
screening must be available for randomisation.  
 
All participants must be given adequate information about the study together with a Participant 
Information Leaflet (Appendix VII) and be given an opportunity to ask questions about the study. 
There will be separate Participant Information Leaflets for each cohort. Study staff will be asked to 
maintain a log of participants who are not eligible or do not agree to take part in the study.  
 
Study staff will ascertain that the information leaflet has been fully understood and obtain written 
informed consent before any study procedures are carried out. All individuals screened must have 
their name, date of birth and study number recorded in the Trial Register and have appropriate CRFs 
completed. The register must be stored by the investigator in a secure place only accessible to 
appropriate clinical staff. If an individual is not subsequently randomised the reason should be 
recorded in the register.  


 
 
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There will be a clinic interview, during which baseline demographics, clinical and behavioural data 
relevant to the eligibility criteria in Section 3.3 and Section  3.4 will be collected onto a CRF.  
 
Screening will include: 
1. Recording the clinical history, including HIV test results (Resistance test), Hepatitis B (sAg, 
sAb, Core Ab) Hepatitis C serology (HCV Ab and HCV RNA/antigen) and use of ART.  
2. Recording specific clinical details to ensure female candidates are not women of CBP. 
3. Physical examination (including height, weight and blood pressure). 
4. Resting 12-lead ECG. 
5. If results are not already available, routine blood will be taken for: 
a. Full blood count (haemoglobin, haematocrit, white blood cell count (WBC) with 
differential and platelets). 
b. Biochemistry tests (ALT, AST, alkaline phosphatase, total bilirubin, albumin, eGFR, 
creatinine kinase). 
c. Urine Protein Creatinine Ratio (uPCR). 
d. Lipids (total cholesterol, LDL, HDL, triglycerides). 
e. T lymphocyte subsets (total lymphocytes, percent and/or absolute CD3/CD4/CD8). 
f. Viral load measurements. 
g. HbA1C (only if known diabetes mellitus). 
 
Results of the clinical history and evaluations are to be entered on a case report form. Once clinic 
staff are satisfied that the participant is eligible for the study a completed screening CRF should be 
submitted to the RIVER Co-ordinating Centre for verification.  
 
For Cohort I – Recently diagnosed,  confirmation of enrolment will be sent to the site by email and 
also relayed over the telephone. Once this confirmation has been received the participant should be 
commenced on cART treatment as outlined in Section 5.6. Eligibility for randomisation will be 
assessed at Week 22.  For Cohort II – Previously diagnosed, eligibility for randomisation will be 
assessed at screening. Participants will not be randomised until all eligibility criteria have been met, 
see Section 3.3.3, at which time the clinic staff will be informed which arm the participant has been 
allocated to. 
 
PROCEDURES FOR ASSESSING EFFICACY 
6.2
The efficacy of cART will be determined using viral load assays obtained at the local laboratories. In 
particular participants must have a plasma HIV RNA <50 copies/mL (<200 copies/mL if Taqman 2.0 
Roche testing platform used) to be eligible for randomisation, either at week 22 (or any necessary 
repeat visits) or – for Cohort II – at screening. Any evidence of viral rebound during the study must 
be managed in accordance with standard national treatment guidelines.  
 
PROCEDURES FOR ASSESSING SAFETY 
6.3
All standard routine toxicity testing for cART, vaccine and vorinostat will be made according to the 
study visits. In addition, in the event of any abnormal blood test results these will be followed up 
with good clinical practice accordingly. Specific monitoring of the following parameters i.e. FBC, 
renal function (eGFR and uPCR), electrolytes i.e. calcium, magnesium and potassium; LFTs and blood 


 
 
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glucose will be conducted at specific time points in the study commensurate with the vorinostat 
dosing schedule Arm B. 
 
Adverse events will be reported on the case report form. Adverse events (clinical and laboratory) will 
be graded using the 2004 (amended 2009) Division of AIDS toxicity grading table (see Appendix III). 
Serious adverse events will be defined according to principles of GCP, and should be reported to the 
CTU within 24 hours of the site being aware (see Section 7). All adverse events, after randomisation, 
meeting the definitions above should be reported on study CRFs, regardless of their relationship to 
HIV. Prior to randomisation only grade 3 and 4 adverse events and Serious Adverse Events (SAE) are 
collected.  
 
PROCEDURES FOR ASSESSING QUALITY OF LIFE 
6.4
All participants will be asked to complete the EQ-5D-5L questionnaire at enrolment (visit only 
applicable to Cohort I – Recently diagnosed), randomisation, post-randomisation week 08 day 3 
(PR08-3) and the final visit, post-randomisation week 18 (PR18). (Appendix X). 
 
EARLY STOPPING OF FOLLOW-UP 
6.5
If a participant chooses to discontinue their study treatment, they should always be followed up 
providing they are willing, that is, they should be encouraged to not leave the whole study; if they do 
not wish to remain on study follow-up, however, their decision must be respected and the 
participant will be withdrawn from the study completely. The RIVER Co-ordinating Centre should be 
informed of this in writing using the appropriate documentation. Participants withdrawing 
completely have a negative impact on a study's data. 
 
If the medical data collected during the participant’s participation in the study are kept for research 
and analysis purposes, they can be anonymised if necessary. Consent for future use of stored 
samples already collected can be refused when leaving the study early (but this should be 
discouraged and should follow a discussion). 
 
All participants will be followed up in the long-term as part of the RIVER study (see Section 6.9), 
which may include flagging with the NHS Information Centre, ONS or similar approaches. 
 
PARTICIPANT TRANSFERS 
6.6
If a participant moves from the area, every effort should be made for the participant to be seen at 
another participating study site. A copy of the participant’s CRFs should be provided to the new site 
and the participant will need to sign a new consent form. Once this has been done, the new site will 
take over responsibility for the participant; until this has been done, responsibility for the participant 
lies with the original site. 
 
LOSS TO FOLLOW-UP 
6.7
In the statistical analysis, a patient will be classified as ‘lost to follow-up’ if they have not been seen 
in clinic for more than 3 months. For operational management, a patient will be classified as 'lost to 


 
 
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follow-up' (i.e no further efforts to trace the patient are being made) when they have missed 3 
scheduled clinic visits and despite at least 3 documented attempts to contact them. Provided 
patients have consented to the site contacting their GP, the site will attempt to find further 
information on the patient’s clinical status via the GP. Subsequently, if the patient attends clinic and 
a CRF is received by the RIVER Co-ordinating Centre, the ‘lost to follow-up’ status will be reversed. 
 
ASSESSMENTS AT TRIAL CLOSURE 
6.8
At the final study visit (PR18) all blood assessments will be taken for the final study end point. The 
participant will then continue with ART triple therapy and return to standard clinical care in 
consultation with their doctor.  
 
LONG-TERM FOLLOW-UP 
6.9
All participants will be followed-up annually for 5 years following the end of the interventional phase 
of the study. 
 
To gather specific safety information specifically in regards to vorinostat – as the mechanism of 
action of vorinostat is gene modification this may carry unforeseen long-term consequences beyond 
the timeframe of the main study. Specific questions asked will include: 
1. Safety related 
 
Any new or exacerbation of haematological conditions including lab abnormalities. 
 
Any new malignancies or pre-malignancies including skin cancers, anal intraepithelial 
neoplasia (AIN), cervical intraepithelial neoplasia (CIN), Barrett’s oesophagus etc. 
 
Any new or exacerbation of pre-existing medical problems. 
 
Outcome of any pregnancies in female partners. 
2. To gather HIV related information: 
 Antiretroviral drug use. 
 T-cells and viral load. 
 AIDS-defining illness (ADI) or serious non-AIDS (SNA) events. 
3. To obtain longer-term follow up on impact of the intervention on measures of viral reservoir 
beyond the scope of the current research study a 40mL blood draw for HIV reservoir 
assessment (DNA) and gene transcription studies will be collected at each annual visit. 
 


 
 
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7 
SAFETY REPORTING 
The principles of GCP require that both investigators and sponsors follow specific procedures when 
notifying and reporting adverse events or reactions in clinical studies. These procedures are 
described in this section of the protocol. Section 7.1 lists definitions, Section 7.3 gives details of the 
investigator responsibilities and Section 7.4 provides information on the RIVER Co-ordinating Centre 
responsibilities. 
 
DEFINITIONS 
7.1
The definitions of the EU Directive 2001/20/EC Article 2 based on the principles of GCP apply to this 
study protocol. These definitions are given in Table 6.  
 
Table 6 Definitions 
TERM 
DEFINITION 
Adverse Event (AE) 
Any untoward medical occurrence in a participant or clinical 
study subject to whom a medicinal product has been 
administered including occurrences that are not necessarily 
caused by or related to that product. 
Adverse Reaction (AR) 
Any untoward and unintended response to an investigational 
medicinal product related to any dose administered. 
Unexpected Adverse Reaction (UAR) 
An adverse reaction, the nature or severity of which is not 
consistent with the information about the medicinal product in 
question set out in the Summary of Product Characteristics 
(SmPC) or Investigator Brochure (IB) for that product. 
Serious Adverse Event (SAE) or Serious 
Adverse Reaction (SAR) or Suspected 
Unexpected Serious Adverse Reaction 
(SUSAR) 
Respectively any adverse event, adverse reaction or unexpected 
adverse reaction that:  
 
Results in death 
 
Is life-threatening‡‡‡ 
 
Requires hospitalisation or prolongation of existing 
hospitalisation§§§ 
 
Results in persistent or significant disability or 
incapacity 
 
Consists of a congenital anomaly or birth defect 
 
Is another important medical condition**** 
                                                             
‡‡‡ The term life-threatening in the definition of a serious event refers to an event in which the participant is at risk of 
death at the time of the event; it does not refer to an event that hypothetically might cause death if it were more 
severe, for example, a silent myocardial infarction. 
§§§ Hospitalisation is defined as an inpatient admission, regardless of length of stay, even if the hospitalisation is a 
precautionary measure for continued observation. Hospitalisations for a pre-existing condition, that has not 
worsened or for an elective procedure do not constitute an SAE. 
**** Medical judgement should be exercised in deciding whether an AE or AR is serious in other situations. The following 
should also be considered serious: important AEs or ARs that are not immediately life-threatening or do not result 
in death or hospitalisation but may jeopardise the subject or may require intervention to prevent one of the other 
outcomes listed in the definition above; for example, a secondary malignancy, an allergic bronchospasm requiring 
intensive emergency treatment, seizures or blood dyscrasias that do not result in hospitalisation or development of 
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MEDICINAL PRODUCTS 
7.1.1
An investigational medicinal product is defined as the tested investigational medicinal product and 
the comparators used in the study. (EU guidance ENTR/CT 3, April 2006 revision). In the RIVER study 
this includes: 
 
 
Vorinostat 
 
Raltegravir 
 
Combination ART backbone treatment 
 
ChAdV63.HIVconsv.  
 
MVA.HIVconsv vaccine 
 
 
ADVERSE EVENTS 
7.1.2
Adverse Events include: 
 
An exacerbation of a pre-existing illness. 
 
An increase in frequency or intensity of a pre-existing episodic event or condition. 
 
A condition (even though it may have been present prior to the start of the study) detected 
after study drug administration. 
 
Continuous persistent disease or a symptom present at baseline that worsens following 
administration of the study treatment. 
 
Adverse Events do not include: 
 
Medical or surgical procedures; the condition that leads to the procedure is the adverse 
event. 
 
Pre-existing disease or a condition present before treatment that does not worsen. 
 
Hospitalisations where no untoward or unintended response has occurred, e.g., elective 
cosmetic surgery, social admissions. 
 
Accidental overdose of medication without signs or symptoms. 
 
 
 
DISEASE-RELATED EVENTS 
7.1.3
All adverse events meeting the definitions above, regardless of their relationship to HIV and should 
be graded (see Appendix III). For AE reporting requirements refer to Section 7.4. 
 
In particular, all deaths should be reported as fatal SAEs.  
 
OTHER STUDY-SPECIFIC REQUIREMENTS & EXPLORATORY OUTCOMES 
7.2
 
LARGE VOLUME BLOOD DRAW 
7.2.1
The total blood draw over the study for both cohorts is approximately 1500 ml. The largest blood 
draws occur at randomisation (390ml) and post-randomisation week 16, PR16 (387ml). The UK blood 
transfusion service (www.blood.co.uk/giving-blood) recommends the following in regards to 
donating blood: 
 
1. Aged 17-65 years and generally in good health. 
2. Male donors can donate 4 times in a 12-month period, with each blood donation equal to 
470 ml i.e. a total of 1880 ml/annum. 
3. Female donors can donate 470mLs every 16 weeks, this is to reduce the risk of iron 
deficiency anaemia in those still menstruating. 


 
 
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4. Weight must be at least 50 kg, but in females under 20 years of age and weighing <65kg and 
less than 168cm in height, blood volume needs to be estimated before donation. 
 
In the RIVER protocol, the risks of the blood draws are minimised through the following: 
1. Haemoglobin (Hb) within the normal range and weight ≥50kg as inclusion criteria for 
participation; women of CBP are excluded from participation, and none of the women 
included will be menstruating. 
2. Cohort I – Recently diagnosed participants have primary HIV infection and it is most unlikely 
that there will be any impact on the haematological axis in such participants. 
3. Hb checks prior to the larger volume blood draws at randomisation and PR16 i.e. at week 
22/screening and PR12 respectively.  
4. Participants in Cohort II – Previously diagnosed are excluded if in the 3 months prior to 
screening ≥40ml of blood has been taken.  
5. Sites are advised that the participant should not have any large blood draws for 3 months 
after the last study visit, PR18.   
 
 
EXPLORATORY OUTCOMES – HUMAN ENDOGENOUS RETROVIRUSES  
7.2.2
Some human endogenous retroviruses (HERVs) types have been associated with disease states 
including lymphoma and multiple sclerosis but the exact role (if any) that HERVs play in their 
aetiology remains to be determined. The effect of vorinostat on human endogenous retroviruses 
(HERVs) is unknown. Any elevation of HERVS that might occur as a consequence of exposure to 
vorinostat is unlikely to be sustained, as exposure to vorinostat is restricted to 10 doses only. 
Information on incident cancers including lymphoma will be collected for the duration of the study 
and 5 years after the interventional phase of the study (see Section 6.9). The levels of these viruses 
may be measured under two circumstances, first if an excess of malignancies in which HERVS could 
be plausibly be involved is seen; or second, as an additional exploratory analysis.  
 
OTHER NOTABLE EVENTS 
7.3
There are several other notable events which if they occur during the study should be recorded in 
the participant’s medical notes and reported to the RIVER Co-ordinating Centre. Notable events may 
also be reportable as an SAE if any of the criteria listed in Table 6 are met. Refer to Appendix IV for a 
full list of notable events.  
 
 
VACCINE RELATED EVENTS  
7.3.1
GSK, as owners of the ChAd vector, have a list of vaccine related adverse events which are of specific 
interest to them. Information on notable events will be collected on a study CRF, and further 
information on the event may be requested.  
 
 
CANCERS 
7.3.2
Despite the fact that vorinostat is an HDACi licensed in the USA for the treatment of cutaneous T-cell 
lymphoma and multiple myeloma, in regards to the non-clinical toxicology of the agent, 
carcinogenicity studies have not been performed. However, vorinostat is mutagenic in vitro in the 
bacterial reverse mutation assays causing chromosomal aberrations in vitro in Chinese hamster 
ovary and increased incidence of micro-nucleated erythrocytes when administered to mice (mouse 
micronucleus assay). The risk of malignancy in participants exposed to vorinostat, even for short 
periods, is unknown.  
 


 
 
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For this reason any diagnosis of cancer (or worsening cancer) throughout the study should be 
reported on a cancer specific study CRF.  
 
Information on any new malignancies will also be collected during long-term follow up, where 
participants will be followed up annually for 5 years following the completion of the interventional 
phase of the study (see Section 6.9). 
 
 
PREGNANCY 
7.3.3
Women of child-bearing potential cannot participate in this study. In pre-clinical studies, there were 
chromosomal abnormalities induced by vorinostat in hamster ovary lines. It is unknown what 
impact, short exposure to vorinostat might have on the human ovary. Should the participant in the 
study father a child within 1 year of completing the course of vorinostat consent from the mother of 
the child will be sought to allow follow-up to the birth of the child.  
 
Pregnancy in a partner should be reported as a notable event.  
 
INVESTIGATOR RESPONSIBILITIES 
7.4
All non-serious AEs and ARs, whether expected or not, should be recorded in the participant’s 
medical notes and dependent on what stage of the study the participant has reached may need to 
be reported to the RIVER Co-ordinating Centre: 
 
- 
Participants in Cohort I – Recently diagnosed will be on cART alone for 22 weeks prior to 
randomisation. During this period, prior to randomisation, only grade 3 and 4 adverse events 
need to be reported on study CRFs.  
- 
From randomisation up until the participant’s last study visit (PR18), in addition to grade 3 or 
4 events, all non-serious AEs and ARs, whether expected or not, should also be recorded in 
the participant’s medical notes and reported on the relevant study CRF.  
- 
Adverse events should be sent to the RIVER Co-ordinating Centre within the agreed 
timescale of 7 days from awareness of the event.  
- 
SAEs, SARs and Notable Events should be notified to the RIVER Co-ordinating Centre within 
24 hours of the investigator becoming aware of the event.  
 
 
INVESTIGATOR ASSESSMENT 
7.4.1
7.4.1.A SERIOUSNESS 
When an AE or AR occurs, the investigator responsible for the care of the participant must first 
assess whether or not the event is serious using the definition given in Section 7.1. If the event is 
serious, then an SAE Form must be completed and the RIVER Co-ordinating Centre notified within 24 
hours. 
 
7.4.1.B SEVERITY OR GRADING OF ADVERSE EVENTS 
The severity of all AEs and/or ARs (serious and non-serious) in this study should be graded using the 
toxicity grading table in Appendix III. 
 
7.4.1.C CAUSALITY 
The investigator must assess the causality of all serious events or reactions in relation to the study 
therapy using the definitions in Table 7. There are five categories: unrelated, unlikely, possible, 
probable, and definitely related. If the causality assessment is unrelated or unlikely to be related, the 


 
 
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event is classified as an SAE. If the causality is assessed as possible, probable or definitely related, 
then the event is classified as an SAR. 
 
If an SAE is considered to be related to study treatment and drug is stopped or the dose modified, 
refer to Section 5.8. 
 
Table 7 Assigning Type of SAE Through Causality 
RELATIONSHIP 
DESCRIPTION 
SAE TYPE 
Unrelated 
There is no evidence of any causal relationship 
Unrelated SAE 
Unlikely 
There is little evidence to suggest that there is a causal 
relationship (for example, the event did not occur within a 
reasonable time after administration of the study medication). 
There is another reasonable explanation for the event (for 
example, the participant’s clinical condition, other concomitant 
treatment). 
Unrelated SAE 
Possible 
There is some evidence to suggest a causal relationship (for 
example, because the event occurs within a reasonable time 
after administration of the study medication). However, the 
influence of other factors may have contributed to the event (for 
example, the participant’s clinical condition or other 
concomitant treatments). 
SAR 
Probable 
There is evidence to suggest a causal relationship and the 
influence of other factors is unlikely. 
SAR 
Definitely 
There is clear evidence to suggest a causal relationship and other 
possible contributing factors can be ruled out. 
SAR 
 
7.4.1.D EXPECTEDNESS 
If there is at least a possible involvement of the study treatment (or comparator), the investigator 
must assess the expectedness of the event. An unexpected adverse reaction is one not previously 
reported in the current Summary of Product Characteristics (SmPC) or one that is more frequent or 
more severe than previously reported. The definition of an unexpected adverse reaction (UAR) is 
given in Table 6. If a SAR is assessed as being unexpected, it becomes a SUSAR. 
 
Please see Appendix II for details of expected toxicities associated with the drugs being used in this 
study.  
 
7.4.1.E 
NOTIFICATION 
The RIVER Co-ordinating Centre should be notified by the investigator of all SAEs within 24 hours of 
the investigator becoming aware of the event. 
 
Investigators should notify the RIVER Co-ordinating Centre of any SAEs from the point the 
participant is recruited into the study. For Cohort I – Recently diagnosed participants investigators 
should notify the RIVER Co-ordinating Centre of any SAEs occurring from the time of enrolment until 
12 weeks after the participant’s last study visit (up until post-randomisation week 30). For Cohort II – 
Previously diagnosed participants investigators should notify the RIVER Co-ordinating Centre of any 
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(up until post-randomisation week 30). Any subsequent events that may be attributed to treatment 
should be reported to the MHRA using the yellow card system. 
 
Having reviewed and checked SAEs, the RIVER Co-ordinating Centre will then be responsible for 
reporting these to the sponsor within 7 days.  
 
 
NOTIFICATION PROCEDURE 
7.4.2
1. The SAE Form must be completed by an investigator (a consultant named on the Signature 
List and Delegation of Responsibilities Log who is responsible for the participant’s care), with 
due care being paid to the grading, causality and expectedness of the event as outlined 
above. In the absence of the responsible investigator, the form should be completed and 
signed by a member of the site study team and faxed or emailed as appropriate. The 
responsible investigator should subsequently check the SAE Form, make changes as 
appropriate, sign and then re-fax to the RIVER Co-ordinating Centre as soon as possible. The 
initial report must be followed by detailed, written reports as appropriate.  
 
The minimum criteria required for reporting an SAE are the study number, name of 
investigator reporting, the event, and why it is considered serious. 
 
2. The SAE Form must be sent by fax to the RIVER Co-ordinating Centre Fax: +44 (0) 20 7670 
4817 or password-protected email to mrcctu.river@ucl.ac.uk 
 
3. Follow-up: participants must be followed up until clinical recovery is complete and 
laboratory results have returned to normal or baseline, or until the event has stabilised. 
Follow-up should continue after completion of protocol treatment if necessary. A further 
SAE Form, indicated as ‘Follow-up’ should be completed and faxed to the RIVER Co-
ordinating Centre as information becomes available. Extra, annotated information and/or 
copies of test results may be provided separately. The participant must be identified by 
study number, 3 letter code and year of birth only. The participant’s name should not be 
used on any correspondence and should be deleted from any test results. 
 
4. Staff should follow their institution’s procedure for local notification requirements. 
 
 
 
RIVER CO-ORDINATING CENTRE RESPONSIBILITIES 
7.5
Medically-qualified staff at the MRC CTU (RIVER co-ordinating Centre) and/or the Chief Investigator 
(or a medically-qualified delegate) will review all SAE reports received. The causality assessment 
given by the local investigator at the hospital cannot be overruled; in the case of disagreement, both 
opinions will be provided in any subsequent reports. 
 
SAE REPORTING 
Within 24 hours of becoming aware of an SAE, please fax a 
completed SAE form to the RIVER Co-ordinating Centre on: 
Fax: +44 (0) 20 7670 4817 or email information to mrcctu.river@ucl.ac.uk 


 
 
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The sponsor has delegated responsibility to MRC CTU who will be responsible for the reporting of 
SUSARs and other SARs to the regulatory authority (MHRA) and the research ethics committee, as 
appropriate. Fatal and life-threatening SUSARs must be reported to the competent authority within 
7 days of the RIVER Co-ordinating Centre becoming aware of the event; other SUSARs must be 
reported within 15 days. 
 
The RIVER Co-ordinating Centre will also keep all investigators informed of any safety issues that 
arise during the course of the study and will submit Development Safety Update Reports (DSUR) to 
Competent Authorities (Regulatory Authority and Ethics Committee) and provide to drug companies 
as necessary. 
 
Any drug companies involved (MSD and GSK) will also be notified of all reportable (serious and 
unexpected and drug-related/unknown relationship) events. The RIVER Co-ordinating Centre will 
also provide companies with a copy of the Annual Safety Report. 


 
 
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8 
QUALITY ASSURANCE & CONTROL 
 
RISK ASSESSMENT 
8.1
The Quality Assurance (QA) and Quality Control (QC) considerations have been based on a formal 
Risk Assessment, which acknowledges the risks associated with the conduct of the study and how to 
address them with QA and QC processes. QA includes all the planned and systematic actions 
established to ensure the study is performed and data generated, documented and/or recorded and 
reported in compliance with the principles of GCP and applicable regulatory requirements. QC 
includes the operational techniques and activities done within the QA system to verify that the 
requirements for quality of the study-related activities are fulfilled. This Risk Assessment has been 
reviewed by the Research Governance Committee (RGC) and has led to the development of several 
Quality Management Documents which will be kept separately. 
 
CENTRAL MONITORING AT THE RIVER CO-ORDINATING CENTRE 
8.2
Data will be entered at each site onto Case Report Forms (CRFs). These CRFs will be checked at the 
RIVER Co-ordinating Centre for missing or unusual values (range checks) and checked for consistency 
within participants over time. If any such problems are identified, the site will be contacted and 
asked to verify or correct the entries made on the CRFs. The RIVER Co-ordinating Centre will also 
send reminders for any overdue and/or missing data with regular inconsistency reports of errors. 
 
Other essential study issues, events and outputs will be detailed in the Data Management, 
Monitoring and Safety Management Plans that are based on the study-specific Risk Assessment. 
 
ON-SITE MONITORING 
8.3
Staff from MRC CTU will visit clinical sites, central pharmacy and laboratories to validate and monitor 
data and procedures. The frequency, type and intensity of routine monitoring and the requirements 
for triggered monitoring will be risk based, the details of which will be documented in a study 
Monitoring Plan. This plan will also detail the procedures for review and sign-off. 
 
A site initiation visit with training will be performed at each study site by staff from the MRC CTU. 
The site initiation visits will include training in the administration of study drug, as well as the study 
procedures. All laboratories will be required to provide evidence of certification before site 
initiation. The monitoring will adhere to the principles of GCP and the Monitoring Plan. 
 
Monitors will: 
 
Verify completeness of the Investigator Site File. 
 
Confirm adherence to protocol. 
 
Review eligibility verification and consent procedures. 
 
Look for missed clinical event reporting. 
 
Verify completeness, consistency and accuracy of data being entered on CRFs. 
 
Evaluate drug accountability. 
 
Provide additional training as needed. 
 


 
 
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The monitors will require access to all participant medical records including, but not limited to, 
laboratory test results and prescriptions. The investigator (or delegated deputy) should work with 
the monitor to ensure that any problems detected are resolved. 
 
 
DIRECT ACCESS TO PARTICIPANT RECORDS 
8.3.1
Participating investigators should agree to allow study-related monitoring, including audits, ethics 
committee review and regulatory inspections by providing direct access to source data and 
documents as required. Participants’ consent for this must be obtained. Such information will be 
treated as strictly confidential and will in no circumstances be made publicly available. 
 
The following data should be verifiable from source documents: 
 
All signed consent forms 
 
Dates of assessments including dates specimens were taken and processed in the 
laboratory 
 
Eligibility and baseline values for all participants 
 
All clinical endpoints 
 
All serious/severe adverse events 
 
Routine participant clinical and laboratory data 
 
Drug compliance 
 
Dates drug dispensed and (if necessary) drugs returned 
 
Pharmacy/clinic drug logs 
 
Concomitant medication.  
 
 
CONFIDENTIALITY 
8.3.2
The investigator must ensure that participants’ anonymity will be maintained and that their 
identities are protected from unauthorised parties. Participants will be assigned a study 
identification number and this will be used on CRFs; participants will not be identified by their name. 
The investigator will keep securely a participant study register showing identification numbers, 
surnames and date of birth. This unique study number will identify all laboratory specimens, case 
report forms, and other records and no names will be used, in order to maintain confidentiality, 
following the principles of the UK DPA. All records will be kept in locked locations for 15 years after 
the end of the study (Section 11.1). Clinical information will not be released without written 
permission, except as necessary for monitoring, auditing and inspection purposes. 


 
 
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9 
STATISTICAL CONSIDERATIONS 
 
METHOD OF RANDOMISATION 
9.1
Participants will be randomised centrally using a computer-generated algorithm based on random 
permuted blocks (practical details will be detailed in the Statistical Master File). Randomisation will 
be stratified by Cohort I and Cohort II. 
 
OUTCOME MEASURES 
9.2
Analyses will compare the two arms on the following outcome measures: 
 
 
PRIMARY OUTCOME MEASURE 
9.2.1
The primary outcome measure is total HIV DNA from CD4 T-cells averaged across 
post-randomisation weeks 16 and 18.  
 
 
SECONDARY OUTCOME MEASURES 
9.2.2
Secondary outcome measures include  
 
Clinical and laboratory adverse events 
 
Further assessment of the HIV reservoir e.g. HIV integrated DNA; HIV cell associated RNA; 
plasma HIV RNA measured with an ultra-low copy assay i.e. with a threshold of <1 copy/ml 
and viral outgrowth assays. 
 
Studies of immune function including measuring the latently-infected resting memory T-
cells and cytotoxic immune responses 
 
Changes in inflammatory biomarkers 
 
SAMPLE SIZE 
9.3
The sample size calculation is based on the primary endpoint which will be analysed on a log10-scale. 
The following assumptions are made: 
 
The combination intervention will confer a 50% reduction in the primary outcome measure 
when compared with cART alone. On a log10-scale this corresponds to a difference between 
the two arms of log10 (2) (approximately 0.3). The effect is assumed to be the same in both 
cohorts (recently and previously diagnosed participants).  
 
Standard deviation (SD) is 0.4 for a single measurement in both arms based on two 
publications:  
o Reported on data from 31 participants treated with HAART at PHI in the French 
PRIMO study. The median (IQR) at 6 and 12 months after starting treatment were 
2.30 (2.10, 2.70) and 2.10 (1.80, 2.40) log10 DNA copies/106 PBMC respectively 
suggesting a SD of 0.45 at both time points57.  
o Reported on 8 participants with PHI. At week 52, the median (IQR) was 494 (250 - 
694) for total HIV-1 DNA copies/106 CD4+ T-cells suggesting a SD (in log scale) of 
0.3349. 
 
1:1 allocation of participants in the two study arms. 
 
Method of analysis: comparing the treatment arms in terms of absolute HIV total DNA level 
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(analysis of covariance; ANCOVA); one baseline measurement and two follow-up 
measurements (at PR16 and 18) will be taken for an individual participant. 
 
A correlation coefficient of 0.5 between a baseline measurement and a PR 16/18 
measurement, and a correlation coefficient of 0.7 for measurements at PR 16 and 18. 
 
Two-sided α = 0.05 for the null hypothesis that there is no difference between the two arms 
in the primary endpoint. 
 
Under the above assumptions, a sample size of 52 individuals would provide 94% power to detect a 
50% reduction in HIV total DNA (86% power for a 45% reduction ). 
 
Assuming that some individuals enrolled will not reach visits PR 16/18 (due to failing the eligibility 
criteria for randomisation in cohort I, or withdrawal) it is planned to enrol a total of 60 individuals 
overall (both cohorts combined). 
 
INTERIM MONITORING & ANALYSES 
9.4
An Independent Data Monitoring Committee (IDMC) will monitor the study, an IDMC Charter will be 
drawn up that describes the membership of the IDMC, relationships with other committees, terms 
of reference, decision-making processes, and the timing and frequency of interim analyses. 
 
The IDMC will meet once before the start of the study, and approximately at 6-month intervals after 
start of enrolment. In addition, an IDMC meeting may be requested by IDMC members, the Chief 
Investigator or the PMG at any time 
 
ANALYSIS PLAN (BRIEF) 
9.5
The analyses will be described in detail in a full Statistical Analysis Plan. This section summarises the 
main issues. 
 
HIV total DNA from CD4 T-cells average at post-randomisation weeks 16 and 18 (PR16 and PR18) will 
be compared between the two groups as allocated (intention to treat, ITT) by analysis of covariance 
with adjustment for values at randomisation. The analysis will be performed on all eligible 
participants randomised taking into account stratification factors. An imputation method will be 
used to estimate missing HIV total DNA values in participants with unobserved values and this will be 
defined in the Statistical Analysis Plan. 
 
The frequency of grade 3 and 4 adverse events will be tabulated by body systems and randomised 
group and the groups will be compared using Fisher’s exact test. 
 


 
 
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10 PARTICIPANT AND PUBLIC INVOLVEMENT 
A representation from people living with HIV sits on the RIVER Trial Management Group and has 
been closely involved in the development of the protocol. In addition there is another patient 
representative on the Trial Steering Committee (Appendix V) and has provided input on the protocol 
and participant information leaflets. This representative also forms, with others, a community 
advisory board (CAB) for the CHERUB collaboration who will help disseminate the study’s results 
beyond the academic and healthcare professional community to other participant groups and the 
wider public. 


 
 
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11 REGULATORY & ETHICAL ISSUES 
All regulatory requirements (including safety reporting, Section 7 and below) will be met by the 
sponsor or their delegated authorities. We will follow the statutory requirements for consent as set 
out in the Medicines for Human Use (Clinical Trials) regulations.  
 COMPLIANCE 
11.1
The end of the interventional phase of the study is defined as being 12 weeks after each 
participant’s last visit and investigators should continue to notify the RIVER Co-ordinating Centre of 
all SAEs for this period. After this time the participant’s long-term follow-up phase will commence 
(Section 6.9). The study will end after the last participant completes their 5th annual visit.  
 
 REGULATORY COMPLIANCE 
11.1.1
The study complies with the principles of the Declaration of Helsinki (1996).  
 
It will also be conducted in compliance with the approved protocol, the principles of Good Clinical 
Practice (GCP) as laid down by the Commission Directive 2005/28/EC with the implementation in 
national legislation in the UK by Statutory Instrument 2004/1031 (The Medicines for Human Use 
[Clinical Trials] Regulations 2004) and subsequent amendments, the UK Data Protection Act (DPA 
number: Z6364106), and the National Health Service (NHS) Research Governance Framework for 
Health and Social Care (RGF). 
 
 SITE COMPLIANCE 
11.1.2
All sites will comply with the above. An agreement will be in place between the site and the sponsor, 
Imperial College London, setting out respective roles and responsibilities.  
 
The site will inform the Trials Unit as soon as they are aware of a possible serious breach of 
compliance, so that the Trials Unit can report this breach if necessary within 7 days as per the UK 
regulatory requirements. For the purposes of this regulation, a 'serious breach' is one that is likely to 
affect to a significant degree: 
 
The safety or physical or mental integrity of the subjects in the study, or  
 
The scientific value of the study 
 
 DATA COLLECTION & RETENTION 
11.1.3
CRFs, clinical notes and administrative documentation should be kept in a secure location (for 
example, locked filing cabinets in a room with restricted access) and held for 15 years after the end 
of the study. During this period, all data should be accessible to the competent or equivalent 
authorities, the Sponsor with suitable notice. The data may be subject to an audit by the competent 
authorities. 
 ETHICAL CONDUCT OF THE STUDY 
11.2
Written, informed consent will be obtained from all participants before enrolment by the site 
principal investigator or an appropriately trained Consultant, Specialist Registrar, or Research Nurse 


 
 
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(as delegated by the Principal Investigator). Participants will be free to withdraw from the study at 
any time, and this will be explicitly stated in participant information leaflets. 
 
 ETHICAL CONSIDERATIONS 
11.2.1
The success of current ART has converted HIV from a life-threatening disease into a chronic illness 
that does not significantly impair life-span compared to HIV infected counterparts. Importantly, the 
START study was stopped early, in May 2015, as there was a clear clinical benefit to starting ART 
with high CD4+ T-cell count (including above 500 cells/mm3) compared to deferring to the current 
threshold of 350 cells/mm3 58. BHIVA guidelines have been amended to reflect this definitive data in 
support of universal treatment. Hence initiation of immediate ART for individuals with PHI is now 
within routine practice59.  
 
There is an unknown long-term risk of toxicity following use of vorinostat. The recent presentation is 
the first multiple dosing data for HIV+ individuals and has been shown to be safe and well tolerated 
in the short-term – follow-up of over a year – with only minimal side effects 8.  
 
The vaccine strategy has been given to HIV uninfected individuals and is safe and well tolerated. 
Further data on the safety of the vaccines used in the RIVER study is described in Section 1.2.5.  
 
Participants will be given a small sum of money towards the cost of their travel to their clinic. For 
Arm B patients only, reasonable costs for return travel to the vaccination centre located at the Royal 
Free Hospital (study visit at PR 00 and 08) will be reimbursed. 
 
 ETHICAL APPROVALS 
11.2.2
Before initiation of the study at each clinical site, the protocol, all informed consent forms, and 
information materials to be given to the prospective participant will be submitted to ethics 
committee for approval. Any further amendments will be submitted and approved by the designated 
ethics committee. 
 
The rights of the participant to refuse to participate in the study without giving a reason must be 
respected. After the participant has entered into the study, the clinician must remain free to give 
alternative treatment to that specified in the protocol, at any stage, if he/she feels it to be in the 
best interest of the participant. The reason for doing so, however, should be recorded; the 
participant will remain within the study for the purpose of follow-up and for data analysis by the 
treatment option to which they have been allocated. Similarly, the participant must remain free to 
change their mind at any time about the protocol treatment and study follow-up without giving a 
reason and without prejudicing his/her further treatment. 
 COMPETENT AUTHORITY APPROVALS 
11.3
This protocol will be submitted to the national competent authority (MHRA). This is a Clinical Trial of 
an Investigational Medicinal Product (IMP) as defined by the EU Directive 2001/20/EC. Therefore, a 
CTA is required in the UK. The EudraCT number for the study is 2014-001425-32. 
 
The progress of the study and safety issues will be reported to the competent authority in 
accordance with local requirements and practices in a timely manner. Safety reports, including 
expedited reporting and SUSARs will be submitted to the competent authority in accordance with 
their requirements in a timely manner. 


 
 
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 OTHER APPROVALS 
11.4
The protocol will be submitted by those delegated to do so to the relevant R&D department of each 
participating site or to other local departments for approval as required. A copy of the local R&D 
approval (or other relevant approval as above) and of the Participant Information Leaflet (PIL) and 
Informed Consent Form (ICF) on local headed paper must be forwarded to the RIVER Co-ordinating 
Centre before the site can be opened. 
 


 
 
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12 INDEMNITY 
The sponsor of the study, Imperial College, holds Public Liability (“negligent harm”) and Clinical Trial 
(“non-negligent harm”) insurance policies which apply to this study.  
 
If it can be demonstrated that a participant experienced serious and enduring harm as a result of 
their participation in this study, they may be eligible to claim compensation without having to prove 
that Imperial College is at fault. If the injury resulted from any procedure which is not part of the 
study, Imperial College will not be required to compensate them in this way. Their legal rights to 
claim compensation for injury where it can be proven as negligence are not affected.  


 
 
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13 FINANCE 
The study is supported by grant funding from the Medical Research Council (Ref: MR/L00528X/1).  
 
The study will be co-ordinated by the MRC CTU. A written agreement with the NHS Trust or Board of 
each site principal investigator (PI) and the MRC CTU will set out the obligations of the parties to the 
agreement, their respective roles and responsibilities and cover arrangements for budgets and 
financial transfers and reporting. The study will also be registered through the NIHR portfolio system 
for adoption by the Comprehensive Local Research Network (CLRN). 
 
Raltegravir and vorinostat - Are manufactured by Merck Sharp and Dohme (MSD). MSD have agreed 
to supply the study drugs free of charge for participants participating in the study.  
 
ChAdV63.HIVconsv and MVA.HIVconsv Vaccines - The vaccine manufacture and all pre-clinical and 
clinical work to date for these vaccines has been provided free of charge to the RIVER study by Lucy 
Dorrell and Tom Hanke utilising their existing MRC grants. GSK own the ChAd vector and have 
reviewed the RIVER protocol and have approved the use of the ChAdV63.HIVconsv. in the RIVER 
study.  
 
Participants will receive reimbursement for their commitment to the study.  


 
 
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14 OVERSIGHT & TRIAL COMMITTEES 
There are a number of committees involved with the oversight of the study. These committees are 
detailed below, and the relationship between them expressed in the Figure 7 below. 
 
Figure 7 Trial Organogram 
 
 
 TRIAL MANAGEMENT TEAM (TMT) 
14.1
A Trial Management Team (TMT) will be formed to conduct the day-to-day management of the 
study at the MRC CTU. This will include the Chief Investigator, Trial Statistician, Trial Physician, 
Clinical Project Manager (MRC CTU), Trial Manager and Data Manager. The group will meet at least 
once per month, although may meet more or less often as required. The group will discuss issues 
related to the progress of the study at the site and ensure that the study is running well. 
 PROJECT MANAGEMENT GROUP (PMG) 
14.2
A Project Management Group (PMG) will be formed, comprising of the Chief Investigator, other lead 
investigators (clinical and non-clinical), members of the MRC CTU (RIVER Co-ordinating Centre) 
representatives of the sponsor and  participant representative. The PMG will be responsible for the 
day-to-day running and management of the study. This group will be chaired by the Chief 
Investigator and all decisions regarding the overall running of the study will be made in this forum 


 
 
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with the exception of matters of fundamental importance to the viability of the study or that require 
major changes to the protocol. These will be referred to the Trial Steering Committee (TSC). The full 
details can be found in the PMG Charter. It will meet approximately three times a year, at least one 
of which will be in-person. At these meetings, progress and challenges will be summarised and 
difficulties discussed. 
 TRIAL STEERING COMMITTEE (TSC) 
14.3
The Trial Steering Committee (TSC) has membership from the PMG plus independent members, 
including the Chair. The role of the TSC is to provide overall supervision for the study and provide 
advice through its independent Chair. The ultimate decision for the continuation of the study lies 
with the TSC. Further details of TSC functioning are presented in the TSC Charter. See Appendix V for 
membership. 
 INDEPENDENT DATA MONITORING COMMITTEE (IDMC) 
14.4
An Independent Data Monitoring Committee (IDMC) will be formed. The IDMC will be the only group 
which sees the confidential, accumulating data for the study separately by randomised group. 
Reports to the IDMC will be produced by the MRC CTU statisticians. The IDMC will review study data 
on recruitment, safety, adherence to randomised strategies and efficacy, as well as consider findings 
from any other relevant studies. The frequency of meetings will be dictated in the IDMC charter. The 
IDMC will consider data using the statistical analysis plan and will advise the TSC. The IDMC can 
recommend premature closure or reporting of the study, or that recruitment be discontinued. 
 
Further details of IDMC functioning and the procedures for interim analysis and monitoring are 
provided in the IDMC Charter. See Appendix V for membership. 
 ROLE OF STUDY SPONSOR 
14.5
The study will be sponsored by Imperial College London (Imperial) with responsibilities defined by a 
written agreement.  
 


 
 
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15 PUBLICATION 
The results from different centres will be analysed together and published as soon as possible after 
the end of the study. Individual clinicians must not publish data concerning their participants that 
are directly relevant to questions posed by the study until the PMG has published its report. The 
PMG together with the RIVER collaborators will form the basis of the writing committee and decide 
on the nature of publications. Any release, of efficacy or safety data, presentation or publication will 
be agreed with the TSC according to the terms of their charter. 
 
All publications will acknowledge the participating centres and clinicians, and these will be detailed 
in an appendix to the main report. Papers will have named authors determined by the PMG 
according to the following principles: 
 
 
To be as inclusive as possible where this is practicable 
 
To ensure that there is justification for anyone to be named as an author 
 
Reasons for nomination for authorship may include: study design; grant holding; day-to-day 
study oversight (PMG membership); analysis; discussion and interpretation of data; 
representation for key groups; active participation at large recruiting sites. It should be 
accepted that the people qualifying for authorship will vary over time. In addition, key 
positions will vary depending on the nature of the publication: clinical lead for clinical 
papers, statistician lead for methodology papers, translational papers may be led by authors 
not on the main PMG if appropriate. In the event of any dispute related to authorship or 
data release, the TSC will be responsible for making the executive decision. 
 
In the manuscript, a full list of sites and the number of participants recruited will be provided. In the 
presentations, this list of sites will also be shown. The term “the RIVER investigators” will clearly be 
stated and relevant names included in the presentation credits. 
 
 


 
 
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16 PROTOCOL AMENDMENTS 
Protocol v1.0 24-Oct-2014 approved by REC 23-Dec-2014 and MHRA 13-Jan-2015
Protocol v2.0 03-Jun-2015 approved by REC 25-Jun-2015. Not accepted by MHRA. 
Changes made 
Sections updated 
Schedule amended to allow for repeat testing of a participant’s 
viral load, until this falls below the level of detectability. Trial 
assessment schedule has been split into two stages, pre and 
post-randomisation, with randomisation becoming a separate 
visit to ensure all participants have a common baseline. All visits 
after randomisation are now referred to as post-randomisation 
weeks (PR week), which has been updated throughout.  
Table 1 – Trial Assessment Schedule 
Table 2 – Visit names and codes  
Figure 1 Trial Entry, Randomisation 
and Treatment 
3.2 Criteria for Randomisation 
3.3 Number of participants  
4. Screening, Enrolment & 
Randomisation 
Eligibility assessments including routine blood results and resting 
12-lead ECG need to be within 14 days of randomisation. 
Table 1 – Trial Assessment Schedule 
3.2 Criteria for Randomisation 
Wording clarified for enrolment exclusion criteria 22. 
3.1.2 Enrolment Exclusion Criteria 
Removed the requirement for participants to attend visits fasted. 
Table 1 – Trial Assessment Schedule 
6.1.1 Screening and Enrolment 
(Week 0) 
Changes to the trial assessment schedule only: 
 Screening/baseline visit is now referred to as screening only. 
 Follow up visit at week 08 has been removed 
 For several visits the volumes and timings of blood samples 
have been changed. Total blood volume taken across the 
protocol has increased by 17ml.  
 Visits where quality of life questionnaires are required have 
changed.  
Table 1 – Trial Assessment Schedule 
Further clarification on the vaccination visits has been included:  
 Specified that the first vaccination (Chad) at PR week 00 must 
take place within 1 week of randomisation. For participants is 
Arm A, this visit can be completed over the phone.  
 There is a window of 7 days between the two vaccinations 
given at PR week 00 and PR08 Day 1.  
Table 1 – Trial Assessment Schedule 
5.3 Post-Randomisation (PR) 
Treatment 
5.5.3 Vaccines 
 Preliminary results from the BCN01 study are now available. 
 Results from the START study are now available  
1.2.5.C Use of ChAdV63.HIVconsv 
and MVA.HIVconsv in HIV Infection 
11.2.1 Ethical Considerations 
Event reporting section has been updated : 
 Only grade 3 adverse events are reportable prior to 
randomisation. Grade 4 events are reportable throughout 
the study as SAEs.  
 Pregnancy in a partner is now considered a notable event 
7.3 Other Notable Events
7.3.1 Vaccine related events 
7.4 Investigator Responsibilities 
7.4.2 Notification Procedure 


 
 
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 Vaccine related events have been added to the notable 
events and are listed in Appendix IV.  
 For SAEs, participants must be identified by study number, 3 
letter code and year of birth only. 
 Clarification that HERVs may be investigated as an 
exploratory outcome.  
 Re-clarification of the end of the interventional phase of the 
study and end of study.  
7.4.1.E Notification 
11.1 Compliance 
Change in staff at the RIVER Co-ordinating Centre and PI at Brighton and Sussex University Hospitals 
NHS Trust.  
Protocol version number and date updated on first page and on all page headers.  
Protocol v3.0  23-Jul-2015 approved by REC 29-Jul-2015 and MHRA 25-Aug-2015
Changes made
Sections updated
Re-clarification of the investigator’s event reporting
responsibilities.  
7.4.1.E Notification 
Protocol version number and date updated on first page and on all page headers. 
Protocol v4.0  18-May-2016 approved by REC 16-Jun-2016 and MHRA 22-Jun-2016
Changes made
Sections updated
Additional QTc information 
Change of QTc and bradycardia eligibility criteria  
 
 
Trial Assessment Schedule only: 
 Additional ECGs at PR10-1 and PR16 included  
1.1.1.A Pharmacokinetics (PK)
3.1.2 Enrolment Exclusion Criteria 
3.2 Criteria for Randomisation 
5.4 Criteria for Starting Vorinostat 
 
Table 1 – Trial Assessment Schedule 
Eligibility has been updated to:
 
Enable sites to use either Hepatitis C RNA or Hepatitis C 
antigen test to exclude current infection. 
 
Enforce use of the CKD-EPI equation to calculate eGFR. 
3.1.2 Enrolment Exclusion Criteria
3.2 Criteria for Randomisation 
5.4 Criteria for Starting Vorinostat 
Clarification on use of ART prior to enrolment 
1.3 Study Design and Hypothesis
3.1.1 Inclusion Criteria 
5.2 Pre-Randomisation Treatment 
Removed requirement for participants to return empty/part used 
Raltegravir 
5.5.2 Raltegravir 
Removal co-enrolment in UK Register of HIV seroconverters
3.3 Number of participants
4.3 Co-enrolment Guidelines 
6.5 Early Stopping of Follow-up 
Protocol version number and date updated on first page and on all page headers. 
Protocol v5.0 20-Oct-2016
Changes made
Sections updated 
Addition of Cohort II – Previously 
diagnosed participants  
Summary of Trial
Trial Schema 
Figure 1 Trial Entry, Randomisation and Treatment – Cohort I 
- Recently diagnosed  
Figure 2 Trial Entry, Randomisation and Treatment – Cohort 
II - Previously diagnosed 
Table 1 Trial Assessment Schedule – Cohort I - Recently 


 
 
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diagnosed
Table 2 Trial Assessment Schedule – Cohort II - Previously 
diagnosed 
Table 3 Visit names and codes – Cohort I - Recently 
diagnosed 
Table 4 Visit names and codes – Cohort II – Previously 
diagnosed 
1.3 Study Design and Hypothesis 
3 Selection of Participants 
4 Enrolment & Randomisation 
5 Treatment of Participants 
Figure 5 RIVER Treatment Schedule – Cohort I – Recently 
diagnosed  
Figure 6 RIVER Treatment Schedule – Cohort II – Previously 
diagnosed 
7.2.1 Large volume blood draw 
7.4 Investigator Responsibilities 
7.4.1.E Notification 
9 Statistical Considerations 
Additional 18ml blood sample for Merck 
assay at PR11-1 
Table 1 Trial Assessment Schedule – Cohort I - Recently 
diagnosed 
Table 2 Trial Assessment Schedule – Cohort II - Previously 
diagnosed 
Change of eGFR eligibility criteria 
3.3.1 Enrolment Inclusion Criteria
3.3.3 Criteria for Randomisation 
3.4.2 Randomisation Exclusion Criteria 
5.5 Criteria for Starting Vorinostat 
References to TMG updated to PMG 
2.1 Site/Investigator Inclusion Criteria
9.4 Interim Monitoring & Analyses 
14 Oversight & Trial Committees 
15 Publication 
Protocol version number and date updated on first page and on all page headers.
 


 
 
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56. 
CHERUB Website - http://www.cherub.uk.net/. Accessed 29-Jul-2016. 
57. 
Ngo-Giang-Huong N, Deveau C, Da S, I, et al. Proviral HIV-1 DNA in subjects followed since 
primary HIV-1 infection who suppress plasma viral load after one year of highly active 
antiretroviral therapy. AIDS 2001;15:665-73. 
58. 
Lundgren JD, Babiker AG, Gordin F, et al. Initiation of Antiretroviral Therapy in Early 
Asymptomatic HIV Infection. N Engl J Med 2015;373:795-807. doi: 10.1056/NEJMoa1506816. 
Epub 2015 Jul 20. 
59. 
Churchill D, Waters L, Ahmed N, et al. BHIVA guidelines for the treatment of HIV-1 positive 
adults with antiretroviral therapy 2015. 2015. 
 

SAP_001.pdf: 


RIVER Statistical Analysis Plan final version 1.0 
 
04 Dec 2017 

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RIVER Statistical Analysis Plan final version 1.0 
 
04 Dec 2017 

-

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RIVER Statistical Analysis Plan final version 1.0 
 
04 Dec 2017 

9

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RIVER Statistical Analysis Plan final version 1.0 
 
04 Dec 2017 

.

 
&('
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RIVER Statistical Analysis Plan final version 1.0 
 
04 Dec 2017 

+

+ 
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RIVER Statistical Analysis Plan final version 1.0 
 
04 Dec 2017 

=

 
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RIVER Statistical Analysis Plan final version 1.0 
 
04 Dec 2017 

)

 
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RIVER Statistical Analysis Plan final version 1.0 
 
04 Dec 2017 

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RIVER Statistical Analysis Plan final version 1.0 
 
04 Dec 2017 

""

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RIVER Statistical Analysis Plan final version 1.0 
 
04 Dec 2017 

"$

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RIVER Statistical Analysis Plan final version 1.0 
 
04 Dec 2017 

"-

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